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    Summary
    EudraCT Number:2017-002781-48
    Sponsor's Protocol Code Number:MedOPP068
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2019-01-18
    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 number2017-002781-48
    A.3Full title of the trial
    INTERNATIONAL, MULTICENTER, RANDOMIZED, OPEN-LABEL, PHASE II CLINICAL TRIAL TO EVALUATE THE EFFICACY AND SAFETY OF CONTINUATION OF PALBOCICLIB IN COMBINATION WITH SECOND-LINE ENDOCRINE THERAPY IN HORMONE RECEPTOR- POSITIVE/HER2-NEGATIVE ADVANCED BREAST CANCER PATIENTS WHO HAVE ACHIEVED CLINICAL BENEFIT DURING FIRST-LINE PALBOCICLIB-BASED TREATMENT.
    Estudio de fase II, internacional, multicéntrico, randomizado y abierto para evaluar la eficacia y la seguridad de la continuación de palbociclib en combinación con terapia endocrina de segunda línea en pacientes con cáncer de mama avanzado con receptores hormonales positivos y HER2 negativo tras beneficio clínico durante el tratamiento de primera línea basado en palbociclib.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Palbociclib rechallenge in hormone receptor-positive/HER2-negative advanced breast cancer (PALMIRA)
    Retratamiento con palbociclib en cáncer de mama avanzado con receptores hormonales positivos y HER2 negativo (PALMIRA)
    A.3.2Name or abbreviated title of the trial where available
    PALbociclib rechallenge in horMone receptor-posItive/HER2-negative Advanced breast cancer (PALMIRA)
    Retratamiento con PALbociclib en cáncer de Mama avanzado con receptores hormonales posItivos y HER2
    A.4.1Sponsor's protocol code numberMedOPP068
    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 SponsorMedica Scientia Innovation Research (MedSIR)
    B.1.3.4CountrySpain
    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 supportPfizer S.L.U
    B.4.2CountrySpain
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMedica Scientia Innovation Research (MedSIR)
    B.5.2Functional name of contact pointClinical Trial Unit
    B.5.3 Address:
    B.5.3.1Street AddressRambla de Catalunya, 2
    B.5.3.2Town/ cityBarcelona
    B.5.3.3Post code08007
    B.5.3.4CountrySpain
    B.5.4Telephone number34932214135
    B.5.5Fax number34932992382
    B.5.6E-mailpilar.bescos@medsir.org
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name IBRANCE
    D.2.1.1.2Name of the Marketing Authorisation holderPfizer Europe MA EEIG
    D.2.1.2Country which granted the Marketing AuthorisationSpain
    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 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.3.9.1CAS number 571190-30-2
    D.3.9.3Other descriptive namePALBOCICLIB
    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: 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 AuthorisationSpain
    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 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.3.9.1CAS number 571190-30-2
    D.3.9.3Other descriptive namePALBOCICLIB
    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: 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 AuthorisationSpain
    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 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.3.9.1CAS number 571190-30-2
    D.3.9.3Other descriptive namePALBOCICLIB
    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: 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 LETROZOL KERN PHARMA
    D.2.1.1.2Name of the Marketing Authorisation holderKERN PHARMA S.L.
    D.2.1.2Country which granted the Marketing AuthorisationSpain
    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 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.3.9.3Other descriptive nameLETROZOLE
    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: 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 Faslodex 250 mg solution for injection
    D.2.1.1.2Name of the Marketing Authorisation holderAstraZeneca AB
    D.2.1.2Country which granted the Marketing AuthorisationSpain
    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 infusion in pre-filled syringe
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntramuscular use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNFulvestrant
    D.3.9.3Other descriptive nameFULVESTRANT
    D.3.9.4EV Substance CodeSUB13933MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.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
    Hormone receptor-positive/HER2-negative Advanced Breast Cancer
    Cáncer de mama avanzado con receptores hormonales positivos y HER2 negativo
    E.1.1.1Medical condition in easily understood language
    Hormone receptor-positive/HER2-negative Advanced Breast Cancer
    Cáncer de mama avanzado con receptores hormonales positivos y HER2 negativo
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10072737
    E.1.2Term Advanced breast cancer
    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
    To compare the efficacy, defined as progression-free survival (PFS), of continuation of palbociclib treatment combined with second-line endocrine therapy (fulvestrant or letrozole) versus endocrine therapy in pre- and post-menopausal women with HR-positive/HER2-negative ABC
    Comparar la eficacia, definida como la supervivencia libre de progresión (PFS, progression-free survival), de la continuación del tratamiento con palbociclib en combinación con terapia endocrina de segunda línea (fulvestrant o letrozol), en comparación con terapia endocrina sola, en mujeres premenopáusicas y posmenopáusicas con cáncer de mama avanzado RH-positivo/HER2-negativo
    E.2.2Secondary objectives of the trial
    • To compare the safety and tolerability of interventional arm versus control arm.
    • To compare the objective response rate (ORR), the duration of response (DoR), the time to response (TTR), the clinical benefit rate (CBR), the time to progression (TTP), and the overall survival (OS) of interventional arm versus control arm.
    • To compare the patient reported global Quality of Life, functioning and symptoms of interventional arm versus control arm.
    • To perform subgroup analysis for primary and secondary endpoints in stratified groups of patients.
    • To compare the time to first chemotherapy of interventional arm versus control arm.
    • To explore correlations between the intrinsic molecular subtypes and efficacy/safety findings.
    • To explore potential molecular markers of sensitivity and/or resistance for interventional arm and control arm, according to, but not limited to, the results obtained from the BioPER trial (NCT03184090).
    •Comparar seguridad y tolerabilidad del grupo de intervención versus grupo control
    •Comparar tasa de respuesta objetiva, duración de respuesta, tiempo hasta respuesta, tasa de beneficio clínico, tiempo hasta progresión y supervivencia global del grupo de intervención versus grupo control.
    •Comparar registro global de calidad de vida, funcionamiento y síntomas reportados por las pacientes del grupo de intervención versus grupo control
    •Realizar análisis de los criterios de valoración principal y secundarios en base a determinados subgrupos preespecificados de pacientes.
    •Comparar tiempo a la primera quimioterapia del grupo de intervención versus grupo control.
    •Explorar correlaciones entre subtipos moleculares intrínsecos y los resultados de eficacia/seguridad.
    •Explorar potenciales marcadores moleculares de sensibilidad y/o resistencia para el grupo de intervención y el grupo control, en función de, entre otros, los resultados obtenidos en el ensayo clínico BioPER (NCT03184090)
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1.- Female patients ≥18 years of age.
    2.- Pre-menopausal (treated with a LHRH analogue for at least 28 days) or post-menopausal women.
    3.- ECOG 0 - 1.
    4.- Life expectancy ≥12 weeks.
    5.- ABC not amenable to curative treatment.
    6.- HR-positive and/or HER2-negative.
    7.- Disease progression on first-line combination of palbociclib + endocrine therapy (AI or fulvestrant).
    8.- Clinical benefit to a first-line palbociclib-based endocrine regimen.
    9.- Previous palbociclib dose: min 100 mg during the last 2 cycles.
    10.- Last dose of palbociclib administered not later than 8 weeks and not earlier than 7 days from study entry, (except in the adjuvant setting).
    11.- Patients should not have been treated in the advanced setting with at least one of these endocrine therapy options: either fulvestrant or AI.
    Note: Patients treated with adjuvant AI with a disease- free interval ≥ 12 months, and with first-line fulvestrant in the metastatic setting, could receive treatment with an AI in the metastatic setting.
    12.- Measurable or evaluable disease acc. RECIST v.1.1. Patients with only bone lesions are eligible.
    13.- Tumor tissue biopsy (if feasible) from a metastatic site or the primary breast tumor, both at inclusion and after disease progression for exploratory studies. If not feasible, eligibility to be evaluated by Sponsor’s designee.
    14.- Patients agree to collection of blood samples (liquid biopsy) at inclusion, after 2 weeks of treatment, and upon progression or study termination.
    15.- Adequate organ function.
    16.- Patients who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
    17.- Patients informed and signed informed consent.
    18.- Resolution of all acute toxic effects of prior anti- cancer therapy to grade </= 1 (NCI-CTCAE) v.5.0 (except for alopecia or other toxicities, such as myelosuppression, not considered a safety risk for the patient at investigator's discretion).
    1. Mujeres de 18 años de edad o más.
    2. Mujeres premenopáusicas tratadas con análogos de LHRH durante al menos 28 días (si es durante menos tiempo, deben confirmarse analíticamente los niveles posmenopáusicos de estradiol/hormona foliculoestimulante en suero antes de la inclusión en el estudio), o mujeres posmenopáusicas.
    3. Puntuación en el estado funcional ECOG (Eastern Cooperative Oncology Group) inferior o igual a 1.
    4. Esperanza de vida superior o igual a 12 semanas.
    5. Confirmación histológica de cáncer de mama avanzado no tributario de tratamiento curativo.
    6. Pacientes con cáncer de mama avanzado con una recurrencia documentada RE-positivo y/o receptor de progesterona (PR)-positivo y HER2-negativo.
    7. Evidencia radiológica o clínica de progresión de la enfermedad a una primera línea de palbociclib en combinación con terapia endocrina (inhibidor de la aromatasa [AI] o fulvestrant). Se excluirán a las pacientes tratadas previamente con la combinación de palbociclib y tamoxifeno.
    8. Pacientes que hayan alcanzado criterios de beneficio clínico con un régimen endocrino de primera línea basado en palbociclib (definido como enfermedad estable durante al menos 24 semanas, o bien que hayan tenido una respuesta parcial o completa a este tratamiento, confirmada o no confirmada).
    Nota: Las pacientes que presenten recidiva a un tratamiento adyuvante basado en palbociclib en adyuvancia serán aptas para el estudio si la progresión de la enfermedad se confirma después de al menos 12 meses de tratamiento con palbociclib pero no más de 12 meses después de completar el tratamiento adyuvante con palbociclib.
    9. Pacientes que hayan sido tratadas con una dosis mínima y estable de 100 mg de palbociclib durante los últimos 2 ciclos de tratamiento en el anterior régimen basado en palbociclib.
    10. La última dosis de palbociclib no debe haberse administrado más de 8 semanas después, y no menos de 7 días antes de la entrada en el estudio, con la excepción de las pacientes con recidiva durante el tratamiento adyuvante basado en palbociclib.
    11. Las pacientes no deben haber sido tratadas en el contexto avanzado con al menos una de estas opciones de terapia endocrina: fulvestrant o AI.
    Nota: Las pacientes tratadas con AI adyuvante con un intervalo libre de enfermedad ≥ 12 meses y con fulvestrant de primera línea en el contexto metastásico, podrían recibir tratamiento con un AI en el contexto metastásico.
    12. Las pacientes deben tener enfermedad medible o enfermedad evaluable conforme a los criterios RECIST versión 1.1. Las pacientes que solamente presentan lesiones óseas metastásicas son elegibles.
    13. Disposición y capacidad para proporcionar una biopsia del tumor de la metástasis o del tumor de mama primario (si es posible) tanto en el momento de la inclusión, como después de la progresión de la enfermedad, para poder realizar estudios exploratorios. Si no fuera posible, la elegibilidad de la paciente deberá ser evaluada por un representante cualificado del promotor.
    14. Las pacientes aceptan la recogida de muestras de sangre (biopsia líquida) en el momento de la inclusión, después de 2 semanas de tratamiento, y tras la progresión o la finalización del estudio.
    15. Función orgánica adecuada.
    16. Pacientes dispuestas a y capaces de cumplir las visitas programadas, el plan de tratamiento, los análisis clínicos y otros procedimientos del estudio.
    17. Las pacientes han sido informadas de la naturaleza del estudio, han aceptado participar y han firmado el formulario de consentimiento informado (CI) antes de realizar cualquier actividad relacionada con el estudio.
    18. Resolución de todos los efectos tóxicos agudos de los tratamientos antineoplásicos previos a grado </= 1 según lo determinado por los criterios terminológicos comunes para acontecimientos adversos del (NCI-CTCAE) versión 5.0 (excepto la alopecia u otras toxicidades, como la mielosupresión, que no se consideren como un riesgo para la seguridad de la paciente según el criterio del investigador).
    E.4Principal exclusion criteria
    1. HR or HER2 unknown disease.
    2. HER2-positive disease based on local laboratory results
    (performed by IHC / ISH test).
    3. Locally ABC candidate for curative treatment.4. Formal contraindication to endocrine therapy defined as visceral crisis and rapidly or symptomatic progressive visceral disease.
    5. Prior therapy with any other CDK4/6 inhibitor different from palbociclib.
    6. Known active uncontrolled or symptomatic Central Nervous System (CNS) metastases, carcinomatous meningitis, or leptomeningeal disease as indicated by clinical symptoms, cerebral edema, and/or progressive growth. Patients with a history of CNS metastases or cord compression are eligible if they have been definitively treated (e.g., radiotherapy, stereotactic surgery) and are clinically stable off anticonvulsants and steroids for at least 4 weeks before randomization.
    7. Patients are currently receiving food or drugs known to be strong inducers or inhibitors of CYP3A4 (see Section 3.5 for details on prohibited medications).
    8. Current or prior malignancy which could affect compliance with the protocol or interpretation of results. Patients with curatively- treated non-melanoma skin cancer, non-muscle-invasive bladder cancer, or carcinoma in situ, among others, are generally eligible.
    9. No other systemic therapy for metastatic disease including chemotherapy, immunotherapy, targeted therapy (small molecules/ monoclonal antibodies), or endocrine therapy excluding first-line palbociclib-based regimen.
    10. Major surgery (defined as requiring general anesthesia) or significant traumatic injury within 2 weeks of start of study drug, or patients who have not recovered from the side effects of any major surgery, or patients who may require major surgery during the study.
    11. Radiotherapy or limited-field palliative radiotherapy within 7 days prior to study enrolment, or patients who have not recovered from radiotherapy-related toxicities to baseline or grade ≤ 1 and/or from whom ≥ 25% of the bone marrow has been previously irradiated.
    12. Use of concurrent investigational agents or other concomitant anticancer therapies.
    13. Active bleeding diathesis, previous history of bleeding diathesis, or chronic anti-coagulation treatment (the use of low molecular weight heparin is allowed as soon as it is used as prophylaxis intention).
    14. Serious concomitant systemic disorder (e.g., active infection including HIV, or cardiac disease) incompatible with the study (at the discretion of investigator).
    15. Unable to swallow capsules or tablets.
    16. History of malabsorption syndrome or other condition that would
    interfere with enteral absorption.
    17. Any of the following within 6 months of randomization:
    myocardial infarction, severe/unstable angina, ongoing cardiac dysrhythmias of NCI-CTCAE v.5.0 grade ≥2, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident including transient ischemic attack, or
    symptomatic pulmonary embolism.
    18. Uncontrolled electrolyte disorders of NCI-CTCAE v.5.0 grade ≥2. 19. Known hypersensitivity to palbociclib or any of its excipients.
    1. Enfermedad con RH o HER2 desconocido.
    2. Enfermedad HER2-positiva según los resultados del laboratorio
    local (realizado mediante IHC/ISH tests).
    3. Cáncer de mama avanzado local candidato para tratamiento
    curativo.
    4. Contraindicación para recibir terapia endocrina definida como
    una crisis visceral o la presencia de enfermedad visceral
    progresiva sintomática o rápidamente progresiva.
    5. Tratamiento previo con un inhibidor de CDK4/6 diferente a
    palbociclib.
    6. Metástasis no controladas activas o sintomáticas del sistema
    nervioso central (SNC), meningitis carcinomatosa o enfermedad leptomeníngea que presentan síntomas clínicos, edema cerebral y/o crecimiento progresivo. Las pacientes con antecedentes de metástasis del SNC o compresión medular son elegibles si han recibido tratamiento definitivo (p.ej., radioterapia, cirugía estereotáctica) y han estado clínicamente estables sin anticonvulsivos ni corticosteroides durante un mínimo de 4 semanas antes de la randomización.
    7. Pacientes que estén recibiendo actualmente alimentos o fármacos inhibidores o inductores potentes de CYP3A4 (véanse los detalles sobre medicamentos prohibidos en el apartado 3.5).
    8. Enfermedad maligna actual o previa que podría afectar al cumplimiento del protocolo o a la interpretación de los resultados. Pacientes tratadas de forma curativa de un cáncer de piel no melanoma, de un cáncer de vejiga sin invasión de la capa muscular, o de un carcinoma in situ, entre otros, son generalmente elegibles.
    9. Ningún otro tratamiento sistémico para la enfermedad metastásica, incluyendo quimioterapia, inmunoterapia, tratamiento dirigido (moléculas pequeñas/anticuerpos monoclonales) o terapia endocrina, salvo el tratamiento de primera línea basado en palbociclib.
    10. Cirugía mayor (definida como la que precisa anestesia general) o lesión traumática significativa en las 2 semanas previas al inicio de la administración del fármaco del estudio, o pacientes que no se hayan recuperado de los efectos secundarios de alguna cirugía mayor, o pacientes que puedan requerir una cirugía mayor durante el estudio.
    11. Radioterapia o radioterapia paliativa de campo limitado en los 7 días previos a la inclusión en el estudio, o pacientes que no se hayan recuperado de toxicidades relacionadas con la radioterapia hasta el nivel inicial o grado ≤ 1 y/o en quienes se haya irradiado previamente ≥ 25 % de la médula ósea.
    12.Uso concurrente de agentes en investigación u otros tratamientos antineoplásicos concomitantes.
    13. Diátesis hemorrágica activa, antecedentes de diátesis hemorrágica o tratamiento anticoagulante crónico (se permite el uso de heparina de bajo peso molecular siempre y cuando se use de forma profiláctica).
    14. Trastornos sistémicos concomitantes graves (p. ej., infección activa, incluido el VIH, o cardiopatía) incompatible con el estudio (a criterio del investigador).
    15. Incapacidad para tragar cápsulas o comprimidos.
    16.Antecedentes de síndrome de malabsorción u otras
    enfermedades que pudieran interferir en la absorción intestinal.
    17. Cualquiera de las siguientes entidades en los 6 meses anteriores a la randomización: infarto agudo de miocardio, angina de pecho grave/inestable, arritmias cardíacas en curso de grado ≥2 según los NCI-CTCAE versión 5.0, bypass coronario o arterial periférico, insuficiencia cardíaca congestiva sintomática, accidente cerebrovascular que incluye accidente
    isquémico transitorio, o embolia pulmonar sintomática.
    18. Trastornos electrolíticos no controlados de grado ≥ 2 según los
    NCI-CTCAE versión 5.0.
    19. Hipersensibilidad conocida a palbociclib o a cualquiera de sus
    excipientes.
    E.5 End points
    E.5.1Primary end point(s)
    From a clinical point of view, the primary endpoint for this study is the PFS assessed by RECIST criteria v.1.1, of continuation of palbociclib treatment combined with second-line endocrine therapy (letrozole or fulvestrant) versus endocrine therapy in pre- and post- menopausal women with HR-positive/HER2-negative ABC.
    Desde un punto de vista clínico, el criterio principal de valoración de este estudio es la PFS evaluada según los criterios RECIST versión 1.1, de la continuación del tratamiento con palbociclib en combinación con terapia endocrina de segunda línea (fulvestrant o letrozol), en comparación con terapia endocrina sola, en mujeres premenopáusicas y posmenopáusicas con cáncer de mama avanzado RH-positivo/HER2-negativo.
    E.5.1.1Timepoint(s) of evaluation of this end point
    From randomization until objective tumor progression or death.
    Desde la randomización hasta la progresión tumoral objetiva o la muerte de la paciente.
    E.5.2Secondary end point(s)
    -Patient safety and adverse events (AEs) will be evaluated using
    the NCI-CTCAE v.5.0. Grade 3 and 4 AEs and serious adverse events (SAEs) will be assessed to determine the safety and tolerability of the different treatment arms.
    -ORR, CBR, DoR, TTR, TTP, OS of continuation of palbociclib treatment combined with second-line endocrine therapy
    (letrozole or fulvestrant) versus endocrine therapy.
    -Overall change from baseline in patient reported global QOL,
    general health status, functioning and symptoms.
    -Time to deterioration in global quality of life.
    -Time to deterioration in pain.
    -Time to first chemotherapy.
    -Tumor biopsies taken at baseline will be processed to perform correlation between intrinsic molecular subtypes, based on the 50-gene intrinsic subtype classifier PAM50, and the efficacy endpoints (PFS, ORR, CBR, DoR, TTR, TTP, OS, QOL).
    -Potential molecular markers of sensitivity/resistance and molecular alterations involved in Rb-cell-cycle dependent and endocrine-related pathways as a result of CDK4/6 inhibition in patients treated with palbociclib in combination with second-line endocrine therapy.
    -La seguridad de las pacientes y los acontecimientos adversos
    (AEs, Adverse Events) se evaluarán utilizando los criterios NCI- CTCAE (National Cancer Institute-Common Terminology Criteria for Adverse Events) versión 5.0. Se evaluarán los AEs de grado 3 y 4 y los acontecimientos adversos graves (SAEs, Serious Adverse Events,) para determinar la seguridad y tolerabilidad de los distintos grupos de tratamiento.
    -ORR, CBR, DoR, TTR, TTP y OS de la continuación deltratamiento con palbociclib en combinación con terapia endocrina de segunda línea (fulvestrant o letrozol), en comparación con terapia endocrina sola.
    -Variación global en la calidad de vida, estado general de salud, funcionamiento y síntomas reportados por la paciente con respecto a los presentados al inicio del tratamiento.
    -Tiempo hasta el deterioro en la calidad de vida global.
    -Tiempo hasta el deterioro del dolor.
    -Tiempo hasta la administración de la primera quimioterapia.
    -Las biopsias tumorales obtenidas en el momento basal serán procesadas para evaluar la correlación entre los subtipos moleculares intrínsecos, según la plataforma PAM50, y los criterios de valoración de la eficacia (PFS, ORR, CBR, DoR, TTR, TTP, OS y QOL).
    -Investigar potenciales marcadores moleculares de sensibilidad/resistencia que intervienen en las vías relacionadas con el sistema endocrino y en aquellas dependientes del ciclo celular-Rb como consecuencia de la inhibición de CDK4/6 en pacientes tratadas con palbociclib en combinación con terapia endocrina de segunda línea (fulvestrant o letrozol).
    E.5.2.1Timepoint(s) of evaluation of this end point
    From randomization until objective tumor progression or death.
    Desde la randomización hasta la progresión tumoral objetiva o la muerte de la paciente.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic Yes
    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 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 concerned27
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA58
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    última visita último paciente
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months3
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months3
    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: 50
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 148
    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 state88
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 198
    F.4.2.2In the whole clinical trial 198
    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)
    Standard of care
    Práctica clínica habitual
    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 Decision2019-02-08
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-01-30
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2023-02-02
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