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    Summary
    EudraCT Number:2016-001271-68
    Sponsor's Protocol Code Number:AP32788-15-101
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2019-04-11
    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 number2016-001271-68
    A.3Full title of the trial
    A Phase 1/2 Study of the Safety, Pharmacokinetics, and Anti-Tumor Activity of the Oral EGFR/HER2 Inhibitor TAK-788 (AP32788) in Non-Small Cell Lung Cancer
    Estudio de fase I/II de la seguridad, la farmacocinética y la actividad antitumoral del inhibidor oral de EGFR/HER2, TAK-788 (AP32788), en el cáncer de pulmón no microcítico
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    TAK-788 (AP32788) in Patients With Non-Small Cell Lung Cancer
    TAK-788 (AP32788) en Pacientes con cáncer de pulmón no microcítico
    A.4.1Sponsor's protocol code numberAP32788-15-101
    A.5.3WHO Universal Trial Reference Number (UTRN)U1111-1217-7205
    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., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited
    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 supportMillennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda 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 organisationMillennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited
    B.5.2Functional name of contact pointStudy Registration Call Center
    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+1866835-2233
    B.5.6E-mailGlobalOncologyMedinfo@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 nameTAK-788
    D.3.2Product code TAK-788 (formerly AP32788)
    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 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.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 (NSCLSC)
    Cáncer de pulmón no microcítico (CPNM)
    E.1.1.1Medical condition in easily understood language
    Non-Small Cell Lung Cancer (NSCLSC)
    cáncer de pulmón no microcítico (CPNM)
    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 10061873
    E.1.2Term Non-small cell lung cancer
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10029521
    E.1.2Term Non-small cell lung cancer stage IIIB
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10029522
    E.1.2Term Non-small cell lung cancer stage IV
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    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.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10025054
    E.1.2Term Lung cancer non-small cell stage IIIB
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10025055
    E.1.2Term Lung cancer non-small cell stage IV
    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 determine the efficacy of TAK-788, as evidenced by confirmed ORR, as assessed by the IRC, in patients with locally advanced or metastatic NSCLC harboring EGFR in-frame exon 20 insertion mutations and who have received at least 1 prior line of therapy for locally advanced or metastatic NSCLC.
    Determinar la eficacia de TAK-788, en base a la TRO confirmada, según lo evaluado por el CRI, en pacientes con CPNM localmente avanzado o metastásico que presentan mutaciones de inserción dentro del marco del exón 20 del EGFR y que hayan recibido al menos 1 línea anterior de tratamiento para el CPNM metastásico o localmente avanzado.
    E.2.2Secondary objectives of the trial
    1. To further characterize the efficacy of TAK-788 as shown by confirmed ORR, as assessed by the investigator, duration of response, progression free survival (PFS), disease control rate (DCR), time to response, and overall survival (OS)
    2. To assess the safety and tolerability of TAK-788
    3. To collect sparse plasma concentration-time data of TAK 788 and its active metabolites, AP32960 and AP32914, to contribute to population PK and exposure response analyses
    4. To assess change from baseline in overall global quality of life (the Global Health Status/QoL Scale) with the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30 and change from baseline in the Dyspnea Scale, based on the EORTC lung cancer module QLQ LC13
    1. Caracterizar mejor la eficacia de TAK-788 en base a la TRO confirmada, según lo evaluado por el investigador, la duración de la respuesta, la supervivencia sin progresión (SSP), la tasa de control de la enfermedad (TCE), el tiempo hasta la respuesta y la supervivencia general (SG
    2. Evaluar la seguridad y la tolerabilidad de TAK-788.
    3. Recopilar datos dispersos de la concentración plasmática en el tiempo de TAK-788 y sus metabolitos activos, AP32960 y AP32914, para contribuir a los análisis de FC poblacional y de exposición-respuesta.
    4. Evaluar el cambio desde el inicio en la calidad de vida general (escala de estado de salud general/CdV) mediante el cuestionario de calidad de vida de 30 ítems (QLQ-C30) de la Organización Europea para la Investigación y el Tratamiento del Cáncer (European Organisation for Research and Treatment of Cancer, EORTC) y el cambio desde el inicio en la escala de disnea, en base al módulo de cáncer de pulmón QLQLC13 de la EORTC.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    General
    1.Have histologically or cytologically confirmed locally advanced (and not a candidate for definitive therapy) or metastatic disease (Stage IIIB or IV). For all cohorts except Expansion Cohort 7, the locally advanced or metastatic disease is NSCLC.
    2.Must have sufficient tumor tissue available for analysis (see Study Reference Manual for specific requirements). For patients in the expansion cohorts and in the extension cohort, tumor tissue obtained after progression on the most recent prior therapy is preferred.
    3.Must have measurable disease by RECIST v1.1 (Appendix B).
    4.Male or female patients ≥18 years old. For patients in Japan, aged ≥20 years.
    5.Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1 (Appendix A).
    6.Minimum life expectancy of 3 months or more.
    7.Adequate renal and hepatic function as defined by the following criteria:
    a.Total serum bilirubin ≤1.5 × upper limit of normal (ULN) (≤3.0 × ULN for patients with Gilbert syndrome or if liver function abnormalities are due to underlying malignancy);
    b.Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 × ULN (or ≤5 × ULN if liver function abnormalities are due to underlying malignancy);
    c.Estimated creatinine clearance ≥30 mL/min (calculated by using the Cockcroft-Gault equation);
    d.Serum albumin ≥2 g/dL; and
    e.Serum lipase/amylase ≤1.5 × ULN.
    8.Adequate bone marrow function as defined by the following criteria:
    a.Absolute neutrophil count (ANC) ≥1.5 × 109/L;
    b.Platelet count ≥75 × 109/L; and
    c.Hemoglobin ≥9.0 g/dL.
    9.Normal QT interval on screening electrocardiogram (ECG), defined as QTcF of ≤450 ms in males or ≤470 ms in females.
    10.All toxicities from prior therapy have resolved to ≤ grade 1 according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE v5.0 [18]), or have resolved to baseline, at the time of first dose of TAK 788. Note: treatment-related grade >1 alopecia or treatment-related grade 2 peripheral neuropathy are allowed if deemed irreversible.
    11.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, from the time of signing the informed consent through 30 days after the last dose of study drug, 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 during the entire study treatment period and through 30 days after the last dose of study drug, 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.)

    Extension Phase specific
    1.Have a documented EGFR in-frame exon 20 insertion (including A763_Y764insFQEA, V769_D770insASV, D770_N771insNPG, D770_N771insSVD, H773_V774insNPH, or any other in-frame exon 20 insertion mutation) by a local test and sufficient tumor tissue available for central analysis (see Study Reference Manual). The EGFR exon 20 insertion mutation can be either alone or in combination with other EGFR or HER2 mutations. Note: central confirmation is not required for enrollment.
    2.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 prior to the first dose of TAK-788.
    3.Must have received at least 1 prior line of therapy for locally advanced or metastatic disease and no more than 2 regimens of systemic anticancer chemotherapies for locally advanced or metastatic disease.
    –Note: A systemic anticancer chemotherapy regimen will be counted if it is administered over at least 1 cycle. A new antineoplastic chemotherapy used as maintenance therapy will be counted as a new regimen. Neoadjuvant or adjuvant systemic anticancer chemotherapy will be counted as a prior regimen if completion of the (neo)adjuvant therapy occurred <12 months prior to enrollment.
    –Prior treatment with an EGFR TKI is allowed unless the patient had an objective response and subsequent progression as assessed by the investigator or treating physician during treatment with that prior TKI.

    1.Tener enfermedad localmente avanzada (y no ser candidato para tratamiento definitivo) o metastásica (estadio IIIB o IV) histológica o citológicamente confirmada. Para todas las cohortes, excepto la cohorte de expansión 7, la enfermedad localmente avanzada o metastásica es el CPNM. Para la cohorte de expansión 7, la enfermedad localmente avanzada o metastásica es cualquier tumor sólido distinto de CPNM. 2.Debe tener suficiente tejido tumoral disponible para el análisis (véase el Manual de referencia del estudio para conocer los requisitos específicos). Para los pacientes de las cohortes de expansión y la cohorte de extensión, se prefiere el tejido tumoral obtenido después de la progresión con el tratamiento anterior más reciente. 3. Deben tener enfermedad cuantificable según los criterios RECIST v1.1 4. Pacientes de ambos sexos de ≥18 años de edad. Para los pacientes de Japón, edad ≥20 años 5. Estado funcional del Grupo Oncológico Cooperativo del Este (Eastern Cooperative Oncology Group, ECOG) de 0 a 1 (Apéndice A) 6. Esperanza de vida mínima de 3 meses o más. 7. Función renal y hepática adecuada según el protocolo 9.Intervalo QT normal en el electrocardiograma (ECG) de selección, definido como QTcF ≤450 ms hombres o ≤470 ms mujeres. 10.Todas las toxicidades de un tratamiento previo se han resuelto a grado ≤1 de acuerdo con los Criterios CTCAE del NCI, v5.0 [18]) o se han resuelto hasta el valor inicial en el momento de la primera dosis de TAK-788. Nota: se permiten la alopecia de grado >1 relacionada con el tratamiento o la neuropatía periférica de grado 2 relacionada con el tratamiento si se consideran irreversibles. 11.Ser una mujer que: • haya tenido la menopausia durante al menos 1 año antes de la visita de selección, O BIEN • se haya sometido a esterilización quirúrgica, O BIEN • si tiene capacidad de concebir, acceda a utilizar simultáneamente 1 método anticonceptivo no hormonal altamente eficaz y 1 método eficaz adicional (de barrera) desde la firma del consentimiento informado hasta 30 días después de la última dosis del fármaco del estudio, O BIEN • acepte mantener una abstinencia total, cuando ello esté en consonancia con el estilo de vida preferido y habitual del sujeto. (La abstinencia periódica [p. ej., métodos del calendario, sintotérmico, de postovulación], la marcha atrás, el uso de espermicidas solamente, y la amenorrea de lactancia no son métodos anticonceptivos aceptables. No deben usarse conjuntamente preservativos masculinos y femeninos).Ser varón, incluso si se ha sometido a esterilización quirúrgica (es decir, estado posterior a la vasectomía), que: acepte practicar anticoncepción de barrera eficaz durante el período completo del tratamiento del estudio y durante los 30 días siguientes a la administración de la última dosis del fármaco del estudio, O BIEN acepte mantener una abstinencia total, cuando ello esté en consonancia con el estilo de vida preferido y habitual del sujeto. (La abstinencia periódica [p. ej., métodos del calendario, sintotérmico, de postovulación], la marcha atrás, el uso de espermicidas solamente, y la amenorrea de lactancia no son métodos anticonceptivos aceptables. No deben usarse conjuntamente preservativos masculinos y femeninos). Fase de extensión Específica 1. Tener una inserción dentro del marco del exón 20 documentada (incluidas A763_Y764insFQEA, V769_D770insASV, D770_N771insNPG, D770_N771insSVD, H773_V774insNPH, o cualquier otra mutación de inserción dentro del marco del exón 20) mediante una prueba local y suficiente tejido tumoral disponible para el análisis central (véase el Manual de referencia del estudio). La mutación de inserción del exón 20 del EGFR puede presentarse sola o en combinación con otras mutaciones de EGFR o HER2. Nota: no se precisa confirmación central para la inclusión 2. Se permiten metástasis cerebrales si han sido tratadas con cirugía o radioterapia y han estado estables sin necesidad de corticoesteroides para el control de los síntomas en los 7 días anteriores a la primera dosis de TAK-788. 3. Deben haber recibido al menos 1 línea de tratamiento previo para la enfermedad localmente avanzada o metastásica y no más de 2 pautas de quimioterapia antineoplásica sistémica para la enfermedad localmente avanzada o metastásica. – Nota: una pauta de quimioterapia antineoplásica sistémica se contará si se administra durante al menos 1 ciclo. Una quimioterapia antineoplásica nueva usada como tratamiento de mantenimiento se contará como una nueva pauta. La quimioterapia antineoplásica sistémica neoadyuvante o adyuvante se considera una pauta previa si la finalización del tratamiento (neo)adyuvante se produjo <12 meses antes de la inclusión.Se permite el tratamiento previo con un TKI del EGFR a menos que el paciente tuviera una respuesta objetiva y posterior progresión evaluada por el investigador o el médico a cargo durante el tratamiento con dicho TKI anterior.
    E.4Principal exclusion criteria
    1.Previously received TAK-788.
    2.Received small-molecule anticancer therapy (including cytotoxic chemotherapy and investigational agents) ≤14 days prior to first dose of TAK 788 (except for reversible EGFR TKIs [ie, erlotinib or gefitinib], which are allowed up to 7 days prior to the first dose of TAK 788).
    3.Received antineoplastic monoclonal antibodies including immunotherapy within 28 days of the first dose of TAK-788.
    4.Have been diagnosed with another primary malignancy other than NSCLC except for adequately treated non-melanoma skin cancer or cervical cancer in situ; definitively treated non-metastatic 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. Note: This exclusion criterion does not apply to Expansion Cohort 7.
    5.Received radiotherapy ≤14 days prior to the first dose of TAK 788. SRS, stereotactic body radiotherapy, and palliative radiation outside the chest and brain are allowed up to 7 days prior to the first dose.
    6.Received a strong CYP3A inhibitor or strong CYP3A inducer within 2 weeks prior to first dose of TAK 788 (see Appendix C).
    7.Have undergone major surgery within 28 days prior to first dose of TAK 788. Minor surgical procedures, such as catheter placement or minimally invasive biopsy, are allowed.
    8.Have symptomatic CNS metastases (parenchymal or leptomeningeal) at screening or asymptomatic disease requiring corticosteroids to control symptoms within 7 days prior to the first dose of TAK 788.
    Note: If a patient has worsening neurological symptoms or signs due to CNS metastases, the patient needs to complete local therapy and be neurologically stable (with no requirement for corticosteroids or use of anticonvulsants) for 7 days prior to the first dose of TAK-788. Patients with no prior history of signs or symptoms of CNS metastases but who receive prophylactic steroids or anticonvulsants are allowed.
    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, including, but not restricted to:
    a.Myocardial infarction (MI) within 6 months prior to the first dose of study drug;
    b.Unstable angina within 6 months prior to first dose;
    c.Congestive heart failure (CHF) within 6 months prior to first dose;
    d.History of clinically significant (as determined by the treating physician) atrial arrhythmia;
    e.Any history of ventricular arrhythmia; or
    f.Cerebrovascular accident or transient ischemic attack within 6 months prior to first dose.
    11.Have a known history of uncontrolled hypertension. Patients with hypertension should be under treatment on study entry to control blood pressure.
    12.Have prolonged QTcF interval, or being treated with medications known to be associated with the development of Torsades de Pointes (Appendix D).
    13.(Parts 1 and 2 [dose escalation and expansion cohorts] only) Have an ongoing or active infection including, but not limited to, the requirement for intravenous (IV) antibiotics, or a known history of human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV). Testing is not required in the absence of history.
    (Part 3 [extension cohort] only) Have an ongoing or active infection including, but not limited to, the requirement for IV antibiotics, or a known history of HIV. Testing is not required in the absence of history.
    (Part 3 [extension cohort] only) Hepatitis B surface antigen (HBsAg) positive patients are allowed to enroll if HBV DNA is below 1000 copies/mL in the plasma. Patients who are positive for anti-HCV antibody (HCVAb) can be enrolled but must not have detectable HCV RNA in the plasma.
    14.Currently have or have a history of interstitial lung disease, radiation pneumonitis that required steroid treatment, or drug-related pneumonitis.
    15.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.
    16.Have gastrointestinal illness or disorder that could affect oral absorption of TAK 788.
    17.Have any condition or illness that, in the opinion of the investigator, might compromise patient safety or interfere with the evaluation of the safety of the drug.
    1. Tratamiento previo con TAK-788. 2. Haber recibido tratamiento neoplásico de molécula pequeña (incluida la quimioterapia citotóxica y fármacos en fase de investigación) ≤14 días antes de la primera dosis de TAK-788 (a excepción de los TKI del EGFR reversibles [es decir, erlotinib y gefitinib], que se permiten hasta 7 días antes de la primera dosis de TAK-788). 3. Haber recibido inmunoterapia con anticuerpos monoclonales antineoplásicos dentro de los 28 días anteriores a la primera dosis de TAK-788. 4. Haber sido diagnosticado de otra neoplasia maligna primaria distinta de CPNM, excepto cáncer de piel no melanoma o cáncer de cuello uterino in situ tratados adecuadamente; cáncer de próstata no metastásico tratado definitivamente; o pacientes con otra neoplasia maligna primaria con confirmación de ausencia de recidivas y con al menos 3 años transcurridos desde el diagnóstico de la otra neoplasia maligna primaria. Nota: este criterio de exclusión no se aplica a la cohorte de expansión 7. 5. Haber recibido radioterapia ≤14 días antes de la primera dosis de TAK-788. Se permiten la RCE, la radioterapia estereotáctica corporal y la radiación paliativa fuera del tórax y el cerebro hasta 7 días antes de la primera dosis. 6. Haber recibido un potente inhibidor o inductor de CYP3A en el plazo de 2 semanas antes de la primera dosis de TAK-788 . 7. Haberse sometido a cirugía mayor en los 28 días previos a la primera dosis de TAK-788. Se permiten las intervenciones quirúrgicas menores, como la colocación de un catéter o la biopsia mínimamente invasiva. 8. Tener metástasis sintomáticas del SNC (leptomeníngeas o parenquimatosas) en la selección o enfermedad asintomática que requiera corticoesteroides para el control de los síntomas en los 7 días previos a la primera dosis de TAK-788. 9. Presencia actual de compresión medular (sintomática o asintomática y detectada mediante estudios radiográficos) o enfermedad leptomeníngea (sintomática o asintomática). 10. Tener una enfermedad cardiovascular significativa, no controlada o activa, incluidos, entre otros: a. Infarto de miocardio (IM) en los 6 meses anteriores a la primera dosis del fármaco del estudio b. Angina inestable en los 6 meses previos a la primera dosis c. Insuficiencia cardíaca congestiva (ICC) en los 6 meses previos a la primera dosis d. Antecedentes de arritmia auricular clínicamente significativa (según el criterio del médico responsable del tratamiento) e. Cualquier antecedente de arritmia ventricular f. Accidente cerebrovascular o accidente isquémico transitorio en los 6 meses previos a la primera dosis del fármaco del estudio 11. Tener antecedentes conocidos de hipertensión no controlada. Los pacientes con hipertensión deben estar en tratamiento en el momento de inclusión en el estudio para el control de la presión arterial. 12. Tener un intervalo QTcF prolongado, o recibir tratamiento con medicamentos que se sabe que están asociados con el desarrollo de torsades de pointes (Apéndice D). 13. (Partes 1 y 2 [cohortes de incremento de la dosis y expansión]) Tener una infección activa o en curso, incluidos, entre otros, la necesidad de antibióticos intravenosos (i.v.), o antecedentes conocidos de virus de la inmunodeficiencia humana (VIH), virus de la hepatitis B (VHB) o virus de la hepatitis C (VHC). No es necesario realizar pruebas en ausencia de antecedentes. (Parte 3 [cohorte de extensión] solo) Tener una infección activa o en curso, incluidos, entre otros, la necesidad de antibióticos i.v. o antecedentes conocidos de VIH. No es necesario realizar pruebas en ausencia de antecedentes. (Parte 3 [cohorte de extensión] solo) A los pacientes con antígeno de superficie de la hepatitis B (AgsHB) positivo se les permite la inclusión si el ADN del VHB es inferior a 1000 copias/ml en plasma. Los pacientes que sean positivos para anticuerpos contra el VHC (AcVHC) se puedenincluir, pero no deben presentar ARN de VHC detectable en el plasma. 14. Antecedentes o presencia de enfermedad pulmonar intersticial, neumonitis por radiación que haya necesitado tratamiento con corticoesteroides o neumonitis relacionada con el fármaco. 15. Mujeres que se encuentran en período de lactancia o que han tenido un resultado positivo en una prueba de embarazo en orina o suero durante el período de selección. Nota: las pacientes que estén en periodo de lactancia serán aptas si suspenden la lactancia materna. 16. Tener una enfermedad o trastorno digestivo que pudiera afectar a la absorción oral de TAK-788.
    17. Tener cualquier afección o enfermedad que, en opinión del investigador, podría comprometer la seguridad del paciente o interferir en la evaluación de la seguridad del fármaco.
    E.5 End points
    E.5.1Primary end point(s)
    Confirmed ORR, as assessed by the IRC, per RECIST v1.1
    TRO confirmada, evaluada por el CRI, según los criterios RECIST v1.1
    E.5.1.1Timepoint(s) of evaluation of this end point
    The primary analysis of the primary endpoint, confirmed ORR as assessed by the IRC, will be performed in the full analysis set when all ongoing patients have completed their Cycle 6 disease assessment. A futility analysis will be planned for the primary endpoint when approximately 20 patients have completed their Cycle 4 disease assessment.
    El análisis principal del criterio de valoración principal, la TRO confirmada evaluada por el CRI, se realizará en el conjunto de análisis completo cuando todos los pacientes hayan completado su evaluación de la enfermedad del ciclo 6. Se programará un análisis de la futilidad para el criterio de valoración principal cuando aproximadamente 20 pacientes hayan completado su evaluación de la enfermedad del ciclo 4.
    E.5.2Secondary end point(s)
    1.Confirmed ORR, as assessed by the investigator, per RECIST v1.1
    2.Duration of response, as assessed by the IRC and the investigator
    3.Time to response, as assessed by the IRC and the investigator
    4.DCR (the percentage of patients with best response of complete response [CR], partial response [PR], or SD), as assessed by the IRC and the investigator, per RECIST v1.1
    5.PFS, as assessed by the IRC and the investigator
    6.OS
    7.Change from baseline in overall global quality of life (the Global Health Status/QoL Scale) with the EORTC QLQ-C30 and change from baseline in the Dyspnea Scale, based on the QLQ-LC13
    1. TRO confirmada, evaluada por el investigador, según los criterios RECIST v 1.1
    2. Duración de la respuesta, evaluada por el CRI y el investigador
    3. Tiempo hasta la respuesta, evaluado por el CRI y el investigador
    4. TCE (el porcentaje de pacientes con mejor respuesta de respuesta completa [RC], respuesta parcial [RP], o EE) evaluada por el CRI y el investigador, según los criterios RECIST v1.1
    5. SSP evaluada por el CRI y el investigador
    6. SG
    7. Cambio desde el inicio en la calidad de vida general (escala de estado de salud general/CdV) con el QLQ-C30 de la EORTC y el cambio desde el inicio en la escala de disnea, según QLQ-LC13.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Two-sided exact 95% binomial confidence intervals will be computed for all binary secondary endpoints, including confirmed ORR as assessed by the investigator and DCR as assessed by the IRC and the investigator. Kaplan Meier methods, including medians and confidence intervals, will be used to estimate PFS as assessed by the IRC and the investigator, duration of response as assessed by the IRC and the investigator, and OS. Descriptive statistics will be used to summarize time to response in responders and time on treatment. Patient-reported outcome assessments will be assessed at each cycle using descriptive summary statistics.
    Se proporcionarán intervalos de confianza binomiales exactos del 95 % para todos los criterios de valoración secundarios binarios, incluida la TRO confirmada evaluada por el investigador y la TCE evaluada por el CRI y el investigador. Los métodos de Kaplan-Meier, incluidas las medianas y los intervalos de confianza, se utilizarán para calcular la SSP evaluada por el CRI y el investigador, la duración de la respuesta evaluada por el CRI y el investigador y la SG. Se utilizarán estadísticos descriptivos para resumir el tiempo hasta la respuesta en pacientes con respuesta y el tiempo de tratamiento. Las evaluaciones de resultados notificados por el paciente se evaluarán en cada ciclo empleando estadísticos descriptivos de resumen.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis Yes
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) Yes
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E.7.1.3.1Other trial type description
    All patients that are planned to be enrolled in Spain will participate only phase II (Part 3)
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned12
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA35
    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
    China
    France
    Germany
    Italy
    Japan
    Korea, Republic of
    Spain
    Taiwan
    United Kingdom
    United States
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    End of study (completion) date is approximately 3 years after the last patient has enrolled in Part 3 (the extension cohort) or when all patients have completed all study visits or have otherwise discontinued from the study.
    La Fecha Fin de estudio (terminación) es aproximadamente 3 años después del ultimo paciente incluido en la Parte 3(cohorte de extensión) o cuando todos los pacientes hayan completado todas las visitas de estudio o que por el contrario hayan discontinuado del estudio.
    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 months6
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months1
    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: 80
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 11
    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 state12
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 20
    F.4.2.2In the whole clinical trial 91
    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 will revert to standard clinical management as directed by attending personal physician.
    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 Decision2019-04-29
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-04-12
    P. End of Trial
    P.End of Trial StatusOngoing
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