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    Summary
    EudraCT Number:2019-002956-18
    Sponsor's Protocol Code Number:ZWI-ZW25-202
    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:2020-01-23
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedSpain - AEMPS
    A.2EudraCT number2019-002956-18
    A.3Full title of the trial
    Phase 2a Study of ZW25 in Combination with Palbociclib Plus Fulvestrant
    Estudio de fase 2a de ZW25 en combinación con palbociclib más fulvestrant
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study to evaluate the safety and tolerability of ZW25 in combination with palbociclib plus fulvestrant
    Estudio para evaluar la seguridad y tolerabilidad de ZW25 en combinación con palbociclib más fulvestrant
    A.4.1Sponsor's protocol code numberZWI-ZW25-202
    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 SponsorZymeworks Inc.
    B.1.3.4CountryCanada
    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 supportZymeworks Inc.
    B.4.2CountryCanada
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationPPD
    B.5.2Functional name of contact pointProject Management
    B.5.3 Address:
    B.5.3.1Street AddressC/Titan, 15 6th Floor
    B.5.3.2Town/ cityMadrid
    B.5.3.3Post code28045
    B.5.3.4CountrySpain
    B.5.4Telephone number+34900834223
    B.5.6E-mailRegistroEspanolDeEstudiosClinicos@druginfo.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameZW25
    D.3.2Product code ZW25
    D.3.4Pharmaceutical form Concentrate for solution for injection/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 INNNot yet assigned
    D.3.9.1CAS number 2169946-15-8
    D.3.9.2Current sponsor codeZW25
    D.3.9.3Other descriptive nameNot available
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number15 to 20
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Ibrance
    D.2.1.1.2Name of the Marketing Authorisation holderPfizer Europe MA EEIG
    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 nameIbrance
    D.3.4Pharmaceutical form Capsule, hard
    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 INNPALBOCICLIB
    D.3.9.3Other descriptive nameIbrance
    D.3.9.4EV Substance CodeSUB177204
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number125
    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.2.1.1.1Trade name Ibrance
    D.2.1.1.2Name of the Marketing Authorisation holderPfizer Europe MA EEIG
    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 nameIbrance
    D.3.4Pharmaceutical form Capsule, hard
    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 INNPALBOCICLIB
    D.3.9.3Other descriptive nameIbrance
    D.3.9.4EV Substance CodeSUB177204
    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: 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.2.1.1.1Trade name Ibrance
    D.2.1.1.2Name of the Marketing Authorisation holderPfizer Europe MA EEIG
    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 nameIbrance
    D.3.4Pharmaceutical form Capsule, hard
    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 INNPALBOCICLIB
    D.3.9.3Other descriptive nameIbrance
    D.3.9.4EV Substance CodeSUB177204
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number75
    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.2.1.1.1Trade name Faslodex
    D.2.1.1.2Name of the Marketing Authorisation holderAstraZeneca AB
    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 nameFulvestrant
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntramuscular use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNFulvestrant
    D.3.9.3Other descriptive nameFULVESTRANT
    D.3.9.4EV Substance CodeSUB13933MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number250
    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
    Breast cancer patients including those with locally advanced (unresectable) or metastatic HER2-positive, HR-positive breast cancer.
    Pacientes con cáncer de mama incluyendo a aquellos con localmente avanzado (irresecable) y/o metastásico positivo para el receptor 2 del factor de crecimiento epidérmico humano (HER2) y positivo para receptores hormonales (RH).
    E.1.1.1Medical condition in easily understood language
    Breast Cancer patients with locally advanced or metastatic cancer, that overexpress HER2 protein (receptor for the Human epidermal growth factor receptor 2), and are hormone receptor positive
    Pacientes con cáncer de mama localmente avanzado o metastásico, que sobreexpresan la proteína HER2 (receptor 2 del factor de crecimiento epidérmico humano) y son receptores de hormonas positivos
    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
    Part 1
    To evaluate the safety and tolerability of ZW25 in combination with palbociclib plus fulvestrant in patients with locally advanced (unresectable) and/or metastatic human epidermal growth factor receptor 2 (HER2)-positive, hormone receptor (HR)-positive breast cancer

    Part 2
    To evaluate the anti-tumor activity of ZW25 in combination with palbociclib plus fulvestrant in patients with locally advanced (unresectable) and/or metastatic HER2+, HR+ breast cancer
    Parte 1
    Evaluar la seguridad y la tolerabilidad de ZW25 en combinación con palbociclib más fulvestrant en pacientes con cáncer de mama localmente avanzado (irresecable) y/o metastásico positivo para el receptor 2 del factor de crecimiento epidérmico humano (HER2) y positivo para receptores hormonales (RH).

    Parte 2
    Evaluar la actividad antitumoral de ZW25 en combinación con palbociclib más fulvestrant en pacientes con cáncer de mama localmente avanzado (irresecable) o metastásico HER2+ y RH+.
    E.2.2Secondary objectives of the trial
    Part 1
    To recommend a dose for ZW25 in combination with palbociclib + fulvestrant for Part 2
    To evaluate PK of ZW25 in combination with palbociclib + fulvestrant
    To evaluate immunogenicity of ZW25 in combination with palbociclib+fulvestrant
    Exploratory:
    To explore the utility of potential serum & tumor biomarkers
    Part 2
    To evaluate safety & tolerability of ZW25 in combination with palbociclib + fulvestrant
    To evaluate PK of ZW25 in combination with palbociclib + fulvestrant
    To evaluate immunogenicity of ZW25 in combination with palbociclib + fulvestrant
    Exploratory:
    ● To explore the utility of potential serum & tumor biomarkers

    To evaluate the safety and tolerability of ZW25 in combination with palbociclib plus fulvestrant
    To evaluate the PK of ZW25 in combination with palbociclib plus fulvestrant
    To evaluate the immunogenicity of ZW25 in combination with palbociclib plus fulvestrant
    Exploratory:
    To explore the utility of potential serum and tumor biomarkers
    Parte 1
    ● Recomendar una dosis de ZW25 en combinación con palbociclib más fulvestrant para la parte 2.
    ● Evaluar la farmacocinética (FC) de ZW25 en combinación con palbociclib más fulvestrant.
    ● Evaluar la inmunogenicidad de ZW25 en combinación con palbociclib más fulvestrant.
    Exploratorios:
    ● Investigar la utilidad de posibles biomarcadores séricos y tumorales.
    Parte 2
    ● Evaluar la seguridad y la tolerabilidad de ZW25 en combinación con palbociclib más fulvestrant.
    ● Evaluar la FC de ZW25 en combinación con palbociclib más fulvestrant.
    ● Evaluar la inmunogenicidad de ZW25 en combinación con palbociclib más fulvestrant.
    Exploratorios:
    ● Investigar la utilidad de posibles biomarcadores séricos y tumorales.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1.Pathologically-confirmed diagnosis of breast cancer with evidence of locally advanced (unresectable) and/or metastatic disease. All patients in both Parts 1 and 2 must have HER2+ and HR+ disease as follows:
    •HER2+ based on the HER2 Testing in Breast Cancer: American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) Clinical Practice Guidelines.
    •HR+ defined as estrogen-receptor positive (ER+) and/or progesterone-receptor positive (PgR+) disease based on the ASCO/CAP Guideline Recommendations for Immunohistochemical Testing of Estrogen and Progesterone Receptors in Breast Cancer.
    2.Able to provide a new formalin-fixed, paraffin-embedded (FFPE) tumor sample (preferred) or archived tumor tissue (most recent sample available) for retrospective central review of HER2 status.
    Local assessments performed on a new tumor sample or archived tumor tissue in a Clinical Laboratory Improvements Amendments (CLIA)-certified lab using a combination of IHC and ISH/FISH methods may be used to determine HER2 and HR status for study eligibility. IHC must be used to determine HR status. Unless otherwise approved by the sponsor medical monitor, specimens should be provided for centralized retrospective review of HER2 status.
    3.Disease that has progressed on or been refractory to prior treatment with trastuzumab, pertuzumab, AND ado-trastuzumab emtansine (T-DM1). Patients in any part of the study who did not receive pertuzumab or T-DM1 because of lack of access (e.g., due to insurance coverage or because they were treated prior to regulatory agency approval of the agent in a relevant indication) or due to medical ineligibility for treatment with T-DM1 (e.g., history of severe infusion reactions to trastuzumab, ≥ Grade 2 peripheral neuropathy, or platelet count < 100 x 10E9/L) may be eligible for the study after discussion with and approval from the sponsor medical monitor. Prior treatment with endocrine therapy in the neoadjuvant, adjuvant, and/or metastatic setting is permitted.
    4.Sites of disease assessible per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (both measurable and non-measurable disease allowed)
    5.Male and female patients aged 18 years or older
    6.An Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1
    7.Life expectancy of at least 3 months in the opinion of the investigator
    8.The following baseline laboratory data:
    a.Absolute neutrophil count (ANC) ≥ 1.5 x 10E9/L
    b.Platelet count ≥ 75 x 10E9/L
    c.Hemoglobin ≥ 9 g/dL
    d.Prothrombin time (PT) and/or International Normalized Ratio (INR) and partial thromboplastin time (PTT)≤ 1.5 x upper limit of normal (ULN), unless on medication known to alter the INR or PTT
    e.Total bilirubin ≤ 1.5 x ULN per institutional values (patients with known Gilbert’s Syndrome may enroll with 2.5 x ULN provided the direct bilirubin is ≤ 1.5 mg/dL)
    f.Alanine transaminase (ALT) ≤ 3.0 x ULN per institutional values (if liver metastases are present, ≤ 5.0 x ULN)
    g.Aspartate transaminase (AST) ≤ 3.0 x ULN per institutional values (if liver metastases are present, ≤ 5.0 x ULN)
    h.Serum creatinine ≤ 1.5 X ULN or calculated glomerular filtration rate 50 mL/min
    9.Adequate cardiac left ventricular function, as defined by LVEF ≥ institutional standard of normal
    10.All toxicity related to prior cancer therapies must have resolved to ≤ Grade 1, with the exception of alopecia or ≤ Grade 2 neuropathy
    11.If female and of child-bearing potential, must have a negative pregnancy test ≤ 3 days prior to the first dose of ZW25
    12.For female patients who are not surgically sterile or post-menopausal and for male patients with a partner of child-bearing potential, willingness to use 2 methods of birth control with a failure rate of less than 1% per year during the study and for 12 months after the last dose of study drug (ZW25, palbociclib, and/or fulvestrant). These include, but are not limited to, established use of oral, implanted, or injected hormonal contraceptives; placement of intra-uterine device or intra-uterine system; or use of barrier methods, such as condom or diaphragm together with a spermicidal product.
    13.Female patients must agree not to breastfeed or donate ova starting at screening and throughout the study period, and for at least 12 months after the last dose of study drug (ZW25, palbociclib, and/or fulvestrant)
    14.Male patients must not donate sperm starting at screening and throughout the study period, and for at least 12 months after the last dose of study drug (ZW25, palbociclib, and/or fulvestrant)
    15.Signed informed consent prior to any study procedures not considered standard of care
    1. Diagnóstico confirmado anatomopatológicamente de cáncer de mama con signos de enfermedad localmente avanzada (irresecable) o metastásica. Todos los pacientes de las partes 1 y 2 deberán presentar un cáncer HER2+ y RH+ según lo siguiente:
    · HER2+ conforme a las directrices de práctica clínica de la ASCO/CAP para el análisis de HER2 en el cáncer de mama (Wolff 2018).
    · RH+, definida como enfermedad positiva para RE+ o RPg+ según las recomendaciones de las directrices de la ASCO/CAP para el análisis inmunohistoquímico de los receptores de estrógenos y progesterona en el cáncer de mama (Hammond 2010).
    2. Capacidad de proporcionar una muestra tumoral nueva fijada en formol e incluida en parafina (FFIP, preferible) o tejido tumoral de archivo (la muestra más reciente disponible) para una revisión centralizada retrospectiva de la presencia o ausencia de HER2.
    Para determinar el la presencia o ausencia de HER2 y RH a los efectos de la elegibilidad para el estudio, podrán utilizarse las evaluaciones de una muestra tumoral nueva o de tejido tumoral de archivo realizadas mediante una combinación de métodos de IHQ e HIS/FISH en un laboratorio local certificado por la CLIA. La presencia o ausencia de RH deberá determinarse mediante IHQ. A menos que el monitor médico del promotor apruebe otra cosa, se facilitarán muestras para una revisión retrospectiva centralizada de la presencia o ausencia de HER2.
    3. Progresión de la enfermedad o resistencia durante el tratamiento previo con trastuzumab, pertuzumab Y ado trastuzumab emtansina (T-DM1). Los pacientes de cualquiera de las partes del estudio que no hayan recibido pertuzumab o T DM1 por falta de acceso (p. ej., debido a la cobertura del seguro o porque se trataron antes de que las autoridades sanitarias aprobaran el fco para la indicación pertinente) o por falta de elegibilidad médica para el tto con T-DM1 (p. ej., antecedentes de reacción grave a la infusión de trastuzumab, neuropatía periférica de grado  2 o recuento de plaquetas < 100 x 109/l) podrán participar en el estudio previa consulta con el monitor médico del promotor y con su aprobación. Se permite el tto endocrino previo en el contexto neoadyuvante, adyuvante o metastásico.
    4. Focos de enfermedad evaluables conforme a los Criterios de evaluación de la respuesta en tumores sólidos (RECIST), v1.1 (tanto la enfermedad mensurable como la no mensurable).
    5. Pacientes de cualquier sexo mayores de 18 años.
    6. Estado funcional del ECOG de 0 a 1.
    7. Esperanza de vida de al menos 3 meses en opinión del investigador
    8. Los siguientes datos analíticos basales:
    a. Recuento absoluto de neutrófilos 1,5 × 109/l.
    b. Recuento de plaquetas 75 x 109/l.
    c. Hemoglobina 9 g/dl.
    d. TPo INR y TTP 1,5 veces el LSN), a menos que se administre medicación que altere el CIN o el TTP.
    e. Bilirrubina total  1,5 x LSN según los valores del centro (los pacientes con síndrome de Gilbert conocido podrán participar con 2,5 x LSN siempre que la bilirrubina directa sea  1,5 mg/dl).
    f. Alanina-transaminasa (ALT)  3,0 veces el LSN según los valores del centro (si hay metástasis hepáticas,  5,0 veces el LSN).
    g. Aspartato-transaminasa (AST)  3,0 veces el LSN según los valores del centro (si hay metástasis hepáticas,  5,0 veces el LSN).
    h. Creatinina sérica  1,5 x LSN o filtración glomerular calculada  50 ml/min.
    9. Función adecuada del ventrículo izquierdo, definida por un FEVI  valor normal según el centro.
    10. Toda la toxicidad relacionada con el tratamiento antineoplásico previo deberá haberse resuelto hasta un grado  1, a excepción de la alopecia y la neuropatía de grado  2.
    11. Las mujeres en edad fértil deberán tener una prueba de embarazo negativa en los 3 días previos a la primera dosis de ZW25.
    12. Las pacientes que no estén esterilizadas quirúrgicamente ni sean posmenopáusicas y los pacientes varones con pareja en edad fértil deberán comprometerse a utilizar dos métodos anticonceptivos que tengan una tasa de fracasos inferior al 1% anual durante el estudio y hasta 12 meses después de la última dosis del fármaco del estudio (ZW25, palbociclib o fulvestrant). Entre ellos figuran el uso establecido de anticonceptivos hormonales orales, implantables o inyectables, la colocación de dispositivos o sistemas intrauterinos o el uso de métodos de barrera, como preservativo o diafragma, junto con un espermicida.
    13. Las pacientes deberán comprometerse a no amamantar ni donar óvulos a partir de la selección y durante todo el período del estudio, así como hasta al menos 12 meses después de la última dosis del fármaco del estudio (ZW25, palbociclib o fulvestrant).
    14. Los pacientes varones no deberán donar semen desde la selección, durante todo el período del estudio ni hasta al menos 12 meses después de la última dosis del fármaco del estudio (ZW25, palbociclib y/o fulvestrant).
    15. Firma del CI antes de realizar cualquier procedimiento del estudio que no se considere parte de la asistencia habitual.
    E.4Principal exclusion criteria
    1.Prior treatment with trastuzumab, pertuzumab, lapatinib, T-DM1, or other anti-HER2-targeted therapy ≤ 3 weeks before the first dose of ZW25
    2.Prior treatment with chemotherapy, other anti-cancer therapy not otherwise specified, or hormonal cancer therapy ≤ 3 weeks before the first dose of ZW25
    3.Prior treatment with experimental biologic and non-biologic therapies ≤ 4 weeks before the first dose of ZW25
    4.Prior treatment with radiation therapy other than for central nervous system (CNS) disease ≤ 3 weeks before the first dose of ZW25
    5.Treatment with anthracyclines within 90 days before first dose of ZW25 and/or total lifetime load exceeding 360 mg/m2 Adriamycin or equivalent
    6.Use of any medications or substances that are strong inhibitors or inducers of CYP3A isoenzymes within 7 days of first dose of any study drug
    7.History of life-threatening hypersensitivity to monoclonal antibodies, recombinant proteins, or excipients in the drug formulation
    8.Prior treatment with palbociclib or any other CDK4/6 inhibitors, including experimental agents
    9.Use of corticosteroids administered at doses equivalent to > 15 mg per day of prednisone within 2 weeks of first ZW25 dosing unless otherwise approved by the sponsor medical monitor. Topical, ocular, intra-articular, intranasal, and/or inhalational corticosteroids are permitted.
    10.History of myocardial infarction or unstable angina within 6 months prior to enrollment, troponin levels consistent with myocardial infarction, or clinically significant cardiac disease, such as ventricular arrhythmia requiring therapy, uncontrolled hypertension, or any history of symptomatic congestive heart failure (CHF)
    11.QTc Fridericia (QTcF) >450 ms
    12.Grade 2 or greater pneumonitis and/or interstitial lung disease, including pulmonary fibrosis, or other clinically significant infiltrative pulmonary disease not related to lung metastases
    13.Active hepatitis B or hepatitis C infection
    14.Acute or chronic uncontrolled renal disease, pancreatitis, or severe liver disease (Child-Pugh Class C)
    15.Known infection with Human Immunodeficiency Virus (HIV)-1 or HIV-2 (Exception: patients with well- controlled HIV [e.g., cluster of differentiation 4 (CD4)-positive T cell count >350/mm3 and undetectable viral load] are eligible.)
    16.Major surgery ≤ 3 weeks prior to the first dose of ZW25
    17.Prior or concurrent malignancy whose natural history or treatment has the potential to interfere with the safety or efficacy assessment of the investigational regimen
    18.Any other medical, social, or psychosocial factors that, in the opinion of the investigator, could impact safety or compliance with study procedures
    19.Females who are breastfeeding or pregnant, and females and males planning a pregnancy
    20.Brain metastases: Untreated CNS metastases, symptomatic CNS metastases, or radiation treatment for CNS metastases within 4 weeks of start of study treatment. Stable, treated brain metastases are allowed (defined as patients who are off steroids and anticonvulsants and are neurologically stable for at least 1 month at the time of screening).
    21.Poorly-controlled seizures
    22.Known leptomeningeal disease (LMD). If LMD has been reported radiographically on baseline magnetic resonance imaging (MRI), but is not suspected clinically by the investigator, the patient must be free of neurological symptoms of LMD.
    23.Grade 3 or greater peripheral neuropathy
    1. Tratamiento previo con trastuzumab, pertuzumab, lapatinib, T-DM1 u otro tratamiento dirigido contra HER2 no más de 3 semanas antes de la primera dosis de ZW25.
    2. Tratamiento previo con quimioterapia, otros tratamientos antineoplásicos no especificados u hormonoterapia contra el cáncer no más de 3 semanas antes de la primera dosis de ZW25.
    3. Tratamiento previo con fármacos experimentales biológicos y no biológicos no más de 4 semanas antes de la primera dosis de ZW25.
    4. Tratamiento previo con radioterapia por enfermedad distinta de la del sistema nervioso central (SNC) no más de 3 semanas antes de la primera dosis de ZW25.
    5. Tratamiento con antraciclinas en los 90 días previos a la primera dosis de ZW25 o carga total durante toda la vida superior a 360 mg/m2 de adriamicina o equivalente.
    6. Uso de medicamentos o sustancias que sean inhibidores o inductores potentes de las isoenzimas CYP3A en los 7 días previos a la primera dosis de cualquiera de los fármacos del estudio.
    7. Antecedentes de hipersensibilidad potencialmente mortal a anticuerpos monoclonales, proteínas recombinantes o excipientes de la formulación del fármaco.
    8. Tratamiento previo con palbociclib o cualquier otro inhibidor de CDK4/6, incluidos fármacos experimentales.
    9. Tratamiento con corticoesteroides en dosis equivalentes a más de 15 mg al día de prednisona en las 2 semanas previas a la primera dosis de ZW25, a menos que el monitor médico del promotor lo autorice. Se permiten los corticoesteroides tópicos, oftálmicos, intraarticulares, intranasales o inhalados.
    10. Antecedentes de infarto de miocardio o angina inestable en los 6 meses previos a la inclusión, concentración de troponina compatible con infarto de miocardio o cardiopatía de importancia clínica, como arritmia ventricular que requiera tratamiento, hipertensión no controlada o antecedente de insuficiencia cardíaca congestiva (ICC) sintomática.
    11. QTc según la fórmula de Fridericia (QTcF) > 450 ms.
    12. Neumonitis o neumopatía intersticial de grado 2 o superior, incluida fibrosis pulmonar, u otra neumopatía infiltrativa de importancia clínica no relacionada con metástasis pulmonares.
    13. Infección activa por el virus de la hepatitis B o C.
    14. Nefropatía aguda o crónica no controlada, pancreatitis o hepatopatía grave (clase C de Child-Pugh).
    15. Infección confirmada por el virus de la inmunodeficiencia humana (VIH) de tipo 1 o 2 (excepción: podrán participar pacientes con infección por el VIH bien controlada [por ejemplo, recuento de linfocitos T positivos para el grupo de diferenciación 4 (CD4) > 350/mm3 y viremia indetectable].)
    16. Intervención de cirugía mayor no más de 3 semanas antes de la primera dosis de ZW25.
    17. Neoplasia maligna previa o concomitante cuya evolución natural o tratamiento pueda interferir en la evaluación de la seguridad o la eficacia del régimen en investigación.
    18. Cualquier otro factor médico, social o psicosocial que, en opinión del investigador, pueda afectar a la seguridad o al cumplimiento de los procedimientos del estudio.
    19. Mujeres en período de lactancia o embarazadas y mujeres y varones que tengan previsto un embarazo.
    20. Metástasis cerebrales: metástasis en el SNC no tratadas, metástasis en el SNC sintomáticas o radioterapia por metástasis en el SNC en las 4 semanas previas al inicio del tratamiento del estudio. Se permiten las metástasis cerebrales tratadas estables (definidas por la ausencia de tratamiento con corticoesteroides y antiepilépticos y la presencia de estabilidad neurológica durante al menos 1 mes en el momento de la selección).
    21. Crisis epilépticas mal controladas.
    22. Metástasis leptomeníngeas (MLM) confirmadas. Si las MLM se han identificado en la resonancia magnética (RM) basal en ausencia de sospecha clínica por parte del investigador, el paciente no debe presentar síntomas neurológicos de MLM.
    23. Neuropatía periférica de grado 3 o superior.
    E.5 End points
    E.5.1Primary end point(s)
    Part 1
    Frequency of dose-limiting toxicities (DLTs)
    Frequency and severity of adverse events (AEs)
    Frequency of serious adverse events (SAEs) and deaths
    Frequency and severity of clinical laboratory abnormalities
    Frequency of electrocardiogram (ECG) and left ventricular ejection fraction (LVEF) abnormalities
    Frequency and severity of adverse events of special interest (AESIs), including all cardiotoxicities (e.g., decreases in LVEF 10% points from baseline), all Grade 3 infusion-related reactions, and all Grade 2 events of pneumonitis and/or interstitial lung disease, including pulmonary fibrosis
    Frequency of dose reductions of ZW25
    Frequency of dose reductions of components of combination therapy

    Part 2
    Progression-free survival 6 (PFS6, defined as the % of evaluable patients with PFS 24 weeks)
    Parte 1
    ● Frecuencia de la toxicidad limitante de la dosis (TLD).
    ● Frecuencia e intensidad de los acontecimientos adversos (AA).
    ● Frecuencia de los acontecimientos adversos graves (AAG) y las muertes.
    ● Frecuencia e intensidad de las anomalías analíticas.
    ● Frecuencia de las anomalías en el electrocardiograma (ECG) y la fracción de eyección del ventrículo izquierdo (FEVI).
    ● Frecuencia e intensidad de los acontecimientos adversos de interés especial (AAIE), incluidos todos los acontecimientos de cardiotoxicidad (p. ej., disminución de la FEVI  10% con respecto al valor basal), todas las reacciones relacionadas con la infusión de grado  3 y todos los acontecimientos de neumonitis o neumopatía intersticial de grado  2, incluida la fibrosis pulmonar.
    ● Frecuencia de la reducción de la dosis de ZW25.
    ● Frecuencia de la reducción de la dosis de los componentes del tratamiento combinado.

    Parte 2
    ● Supervivencia sin progresión 6 (SSP6, definida como el porcentaje de pacientes evaluables con SSP  24 semanas).
    E.5.1.1Timepoint(s) of evaluation of this end point
    The DLT-evaluation period will be the first 28 days of treatment. AEs, and SAEs will be collected from the time of consent through 30 days after last dose of study drug (ZW25, palbociclib, and/or fulvestrant) or prior to beginning the next course of anti-cancer therapy, whichever occurs first
    Frequency of electrocardiogram (ECG) and left ventricular ejection fraction (LVEF) abnormalities, severity of adverse events of special interest (AESIs), of dose reductions of ZW25 and of combination therapy will be measure throughout the study when occur.
    Progression-free survival 6 , Objective response rate (ORR), Duration of response (DOR),Disease control rate (DCR), Progression-free survival (PFS) will be measure when occur
    El período de evaluación de la TLD será los primeros 28 días de tratamiento a partir del día 1 del ciclo 1. Los AA se recopilarán desde el momento del consentimiento hasta 30 días después de la última dosis del fármaco del estudio (ZW25, palbociclib o fulvestrant) o hasta antes de comenzar el siguiente tratamiento antineoplásico, lo que ocurra antes.
    E.5.2Secondary end point(s)
    Part 1
    Serum concentrations of ZW25 as a function of time post-dosing
    PK parameters for single (first) dose and multiple doses of ZW25
    Frequency, duration, and time of onset of anti-drug antibodies (ADA) and neutralizing antibodies, if applicable

    Part 2

    Frequency and severity of AEs
    Frequency of SAEs and deaths
    Frequency and severity of clinical laboratory abnormalities
    Frequency of ECG and LVEF abnormalities
    Frequency and severity of AESIs, including all cardiotoxicities (e.g., decreases in LVEF 10% points from baseline), all Grade 3 infusion-related reactions, and all Grade 2 events of pneumonitis and/or interstitial lung disease, including pulmonary fibrosis
    Frequency of dose reductions of ZW25
    Frequency of dose reductions of components of combination therapy
    Serum concentrations of ZW25 as a function of time post-dosing
    PK parameters for single (first) dose and multiple doses of ZW25
    Frequency, duration, and time of onset of ADA and neutralizing antibodies, if applicable
    Parte 1
    Concentración sérica de ZW25 en función del tiempo transcurrido desde la administración.
    Parámetros FC para dosis únicas (primera dosis) y múltiples de ZW25.
    Frecuencia, duración y momento de aparición de los anticuerpos contra el fármaco (ACF) y de los anticuerpos neutralizantes, si procede.

    Parte 2
    Frecuencia e intensidad de los AA.
    Frecuencia de los AAG y las muertes.
    Frecuencia e intensidad de las anomalías analíticas.
    Frecuencia de las anomalías del ECG y la FEVI.
    Frecuencia e intensidad de los AAIE, incluidos todos los acontecimientos de cardiotoxicidad (p. ej., disminución de la FEVI  10% con respecto al valor basal), todas las reacciones relacionadas con la infusión de grado  3 y todos los acontecimientos de neumonitis o neumopatía intersticial de grado  2, incluida la fibrosis pulmonar.
    Frecuencia de la reducción de la dosis de ZW25.
    Frecuencia de la reducción de la dosis de los componentes del tratamiento combinado.
    Concentración sérica de ZW25 en función del tiempo transcurrido desde la administración.
    Parámetros FC para dosis únicas (primera dosis) y múltiples de ZW25.
    Frecuencia, duración y momento de aparición de los ACF y de los anticuerpos neutralizantes, si procede
    E.5.2.1Timepoint(s) of evaluation of this end point
    Serum concentrations of ZW25 will be measured as a function of time post-dosing.
    PK samples timepoint are day 1, 2, 5 and 15 of Cycle 1, days 1 and 15 of Cycle 2, day 1 of every even cycle thereafter, and EoT if patient completed less that 6 months of treatment. Serum samples will be taken pre-dose, end of Infusion and Post dose.
    ADA will be measured day 1 and 15 of Cycle 1 and 2, and Cycle 4 and every even-numbered cycle thereafter.
    On Cycle 1 Day 1 and Cycle 4 Day 1, a 12-lead ECG will be recorded predose and at 1 after the end of the ZW25 infusion. On Day 1 of Cycle 3 and every 3 cycles thereafter a 12-lead ECG will only be recorded predose. ECGs will also be recorded at screening, EOT, and 30-day follow-up visit
    Se medirá la concentración sérica de ZW25 como función del tiempo transcurrido desde la administración.
    Parámetros FC son los días 1, 2, 5 y 15 del C1, los D1 y 15 del C2, el D1 de cada ciclo par a partir de entonces, y EoT si el paciente completó menos de 6 meses de tratamiento. Se tomarán muestras de suero antes de la dosis, al final de la infusión y después de la dosis.
    La ADA se medirá los días 1 y 15 del ciclo 1 y 2, y el ciclo 4 y cada ciclo par después.
    En el C1, D1 y C 4, D1, se registrará un ECG de 12 derivaciones antes de la dosis y al 1 después del final de la infusión de ZW25. El D1 del C3 y cada 3 ciclos posteriores, solo se registrará un ECG de 12 derivaciones antes de la dosis. Los ECG también se registrarán en la evaluación, EOT y en la visita de seguimiento de 30 días.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.3 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 concerned3
    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 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
    Canada
    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
    Patients may continue on study treatment until radiographically-confirmed disease progression as defined by RECIST version 1.1, clinical disease progression, unacceptable toxicity, consent withdrawal, physician decision, pregnancy, protocol violation, start of a subsequent anticancer therapy, or study termination by the sponsor.
    Los pacientes pueden continuar el tratamiento del estudio hasta la progresión de la enfermedad confirmada radiográficamente como se define en la versión 1.1 de RECIST, la progresión de la enfermedad clínica, la toxicidad inaceptable, la retirada del consentimiento, la decisión del médico, el embarazo, la violación del protocolo, el inicio de una terapia anticancerígena posterior o la finalización del estudio por parte del promotor.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months10
    E.8.9.2In all countries concerned by the trial 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: 57
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 19
    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 state15
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 15
    F.4.2.2In the whole clinical trial 76
    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 different from normal treatment on this condition. Satandard of care cosidered by the Investigator.
    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 Decision2020-03-25
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-03-17
    P. End of Trial
    P.End of Trial StatusOngoing
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