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    Summary
    EudraCT Number:2011-001462-17
    Sponsor's Protocol Code Number:WSG-AM06
    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:2011-10-04
    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 number2011-001462-17
    A.3Full title of the trial
    Adjuvant Dynamic marker-Adjusted Personalized Therapy trial optimizing risk assessment and therapy response prediction in early breast cancer
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Trial for the optimisation of risk assessment and therapy success predicition in patients with early breast cancer by the use of biomarkers in advance to therapy decission-making to personalize therapies.
    A.3.2Name or abbreviated title of the trial where available
    ADAPT
    A.4.1Sponsor's protocol code numberWSG-AM06
    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 SponsorWestdeutsche Studiengruppe GmbH
    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 supportGenomic Health , Inc.
    B.4.2CountryUnited States
    B.4.1Name of organisation providing supportRoche Pharma AG
    B.4.2CountryGermany
    B.4.1Name of organisation providing supportCelgene Corp.
    B.4.2CountryGermany
    B.4.1Name of organisation providing supportAmgen
    B.4.2CountryGermany
    B.4.1Name of organisation providing supportTEVA GmbH
    B.4.2CountryGermany
    B.4.1Name of organisation providing supportBayer AG
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationWestdeutsche Studiengruppe GmbH
    B.5.2Functional name of contact pointStudienzentrale
    B.5.3 Address:
    B.5.3.1Street AddressWallstr. 10
    B.5.3.2Town/ cityMoenchengladbach
    B.5.3.3Post code41061
    B.5.3.4CountryGermany
    B.5.4Telephone number004921615662310
    B.5.5Fax number004921615662319
    B.5.6E-mailwsg@wsg-online.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation 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 nameEpirubicin
    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 INNEPIRUBICIN
    D.3.9.1CAS number 56420-45-2
    D.3.9.4EV Substance CodeSUB06571MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/m2 milligram(s)/square meter
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number90mg/m²
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.2Country which granted the Marketing 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 nameCyclophosphamide
    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 INNCYCLOPHOSPHAMIDE
    D.3.9.1CAS number 50-18-0
    D.3.9.3Other descriptive nameCyclophosphamide-H20
    D.3.9.4EV Substance CodeSUB06859MIG
    D.3.10 Strength
    D.3.10.1Concentration unit g gram(s)
    D.3.10.2Concentration typeup to
    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: 3
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation 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: 4
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation 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.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number20 to 40
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 5
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.2Country which granted the Marketing 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 nameAnastrozole
    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.3.9.1CAS number 120511-73-1
    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: 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.2.1.2Country 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 nameLetrozole
    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.3.10 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: 7
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.2Country which granted the Marketing 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 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.3.9.1CAS number 107868-30-4
    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: 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 Kadcyla
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Pharma
    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 emtansine (T-DM1)
    D.3.2Product code RO530-4020/xxx
    D.3.4Pharmaceutical form Powder for 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 INNtrastuzumab emtansine (T-DM1)
    D.3.9.1CAS number 1018448-65-1
    D.3.9.2Current sponsor codeRO5304020
    D.3.9.3Other descriptive nameT-DM1, Trastuzumab-MCC-DM1
    D.3.9.4EV Substance CodeSUB35467
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number160
    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) 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 Yes
    D.3.11.13.1Other medicinal product typeAntibody-drug conjugate comprised of a humanized monoclonal anibody (trastuzumab) and emtansine (DM1)
    D.IMP: 9
    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 150 mg
    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 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 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 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 typehumanized monoclonal antibody
    D.IMP: 10
    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 Abraxane
    D.2.1.1.2Name of the Marketing Authorisation holderCelgene Europe B.V. (the Netherlands)
    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 namePaclitaxel-Albumin
    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.3.9.3Other descriptive namepaclitaxel protein-bound particles for injectable suspension (albumin-bound)
    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 Yes
    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 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.2.5The 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 nameGemcitabine
    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 INNGEMCITABINE
    D.3.9.1CAS number 95058-81-4
    D.3.9.4EV Substance CodeSUB07892MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number38
    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 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.2.5The 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 nameCarboplatin
    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 INNCarboplatin
    D.3.9.3Other descriptive nameCARBOPLATIN
    D.3.9.4EV Substance CodeSUB06614MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 13
    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 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.3.9.2Current sponsor codeRO4368451
    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 Yes
    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 Yes
    D.3.11.13.1Other medicinal product typePertuzumab is a recombinant, humanized immunoglobulin (Ig)G1k monoclonal antibody, which targets HER2
    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.2.5The 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 nameMyocet
    D.3.4Pharmaceutical form Powder for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous bolus use (Noncurrent)
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNDoxorubicin citrate complex
    D.3.9.1CAS number 111266-55-8
    D.3.9.3Other descriptive nameDOXORUBICIN CITRATE
    D.3.9.4EV Substance CodeSUB96038
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2
    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
    Early primary breast cancer, hormone receptor positve or negative, HER2 positive or negative, any nodal status.
    E.1.1.1Medical condition in easily understood language
    Early diagnosed breast cancer at first occurence, with hormone receptor over-expressing tumor and any lymph node involvement (from none to any).
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level LLT
    E.1.2Classification code 10006188
    E.1.2Term Breast cancer female NOS
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The ADAPT trial aims at personalizing therapy in early breast cancer by integration of dynamic response data into clinical management and at sparing unnecessary therapies without compromising patient outcome.

    Primary objective

    ADAPT umbrella
    • Identification of a responder sub-population with intermediate and high risk, which due to therapy has outcome comparable to HR+/RS ≤ 11
    E.2.2Secondary objectives of the trial
    Secondary objectives

    • Relapse-free and overall survival in corresponding groups
    • Overall survival
    • Toxicity
    • Cost-effectiveness
    • distant disease-free survival (DDFS)
    • local and regional relapse-free survival (LRFS and RRFS)


    Further specific objectives are defined within the sub-protocols. Toxicity and cost efficacy are common endpoints of all sub-protocols. Toxicity and general health economic issues within the whole protocol will be analyzed, when results from the sub-protocols are available.
    Additional translational research questions occurring during the trial will be defined in sub-protocols.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Version: 4.8
    Date: 27.09.2017

    ADAPT Hormone Receptor Positive/HER2 Negative Breast Cancer Sub-trial
    Primary objectives
    Run-in Phase:
    Analysis of reproducibility of each biomarker
    Assessment of dropout rate
    Assessment of proportions of marker responders vs. non-responders
    Central/local pathology
    Central/local Ki-67 assessment
    Ki-67 change after endocrine induction therapy
    Comparison of changes in RS, Ki-67, quantitative ER and proliferation group within the RS
    Assessment of distribution of responders/low responders in low (RS≤11), intermediate (RS 12-25) and high-risk (RS≥26) patients with the aim to allow early adjustment of the statistical plan
    Identification of other proliferation markers that drop significantly
    Run-in phase + main phase
    ADAPT HR+/HER2- part I:
    Prospective comparison of EFS in patients with intermediate risk by RS (12-25)/response vs. patients with low risk by RS (RS≤11; N0-1); both groups receiving endocrine therapy only
    ADAPT HR+/HER2- part II:
    Prospective comparison of 5-year EFS of nab-paclitaxel 125mg/m² q1w x 8 versus Paclitaxel 175mg/m² q2w x 4 both followed by conventionally dosed E90C600 x 4 q2w chemotherapy regimens; patients with intermediate risk by RS (12-25)/low response or high risk patients by N0-1/RS ≥26, all N2/3, or Ki-67>40%, >pT1b, and G3 will be treated with chemotherapy

    ADAPT Hormone Receptor Positive/HER2 Negative Breast Cancer Sub-trial
    Run-in Phase:
    Analysis of reproducibility of each biomarker
    Assessment of dropout rate
    Assessment of proportions of marker responders vs. non-responders
    Central/local pathology
    Central/local Ki-67 assessment
    Ki-67 change after endocrine induction therapy
    Comparison of changes in RS, Ki-67, quantitative ER and proliferation group within the RS
    Assessment of distribution of responders/low responders in low (RS≤11), intermediate (RS 12-25) and high-risk (RS≥26) patients with the aim to allow early adjustment of the statistical plan
    Identification of other proliferation markers that drop significantly
    Run-in phase + main phase
    ADAPT HR+/HER2- part I:
    Prospective comparison of EFS in patients with intermediate risk by RS (12-25)/response vs. patients with low risk by RS (RS≤11; N0-1); both groups receiving endocrine therapy only
    ADAPT HR+/HER2- part II:
    Prospective comparison of 5-year EFS of nab-paclitaxel 125mg/m² q1w x 8 versus Paclitaxel 175mg/m² q2w x 4 both followed by conventionally dosed E90C600 x 4 q2w chemotherapy regimens; patients with intermediate risk by RS (12-25)/low response or high risk patients by N0-1/RS ≥26, all N2/3, or Ki-67>40%, >pT1b, and G3 will be treated with chemotherapy

    ADAPT HER2 Positive/Hormone Receptor Positive Breast Cancer Sub-trial
    Primary objectives
    Comparison of the pathological complete response rates in patients with HER2+/HR+ breast cancer (HER2+/HR+: HER2+/ER+ and/or PR+) treated by pre-surgical T-DM1 with or without standard endocrine therapy or trastuzumab with endocrine therapy given for a total of 12 weeks
    Evaluation of dynamic testing (based on proliferation/apoptosis changes in serial biopsy and/or imaging by ultrasound/breast MRI) after three weeks of treatment as a surrogate parameter for response (pCR (residual cancer burden (RCB) 0-1) or resistance/low response (RCB II-III or progressive disease)

    ADAPT Triple Negative (HER2-/HR-) Breast Cancer Sub-trial
    Comparison: pCR in nab-paclitaxel/carboplatin vs. nab-paclitaxel/gemcitabine,
    Comparison: pCR in responders vs. non-responders.

    ADAPT Elderly in HER2 negative Breast Cancer - Sub-trial for Patients beyond 70 years
    Primary objectives
    Run-in Phase:
    Identification of molecular markers correlating with early response/pCR
    Feasibility/reproducibility of assessment of these markers
    Validation of statistical assumptions (toxicity, pCR)
    Run-in phase + main phase
    Primary objectives
    Comparison of pCR rates in patients with early response and no severe toxicity (Group 1) and in other patients (Group 2).
    E.3Principal inclusion criteria
    General Inclusion Criteria:
    • Female patients, age at diagnosis 18 years and above (consider ADAPT Elderly for patients at 70 years and above)
    • Histologically confirmed unilateral primary invasive carcinoma of the breast
    • T1 - T4 (except inflammatory breast cancer)
    • All N
    • Patients should be candidates for adjuvant chemotherapy according to conventional prognostic factors
    • No clinical evidence for distant metastasis (M0)
    • Known HR status and HER2 status (local pathology)
    • Tumor block available for central pathology review
    • Performance Status ECOG <= 1 or KI >= 80%
    • Negative pregnancy test (urine or serum) within 7 days prior to registration in premenopausal patients
    • Written informed consent prior to beginning specific protocol procedures, including expected cooperation of the patients for the treatment and follow-up, must be obtained and documented according to the local regulatory requirements
    • The patient must be accessible for treatment and follow-up


    Additional Inclusion criteria for patients receiving chemotherapy:

    • Laboratory requirements for patients receiving chemotherapy (within 14 days prior to randomization):
    o Leucocytes >= 3.5 10^9/L
    o Platelets >= 100 10^9/L
    o Hemoglobin >= 10 g/dL
    o Total bilirubin <= 1 x ULN
    o ASAT (SGOT) and ALAT (SGPT) <= 2.5 UNL
    o Creatinine <= 175 µmol/L (2 mg/dl)
    • LVEF within normal limits of each institution measured by echocardiography and normal ECG (within 42 days prior to randomization)


    Additional Inclusion Criteria ADAPT HR+/HER2- Breast Cancer:

    In order to be eligible for the participation in the ADAPT HR+/HER2- breast cancer trial, patients who meet the general inclusion/exclusion criteria of the ADAPT trial also have to meet the following additional inclusion criteria:
    ER and/or PR positive and HER2 negative
    Central pathology available (Grading, Ki-67, RS)* (only in patients with induction treatment)
    All patients should be recommended to be treated by adjuvant chemotherapy in the daily routine practice by one of the current guildeines (St. Gallen, AGO Mamma, S3, ESMO) or to be high clinical risk by AdjuvantOnline (breast cancer specific survival of <88%)
    o Clinically N+ or cN0 with one of following features: G3, <35 years old, Ki-67 >14%, cT2-4c, If G1 only if clinical tumor size >3 cm
    o If Clinical decision is based on AdjuvantOnline patients should derive more than 5% 10-year relapse-free survival benefit by use of chemotherapy (3rd generation anthracycline/taxane-based) additional to standard endocrine therapy (using clinical T and N status)

    Additional Inclusion Criteria ADAPT HR+/HER2- Part II
    To be eligible for the participation in the ADAPT HR+/HER2- trial part II (neo)adjuvant chemotherapy question) the patients have to meet one of the following inclusion criteria:
    More than 3 involved lymph nodes (c/pN2-3)*
    N0-1 and RS ≥ 26*
    N0-1 and RS 12-25 with Ki-67post > 10%
    G3 with Ki-67 ≥40% in tumors >1cm*
    To be a candidate for chemotherapy treatment due to high clinical risk irrespective of induction treatment (e.g. by heterogeneous tumor, multifocal tumor etc.)
    *with or without prior endocrine “test” treatment
    Patients with tumors ≥cT2 and/or cN+ are strongly recommended to be treated by neoadjuvant chemotherapy
    Laboratory requirements for patients receiving chemotherapy (within 14 days prior to randomization):
    o Leucocytes >= 3.5 x 109/L
    o Neutrophils >1.5 x 109/L
    o Platelets >= 100 x 109/L
    o Hemoglobin >= 10 g/dL
    o Total bilirubin <= 1 x ULN
    o ASAT (SGOT) and ALAT (SGPT) <= 2.5 x ULN
    o AP<5.0 ULN
    o Creatinine <= 175 ╬╝mol/L (2 mg/dl)
    LVEF within normal limits of each institution measured by echocardiography and normal ECG (within 42 days prior to randomization)
    E.4Principal exclusion criteria
    General Exclusion Criteria:
    • Known hypersensitivity reaction to the compounds or incorporated substances
    • Prior malignancy with a disease-free survival of < 10 years, except curatively treated basalioma of the skin, pTis of the cervix uteri
    • Non-operable breast cancer including inflammatory breast cancer
    • Previous or concurrent treatment with cytotoxic agents for any reason after consultation with the sponsor
    • Concurrent treatment with other experimental drugs. Participation in another interventional clinical trial with or without any any investigational not marketed drug within 30 days prior to study entry
    • Male breast cancer
    • Concurrent pregnancy; patients of childbearing potential must implement a highly effective (less than 1% failure rate) non-hormonal contraceptive measures during the study treatment
    • Breast feeding woman
    • Sequential breast cancer
    • Reasons indicating risk of poor compliance
    • Patients not able to consent

    Additional Exclusion Criteria for patients receiving chemotherapy:

    • Known polyneuropathy ≥ grade 2
    • Severe and relevant co-morbidity that would interact with the application of cytotoxic agents or the participation in the study
    • Uncompensated cardiac function
    • Inadequate organ function including:
    o Leucocytes <= 3.5 x 10^9/l
    o Platelets <= 100 x 10^9/l
    o Bilirubin above normal limits
    o Alkaline phosphatase >= 5 x UNL
    o ASAT and/or ALAT associated with AP > 2.5 UNL

    Additional Exclusion Criteria ADAPT HR+/HER2-
    • Patients with clinical low risk tumors, who are not treated by adjuvant chemotherapy in the daily practice (e.g. cT1, G1, cN0)

    Additional Exclusion Criteria ADAPT HR+/HER2- Part II
    • Known polyneuropathy ≥ grade 2
    • Severe and relevant co-morbidity that would interact with the application of cytotoxic agents or the participation in the study
    • Uncompensated cardiac function
    • Inadequate organ function including:
    o Leucocytes < 3.5 x 109/l
    o Neutrophils <1.5 x 109/l
    o Platelets < 100 x 109/l
    o Bilirubin above normal limits
    o Alkaline phosphatase >= 5 x UNL
    o ASAT and/or ALAT > 2.5 x UNL
    E.5 End points
    E.5.1Primary end point(s)
    As stated in the sub-protocols, primary endpoints for the individual sub-studies are specific to the patient groups considered:

    • HR+/HER2-: Five-year EFS
    • HR+/HER2+: pCR
    • TN: pCR
    • HR+/HER2+: pCR
    • Elderly: pCR

    In addition, for ADAPT umbrella, 5-year EFS will be a primary endpoint for comparisons involving all five substudies: Five-year EFS will be prospectively compared between two groups defined as follows:

    • ADAPT Umbrella Test Group comprising
    - Patients with intermediate risk (RS 12-25) with early good response (and no chemotherapy);
    - Patients with pCR in HR+/HER2+ disease;
    - Patients with pCR in HR+/HER2- disease;
    - Patients with pCR in TN disease
    - Patients with pCR within ELDERLY substudy

    • ADAPT Umbrella Control Group comprising
    - Low-risk HR+/HER2- (RS< 12, N0-1) patients

    ADAPT HR+/HER2- part I:
    Primary Endpoint: Prospective comparison of EFS in “intermediate-RS” N0-1 dynamic responders vs. “low-RS” N0-1 patients (RS ≤ 11 AND N0-1)

    ADAPT HR+/HER2- part II:
    Primary endpoint: Prospective comparison of EFS in nab-paclitaxel vs. paclitaxel based chemotherapy followed by dose dense EC

    ADAPT HER2+/HR+:
    Primary endpoint of the study:
    The study comprises a Run-in phase (n=130) and a Main phase (n=250). The Run-in phase will determine the cut-off for a dynamic test (performed after 3 weeks of therapy) to predict pCR probability in a descriptive manner. During the main phase of the trial, the dynamic test result will define responders and low responders.
    • The primary endpoint of the ADAPT HR+/HER2+ study is pCR after 12 weeks of pre-surgical therapy
    Assuming a drop-out rate of 5%, an ITT test collective of more than 300 patients is expected. The primary hypotheses are tested in this test collective.
    The study will test the hypothesis of higher pCR proportion separately in each of the T-DM1 arms. We expect a 10% rate of pCR in the trastuzumab + endocrine therapy arm. In each T-DM1 arm, 25% pCR is assumed. Assuming total alpha = .05 (one-sided), i.e., alpha =0.025 for each hypothesis, the test has 80% power to detect superiority in each of the T-DM1 containing arms compared to the trastuzumab + endocrine therapy arm.

    Interim analysis on correlation between changes in the sequential biopsy and pCR rates in the first 130 patients (Run-In phase) is planned during ongoing recruitment of patients.

    ADAPT HER2+/HR-:
    The primary endpoint of the study is pCR after 12 weeks of presurgical therapy.

    ADAPT TN:
    Primary endpoint: The primary endpoint of the study is pCR, defined as no invasive tumor in the breast and lymph nodes
    The trial will test two co-primary hypotheses. The family-wise error alpha is controlled for multiple testing at the level 0.05 by an unequal allocation of alpha.
    Hypothesis 1 (primary): Proportion achieving pCR is higher in responders (60 % of TN) than in non-responders (about 40 % of TN).
    Hypothesis 2 (primary): Proportion achieving pCR is is different in the two arms.

    ADAPT Elderly:
    The primary endpoint of the ADAPT Elderly trial is pCR. Early response and
    toxicity (particularly febrile neutropenia) are stratification criteria. The trial is
    designed to test whether therapy switch in patients with either toxicity or
    inadequate early response benefit from the addition of taxanes. To this end, a non-inferiority hypothesis for this group (Group 2) compared to responders without toxicity (Group 1) will be tested with respect to
    the outcome pCR. Patients in Group 1 receive 4 x MC (2 x MC prior to early-response
    assessment, 2 x MC subsequently). Patients in Group 2 receive 2 x MC
    followed by Paclitaxel 80 mg/m2 q1w x 6.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Event-free survival (EFS) is defined as the interval from the date of registration to the date of local, regional or metastatic invasive or both invasive/non-invasive relapse or the date of second primary cancer (with the exception of curatively treated non-melanoma skin cancer or in situ carcinoma of the cervix) or death from any cause, whichever occurs first.
    pCR: The efficacy parameter pCR is defined at the time of surgery as absence of invasive tumor in the breast and lymph nodes. This will also be measured based on provision of data on size of the residual tumor, proportion of vital cells within invasive carcinoma, number of positive lymph nodes and size of the largest lymph node metastasis and ductal carcinoma in situ.

    E.5.2Secondary end point(s)
    In all sub-studies and for groups within the studies, the following secondary endpoints (defined below) will be prospectively evaluated:
    Overall survival
    Relapse free survival
    Distant disease-free survival
    Local and regional relapse-free survival (LRFS and RRFS)
    Quality of life
    Toxicity

    In the ADAPT Umbrella project, these endpoints will be utilized in analyses including

    • Translational research/prognostic factor analysis
    • Cost-effectiveness analysis
    • Comparisons with historical, evidence based outcome estimates (e.g., using Adjuvant Online)


    ADAPT HR+/HER2- part II secondary endpoints:
    • Interim safety
    • pCR rates in the neoadjuvant treatment of dose dense paclitaxel-EC vs. nab-paclitaxel-EC arms

    ADAPT HER2+/HR+ secondary endpoints:
    • will be analyzed in an exploratory manner

    ADAPT TN secondary endpoints:
    • The following secondary endpoints (defined below) will be prospectively evaluated:
    Overall survival
    Relapse free survival
    Distant disease-free survival
    Local/regional relapse-free survival
    Evaluation of proliferation/apoptosis changes as surrogate marker for 5 year EFS.
    Relation of survival to study arm.

    ADAPT Elderly secondary endpoints:
    Comparison of toxicity in the two arms (MC vs MC->pac) allows evaluating whether the presumed higher risk of toxicity in the taxane-containing arm may be outweighed by the higher response rate in poor responders.
    E.5.2.1Timepoint(s) of evaluation of this end point
    HR+/HER2- run-in: An interim safety analysis is planned after recruitment of 120 patients in both study arms.

    In this protocol, time to event (EFS, DDFS, LRFS and OS) will be defined as follows:

    • For all analyses related to endocrine-only patients (HR+/HER2-), time-to-event endpoints will start at the date of registration of patients
    • For all analysis related to chemotherapy application, time-to-event endpoints will start at the date of registration for the trial
    • For all HER2+, HER2+/HR+ and TNBC patients, time will start at the date of the registration for the trial

    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 No
    E.6.5Efficacy No
    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 Yes
    E.6.13.1Other scope of the trial description
    Prognosis and prediction of benefit from therapy.
    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) 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 Yes
    E.8.2.3.1Comparator description
    Paclitaxel (HR+/HER2-, Elderly, HER2+/HR-), Trastuzumab (HER2+/HR+), none (HR-/HER2-)
    E.8.2.4Number of treatment arms in the trial11
    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 concerned80
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years11
    E.8.9.1In the Member State concerned months0
    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: 4189
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 1047
    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 state5236
    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)
    5 years follow-up according to German aftercare plan
    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 Decision2011-11-11
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-03-29
    P. End of Trial
    P.End of Trial StatusOngoing
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