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    Summary
    EudraCT Number:2019-001845-42
    Sponsor's Protocol Code Number:TAK-788-3001
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Temporarily Halted
    Date on which this record was first entered in the EudraCT database:2020-01-10
    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 number2019-001845-42
    A.3Full title of the trial
    A Randomized Phase 3 Multicenter Open-label Study to Compare the Efficacy of TAK-788 as First-line Treatment Versus Platinum-Based Chemotherapy in Patients With Non-Small Cell Lung Cancer With EGFR Exon 20 Insertion Mutations
    Estudio de fase 3 abierto, aleatorizado y multicéntrico para comparar la eficacia de TAK-788 como tratamiento de primera línea frente a quimioterapia a base de platino en pacientes con cáncer de pulmón no microcítico con mutaciones de EGFR por inserción en el exón 20
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    TAK-788 as First-line Treatment Versus Platinum-Based Chemotherapy for NSCLC With EGFR Exon 20 Insertions
    TAK-788 como tratamiento de primera línea frente a quimioterapia a base de platino en pacientes con cáncer de pulmón no microcítico con mutaciones de EGFR por inserción en el exón 20
    A.3.2Name or abbreviated title of the trial where available
    TAK-788 as First-line Treatment Versus Platinum-Based Chemotherapy for NSCLC With EGFR Exon 20 Inser
    TAK-788 como tto de 1ª línea v quimio de platino en pacient con CPNM con mutaciones EGFR en exon 20
    A.4.1Sponsor's protocol code numberTAK-788-3001
    A.5.3WHO Universal Trial Reference Number (UTRN)U1111-1232-6059
    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 SponsorMillennium Pharmaceuticals, Inc. Millennium Pharmaceuticals is a wholly owned subsidiary of Takeda Pharmaceutical
    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 supportTakeda Pharmaceutical Company Limited
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationTakeda Pharmaceuticals International, Co
    B.5.2Functional name of contact pointGlobal Medical Information
    B.5.3 Address:
    B.5.3.1Street Address40 Landsowne Street
    B.5.3.2Town/ cityCambridge, MA
    B.5.3.3Post code02139
    B.5.3.4CountryUnited States
    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 nameTAK-788
    D.3.2Product code TAK-788
    D.3.4Pharmaceutical form Capsule
    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 INNnot yet assigned
    D.3.9.1CAS number 1847461-43-1
    D.3.9.2Current sponsor codeTAK-788
    D.3.9.3Other descriptive nameAP32788
    D.3.9.4EV Substance CodeSUB195427
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number40
    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 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 Alimta
    D.2.1.1.2Name of the Marketing Authorisation holderEli Lilly Nederland B.V
    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 namePemetrexed
    D.3.4Pharmaceutical form Powder for concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNPEMETREXED
    D.3.9.1CAS number 137281-23-3
    D.3.9.4EV Substance CodeSUB09655MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number500
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 3
    D.1.2 and D.1.3IMP RoleComparator
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Cisplatin-Losung-Ribosepharm
    D.2.1.1.2Name of the Marketing Authorisation holderHikma Farmacêutica (Portugal), S.A.
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameCisplatin
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNCISPLATIN
    D.3.9.1CAS number 15663-27-1
    D.3.9.4EV Substance CodeSUB07483MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number0.5
    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: 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 Ribocarbo
    D.2.1.1.2Name of the Marketing Authorisation holderHikma Farmacêutica (Portugal), S.A.
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameCarboplatin
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNnot yet defined
    D.3.9.1CAS number 41575-94-4
    D.3.9.3Other descriptive nameCARBOPLATIN
    D.3.9.4EV Substance CodeSUB06614MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number600
    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
    Non-Small Cell Lung Cancer (NSCLC) with EGFR exon 20 insertion mutations
    Cáncer de pulmón no microcítico con mutaciones de EGFR por inserción en el exón 20
    E.1.1.1Medical condition in easily understood language
    Non-Small Cell Lung Cancer (NSCLC)
    Cáncer de pulmón no microcítico
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level LLT
    E.1.2Classification code 10029514
    E.1.2Term Non-small cell lung cancer NOS
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To compare the efficacy of TAK-788 as first-line treatment with that of platinum-based chemotherapy in patients with locally advanced or metastatic NSCLC whose tumors harbor EGFR exon 20 insertion mutations, as evidenced by progression-free survival (PFS) as assessed by blinded independent review committee (IRC) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
    Comparar la eficacia de TAK 788 como tratamiento de primera línea con la de la quimioterapia a base de platino en pacientes con CPNM localmente avanzado o metastásico cuyos tumores albergan mutaciones de EGFR por inserción en el exón 20, demostrada por la supervivencia sin progresión (SSP) evaluada por un comité de revisión independiente (CRI) enmascarado conforme a los Criterios de evaluación de la respuesta en tumores sólidos (RECIST), versión 1.1.
    E.2.2Secondary objectives of the trial
    -To compare secondary measures of clinical efficacy of TAK-788 to that of platinum-based chemotherapy, as evidenced by confirmed objective response rate (ORR), time to response, duration of response, disease control rate (DCR), and overall survival (OS).

    -To compare patient-reported symptoms (particular core symptoms of lung cancer), functioning, and health-related quality of life (HRQoL) with the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30 and the EORTC lung cancer module, QLQ-LC13, in patients treated with TAK-788 compared with those treated with platinum-based chemotherapy.

    -To collect pharmacokinetics (PK) of TAK-788 and its active metabolites, AP32960 and AP32914, to contribute to population PK and exposure-response analyses (TAK-788 group only).
    - Comparar las variables secundarias de eficacia clínica de TAK 788 con las de la quimioterapia basada en platino, demostrada por la tasa de respuestas objetivas (TRO) confirmadas, el tiempo hasta la respuesta, la duración de la respuesta, la tasa de control de la enfermedad (TCE) y la supervivencia global (SG).
    - Comparar los síntomas comunicados por los pacientes (en particular, los síntomas básicos del cáncer de pulmón), la función y la calidad de vida relacionada con la salud (CVRS) con el Cuestionario de calidad de vida (QLQ) C30 de la Organización Europea para la Investigación y el Tratamiento del Cáncer (EORTC) y el módulo de cáncer de pulmón de la EORTC, QLQ LC13, en pacientes tratados con TAK 788 en comparación con los tratados con quimioterapia basada en platino.
    - Obtener muestras para farmacocinética (FC) de TAK 788 y sus metabolitos activos, AP32960 y AP32914, para contribuir a los análisis de FC poblacional y de exposición respuesta (solo en el grupo de TAK 788).
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Each patient must meet all the following inclusion criteria to be randomized to treatment:
    1. Male or female adult patients (aged 18 years or older, or as defined per local regulations).
    2. Histologically or cytologically confirmed locally advanced not suitable for definitive therapy, recurrent, or metastatic (Stage IV) NSCLC.
    3. A documented EGFR in-frame exon 20 insertion mutation (including A763_Y764insFQEA, V769_D770insASV, D770_N771insNPG, D770_N771insSVD, H773_V774insNPH, or any other in-frame exon 20 insertion mutation) assessed by a Clinical Laboratory Improvements Amendment (CLIA)-certified (United States [US] sites) or an accredited (outside of the US) local laboratory. The local molecular testing reports may be required by the sponsor to confirm the exon 20 insertion mutation status. The EGFR exon 20 insertion mutation can be either alone or in combination with other EGFR or HER2 mutations except EGFR mutations for which there are approved EGFR TKIs (ie, exon 19 del, L858R, T790M, L861Q, G719X, or S768I, where X is any other amino acid).
    4. Adequate tumor tissue available, either from primary or metastatic sites, for central laboratory confirmation of EGFR in-frame exon 20 insertion mutation (see laboratory manual). Note: confirmation of central test positivity is not required before randomization.
    5. At least 1 measurable lesion per RECIST version 1.1 (Appendix D). Previously irradiated lesions may not be used for target lesions, unless there is unambiguous radiological progression after radiotherapy.
    6. Life expectancy ≥3 months.
    7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 (Appendix E).
    8. Adequate organ and hematologic function, as determined by the following:
    a) Alanine aminotransferase/aspartate aminotransferase ≤2.5 times the upper limit of the normal range (ULN; ≤5 times the ULN is acceptable if liver metastases are present).
    b) Total serum bilirubin ≤1.5 times the ULN (≤3.0 times the ULN for patients with Gilbert syndrome or if liver metastases are present).
    c) Estimated creatinine clearance ≥45 mL/min (calculated by using the Cockcroft-Gault equation) [35].
    d) Serum albumin ≥2 g/dL.
    e) Serum lipase ≤1.5 times the ULN.
    f) Serum amylase ≤1.5 times the ULN unless the increased serum amylase is due to salivary isoenzymes.
    g) Absolute neutrophil count ≥1500/μL.
    h) Platelets ≥100,000/μL.
    i) Hemoglobin ≥9 g/dL.
    9. Normal QT interval on screening ECG evaluation, defined as QT interval corrected (Fridericia) (QTcF) of ≤450 milliseconds in males or ≤470 milliseconds in females.
    10. 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 1 highly effective, nonhormonal method of contraception and 1 additional effective (barrier) method at the same time (Table 8.f), from the time of signing the informed consent through 30 days after the last dose of study drug if they are randomized to the TAK-788 group or to practice the guidelines in the approved product labels for chemotherapy through 180 days after the last dose of pemetrexed if they are randomized to the chemotherapy group, OR
    • 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.)
    Male patients, even if surgically sterilized (ie, status postvasectomy), who:
    • Agree to practice effective barrier contraception (see Table 8.f for list of effective barrier methods) during the entire study treatment period and through 30 days after the last dose of study drug if they are randomized to the TAK 788 group or 180 days after the last dose of pemetrexed if they are randomized to the chemotherapy group, OR
    • 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.)
    11. 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.
    12. Willingness and ability to comply with scheduled visits and study procedures.
    Cada paciente deberá cumplir todos los criterios de inclusión siguientes para que se le asigne aleatoriamente un tratamiento: 1.Pacientes adultos de ambos sexos (de 18 o más años de edad, o según lo defina la normativa local).2.CPNM localmente avanzado confirmado histológica o citológicamente no adecuado para tratamiento definitivo, recurrente o metastásico (estadio IV).3.Se documenta la mutación de EGFR por inserción en el exón 20 en el marco de lectura (incluidos A763_Y764insFQEA, V769_D770insASV, D770_N771insNPG, D770_N771insSVD, H773_V774insNPH o cualquier otra mutación de inserción en el exón 20 en el marco de lectura) evaluada mediante un laboratorio local certificado por la Enmienda de Mejora de Laboratorios Clínicos (centros de Estados Unidos [EE.UU.]) o un laboratorio local acreditado (fuera de EE.UU.). El promotor podrá solicitar los informes del análisis molecular local para confirmar el estado de mutación de inserción en el exón 20. La mutación de inserción en el exón 20 de EGFR puede ser la única o ir en combinación con otras mutaciones de EGFR o HER2, excepto mutaciones de EGFR para las que existen TKI del EGFR aprobados (es decir, deleción del exón 19, L858R, T790M, L861Q, G719X o S768I, siendo X cualquier otro aminoácido). 4.Disponibilidad de tejido tumoral adecuado, ya sea de focos primarios o metastásicos, para la confirmación por el laboratorio central de la mutación de EGFR por inserción en el exón 20 (véase el manual de laboratorio). Nota: no es necesaria la confirmación de la positividad de la prueba central antes de la aleatorización. 5.Al menos una lesión medible según los criterios RECIST, versión 1.1 (Apéndice D). Las lesiones irradiadas previamente no podrán utilizarse para tratar lesiones diana, a menos que exista progresión radiológica inequívoca después de la radioterapia. 6.Esperanza de vida ≥ 3 meses.
    7.Estado general del ECOG de 0 a 1 (Apéndice E). 8.Función orgánica y hematológica adecuadas, determinadas por lo siguiente: a)Alanina aminotransferasa/aspartato aminotransferasa ≤ 2,5 veces el LSN se acepta ≤ 5 veces el LSN si hay metástasis hepáticas. b)Bilirrubina sérica total ≤ 1,5 veces el LSN (≤ 3,0 veces el LSN en los pacientes con síndrome de Gilbert o presencia de metástasis hepáticas).c)Aclaramiento de creatinina estimado ≥ 45 ml/min d)Albúmina sérica ≥ 2 g/dl.e)Lipasa sérica ≤ 1,5 veces el LSN.f)Amilasa sérica ≤ 1,5 veces el LSN a menos que la elevación de la amilasa sérica se deba a isoenzimas salivales.g)Recuento absoluto de neutrófilos ≥1500/μl.h)Recuento de plaquetas ≥ 100.000/μl.i)Hb ≥ 9 g/dl.
    9.Intervalo QT normal en la evaluación del ECG de selección, (QTcF) ≤ 450 milisegundos en los varones o ≤ 470 milisegundos en las mujeres.10.Las mujeres deberán: •Ser posmenopáusicas durante al menos 1 año antes de la visita de selección, O •Haberse sometido a esterilización quirúrgica, O •Si son potencialmente fértiles, comprometerse a utilizar al mismo tiempo 1 método anticonceptivo no hormonal muy eficaz y 1 método (de barrera) eficaz adicional desde el momento de la firma del consentimiento informado hasta 30 días después de la última dosis del fármaco del estudio si son aleatorizadas al grupo de TAK 788 o para seguir las directrices de las fichas técnicas aprobadas de la quimioterapia hasta 180 días después de la última dosis de pemetrexed si son aleatorizadas al grupo de quimioterapia, O Comprometerse a practicar una abstinencia real cuando esté de acuerdo con su modo de vida preferido y habitual , el coito interrumpido, el uso exclusivo de espermicidas y la amenorrea por lactancia no son métodos anticonceptivos aceptables. No deberán utilizarse juntos preservativos femeninos y masculinos.). Los varones, aunque se hayan sometido a esterilización quirúrgica (es decir, se hayan hecho una vasectomía), deberán: •Comprometerse a utilizar un método anticonceptivo de barrera eficaz durante todo el período de tratamiento del estudio y hasta 30 días después de la última dosis del fármaco del estudio en caso de ser aleatorizados al grupo de TAK 788 o 180 días después de la última dosis de pemetrexed si son aleatorizados al grupo de quimioterapia, O •Comprometerse a practicar una abstinencia real cuando esté de acuerdo con su modo de vida preferido y habitual. (La abstinencia periódica [por ejemplo, métodos del calendario, ovulación, sintotérmico o postovulatorio], el coito interrumpido, el uso exclusivo de espermicidas y la amenorrea por lactancia no son métodos anticonceptivos aceptables. No deberán utilizarse juntos preservativos femeninos y masculinos.)11.Debe obtenerse el consentimiento voluntario por escrito del paciente antes de llevar a cabo cualquier procedimiento relacionado con el estudio que no forme parte de la atención médica habitual; el paciente podrá retirar su consentimiento sin perjuicio alguno para la atención médica que reciba en el futuro.
    12.Disposición y capacidad para cumplir las visitas programadas y los procedimientos del estudio.
    E.4Principal exclusion criteria
    Patients meeting any of the following exclusion criteria are not to be randomized to treatment.
    1. Female patients who are lactating and breastfeeding or have a positive urine or serum pregnancy test during the screening period.
    Note: Female patients who are lactating will be eligible if they discontinue breastfeeding.
    2. Current treatment in another therapeutic clinical study.
    3. Received prior systemic treatment for locally advanced or metastatic disease (with the exception below):
    Neoadjuvant or adjuvant chemotherapy/immune therapy for Stage I to III or combined modality chemotherapy/radiation for locally advanced disease is allowed if completed >6 months before the development of metastatic disease.
    4. Received radiotherapy ≤14 days before randomization or has not recovered from radiotherapy-related toxicities. Palliative radiation administered outside the chest and brain, stereotactic radiosurgery, and stereotactic body radiotherapy are allowed up to 7 days before randomization.
    5. Received a moderate or strong cytochrome P-450 (CYP)3A inhibitor or moderate or strong CYP3A inducer (Appendix F) within 10 days before randomization.
    6. Had major surgery within 28 days before randomization. Minor surgical procedures such as catheter placement or minimally invasive biopsies are allowed.
    7. Have been diagnosed with another primary malignancy other than NSCLC, except for adequately treated nonmelanoma skin cancer or cervical cancer in situ; definitively treated nonmetastatic prostate cancer; or patients with another primary malignancy who are definitively relapse-free with at least 3 years elapsed since the diagnosis of the other primary malignancy.
    8. Have known active brain metastases (have either previously untreated intracranial CNS metastases or previously treated intracranial CNS metastases with radiologically documented new or progressing CNS lesions). Brain metastases are allowed if they have been treated with surgery and/or radiation and have been stable without requiring corticosteroids to control symptoms within 7 days before randomization and have no evidence of new or enlarging brain metastases.
    9. Have current spinal cord compression (symptomatic or asymptomatic and detected by radiographic imaging) or leptomeningeal disease (symptomatic or asymptomatic).
    10. Have significant, uncontrolled, or active cardiovascular disease, specifically including, but not restricted to:
    a) Myocardial infarction within 6 months before randomization.
    b) Unstable angina within 6 months before randomization.
    c) Congestive heart failure within 6 months before randomization.
    d) History of clinically significant (as determined by the treating physician) atrial arrhythmia.
    e) Any history of ventricular arrhythmia.
    f) Cerebrovascular accident or transient ischemic attack within 6 months before randomization.
    11. Have uncontrolled hypertension. Patients with hypertension should be under treatment on study entry to control blood pressure.
    12. Currently being treated with medications known to be associated with the development of torsades de pointes (Appendix G).
    13. Currently have or have had a history of interstitial lung disease, radiation pneumonitis that required steroid treatment, or drug-related pneumonitis.
    14. Have an ongoing or active infection including, but not limited to, the requirement for IV antibiotics, or a known history of HIV. Testing for HIV is not required in the absence of history.
    Note: Hepatitis B surface antigen (HBsAg)-positive patients are allowed to enroll if hepatitis B virus (HBV) DNA is below 1000 copies/mL in the plasma. Patients who are positive for anti–hepatitis C virus antibody (HCVAb) can be enrolled but must not have detectable hepatitis C virus (HCV) RNA in the plasma.
    15. Have a known or suspected hypersensitivity to TAK-788 or its excipients.
    16. Have a history of or suspected severe hypersensitivity reaction to platinum-containing drugs, pemetrexed, or any known excipients of these drugs.
    17. Grade ≥1 peripheral neuropathy (NCI CTCAE version 5.0).
    18. Have gastrointestinal illness or disorder that could affect oral absorption of TAK-788.
    19. Have any condition or illness that, in the opinion of the investigator, would compromise patient safety or interfere with evaluation of the study drug.
    No se podrá asignar aleatoriamente un tratamiento a los pacientes que cumplan cualquiera de los siguientes criterios de exclusión:
    1. Mujeres que estén dando el pecho o tengan una prueba de embarazo en orina o suero positiva durante el período de selección.
    Nota: Las mujeres que estén dando el pecho podrán participar si dejan de hacerlo.
    2. Tratamiento actual en otro estudio clínico terapéutico.
    3. Haber recibido tratamiento sistémico previo para la enfermedad localmente avanzada o metastásica (con la excepción siguiente):
    Se permite la quimioterapia/inmunoterapia neoadyuvante o adyuvante para la enfermedad en estadio I a III o la combinación de quimioterapia/radioterapia para la enfermedad localmente avanzada si se ha completado > 6 meses antes del desarrollo de enfermedad metastásica.
    4. Haber recibido radioterapia ≤ 14 días antes de la aleatorización o ausencia de recuperación de la toxicidad relacionada con la radioterapia. Se permite la radioterapia paliativa administrada fuera del tórax y el cerebro, la radiocirugía estereotáctica y la radioterapia estereotáctica corporal hasta 7 días antes de la aleatorización.
    5. Haber recibido un inhibidor moderado o potente del citocromo P 450 (CYP)3A o un inductor moderado o potente del CYP3A (Apéndice F) en los 10 días previos a la aleatorización.
    6. Haberse sometido intervención de cirugía mayor en los 28 días previos a la aleatorización. Se permiten procedimientos de cirugía menor, como colocación de catéteres o biopsias mínimamente invasivas.
    7. Haber sido diagnosticado de otra neoplasia maligna primaria distinta del CPNM, excepto cáncer de piel distinto del melanoma o cáncer de cuello uterino in situ debidamente tratados, cáncer de próstata no metastásico tratado definitivamente o pacientes con otra neoplasia maligna primaria que estén definitivamente sin recidiva y hayan transcurrido al menos 3 años desde el diagnóstico de la otra neoplasia maligna primaria.
    8. Presentar metástasis cerebrales activas conocidas (tener metástasis intracraneales del SNC no tratadas previamente o metástasis intracraneales del SNC tratadas previamente con lesiones nuevas o en progresión del SNC documentadas radiológicamente). Se permiten las metástasis cerebrales si han sido tratadas con cirugía o radioterapia y se han mantenido estables sin necesidad de corticosteroides para controlar los síntomas en los 7 días previos a la aleatorización y no presentan signos de metástasis cerebrales nuevas o que hayan aumentado de tamaño.
    9. Presencia de compresión medular (sintomática o asintomática y detectada mediante estudios radiológicos) o enfermedad leptomeníngea (sintomática o asintomática).
    10. Presencia de una enfermedad cardiovascular significativa, no controlada o activa, incluidas, entre otras, las siguientes:
    a) Infarto de miocardio en los seis meses previos a la aleatorización.
    b) Angina de pecho inestable en los 6 meses previos a la aleatorización.
    c) Insuficiencia cardíaca congestiva en los 6 meses previos a la aleatorización.
    d) Antecedentes de arritmia auricular clínicamente significativa (según lo determinado por el médico responsable del tratamiento).
    e) Cualquier antecedente de arritmia ventricular
    f) Accidente cerebrovascular o accidente isquémico transitorio en los 6 meses previos a la aleatorización.
    11. Tener hipertensión no controlada. Los pacientes con hipertensión deben estar en tratamiento al entrar en el estudio para controlar la presión arterial.
    12. Estar recibiendo tratamiento actual con medicamentos que se sabe que se asocian al desarrollo de taquicardia helicoidal (torsades de pointes) (Ap G).
    13. Presencia o antecedentes de neumopatía intersticial, neumonitis por radiación con necesidad de tratamiento con esteroides o neumonitis relacionada con el fármaco.
    14. Tener una infección activa o en curso, por ejemplo, necesidad de antibióticos IV o antecedentes conocidos de infección por el VIH. La prueba del VIH no es necesaria en ausencia de antecedentes.
    Nota: Se permite la inclusión de pacientes positivos para el antígeno de superficie (HBsAg) del virus de la hepatitis B (VHB) si el ADN del virus de la hepatitis B es inferior a 1000 copias/ml en el plasma. Podrán participar pacientes con anticuerpos contra el virus de la hepatitis C (HCVAb), pero no podrán tener ARN del virus de la hepatitis C (VHC) detectable en el plasma.
    15. Tener hipersensibilidad confirmada o sospechada a TAK 788 o a sus excipientes.
    16. Antecedentes o sospecha de reacción de hipersensibilidad grave a los fármacos que contienen platino, pemetrexed o cualquiera de los excipientes conocidos de estos fármacos.
    17. Neuropatía periférica de grado ≥ 1 (CTCAE del NCI, versión 5.0).
    18. Presentar una enfermedad o trastorno digestivo que pueda afectar a la absorción oral de TAK 788.
    19. Presentar cualquier trastorno o enfermedad que, en opinión del investigador, pueda comprometer la seguridad del paciente o interferir en la evaluación del fármaco del estudio.
    E.5 End points
    E.5.1Primary end point(s)
    PFS, as assessed by the IRC, per RECIST version 1.1.
    El criterio de valoración principal de este estudio es la SSP, evaluada por el CRI, conforme a los criterios RECIST, versión 1.1
    E.5.1.1Timepoint(s) of evaluation of this end point
    The final analyses for the primary endpoint will be conducted after approximately 227 to 270 IRC-assessed PFS events (PD or death) have occurred. The number of events required will be determined according to a prespecified event size adaptation rule (see Section 13.2). The estimated time frame for primary completion is 32 to 40 months after the first patient is randomized. The final analysis (FA) for the primary endpoint could occur earlier if the interim analysis (IA) results are statistically significant
    Los análisis finales del criterio de valoración principal se harán cuando se hayan producido aproximadamente entre 227 y 270 episodios de SSP (PE o muerte) evaluados por el comité de revisión independiente. El número de acontecimientos necesarios se determinará con una regla de adaptación a la cantidad de acontecimientos especificada de antemano (véase la sección 13.2). El plazo estimado para la finalización principal es de 32 a 40 meses después de la aleatorización del primer paciente. El análisis final (AF) del criterio de valoración principal podría realizarse antes si los resultados del análisis intermedio (AI) son estadísticamente significativos.
    E.5.2Secondary end point(s)
    The key secondary endpoints are:
    • Confirmed ORR, as assessed by the IRC, per RECIST version 1.1.
    • OS.

    The other secondary endpoints are:
    • PFS, as assessed by the investigator.
    • Confirmed ORR, as assessed by the investigator.
    • Duration of response, as assessed by the IRC and the investigator.
    • Time to response, as assessed by the IRC and the investigator.
    • DCR, as assessed by the IRC and the investigator.
    • Patient-reported symptoms (particular core symptoms of lung cancer), functioning, and HRQoL with the EORTC QLQ-C30 and QLQ-LC13.
    Los criterios de valoración secundarios fundamentales de este estudio son
    • TRO, evaluada por el CRI, conforme a los criterios RECIST, versión 1.1
    • SG
    Otros criterios de valoración secundarios de este estudio son la SSP y la TRO confirmada, evaluadas por el investigador; la duración de la respuesta, evaluada por el CRI y el investigador; el tiempo hasta la respuesta, evaluado por el CRI y el investigador; la TCE, evaluada por el CRI y el investigador; y los síntomas comunicados por los pacientes (síntomas básicos específicos del cáncer de pulmón), la función y la CVRS con los cuestionarios QLQ C30 y QLQ LC13 de la EORTC.
    E.5.2.1Timepoint(s) of evaluation of this end point
    At the time of the primary endpoint analysis
    En el momento del criterio de valoración de valoración principal
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic 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) 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 Yes
    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 concerned14
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA75
    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
    Australia
    Austria
    Belgium
    Brazil
    Canada
    China
    Denmark
    France
    Germany
    Greece
    Hong Kong
    Israel
    Italy
    Japan
    Korea, Republic of
    Portugal
    Russian Federation
    Singapore
    Spain
    Sweden
    Switzerland
    Taiwan
    Turkey
    Ukraine
    United Kingdom
    United States
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LPLV
    La última visita del último paciente
    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 months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years5
    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: 218
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 100
    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 For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2020-01-10. Yes
    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 state18
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 150
    F.4.2.2In the whole clinical trial 318
    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)
    Terminated for those who no longer benefit from TAK-788, the benefit-risk no longer favors the individual, if TAK-788 becomes available either commercially or via another access mechanism, or when an alternative appropriate therapy becomes available. Posttrial access may be terminated in a country or geographical region where marketing authorization has been rejected, the development of TAK 788 has been suspended or stopped by the sponsor, or TAK-788 can no longer be supplied
    Finalizado para aquellos que ya no se benefician de TAK-788, el benefi riesgo ya no favorece al individuo, si se puede acceder a TAK-788 bien de forma comercial o bien a través de otro mecanismo o cuando se puede acceder a un tto alternativo adecuado. El acceso después del ensayo puede terminarse en un país o una región geográfica en donde se rechace la autorización de comercialización, cuando el promotor suspenda o paralice el desarrollo de TAK-788, o cuando TAK-788 ya no se pueda suministrar.
    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 Decision2020-02-19
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-02-11
    P. End of Trial
    P.End of Trial StatusTemporarily Halted
    The status of studies in GB is no longer updated from 1.1.2021
    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
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