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    Summary
    EudraCT Number:2018-003069-33
    Sponsor's Protocol Code Number:DS8201-A-U303
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2019-04-12
    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 ConcernedSpain - AEMPS
    A.2EudraCT number2018-003069-33
    A.3Full title of the trial
    A phase 3, multicenter, randomized, open-label, active-controlled trial of DS-8201a, an anti-HER2-antibody drug conjugate (ADC), versus treatment of physician’s choice for HER2Low, unresectable and/or metastatic breast cancer subjects
    Estudio en fase III, multicéntrico, aleatorizado, abierto y controlado con principio activo de DS-8201a, un conjugado de fármaco y anticuerpo (CAF) anti-HER2, en comparación con el tratamiento elegido por el médico en sujetos con cáncer de mama irresecable o metastásico (o ambos) con expresión baja de HER-2
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Testing a new targeted therapy (DS-8201a) against other targeted chemotherapy (selected by your doctor) for patients with advanced-stage breast cancer.
    Probar una nueva terapia dirigida (DS-8201a) contra otra quimioterapia dirigida (seleccionada por su médico) para pacientes con cáncer de mama en estadio avanzado.
    A.4.1Sponsor's protocol code numberDS8201-A-U303
    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 SponsorDaiichi Sankyo Inc.
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportDaiichi Sankyo Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationDaiichi Sankyo Inc.
    B.5.2Functional name of contact pointNot Available
    B.5.3 Address:
    B.5.3.1Street Address211 Mt Airy Rd
    B.5.3.2Town/ cityBasking Ridge
    B.5.3.3Post codeNJ 07920
    B.5.3.4CountryUnited States
    B.5.4Telephone number+349133030007768
    B.5.6E-maileu_cta@dsi.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.2Product code DS-8201a
    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 deruxtecan
    D.3.9.2Current sponsor codeDS-8201a
    D.3.9.3Other descriptive nameAnti-HER2 antibody-drug conjugate
    D.3.9.4EV Substance CodeSUB188940
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    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 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 Capecitabine Tablets
    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 Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNCapecitabine
    D.3.9.3Other descriptive nameCapecitabine
    D.3.9.4EV Substance CodeSUB12474MIG
    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 Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 3
    D.1.2 and D.1.3IMP RoleComparator
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Capecitabine Tablets
    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 Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNCapecitabine
    D.3.9.3Other descriptive nameCapecitabine
    D.3.9.4EV Substance CodeSUB12474MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number500
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 4
    D.1.2 and D.1.3IMP RoleComparator
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Halaven
    D.2.1.1.2Name of the Marketing Authorisation holderEisai Europe 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.3.4Pharmaceutical 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 253128-41-5
    D.3.9.3Other descriptive nameERIBULIN
    D.3.9.4EV Substance CodeSUB31134
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number0.88
    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.2.1.1.1Trade name Abraxane
    D.2.1.1.2Name of the Marketing Authorisation holderCelgene Europe BV
    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 suspension 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 INNPACLITAXEL ALBUMIN-BOUND
    D.3.9.3Other descriptive namePACLITAXEL ALBUMIN-BOUND
    D.3.9.4EV Substance CodeSUB127678
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    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.2.1.1.1Trade name Gemcitabine
    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 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 INNGemcitabine
    D.3.9.1CAS number 95058-81-4
    D.3.9.3Other descriptive nameGemcitabine
    D.3.9.4EV Substance CodeSUB07892MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1000
    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.2.1.1.1Trade name Paclitaxel
    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 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.3.9.3Other descriptive namePaclitaxel
    D.3.9.4EV Substance CodeSUB09583MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number300
    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
    Unresectable and/or metastatic breast cancer that is human epidermal growth factor receptor 2 (HER2)-low
    Cáncer de mama irresecable o metastásico (o ambos) con expresión baja del factor de crecimiento epidérmico humano 2 (HER2)
    E.1.1.1Medical condition in easily understood language
    Advanced-stage breast cancer
    Cáncer de mama en etapa avanzada
    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
    To compare the progression-free survival (PFS) benefit of DS-8201a to physician’s choice in HER2-low, hormone receptor (HR)-positive breast cancer, based on blinded independent central review (BICR).
    Comparar el beneficio en la supervivencia sin progresión (SSP) de DS-8201a en comparación con la elección del médico en el cáncer de mama con receptores hormonales y con expresión baja de HER2, en función de una revisión central independiente enmascarada (RCIE)
    E.2.2Secondary objectives of the trial
    • To investigate the efficacy of DS-8201a compared to physician’s choice on the following parameters:
    - PFS in HR-positive subjects, based on Investigator assessment
    - Overall survival (OS) in HR-positive subjects
    - Confirmed objective response rate (ORR), based on BICR and Investigator assessment in HR-positive subjects
    - Duration of response (DoR), based on BICR and Investigator assessment in HR-positive subjects
    - PFS, OS, ORR, and DoR in all subjects, regardless of HR status.
    • To determine pharmacokinetics (PK) of DS-8201a
    • To evaluate safety of DS-8201a compared to physician’s choice of treatment
    • To evaluate Health Economics and Outcomes Research (HEOR) endpoints for DS-8201a compared to physician’s choice
    Investigar la eficacia de DS-8201a en comparación con la elección del médico en los siguientes parámetros:
     SSP en los sujetos con HR, basándose en la evaluación del investigador
     Supervivencia general (SG) en los sujetos con HR
     Tasa de respuesta objetiva (TRO) confirmada, basándose en la RCIE y en la evaluación del investigador en sujetos con expresión de HR
     Duración de la respuesta (DdR), basándose en la RCIE y en la evaluación del investigador en sujetos con expresión de HR
     SSP, SG, TRO y DdR en todos los sujetos, independientemente del estado de HR.
    • Determinar la farmacocinética (FC) de DS-8201a
    • Evaluar la seguridad de DS-8201a en comparación con el tratamiento elegido por el médico
    • Evaluar los criterios de valoración de la Investigación de la economía y los resultados sanitarios (Health Economics and Outcomes Research, HEOR) para DS-8201a en comparación con el tratamiento elegido por el médico
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Men or women ≥18 years old. (Please follow local regulatory requirements if the legal age of consent for study participation is >18 years old.)
    • Pathologically documented breast cancer that:
    - Is unresectable or metastatic.
    - Has a history of low HER2 expression, defined as IHC 2+/ISH- or IHC 1+ (ISH- or untested).
    - Is assessed as low HER2 expression, defined as IHC 2+/ISH- or IHC 1+ according to American Society of Clinical Oncology – College of American Pathologists (ASCO-CAP) 2018 guidelines (adapted by Daiichi Sankyo Inc. and Ventana – please see the study laboratory manual for details) evaluated at a central laboratory.
    - Is HR-positive or HR-negative. After ~60 HR-negative subjects are enrolled, further enrollment will be limited to only subjects who are HR-positive (either estrogen receptor positive or progesterone receptor positive per ASCO-CAP 2018 guidelines (adapted by Daiichi Sankyo Inc. and Ventana – please see the study laboratory manual for details)
    - Is documented refractory to endocrine therapy, defined as having progressed on at least 1 endocrine therapy and determined by the Investigator that subject would no longer benefit from further treatment from endocrine therapy.
    - If HR-positive, has or has not been treated with a CDK4/6 inhibitor. After ~240 HR-positive subjects have been enrolled who have not had prior therapy with a CDK4/6 inhibitor, further enrollment of HR-positive subjects will be limited to subjects who have had prior therapy with a CDK4/6 inhibitor.
    - Has been treated with at least 1 and at most 2 prior lines of chemotherapy in the metastatic setting. If recurrence occurred within 6 months of adjuvant chemotherapy, adjuvant therapy would count as 1 line of chemotherapy.
    - Was never previously HER2-positive (IHC 3+ or ISH+) on prior pathology testing (per ASCO-CAP 2018 guidelines [adapted by Daiichi Sankyo Inc. and Ventana – please see the study laboratory manual for details]).
    - Was never previously treated with anti-HER2 therapy.
    • Documented radiologic progression (during or after most recent treatment).
    • Must have an adequate archival tumor sample available for assessment of HER2 status by central laboratory (based on
    most recent available tumor tissue sample). If archival tissue is not available, a fresh biopsy is required.
    • All subjects must have a recent tumor sample after the most recent treatment regimen or agree to undergo a tissue biopsy
    prior to randomization.
    • Presence of at least 1 measurable lesion based on computed tomography (CT) or magnetic resonance imaging (MRI), per
    modified Response Evaluation Criteria in Solid Tumors (mRECIST) version 1.1
    • Left ventricular ejection fraction (LVEF) ≥50%
    • Adequate renal function, defined as:
    - Creatinine clearance ≥30 mL/min, as calculated using the Cockcroft-Gault equation
    • Adequate hepatic function, defined as:
    - Aspartate aminotransferase (AST)/ alanine aminotransferase (ALT) ≤5 × upper limit of normal (ULN)
    - Total bilirubin ≤1.5 × ULN) if no liver metastases or <3 × ULN in the presence of documented Gilbert’s syndrome (unconjugated hyperbilirubinemia) or liver metastases at baseline
    • Males and females of reproductive/childbearing potential must agree to follow instructions for method(s) of contraception
    • Hombres o mujeres ≥ 18 años de edad. (Deben respetarse los requisitos legales locales si la edad legal de consentimiento para la participación en el estudio es > 18 años).
    • Cáncer de mama confirmado anatomopatológicamente que:
     sea irresecable o metastásico
     presente antecedentes de expresión baja de HER2, definida como IHQ 2+/HIS- o IHQ 1+ (HIS- o sin tal prueba)
     presente expresión baja de HER2, lo que se define como IHQ 2+/HIS- o IHQ 1+ según las directrices de la Asociación Estadounidense de Oncología Clínica - Colegio Estadounidense de Anatomopatólogos (American Society of Clinical Oncology – College of American Pathologists, ASCO-CAP) de 2018 (adaptadas por Daiichi Sankyo Inc. y Ventana; véase el manual de laboratorio del estudio para obtener más información) evaluada en un laboratorio central
     presente expresión de HR o no Después de la inscripción de ~60 sujetos sin expresión de HR, la inscripción a partir de entonces se limitará únicamente a sujetos con expresión de los HR (ya sea expresión de los receptores estrogénicos o progesterogénicos conforme a las directrices de ASCO-CAP de 2018 [adaptadas por Daiichi Sankyo Inc. y Ventana; véase el manual de laboratorio del estudio para obtener más información])
     Se documentará la resistencia a la hormonoterapia, que se define como haber progresado con, al menos, 1 hormonoterapia y que el investigador determine que el sujeto ya no podría beneficiarse de continuar dicha terapia.
     Si presenta expresión de HR, si ha recibido o no tratamiento con un inhibidor de CDK 4/6. Después de la inscripción de ~240 sujetos con expresión de HR que no hayan recibido tratamiento anterior con un inhibidor CDK 4/6, la inscripción posterior de sujetos con expresión de HR se limitará a los sujetos que hayan recibido tratamiento anterior con un inhibidor CDK 4/6.
     Ha recibido tratamiento con al menos 1 y como máximo 2 líneas de quimioterapia anterior en el marco metastásico. Si la recidiva se produjo en los 6 meses anteriores a recibir la quimioterapia complementaria, tal tratamiento complementario se consideraría 1 línea de quimioterapia.
     No haber presentado nunca con anterioridad expresión de HER2 (IHQ 3+ ni HIS+) en las pruebas de anatomopatología anteriores (conforme a las directrices de ASCO-CAP de 2018 [adaptadas por Daiichi Sankyo Inc. y Ventana; véase el manual de laboratorio del estudio para obtener más información]).
     No haber recibido tratamiento anterior contra HER2.
    • Progresión radiológica documentada (durante o después del tratamiento más reciente).
    • Los pacientes deben disponer de una muestra tumoral de archivo adecuada para la evaluación del estado de HER2 por parte del laboratorio central (basándose en la muestra de tejido tumoral más reciente de la que se disponga). Si no se dispone de una muestra de archivo, es necesario obtener una biopsia fresca.
    • Todos los sujetos deben disponer de una muestra tumoral reciente después del tratamiento más reciente o aceptar someterse a una biopsia tisular antes de la aleatorización.
    • Presencia de al menos una lesión mensurable por tomografía computarizada (TAC) o resonancia magnética (RM), de acuerdo con la versión 1.1 de los Criterios de Evaluación de la Respuesta en Tumores Sólidos modificados (Response Evaluation Criteria in Solid Tumors, RECISTm).
    • Fracción de eyección del ventrículo izquierdo (FEVI) ≥ 50 %
    • Función renal adecuada, definida como:
     Aclaramiento de creatinina ≥ 30 ml/min, calculado mediante la ecuación de Cockcroft-Gault.
    • Función hepática adecuada, definida como:
     Aspartato aminotransferasa (AST) y alanina aminotransferasa (ALT) ≤ 5 veces el límite superior de la normalidad (LSN).
     Bilirrubina total ≤ 1,5 × LSN si no hay metástasis hepáticas o < 3 × LSN en presencia de síndrome de Gilbert documentado (hiperbilirrubinemia no conjugada) o metástasis hepáticas en el momento inicial
    • Los hombres y mujeres en edad reproductiva/fértil deben aceptar seguir las instrucciones sobre los métodos anticonceptivos
    E.4Principal exclusion criteria
    • Ineligible for all 5 of the options in the physician’s choice arm either because of previously receiving treatment in the metastatic setting with the comparator or having a contraindication to treatment
    • Has medical history of myocardial infarction within 6 months before randomization
    • Has history of symptomatic congestive heart failure (New York Heart Association Class II to IV)
    • Has corrected QT interval (QTc) prolongation to >470 ms (females) or >450 ms (male) based on average of Screening triplicate 12-lead electrocardiograms (ECGs)
    • Has a history of (noninfectious) interstitial lung disease (ILD)/pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at Screening.
    • Has spinal cord compression or clinically active central nervous system metastases, defined as untreated or symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms.
    - Subjects with treated brain metastases that are no longer symptomatic and who require no treatment with corticosteroids or anticonvulsants may be included in the study if they have recovered from the acute toxic effect of radiotherapy. A minimum of 2 weeks must have elapsed between the end of whole brain radiotherapy and study enrollment.
    • Paciente que no es idóneo para ninguna de las 5 opciones en el grupo de tratamiento elegido por el médico, ya sea debido a que ha recibido con anterioridad tratamiento en el marco metastásico con el fármaco de comparación o porque presenta una contraindicación al tratamiento
    • Presenta antecedentes de infarto de miocardio en los 6 meses anteriores a la aleatorización
    • Presenta antecedentes de insuficiencia cardíaca congestiva sintomática (clases de II a IV de la New York Heart Association)
    • Presenta prolongación del intervalo QT corregido (QTc) > 470 ms (mujeres) o > 450 ms (varones) según el valor promedio del electrocardiograma (ECG) de 12 derivaciones por triplicado realizado para la selección
    • Presenta antecedentes de neumopatía intersticial (NPI) (no infecciosa) /neumonitis que exigió tratamiento con corticosteroides, presenta NPI/neumonitis en curso o en el caso de que no pueda descartarse la sospecha de NPI/neumonitis mediante diagnóstico por imágenes durante la selección
    • Sufre compresión de la médula espinal o presenta metástasis clínicamente activas en el sistema nervioso central (SNC), lo que se define como no tratadas o sintomáticas, o que requieren tratamiento con corticosteroides y anticonvulsivos para controlar los síntomas asociados
     Puede incluirse en el estudio a sujetos con metástasis cerebrales tratadas que ya no produzcan síntomas y que no requieran tratamiento con corticosteroides ni anticonvulsivos, si se han recuperado del efecto tóxico agudo de la radioterapia Deberán haber transcurrido al menos 2 semanas entre el final de la radioterapia de cerebro completo y la inscripción en el estudio.
    E.5 End points
    E.5.1Primary end point(s)
    PFS, based on BICR
    SSP, basada en la RCIE
    E.5.1.1Timepoint(s) of evaluation of this end point
    The primary analyses for PFS will be performed when ~318 PFS events per BICR are observed in the HR-positive population, which is expected to occur in ~16 months.
    Los análisis principales de la SSP se realizarán cuando se hayan observado ~318 acontecimientos de SSP según la RCIE en la población con expresión de HR, lo cual se prevé que ocurra en ~16 meses.
    E.5.2Secondary end point(s)
    • PFS, based on Investigator assessment
    • OS
    • Confirmed ORR, based on BICR and Investigator assessment
    • DoR, based on BICR and Investigator assessment
    SSP, basándose en la evaluación del investigador
    • SG
    • TRO, basándose en la RCIE y en la evaluación del investigador
    • DdR, basándose en la RCIE y en la evaluación del investigador
    E.5.2.1Timepoint(s) of evaluation of this end point
    The end of the study hypothesis-testing period is defined as the date when approximately 318 PFS events per BICR have been observed in the HR-positive population.
    El final del período de comprobación de la hipótesis del estudio se define como la fecha en la que se hayan observado aproximadamente 318 acontecimientos de SSP conforme a la RCIE en la población con expresión de HR.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic Yes
    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 Yes
    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 concerned10
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA80
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Austria
    Belgium
    Canada
    China
    France
    Germany
    Greece
    Israel
    Italy
    Japan
    Korea, Republic of
    Portugal
    Spain
    Sweden
    Switzerland
    Taiwan
    United Kingdom
    United States
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    The end of the study hypothesis-testing period is defined as the date when approximately 318 PFS events per BICR have been observed in the HR-positive population. The study closure is defined as the date when the last subject discontinues study treatment and applicable follow-up occurs, or the study is ended by the Sponsor.
    El final del período de comprobación de la hipótesis del estudio se define como la fecha en la que se hayan observado aproximadamente 318 acontecimientos de SSP conforme a la RCIE en la población con expresión de HR. El cierre del estudio se define como la fecha en que el último sujeto interrumpe el tratamiento del estudio y se realiza el seguimiento correspondiente, o el promotor finaliza el estudio.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months24
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial months49
    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: 308
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 232
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    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 state34
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 315
    F.4.2.2In the whole clinical trial 540
    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)
    None. If there is evidence that the subject is receiving benefit from treatment even though the subject has met a criterion for discontinuation as listed above, the subject may remain on study treatment after discussion with and approval from the Sponsor Medical Monitor.
    Ninguna. Si hay evidencia de que el sujeto está recibiendo beneficios del tratamiento, aunque el sujeto haya cumplido con un criterio de interrupción como se indica anteriormente, el sujeto puede permanecer en el tratamiento del estudio después de una discusión y aprobación del Monitor Médico Promotor.
    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 Decision2019-05-08
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-03-19
    P. End of Trial
    P.End of Trial StatusOngoing
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