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    Summary
    EudraCT Number:2018-001957-29
    Sponsor's Protocol Code Number:Brigatinib-3001
    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:2018-09-17
    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 number2018-001957-29
    A.3Full title of the trial
    A Phase 3 Randomized Open-label Study of Brigatinib (ALUNBRIGTM) Versus Alectinib (ALECENSA®) in Advanced Anaplastic Lymphoma Kinase-Positive
    on–Small-Cell Lung Cancer Patients Who Have Progressed on Crizotinib (XALKORI®)
    Estudio en fase III, aleatorizado y abierto de brigatinib (ALUNBRIGTM) en comparación con alectinib (ALECENSA®) en pacientes con cáncer de pulmón no microcítico avanzado positivo para cinasa de linfoma anaplásico que han progresado con crizotinib (XALKORI®)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase 3 Randomized Open-label Study of Brigatinib Versus Alectinib in Advanced ALK-positive Non–Small-Cell Lung Cancer Patients Who Have Progressed on Crizotinib
    Un estudio de fase 3, aleatorizado y abierto de Brigatinib frente a Alectinib pacientes con cáncer de pulmón no microcítico, avanzado y positivo en ALK que han progresado con Crizotinib.
    A.4.1Sponsor's protocol code numberBrigatinib-3001
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02737501
    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 SponsorARIAD Pharmaceuticals, Inc.(a wholly-owned subsidiary of Takeda Pharmaceutical Ltd.)
    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 supportARIAD Pharmaceuticals, Inc.(a wholly-owned subsidiary of Takeda Pharmaceutical Ltd.)
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationTakeda Pharmaceuticals Inc.
    B.5.2Functional name of contact pointAshwata Pokhrel
    B.5.3 Address:
    B.5.3.1Street Address40 Landsdowne Street
    B.5.3.2Town/ cityCambridge
    B.5.3.3Post codeMA 02139
    B.5.3.4CountryUnited States
    B.5.4Telephone number+1617444 3168
    B.5.5Fax number+1617551 3742
    B.5.6E-mailashwata.pokhrei@takeda.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 namebrigatinib
    D.3.2Product code AP26113
    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 INNBRIGATINIB
    D.3.9.1CAS number 1197953-54-0
    D.3.9.2Current sponsor codeAP26113
    D.3.9.3Other descriptive nameAP26133
    D.3.9.4EV Substance CodeSUB184911
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number30
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) 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 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 namebrigatinib
    D.3.2Product code AP26113
    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 INNBRIGATINIB
    D.3.9.1CAS number 1197953-54-0
    D.3.9.2Current sponsor codeAP26113
    D.3.9.3Other descriptive nameAP26133
    D.3.9.4EV Substance CodeSUB184911
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number90
    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 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 namebrigatinib
    D.3.2Product code AP26113
    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 INNBRIGATINIB
    D.3.9.1CAS number 1197953-54-0
    D.3.9.2Current sponsor codeAP26113
    D.3.9.3Other descriptive nameAP26133
    D.3.9.4EV Substance CodeSUB184911
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number180
    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 Alecensa
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration Limited
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product namealectinib
    D.3.2Product code RO5424802/F03
    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 INNALECTINIB
    D.3.9.1CAS number 1256580-46-7
    D.3.9.2Current sponsor codeRO5424802
    D.3.9.3Other descriptive nameALK INHIBITOR
    D.3.9.4EV Substance CodeSUB178557
    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.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
    ALK positive Locally Advanced or Metastatic Non-small Cell Lung Cancer
    Cáncer de pulmón no microcítico avanzado o metastásico ALK positivo
    E.1.1.1Medical condition in easily understood language
    Metastatic or locally advanced non-small cell lung cancer
    Cáncer de pulmón no microcítico avanzado o metastásico.
    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 PT
    E.1.2Classification code 10059515
    E.1.2Term Non-small cell lung cancer metastatic
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    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 of brigatinib to that of alectinib in patients with ALK+ locally advanced or metastatic NSCLC who have progressed on crizotinib as evidenced by PFS as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.
    Comparar la eficacia de brigatinib con la de alectinib en pacientes con CPNM ALK+ localmente avanzado o metastásico que han progresado con crizotinib según la supervivencia sin progresión (SSP) evaluada mediante los Criterios de evaluación de la respuesta en tumores sólidos (RECIST) v1.1.
    E.2.2Secondary objectives of the trial
    1. To compare the efficacy in the CNS of brigatinib to that of alectinib as evidenced by iORR, iDOR, and iPFS as assessed by modified RECIST criteria.
    2. To compare the efficacy of brigatinib to that of alectinib as evidenced by confirmed ORR, time to response, DOR (all as assessed by RECIST v1.1), and overall survival (OS).
    3. To assess the safety and tolerability of brigatinib in comparison with alectinib.
    4. To collect plasma concentration-time data for brigatinib to contribute to population pharmacokinetic (PK) analyses.
    5. To assess patient-reported symptoms and health-related quality of life (HRQoL) with the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) (v3.0) and its Quality of Life Lung Cancer Module (QLQ-LC13), in patients treated with brigatinib compared with those treated with alectinib.
    1. Comparar la eficacia en el sistema nervioso central de brigatinib con la de alectinib según la tasa de respuesta objetiva intracraneal, la duración de la respuesta intracraneal y la supervivencia sin progresión intracraneal según RECIST modificados.
    2. Comparar la eficacia de brigatinib con la de alectinib según la tasa de respuesta objetiva confirmada, el tiempo hasta la respuesta, la duración de la respuesta y la supervivencia general.
    3. Evaluar la seguridad y la tolerabilidad de brigatinib en comparación con alectinib.
    4. Recopilar datos de concentración plasmática frente al tiempo de brigatinib para contribuir a los análisis de farmacocinética poblacional.
    5. Evaluar los síntomas notificados por los pacientes y la calidad de vida relacionada con la salud con el cuestionario básico de 30 preguntas sobre calidad de vida EORTC y su módulo de calidad de vida en el cáncer de pulmón, en pacientes tratados con brigatinib en comparación con aquellos tratados con alectinib.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Adult patients aged 18 years and older.
    2. Have Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.
    3. Have histologically or cytologically confirmed stage IIIB (locally advanced or recurrent) or stage IV NSCLC.
    4. Must meet one of the following criteria:
    a) Have documentation of ALK rearrangement by a positive result from the Vysis ALK Break-Apart fluorescence in situ hybridization (FISH) Probe Kit or the Ventana ALK (D5F3) CDx Assay or Foundation Medicine’s FoundationOne CDx.
    b) Have documented ALK rearrangement by a different test and be able to provide tumor sample to the central laboratory. (Note: central laboratory ALK rearrangement testing results are not required to be obtained before randomization.)
    5. Had PD while on crizotinib, as assessed by the investigator or treating physician. (Note: crizotinib does not need to be the last therapy a patient received. The patient may have received chemotherapy as his/her last therapy.)
    6. Treatment with crizotinib for at least 4 weeks before progression.
    7. Have had no other ALK inhibitor other than crizotinib.
    8. Have had no more than 2 prior regimens of systemic anticancer therapy in the locally advanced or metastatic setting.
    9. Have at least 1 measurable (ie, target) lesion per RECIST v1.1.
    10. Have recovered from toxicities related to prior anticancer therapy to NCI CTCAE v4.03 grade ≤1. (Note: treatment-related alopecia or peripheral neuropathy that are grade >1 are allowed, if deemed irreversible.)
    11. Have adequate organ function, as determined by:
    a) Total bilirubin ≤1.5 times the upper limit of normal (ULN).
    b) Estimated glomerular filtration rate ≥30 mL/minute/1.73 m2, using the modification of diet in renal disease equation.
    c) Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) ≤2.5 × ULN; ≤5 × ULN is acceptable if liver metastases are present.
    d) Serum lipase ≤1.5 × ULN.
    e) Platelet count ≥75 ×109/L.
    f) Hemoglobin ≥9 g/dL.
    g) Absolute neutrophil count ≥1.5 × 109/L.
    12. Suitable venous access for study-required blood sampling (ie, including PK and laboratory safety tests).
    13. Have the willingness and ability to comply with scheduled visits and study procedures.
    14. For female patients of childbearing potential, have a negative pregnancy test documented before randomization.
    15. For female and male patients who are fertile, agree to use a highly effective form of contraception with their sexual partners during the dosing period and for a period of at least 120 days after the end of treatment with either study brigatinib or alectinib.
    16. Female patients who are postmenopausal for at least 1 year before the screening visit, or are surgically sterile, or if they are of childbearing potential, agree to practice:
    a) One highly effective method of contraception, and
    b) One additional effective (barrier) method at the same time, from the time of signing the informed consent through 1 month (whichever is longer) after the last dose of study drug, or
    c) Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together.)
    17. Male patients, even if surgically sterilized (ie, status postvasectomy), who:
    a) Agree to practice effective barrier contraception during the entire study treatment period and through 120 days (or if the drug has a very long half-life, for 90 days plus five half lives) after the last dose of study drug, or
    b) Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together.)
    c) Do not donate semen or sperm during treatment and for 90 days after the last dose of study therapy.
    18. Voluntary written consent must be given before performance of any study related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care.
    (Note: Given that, globally, the patient population who has received crizotinib as the sole ALK inhibitor is decreasing, Takeda reserves the right to amend the inclusion criteria to include crizotinib intolerant patients and/or patients who have progressed on or been found intolerant to ALK inhibitors other than crizotinib, brigatinib, or alectinib.)
    -Pacientes adultos de 18 años en adelante.
    -Tener CPNM en estadio IIIB (localmente avanzado o recurrente) o en estadio IV, confirmado mediante
    histología o citología.
    -Debe cumplir uno de los criterios siguientes:
    *Tener documentado un reordenamiento de la cinasa de linfoma anaplásico (ALK) mediante un resultado positivo en el kit de sonda de hibridación in situ por fluorescencia Vysis ALK Break Apart (FISH) o los ensayos Ventana ALK (D5F3) CDx o FoundationOne CDx de Foundation Medicine.
    *Tener documentado un reordenamiento de ALK mediante una prueba diferente y ser capaz de proporcionar
    una muestra tumoral al laboratorio central. (Nota: no es necesario obtener los resultados de las pruebas de reordenamiento de ALK del laboratorio central antes de la aleatorización.)
    -Haber mostrado progresión de la enfermedad mientras recibía crizotinib, evaluada por el investigador o el
    médico responsable del tratamiento. (Nota: no es preciso que crizotinib sea el último tratamiento recibido por el paciente. Este puede haber recibido quimioterapia como último tratamiento antineoplásico sistémico).
    -Tratamiento con crizotinib durante al menos 4 semanas antes de la progresión.
    -No haber usado ningún otro inhibidor de ALK distinto de crizotinib.
    -No haber recibido más de 2 pautas previas de tratamiento antineoplásico sistémico en un contexto localmente avanzado o metastásico.
    (Nota: una pauta de tratamiento antineoplásico sistémico se contará si se administra durante al menos 1 ciclo. Un nuevo agente antineoplásico utilizado como tratamiento de mantenimiento se contará como una nueva pauta. Un tratamiento antineoplásico sistémico neoadyuvante o adyuvante se contará como un pauta previa si se produce progresión/recurrencia de la enfermedad dentro de los 12 meses siguientes a la finalización de este tratamiento neoadyuvante o adyuvante).
    -Estado funcional de 0 a 2 según el Grupo Oncológico Cooperativo del Este (Eastern Cooperative Oncology Group, ECOG).
    -Tener al menos 1 lesión medible (es decir, diana) según RECIST v1.1.
    -Haberse recuperado de las toxicidades relacionadas con el tratamiento antineoplásico previo hasta alcanzar un grado ≤1 según los Criterios terminológicos comunes para acontecimientos adversos (Common Terminology Criteria for Adverse Events, CTCAE) del Instituto Nacional del Cáncer (National Cancer Institute, NCI)
    estadounidense, versión 4.03. (Nota: la alopecia o la neuropatía periférica relacionadas con el tratamiento que sean de un grado >1 se permiten si se consideran irreversibles).
    -Tener un funcionamiento orgánico adecuado según lo siguiente:
    *Bilirrubina total ≤1,5 veces el límite superior de la normalidad (LSN).
    *Índice de filtración glomerular estimada ≥30 ml/minuto/1,73 m2.
    *Alanina aminotransferasa/aspartato aminotransferasa ≤2,5 × LSN; se admitirán concentraciones ≤5 × LSN si existen metástasis hepáticas.
    *Lipasa en suero ≤1,5 × LSN.
    *Recuento de plaquetas ≥75 × 109/l.
    *Hemoglobina ≥9 g/dl.
    *Recuento absoluto de neutrófilos ≥1,5 × 109/l.
    -Acceso venoso adecuado para obtener las muestras de sangre necesarias para el estudio (es decir, incluidos los análisis clínicos de FC y de seguridad).
    -Mostrar voluntad y capacidad para cumplir con las visitas programadas y los procedimientos del estudio.
    -En el caso de las pacientes con capacidad de concebir, presentar una prueba de embarazo negativa documentada antes de la aleatorización.
    -En el caso de los pacientes de ambos sexos que sean fértiles, aceptar el uso de un método anticonceptivo altamente eficaz con sus parejas sexuales durante el periodo de administración de la dosis y durante al menos 120 días después del fin del tratamiento con brigatinib o alectinib.
    (Nota: dado que en todo el mundo está disminuyendo la población de pacientes que han recibido crizotinib como único inhibidor de ALK, Takeda se reserva el derecho de modificar los criterios de inclusión para incluir a pacientes intolerantes a crizotinib o que hayan progresado o se haya visto que son intolerantes a inhibidores de la ALK distintos de crizotinib, brigatinib o alectinib).
    E.4Principal exclusion criteria
    1. Participation in the control (crizotinib) arm of Study AP26113-13-301 (ALTA 1L).
    2. Received crizotinib within 7 days of randomization.
    3. Have a history or presence at baseline of pulmonary interstitial disease, drug-related pneumonitis, or radiation pneumonitis.
    4. Have uncontrolled hypertension. Patients with hypertension should be under treatment for control of blood pressure upon study entry.
    5. Received systemic treatment with strong cytochrome P-450 (CYP) 3A inhibitors, strong CYP3A inducers, or moderate CYP3A inducers within 14 days before randomization.
    6. Treatment with any investigational systemic anticancer agents within 14 days or 5 half-lives, whichever is longer, before randomization.
    7. Received chemotherapy or radiation therapy within 14 days of randomization except for stereotactic radiosurgery (SRS) or stereotactic body radiation therapy.
    8. Received antineoplastic monoclonal antibodies within 30 days of randomization.
    9. Had major surgery within 30 days of randomization. Minor surgical procedures, such as catheter placement or minimally invasive biopsies, are allowed.
    10. Have symptomatic CNS metastases (parenchymal or leptomeningeal) at screening (patients with asymptomatic brain metastases or patients who have stable symptoms and did not require an increased dose of corticosteroids to control symptoms within 7 days before randomization will be enrolled). Note: If a patient has worsening neurological symptoms or signs due to CNS metastasis, the patient needs to complete local therapy and be neurologically stable (with no requirement for an increasing dose of corticosteroids or use of anticonvulsants) for 7 days before randomization.
    11. Have current spinal cord compression (symptomatic or asymptomatic and detected by radiographic imaging). Patients with leptomeningeal disease and without cord compression are allowed.
    12. Have significant, uncontrolled, or active cardiovascular disease, specifically including, but not restricted to the following:
    a) Myocardial infarction within 6 months before randomization.
    b) Unstable angina within 6 months before randomization.
    c) New York Heart Association Class III or IV heart failure within 6 months before randomization.
    d) History of clinically significant atrial arrhythmia (including clinically significant bradyarrhythmia), as determined by the treating physician.
    e) Any history of clinically significant ventricular arrhythmia.
    13. Had cerebrovascular accident or transient ischemic attack within 6 months before first dose of study drug.
    14. Have malabsorption syndrome or other gastrointestinal illness or condition that could affect oral absorption of the study drug.
    15. Have an ongoing or active infection, including but not limited to, the requirement for intravenous antibiotics.
    16. Have a known history of HIV infection. Testing is not required in the absence of history.
    17. Known hepatitis B surface antigen-positive, or known or suspected active hepatitis C infection.
    18. Any serious medical condition or psychiatric illness that could, in the investigator’s opinion, potentially compromise patient safety or interfere with the completion of treatment according to this protocol.
    19. Have a known or suspected hypersensitivity to brigatinib or alectinib or their excipients.
    20. Life-threatening illness unrelated to cancer.
    21. Female patients who are lactating and breastfeeding.
    22. Admission or evidence of illicit drug use, drug abuse, or alcohol abuse.
    -Participación en el grupo de control (crizotinib) del estudio AP26113-13-301 (ALTA 1L).
    -Haber recibido crizotinib dentro de los 7 días previos a la aleatorización.
    -Tener antecedentes o presencia al inicio de enfermedad pulmonar intersticial, neumonía relacionada con fármacos o neumonía por radiación.
    -Tener hipertensión no controlada. Los pacientes con hipertensión deben estar en tratamiento para el control de la presión arterial en el momento de entrada en el estudio.
    -Haber recibido tratamiento sistémico con inhibidores potentes del citocromo P-450 (CYP) 3A o con inductores potentes o moderados del CYP3A en los 14 días anteriores a la aleatorización.
    -Tratamiento con cualquier antineoplásico sistémico en investigación durante los 14 días o 5 semividas, lo que sea más prolongado, previos a la aleatorización.
    -Haber recibido quimioterapia o radioterapia en los 14 días anteriores a la aleatorización, excepto radiocirugía estereotáctica o radioterapia corporal estereotáctica.
    -Haber recibido anticuerpos monoclonales antineoplásicos dentro de los 30 días previos a la aleatorización.
    -Haberse sometido a cirugía mayor en los 30 días anteriores a la aleatorización. Se permiten las intervenciones quirúrgicas menores, como la colocación de un catéter o las biopsias mínimamente invasivas.
    -Tener metástasis sintomáticas en el SNC (parenquimatosas o leptomeníngeas) en la selección (se incluirá a los pacientes con metástasis cerebrales asintomáticas o con síntomas estables que no hayan requerido un aumento de la dosis de corticoesteroides para el control de los síntomas en los 7 días antes de la aleatorización).
    (Nota: si un paciente experimenta empeoramiento de los síntomas o signos neurológicos debido a metástasis en el SNC, deberá terminar el tratamiento local y estar neurológicamente estable [sin ningún requisito de aumento de la dosis de corticoesteroides o de uso de anticonvulsivos] durante 7 días antes de la aleatorización).
    -Presencia actual de compresión medular (sintomática o asintomática y detectada mediante estudios radiográficos). Se admitirá a pacientes con enfermedad leptomeníngea y sin compresión medular.
    -Tener una enfermedad cardiovascular significativa, no controlada o activa, lo que incluye específicamente, entre otros:
    1. Infarto de miocardio en los 6 meses anteriores a la aleatorización.
    2. Angina de pecho inestable en los 6 meses anteriores a la aleatorización.
    3. Insuficiencia cardíaca de las clases III o IV según la Asociación del Corazón de Nueva York (New York Heart Association) dentro de los 6 meses anteriores a la aleatorización.
    4. Antecedentes de arritmia auricular clínicamente significativa (incluida la bradiarritmia clínicamente significativa), según el criterio del médico responsable del tratamiento.
    5. Cualquier antecedente de arritmia ventricular clínicamente significativa.
    -Haber tenido un accidente cerebrovascular o un accidente isquémico transitorio en los 6 meses anteriores a la primera dosis del fármaco del estudio.
    -Presentar síndrome de malabsorción u otra enfermedad o afección gastrointestinal que pueda afectar a la absorción oral del fármaco del estudio.
    -Tener una infección en curso o activa, lo que incluye, entre otras, la necesidad de antibióticos por vía intravenosa.
    -Tener antecedentes conocidos de infección por el VIH. No es necesario realizar pruebas en ausencia de antecedentes.
    -Positivo conocido para antígeno de superficie de la hepatitis B o infección conocida o sospechada por hepatitis C activa.
    -Cualquier afección médica o enfermedad psiquiátrica grave que, en opinión del investigador, pueda poner en peligro la seguridad del paciente o interferir en la administración completa del tratamiento de conformidad con este protocolo.
    -Tener hipersensibilidad conocida o sospechada a brigatinib o alectinib o a sus excipientes.
    -Enfermedad potencialmente mortal sin relación con el cáncer.
    -Mujeres lactantes
    -Admisión o evidencia de uso ilícito de drogas o abuso de las mismas o del alcohol.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is progression free survival (PFS) as assessed by the blinded Independent Review Committee (BIRC) per RECIST v1.1.
    El criterio de valoración principal es la SSP evaluada por el Comité de revisión independiente con enmascaramiento (CRIE) según RECIST v1.1.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Time interval from the date of randomization until the first date at which disease progression is objectively documented by RECIST, or death due to any cause.
    The interim analysis will be preformed after the first 115 events have been observed; the final analysis will be preformed after 164 events have been observed
    Intervalo de tiempo desde la fecha de aleatorización hasta la fecha en que la progresión de la enfermedad se documenta objetivamente por RECIST o fallecimiento por cualquier causa.
    El análisis intermedio se realizará cuando ocurran los primeros 115 eventos; el análisis final se realizará cuando ocurran 164 eventos.
    E.5.2Secondary end point(s)
    Key Secondary Endpoints:
    1. Intracranial Progression Free Survival (iPFS), as assessed by the BIRC per modified RECIST v1.1.
    2. Overall survival (OS).
    Other Secondary Endpoints:
    1. ORR, as assessed by the investigator and BIRC per RECIST v1.1.
    2. Time to response, as assessed by the investigator and BIRC.
    3. DOR, as assessed by the investigator and BIRC.
    4. iORR, as assessed by BIRC per modified RECIST v1.1 (as described in protocol and BIRC charter).
    5. iDOR, as assessed by the BIRC per modified RECIST v1.1.
    6. HRQoL assessed with the global health status/quality of life and other function and symptom domains from EORTC QLQ-C30 (v3.0) and EORTC QLQ-LC13.
    Criterios de valoración secundarios clave:
    1. SSPi evaluada por el CRIE según los RECIST v1.1 modificados.
    2. SG.
    Otros criterios de valoración secundarios:
    1. TRO evaluada por el investigador y por el CRIE según RECIST v1.1.
    2. Tiempo hasta la respuesta evaluado por el investigador y el CRIE.
    3. DR evaluada por el investigador y el CRIE.
    4. TROi evaluada por el CRIE según los RECIST v1.1 modificados (como se describe en el protocolo y en los estatutos del CRIE).
    5. DRi evaluada por el CRIE según los RECIST v1.1 modificados.
    6. CdVRS evaluada mediante el estado de salud/calidad de vida en general y otros dominios de funciones y síntomas del EORTC QLQ-C30 (v3.0) y EORTC QLQ-LC13.
    E.5.2.1Timepoint(s) of evaluation of this end point
    For the key secondary endpoints formal statistical tests will be performed only once, when PFS per BIRC is statistically significant.
    Se realizarán análisis estadísticos para los criterios de valoración secundarios claves una sola vez, cuando SSP según el CRIE sea estadisticamente significativo.
    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 No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    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 No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned6
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA56
    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
    Argentina
    Austria
    Brazil
    Canada
    Chile
    China
    France
    Germany
    Greece
    Hong Kong
    Hungary
    Italy
    Korea, Republic of
    Mexico
    Romania
    Russian Federation
    Spain
    Taiwan
    Thailand
    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
    Death of the last study subject or 3 years after the last subject started
    study treatment, which ever comes first
    Fallecimiento del último participante o 3 años tras el comienzo del tratamiento del último paciente, lo que ocurra antes.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months0
    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: 166
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 80
    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 state50
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 115
    F.4.2.2In the whole clinical trial 246
    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)
    Subjects can continue treatment with the study drug at the doctor's discretion after the disease progression if they are still benefiting from it as determined by the investigator and after signing the new ICF.
    Los sujetos pueden continuar tratamiento con la medicación en estudio tras progresión a discrección del investigador si se observa beneficio tras firmar el nuevo consentimiento.
    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 Decision2018-10-19
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-10-11
    P. End of Trial
    P.End of Trial StatusOngoing
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
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