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    Summary
    EudraCT Number:2019-004991-20
    Sponsor's Protocol Code Number:ACTION
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2020-02-21
    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 number2019-004991-20
    A.3Full title of the trial
    A phase II triAl of Cabozantinib for hepaTocellular carcInoma patients intOlerant to sorafenib treatment or first line treatment different to sorafeNib. (ACTION trial)
    Ensayo en fase II de Cabozantinib en pacientes con carcinoma hepatocelular intolerantes al tratamiento con Sorafenib u otro tratamiento de primera línea diferente de sorafenib. (ensayo ACTION).
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Cabozantinib trial in patients with liver cancer intolerant to Sorafenib or other treatment. (ACTION trial).
    Ensayo Cabozantinib en pacientes con cancer de hígado intolerantes a Sorafenib u otro tratamiento. (ensayo ACTION).
    A.4.1Sponsor's protocol code numberACTION
    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 SponsorFundació Clinic per a la Recerca Biomèdica
    B.1.3.4CountrySpain
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportIpsen
    B.4.2CountrySpain
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAPICES SOLUCIONES S.L.
    B.5.2Functional name of contact pointClinical Operations department
    B.5.3 Address:
    B.5.3.1Street AddressAvda. Antonio López, 16 1ºA
    B.5.3.2Town/ cityPinto
    B.5.3.3Post code28320
    B.5.3.4CountrySpain
    B.5.4Telephone number0034918166804
    B.5.5Fax number0034918169172
    B.5.6E-mailana.moreno@apices.es
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name COMETRIQ
    D.2.1.1.2Name of the Marketing Authorisation holderIpsen Pharma
    D.2.1.2Country which granted the Marketing AuthorisationSpain
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameCabozantinib
    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 INNCabozantinib
    D.3.9.3Other descriptive nameCabozantinib S-malate
    D.3.9.4EV Substance CodeSUB176318
    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 RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name COMETRIQ
    D.2.1.1.2Name of the Marketing Authorisation holderIpsen Pharma
    D.2.1.2Country which granted the Marketing AuthorisationSpain
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameCabozantinib
    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 INNCabozantinib
    D.3.9.3Other descriptive nameCabozantinib S-malate
    D.3.9.4EV Substance CodeSUB176318
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    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
    Hepatocellular carcinoma
    Carcinoma hepatocelular
    E.1.1.1Medical condition in easily understood language
    Hepatocellular carcinoma
    Carcinoma hepatocelular
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the safety profile established by rate of adverse events (AE) with Common Terminology Criteria for Adverse Events (CTCAE)≥3 excluding palmar-plantar erythordysthesia, rate of related-AEs and rate of death. The rate of AEs leading to treatment discontinuation.
    Evaluar el perfil de seguridad establecido por la tasa de Acontecimientos Adversos (AA) según el Criterio de Terminología Común para Acontecimientos Adversos (CTCAE) ≥3 excluyendo la eritrodisestesia palmo-plantar, la tasa de AAs relacionados y la tasa de muertes. La tasa de acontecimientos adversos que llevaron a la discontinuación del tratamiento.
    E.2.2Secondary objectives of the trial
    Overall survival (OS), objective response rate (ORR), time to progression (TTP), pattern of progression, post-progression survival (PPS), rate of patients who develop new extra-hepatic spread
    Supervivencia global (SG), tasa de Respuesta Objetiva (TRO), tiempo hasta progresión (TP), patrón de progresión, supervivencia tras progresión (STP), tasa de pacientes que desarrollaron una nueva lesión extrahepática.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. HCC diagnosed according to American Association for the Study of Liver Diseases (AASLD) guideline.
    2. Intolerant to sorafenib according to RESORCE trial definition or patients who received treatment different to sorafenib as first-Line treatment (lenvatinib or atezolizumab bevacizumab).
    3. The subject has disease that is not amenable to a curative treatment approach (eg, transplant, surgery, radiofrequency ablation)
    4. Recovery to ≤ Grade 1 according to (CTCAE) v.5.0. from toxicities related to any prior treatments, unless the adverse events are clinically non-significant and/or stable on supportive therapy
    5. Respect the 15 days of first-line treatment washout before starting cabozantinib
    6. Age ≥ 18 years old on the day of consent
    7. ECOG performance status of 0 or 1
    8. Adequate hematologic function, based upon meeting the following laboratory criteria within
    7 days before starting therapy:
    a. absolute neutrophil count (ANC) ≥ 1200/mm3 (≥ 1.2 x 109/L)
    b. platelets ≥ 60,000/mm3 (≥ 60 x 109/L)
    c. hemoglobin ≥ 8 g/dL (≥ 80 g/L)
    9. Adequate renal function, based upon meeting the following laboratory criteria within 7 days before starting therapy:
    a. Serum creatinine ≤ 1.5 × upper limit of normal or calculated creatinine clearance
    ≥ 40 mL/min (using the Cockroft-Gault equation: (140 – age) x weight (kg)/(serum Creatinine x72 [mg/dL]) for males. (For females multiply by 0.85).
    AND
    b. Urine protein/creatinine ratio (UPCR) ≤ 1 mg/mg (≤ 113.1 mg/mmol) or 24-hour urine protein < 1 g
    10. Child-Pugh Score of A
    11. Total bilirubin ≤ 2 mg/dL (≤ 34.2 μmol/L) within 7 days before starting therapy
    12. Serum albumin ≥ 2.8 g/dL (≥28 g/L) within 7 days before starting therapy
    13. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 5.0 upper limit of
    normal (ULN) within 7 days before starting therapy
    14. Hemoglobin A1c (HbA1c) ≤ 8% within 28 days before starting therapy (if HbA1c results are
    unavailable [eg, hemoglobin variant], a fasting serum glucose ≤ 160 mg/dL)
    15. Antiviral therapy per local standard of care if active hepatitis B (HBV) infection
    16. Capable of understanding and complying with the protocol requirements and signed informed consent
    17. Sexually active fertile subjects and their partners must agree to use medically accepted methods of contraception (eg, barrier methods, including male condom, female condom, or diaphragm with spermicidal gel) during the course of the study and for 4 months after the last dose of study treatment
    18. Female subjects of childbearing potential must not be pregnant at screening. Females of
    childbearing potential are defined as premenopausal females capable of becoming pregnant
    (ie, females who have had any evidence of menses in the past 12 months, with the exception
    of those who had prior hysterectomy). However, women who have been amenorrheic for 12
    or more months are still considered to be of childbearing potential if the amenorrhea is
    possibly due to prior chemotherapy, antiestrogens, ovarian suppression, low body weight,
    or other reasons.
    19. Subjects must consent to perform a tumor biopsy within 4 weeks before starting cabozantinib, allowing the acquisition of a tumor sample for performance of correlative studies. A formalin-fixed, paraffin embedded (FFPE) tumor tissue block of tumor sample should be stored at local sites for correlative studies. For these biopsies, subjects must have a soft tissue tumor lesion that can be biopsied at acceptable clinical risk, as judged by the investigator. Subjects must consent to the pre-treatment fresh biopsy as a condition of protocol participation. If adequate tissue is not obtained during the first procedure then a repeat biopsy should be considered based on the investigator’s assessment of clinical risk. However, biopsies at the time of radiological tumor progression are not required to meet eligibility. Tumor biopsy is recommended at the time of tumor progression development. However, patients who develop radiologic tumor progression should have performance status 0/1 and preserved liver function. Finally, patients with symptomatic tumor progression will not be biopsied.
    1. Diagnóstico de CHC según la American Association for the Study of Liver Diseases (AASLD)
    2. Intolerancia a sorafenib según la definición del ensayo RESORCE o pacientes que hayan recibido tratamiento distinto de sorafenib como tratamiento de primera línea (lenvantinib o atezolizumab o bevacizumab).
    3. Los sujetos que tengan la enfermedad no candidata a tratamiento con intención curativa (p.ej., trasplante, cirugía, ablación por radiofrecuencia).
    4. Recuperación a Grado ≤ 1 según CTCAE v 5.0. de toxicidades relacionadas con cualquier tratamiento previo, a menos que los acontecimientos adversos no sean clínicamente relevantes y/o estén estabilizados con tratamiento de soporte.
    5. Al menos 15 días de lavado en relación con el tratamiento de primera línea recibido antes del inicio de cabozantinib.
    6. Edad ≥ 18 años a fecha de consentimiento.
    7. Estado funcional ECOG de 0 o 1.
    8. Función hematológica adecuada, en base al cumplimiento de los siguientes criterios de laboratorio durante los 7 días previos al inicio del tratamiento:
    a. recuento absoluto de neutrófilos (RAN) ≥ 1200/mm3 (≥ 1.2 x 109/L).
    b. plaquetas ≥ 60.000/mm3 (≥ 60 x 109/L)
    c. hemoglobina ≥ 8 g/dL (≥ 80 g/L)
    9. Función renal adecuada, en base al cumplimiento de los siguientes criterios de laboratorio durante los 7 días previos al comienzo del tratamiento:
    a. Creatinina sérica ≤ 1,5 × límite superior de normalidad o aclaramiento de creatinina calculado ≥ 40 mL/min (usando la ecuación de Cokroft-Gault: (140 – edad) x peso (kg)/(creatinina sérica x 72 [mg/dL]) para varones. (Para mujeres multiplicar por 0.85)
    Y
    b. Cociente proteína urinaria/creatinina (UPCR) ≤ 1 mg/mg (≤ 113.1 mg/mmol) o proteína urinaria en orina de 24 h < 1g.
    10. Puntuación Child Pugh de A.
    11. Bilirrubina total ≤ 2 mg/dL (≤ 34.2 μmol/L) en los 7 días previos al comienzo del tratamiento.
    12. Albúmina sérica ≥ 2.8 g/dL (≥28 g/L) durante los 7 días previos al comienzo del tratamiento.
    13. Alanina aminotransferasa (ALT) y aspartato aminotransferasa (AST) < 5.0 veces el límite superior de normalidad (LSN) durante los 7 días previos al comienzo del tratamiento.
    14. Hemoglobina A1c (HbA1c) ≤ 8% durante los 28 días previos al comienzo del tratamiento (si los resultados de HbA1c no están disponibles [p.ej, variante de hemoglobina], la glucosa sérica en ayunas deberá ser ≤ 160 mg/dL)
    15. Pacientes que están recibiendo terapia antiviral para la infección por hepatitis B (VHB) según práctica habitual en cada centro.
    16. Sujetos capaces de comprender y cumplir con los requisitos del protocolo y de firmar el consentimiento informado.
    17. Los sujetos fértiles sexualmente activos y sus parejas deben comprometerse a utilizar un método anticonceptivo médicamente aceptado (p. ej., métodos barrera, incluyendo preservativo masculino, femenino, o diafragmas con gel espermicida) durante el periodo del estudio y durante 4 meses después de la última dosis del tratamiento del estudio.
    18. Las pacientes con capacidad de quedarse embarazadas no deben estar embarazadas al screening. Las mujeres con capacidad de quedarse embarazadas se definen como mujeres premenopáusicas capaces de quedarse embarazadas (p.ej., mujeres que hayan tenido evidencia de menstruación en los últimos 12 meses, con la excepción de aquellas con una histerectomía previa). Sin embargo, las mujeres que hayan sido amenorreicas durante 12 meses o más aún se consideran con capacidad de quedarse embarazadas si la amenorrea es posible debido a quimioterapia previa, antiestrógenos, supresión ovárica, peso corporal bajo u otras razones.
    19. Los sujetos deben consentir la realización de una biopsia tumoral durante las 4 semanas previas al inicio de cabozantinib, permitiendo la obtención de una muestra tumoral para el desarrollo de estudios correlativos. Un bloque de tejido de una muestra tumoral fijada en formalina y embebida en parafina debe ser almacenada en los centros locales para estudios correlativos. Para estas biopsias, los sujetos deben tener una lesión tumoral de tejido blando que pueda ser biopsiada con un riesgo clínico aceptable, a criterio del investigador. Los sujetos deben consentir la biopsia fresca en el pre-tratamiento como una condición para poder participar en el estudio. Si no se obtiene el tejido adecuado durante el primer procedimiento, entonces debe considerarse una biopsia de repetición en base a la evaluación del riesgo clínico por parte del investigador. Sin embargo, las biopsias en el momento de la progresión tumoral no se requieren para cumplir la elegibilidad. Se recomienda obtener una biopsia tumoral a la fecha de documentación de progresión tumoral. Sin embargo, los pacientes que desarrollen progresión tumoral radiológica deben tener un estado funcional 0/1 y preservar la función hepática. Finalmente, los pacientes con progresión tumoral sintomática no serán biopsiados.
    E.4Principal exclusion criteria
    1. Fibrolamellar carcinoma or mixed hepatocellular cholangiocarcinoma
    2. Radiation therapy (eg, I-131 or Y-90) within 4 weeks (2 weeks for radiation for bone metastases or radionuclide treatment within 6 weeks of starting therapy (subject is excluded if there are any clinically relevant ongoing complications from prior radiation therapy)
    3. Prior cabozantinib treatment
    4. Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery (including radiosurgery) and stable for at least 3 months before starting therapy. Eligible subjects must be without corticosteroid treatment at the time of starting therapy.
    5. Concomitant anticoagulation, at therapeutic doses. Low dose aspirin for cardioprotection (per local applicable guidelines), low-dose warfarin (≤ 1 mg/day), and low dose LMWH are permitted.
    6. The subject has uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions
    a. Cardiovascular disorders
    b. Gastrointestinal (GI) disorders including those associated with a high risk of perforation or fistula formation:
    i. Tumors invading the GI tract, active peptic ulcer disease, inflammatory bowel disease (eg, Crohn’s disease), diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, acute pancreatitis or acute obstruction of the pancreatic duct or common bile duct, or gastric outlet obstruction
    ii. Abdominal fistula, GI perforation, bowel obstruction, intra-abdominal abscess within 6 months before starting therapy
    iii. Note: Complete healing of an intra-abdominal abscess must be confirmed prior to starting therapy
    c. Major surgery within 2 months before starting therapy. Complete healing from major surgery must have occurred 1 month before starting therapy. Complete healing from minor surgery (eg, simple excision, tooth extraction) must have occurred at least 7 days before starting therapy. Subjects with clinically relevant complications from prior surgery are not eligible
    d. Cavitating pulmonary lesion(s) or endobronchial disease
    e. Lesion invading a major blood vessel
    f. including, but not limited to: inferior vena cava, pulmonary artery, or aorta). Subjects with lesions invading the portal vasculature are eligible.
    g. Clinically significant bleeding risk including the following within 3 months of starting therapy: hematuria, hematemesis, hemoptysis of >0.5 teaspoon (>2.5 mL) of red blood, or other signs indicative of pulmonary hemorrhage, or history of other significant bleeding if not due to reversible external factors
    h. Other clinically significant disorderssuch as:
    i. Active infection requiring systemic treatment, known infection with human immunodeficiency virus (HIV), or known acquired immunodeficiency syndrome (AIDS)-related illness. Subjects with active hepatitis virus infection controlled with antiviral therapy are eligible.
    ii. Serious non-healing wound/ulcer/bone fracture
    iii. Malabsorption syndrome
    iv. Uncompensated/symptomatic hypothyroidism
    v. Requirement for hemodialysis or peritoneal dialysis
    vi. History of solid organ transplantation
    7. Subjects with untreated or incompletely treated varices with bleeding or high risk for bleeding.
    8. Moderate or severe ascites
    9. Corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms within 7 days before starting therapy
    10. Inability to swallow tablets
    11. Previously identified allergy or hypersensitivity to components of the study treatment formulations
    12. Pregnant or lactating females
    13. Diagnosis of another malignancy within 2 years before starting therapy, except for superficial skin cancers, or localized, low-grade tumors deemed cured and not treated with systemic therapy
    14. History of allergy to study drug components.
    15. Prisoners or subjects who are involuntarily incarcerated
    16. Subjects who are compulsorily detained for treatment of either a psychiatric or physical illness
    17. Inability to comply with restrictions and prohibited activities/treatments.
    1. Carcinoma fibrolamelar o colangiocarcinoma hepatocelular mixto.
    2. Terapia con radiación (p. ej., I-131 o Y-90) durante las 4 semanas (2 semanas para radiación por metástasis óseas o tratamiento con radionucleidos durante las 6 semanas previas al comienzo del tratamiento) (los sujetos son excluidos hay alguna complicación en proceso clínica mente relevante derivada del tratamiento con radiación).
    3. Tratamiento previo con cabozantinib.
    4. Metástasis cerebrales conocidas o enfermedad epidural craneal a menos que estén tratadas adecuadamente con radioterapia y/o cirugía (incluida radiocirugía) y estable durante al menos 3 meses antes de empezar el tratamiento. Los pacientes candidatos deben estar sin tratamiento con corticoides en el momento del comienzo del tratamiento.
    5. Anticoagulación concomitante, a dosis terapéuticas. Están permitidas las dosis bajas de aspirina como cardioprotector (según guías locales), baja dosis de warfarina (≤ 1 mg/día), y bajas dosis de HBPM.
    6. Los sujetos que tengan enfermedad no controlada, significativa, intercurrente o reciente incluyendo, pero no limitado a, las siguientes condiciones:
    a. Alteraciones cardiovasculares
    b. Alteraciones gastrointestinales (GI) incluyendo aquellas asociadas con un alto riesgo de perforación o formación de fístula:
    i. Tumores que invadan el tracto GI, enfermedad por úlcera péptica activa, enfermedad inflamatoria intestinal (p. ej.: enfermedad de Crohn), diverticulitis, colecistitis, colangitis o apendicitis sintomática, pancreatitis aguda u obstrucción aguda del conducto pancreático o conducto biliar común, u obstrucción de la salida gástrica.
    ii. Fístula abdominal, perforación GI, obstrucción intestinal, absceso intraabdominal durante los 6 meses previos al comienzo del tratamiento.
    iii. Nota: Se debe confirmar la curación completa de un absceso intraabdominal antes del comienzo del tratamiento.
    c. Cirugía mayor durante los 2 meses previos al comienzo del tratamiento. Debe de haberse producido la recuperación completa de una cirugía mayor 1 mes antes del comienzo del tratamiento. La recuperación de una cirugía menor (p. ej., escisión simple, extracción dental) debe haber ocurrido al menos 7 días antes del comienzo del tratamiento. Los sujetos con complicaciones clínicas relevantes de una cirugía anterior no son candidatos.
    d. Lesión(es) pulmonar(es) cavitante(s) o enfermedad endobronquial.
    e. Lesiones que invaden un vaso sanguíneo mayor, incluyendo, pero no limitado a: vena cava inferior, arteria pulmonar, o aorta). Son candidatos los sujetos con lesiones que invadan la vasculatura portal.
    f. Riesgo de sangrado clínicamente significativo incluyendo los tres meses siguientes una vez comenzado el tratamiento: hematuria, hematemesis, hemoptisis de > 0,5 cucharada de té (>2,5 mL) de sangre roja, u otros signos indicativos de hemorragia pulmonar, o antecedentes de otros sangrados importantes si no son debidos a factores externos reversibles.
    g. Otras alteraciones clínicamente significativas como:
    i. Infección activa que requirió tratamiento sistémico, infección confirmada con el virus de la inmunodeficiencia humana (VIH), o confirmación de enfermedad relacionada con el síndrome de la inmudeficiencia adquirida (SIDA). Los sujetos con infección activa del virus de la hepatitis controlada con tratamiento antiviral son candidatos.
    ii. Herida/ úlcera/ fractura ósea grave no curada.
    iii. Síndrome de malabsorción.
    iv. Hipotiroidismo descompensado/sintomático.
    v. Pacientes que requieren hemodiálisis o diálisis peritoneal.
    vi. Historial de trasplante de órgano sólido.
    7. Los sujetos con varices con sangrado o alto riesgo de sangrado no tratadas o no tratadas por completo.
    8. Sujetos con ascitis moderada o severa.
    9. Intervalo QT corregido calculado por la fórmula de Fridericia (QTcF) > 500 ms durante los 7 días previos al comienzo del tratamiento.
    10. Sujetos con incapacidad para tragar comprimidos.
    11. Sujetos con alergia o hipersensibilidad identificada previamente a componentes de la formulación del tratamiento del estudio.
    12. Mujeres embarazadas o en periodo de lactancia.
    13. Diagnóstico de otra neoplasia maligna durante los dos años previos al comienzo del tratamiento, excepto para cánceres superficiales de piel, o localizados, tumores de bajo grado considerados curables y no tratados con terapia sistémica.
    14. Historial de alergia a los componentes del fármaco del estudio.
    15. Prisioneros o sujetos que están encarcelados involuntariamente.
    16. Sujetos que están internados forzosamente debido a enfermedad psiquiátrica o física
    17. Incapacidad para cumplir con las restricciones y actividades/tratamientos prohibidos.
    E.5 End points
    E.5.1Primary end point(s)
    Rate of AEs with CTCAE≥3 excluding palmar-plantar erythordysthesia,
    Rate of AEs,
    Rate of related-AEs,
    Rate of death.
    Frecuencia de AAs con CTCAE≥3 excluyendo la eritrodisestesia palmo-plantar,
    Frecuencia de AAs,
    Frecuencia de AAs relacionados,
    Frecuencia de muertes.
    E.5.1.1Timepoint(s) of evaluation of this end point
    During treatment and 30 days after the last dose.
    Durante el tratamiento y 30 días después de la última dosis.
    E.5.2Secondary end point(s)
    Time to progression,
    Pattern of progression,
    Overall survival,
    Post-progression survival,
    Progression free survival,
    Rate of patients who develop new extrahepatic spread.
    ORR
    Tiempo hasta progresión,
    Patrón de progresión,
    Supervivencia global, Supervivencia post-progresión,
    Supervivencia libre de progresión,
    Tasa de pacientes que desarrollan nuevas metástasis extrahepáticas.
    TRO.
    E.5.2.1Timepoint(s) of evaluation of this end point
    During treatment and follow-up period
    Durante el tratamiento y periodo de seguimiento.
    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 No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial1
    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 concerned7
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    UVUP
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days
    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: 20
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 20
    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 state40
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 40
    F.4.2.2In the whole clinical trial 40
    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)
    The expected normal treatment of that condition
    El tratamiento habitual para la enfermedad
    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 Decision2020-04-28
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-04-24
    P. End of Trial
    P.End of Trial StatusOngoing
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