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    Summary
    EudraCT Number:2013-000241-39
    Sponsor's Protocol Code Number:BAY86-9766/16728
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2013-08-08
    Trial results View 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 number2013-000241-39
    A.3Full title of the trial
    A prospective, single-arm, multicenter, uncontrolled, open-label Phase II trial of refametinib (BAY 86-9766) in combination with sorafenib as first line treatment in patients with RAS mutant Hepatocellular Carcinoma (HCC)
    Estudio prospectivo de fase II, abierto, multicéntrico, no controlado, de refametinib (BAY 86-9766) en combinación con Sorafenib en pacientes con carcinoma hepatocelular (HCC) y mutación RAS en primera línea de tratamiento
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Refametinib given in combination with sorafenib to patients with advanced HCC carrying a RAS mutation
    Refametinib en combinación con sorafenib para el tratamiento del HCC con mutación del gen RAS
    A.3.2Name or abbreviated title of the trial where available
    Refametinib in combination with sorafenib in RAS mutant HCC
    A.4.1Sponsor's protocol code numberBAY86-9766/16728
    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 SponsorBayer HealthCare AG
    B.1.3.4CountryGermany
    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 supportBayer HealthCare AG
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationBayer HealthCare AG
    B.5.2Functional name of contact pointBayer Clinical Trials Contact
    B.5.3 Address:
    B.5.3.1Street AddressCPT Team / Ref: "EU CTR"/ Bayer Pharma AG
    B.5.3.2Town/ cityBerlin
    B.5.3.3Post code13342
    B.5.3.4CountryGermany
    B.5.6E-mailclinical-trials-contact@bayerhealthcare.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 nameRefametinib
    D.3.2Product code BAY 86-9766, Capsule 10 mg
    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 INNRefametinib
    D.3.9.1CAS number 923032-37-5
    D.3.9.2Current sponsor codeBAY 86-9766
    D.3.9.3Other descriptive nameRDEA 119
    D.3.9.4EV Substance CodeSUB31563
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameRefametinib
    D.3.2Product code BAY 86-9766, Capsule 20 mg
    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 INNRefametinib
    D.3.9.1CAS number 923032-37-5
    D.3.9.2Current sponsor codeBAY 86-9766
    D.3.9.3Other descriptive nameRDEA 119
    D.3.9.4EV Substance CodeSUB31563
    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.IMP: 3
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameRefametinib
    D.3.2Product code BAY 86-9766, Tablet 50 mg
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNRefametinib
    D.3.9.1CAS number 923032-37-5
    D.3.9.2Current sponsor codeBAY 86-9766
    D.3.9.3Other descriptive nameBAY 86-9766
    D.3.9.4EV Substance CodeSUB31563
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 4
    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 Nexavar
    D.2.1.1.2Name of the Marketing Authorisation holderBayer Pharma AG
    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 Yes
    D.2.5.1Orphan drug designation numberEU/3/06/364
    D.3 Description of the IMP
    D.3.1Product nameNexavar 200 mg
    D.3.2Product code BAY 43-9006, Filmtablet 200 mg
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNSORAFENIB TOSILATE
    D.3.9.1CAS number 475207-59-1
    D.3.9.2Current sponsor codeBAY 43-9006
    D.3.9.4EV Substance CodeSUB22347
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 5
    D.1.2 and D.1.3IMP 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 nameRefametinib
    D.3.2Product code BAY 86-9766, Tablet 30 mg
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNRefametinib
    D.3.9.1CAS number 923032-37-5
    D.3.9.2Current sponsor codeBAY 86-9766
    D.3.9.3Other descriptive nameBAY 86-9766
    D.3.9.4EV Substance CodeSUB31563
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number30
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 6
    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 nameRefametinib
    D.3.2Product code BAY 86-9766, Tablet 20 mg
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNRefametinib
    D.3.9.1CAS number 923032-37-5
    D.3.9.2Current sponsor codeBAY 86-9766
    D.3.9.3Other descriptive nameBAY 86-9766
    D.3.9.4EV Substance CodeSUB31563
    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
    KRAS or NRAS mutant unresectable or metastatic Hepatocellular carcinoma (HCC)
    Pacientes con carcinoma hepatocelular (HCC) no resecable o metastásico con mutación del gen KRAS o NRAS
    E.1.1.1Medical condition in easily understood language
    RAS mutant advanced Hepatocellular carcinoma (HCC )
    Carcinoma hepatocelular (HCC) avanzado
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective is to evaluate the efficacy of refametinib in combination with sorafenib in patients with KRAS or NRAS mutant unresectable or metastatic HCC.
    El objetivo principal es evaluar la eficacia de refametinib en combinación con sorafenib en pacientes con HCC no resecable o metastásico con mutación del gen KRAS o NRAS.
    E.2.2Secondary objectives of the trial
    The secondary objective is to evaluate the safety of refametinib in combination with sorafenib in patients with KRAS or NRAS mutant unresectable or metastatic HCC. Additional objectives are the analysis of biomarkers, pharmacokinetics (PK), and patient reported outcomes (PRO, stage 2 only).
    El objetivo secundario es evaluar la seguridad de refametinib en combinación con sorafenib en pacientes con HCC no resecable o metastásico con mutación del gen KRAS o NRAS. Otros objetivos son los análisis de biomarcadores, la farmacocinética (PK) y los resultados comunicados por el paciente (PRO, solo en la fase 2).
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Eligibility criteria for RAS mutation testing:
    - Ability to understand and willingness to sign written informed consent (IC). Signed informed consent from (ICF) for RAS mutation testing has to be obtained before any study specific procedure.
    - Unresectable or metastatic HCC, confirmed either by histology or clinically according to the American Association for the Study of Liver Disease (AASLD) criteria for cirrhotic patients. For non-cirrhotic patients, histological confirmation is mandatory.
    - Male or female >=18 years of age.
    - ECOG performance state 0 or 1.
    - Life expectancy of at least 12 weeks.
    - No prior use of targeted agents, experimental therapy or systemic anti-cancer treatment.
    - No previous treatment with sorafenib or refametinib.

    Criteria for study treatment eligibility:
    - Ability to understand and willingness to sign written IC. Signed ICF for study treatment eligibility has to be obtained before any study specific procedure.
    - Patient must harbor KRAS or NRAS mutation based on BEAMing plasma test.
    - Patients must have at least one uni-dimensional measurable lesion by CT or MR according to RECIST 1.1 and mRECIST (specified in Appendix 14.4) which is either naïve (not previously treated by local therapy such as surgery, radiation therapy, hepatic arterial therapy, chemoembolization, radiofrequency ablation, percutaneous ethanol injection or cryoablation) or previously treated and has progressed until baseline (both, measureable lesion and/or progressed lesion have to be confirmed by central image review of baseline and progression scan).
    Patients who have received local therapy such as surgery, radiation therapy, hepatic arterial embolization, chemoembolization, radiofrequency ablation, percutaneous ethanol injection, or cryoablation are eligible. Previously treated lesions are only selected as target lesions when they have progressed (to be confirmed by central image review of an initial set of scans taken after the local treatment and another showing progression. At least 8 weeks are needed between the scans). Local therapy has to be completed at least 4 weeks prior to the baseline scan.
    - Resolution of all acute toxic effects of any prior local therapy to Common Toxicity Criteria for Adverse Events (CTCAE 4.03) grade =<1.
    - ECOG performance status of 0 or 1.
    - Liver function status of Child-Pugh Class A.
    - The following laboratory criteria must be met:
    Platelet count >= 60 x 109/L
    Hemoglobin >= 8.5 g/dL
    Absolute neutrophil count (ANC) >= 1.5 x 109/L
    Total bilirubin <= 3.0 mg/dL
    Alanine aminotransferase (ALT) <= 5 x upper limit of normal (ULN)
    Aspartate aminotransferase (AST) <= 5 x ULN
    Albumin <= 2.8 g/dL
    Amylase and lipase <= 1.5 x ULN
    Serum creatinine <= 1.5 x ULN
    Prothrombin time-international normalized ratio (PT-INR) <=2.3, or PT <=6 seconds above control.
    - Patient has within normal range cardiac function confirmed by the enrolling clinical institute as measured by echocardiogram or multiple gated acquisition (MUGA) scan.
    - Patients who are therapeutically anti-coagulated with an agent such as warfarin or heparin are allowed to participate provided that no prior evidence of underlying abnormality in these parameters exists. Close monitoring of at least weekly evaluations will be performed until INR is stable (within Child Pugh class A threshold) based on a measurement at pre-dose, as defined by the local standard of care.
    Criterios de elegibilidad para la evaluación de la mutación del gen RAS:
    - Capacidad para entender y estar dispuestos a firmar el consentimiento informado por escrito. Deberá obtenerse el consentimiento informado (CI) para la evaluación de la mutación del gen RAS antes de realizar cualquier procedimiento específico del ensayo.
    - HCC no resecable o metastásico, confirmado histológica o clínicamente según los criterios de la American Association for the Study of Liver Disease (AASLD) para pacientes con cirrosis. En los pacientes sin cirrosis, es obligatoria la confirmación histológica.
    - Pacientes de ambos sexos >= 18 años.
    - Estado funcional de ECOG 0 o 1;
    - Esperanza de vida de al menos doce semanas.
    - Pacientes que no hayan utilizado previamente fármacos diana, tratamiento en fase de investigación o tratamiento antineoplásico sistémico.
    - No haber recibido tratamiento previo con sorafenib o refametinib.
    Además de estos criterios principales, se deben considerar los criterios descritos a continuación, en el apartado de criterios de inclusión y exclusión en los que se prohíbe la participación de determinados pacientes en el ensayo.


    Criterios de elegibilidad para el tratamiento del estudio
    - Capacidad de entender y estar dispuestos a firmar el CI por escrito. Deberá obtenerse el CI para determinar la elegibilidad para el tratamiento del estudio antes de realizar cualquier procedimiento específico del ensayo.
    - El paciente debe presentar la mutación del gen KRAS o NRAS, según la evaluación del plasma realizado mediante la tecnología BEAMing.
    - Los pacientes deben tener al menos una lesión unidimensional medible determinada mediante TC o RM, según los criterios RECIST 1.1 y RECISTm (especificados en el Anexo 14.4), que no haya sido tratada previamente (con tratamiento local como cirugía, radioterapia, tratamiento a través de la arteria hepática, quimioembolización, ablación por radiofrecuencia, inyección percutánea de etanol o crioablación) o que sí se haya tratado anteriormente y que haya experimento progresión hasta el periodo basal (las lesiones medibles y/o las lesiones con progresión deben confirmarse mediante una revisión centralizada de las imágenes de la exploración radiológica realizada en el periodo basal y en el momento en el que se produjo la progresión).
    - Se podrá incluir en el ensayo a los pacientes que hayan recibido tratamiento local, como cirugía, radioterapia, embolización de la arteria hepática, quimioembolización, ablación por radiofrecuencia, inyección percutánea de etanol o crioablación. Las lesiones tratadas previamente solo se seleccionarán como lesiones diana cuando se haya producido una progresión de las mismas (se debe confirmar mediante una revisión central de las imágenes de las exploraciones radiológicas iniciales obtenidas tras el tratamiento local y de otras en las que se muestre la progresión. Es necesario dejar un intervalo de 8 semanas entre cada exploración radiológica). El tratamiento local debe haber finalizado al menos 4 semanas antes de la exploración radiológica basal.
    - Resolución de todas las toxicidades agudas relacionadas con cualquier tratamiento local previo hasta un grado =< 1, según los Criterios comunes de toxicidad para acontecimientos adversos (CTCAE 4.03).
    - Estado funcional del ECOG de 0 o 1.
    - Estado de la función hepática de grado A según la escala Child-Pugh.

    - Se deben cumplir los siguientes criterios analíticos:
    Cifra de plaquetas >= 60 x 109/l
    Hemoglobina >= 8,5 g/dl
    Recuento absoluto de neutrófilos (RAN) >= 1,5 x 109/l
    Bilirrubina total <= 3,0 mg/dl
    Alanina-aminotransferasa (ALT) <= 5 x límite superior de la normalidad (LSN)
    Aspartato-aminotransferasa (AST) <= 5 x LSN
    Albúmina <= 2,8 g/dl
    Amilasa y lipasa <= 1,5 x LSN
    Creatinina sérica <= 1,5 x LSN.
    Tiempo de protrombina-índice internacional normalizado (TP-INR) <= 2,3 o TP <= 6 segundos por encima del valor de control.
    - El paciente ha de tener la función cardíaca dentro del intervalo normal, confirmada por el centro clínico encargado de la inclusión mediante un ecocardiograma o una ventriculografía nuclear (MUGA).
    - Los pacientes que estén recibiendo tratamiento anticoagulante con un fármaco como warfarina o heparina pueden participar siempre que no existan indicios previos de anomalías subyacentes a estos parámetros. Se realizará un estrecho control con análisis semanales hasta que el INR sea estable (umbral de la clase A de la escala Child Pugh) según el resultado obtenido antes de la administración, conforme se defina en las normas asistenciales locales.
    E.4Principal exclusion criteria
    - Any Cancer curatively treated < 3 years prior to study entry, except cervical carcinoma in situ, treated basal cell carcinoma, and superficial bladder tumors (Staging: Ta, Tis and T1).
    - Patients who are eligible for surgery, liver transplantation, ablation or transarterial chemoembolization for HCC.
    - Renal failure requiring hemo- or peritoneal dialysis.
    - History of cardiac disease
    Congestive heart failure New York Heart Association (NYHA) > class 2.
    Unstable angina (angina symptoms at rest, new-onset angina i.e. within the last 3 months) or myocardial infarction (MI) within the past 6 months prior to start of screening.
    Cardiac arrhythmias requiring anti-arrhythmic therapy.
    - Uncontrolled hypertension (systolic blood pressure [BP] >150 mmHg or diastolic blood pressure >90 mmHg despite optimal medical management).
    - Ongoing infection > Grade 2 according to NCI-CTCAE version 4.03. Hepatitis B is allowed if no active replication (defined as abnormal ALT >2xULN associated with HBV DNA >20,000 IU/mL ) is present (45). Hepatitis C is allowed if no antiviral treatment is required.
    - Known human immunodeficiency virus (HIV) infection.
    - Known history of, or symptomatic metastatic brain or meningeal tumors (head CT or MR at Screening to confirm the absence of central nervous system [CNS] disease if patient had symptoms suggestive or consistent with CNS disease).
    - History of interstitial lung disease (ILD).
    - History of hepatic encephalopathy.
    - Clinically significant GI bleeding (CTCAE 4.03 grade 3 or higher) within 30 days prior to start of screening
    - Thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks) within 6 months prior to start of screening.
    - History of organ allograft, cornea transplantation will be allowed.
    - Substance abuse, medical, psychological or social conditions that may interfere with the patients participation in the study or evaluation of the study results.
    - Known or suspected hypersensitivity to any of the study drugs, study drug classes, or components in the formulation given during the course of this study.
    - Pregnant or lactating women. Women of childbearing potential not employing adequate contraception. Women of childbearing potential must have a negative serum pregnancy test performed within 7 days prior to start of screening and a negative result must be documented before first dose of study drug . Note: Women of childbearing potential and men enrolled in this trial must agree to use adequate contraception (barrier method of birth control) since signing of the ICF until at least 3 months after the last study treatment administration. Adequate contraception is defined in this study as any medically recommended method (or combination of methods) as per standard of care.
    - Uncontrolled ascites (defined as not easily controlled with diuretic treatment).
    - History or current evidence of retinal vein occlusion (RVO) or central serous retinopathy (CSR).
    - Visible retinal pathology as assessed by ophthalmologic exam that is considered a risk factor for RVO or CSR.
    - Non-healing wound, ulcer, or bone fracture.
    - Patients with large esophageal varices at risk of bleeding that are not being treated with conventional medical intervention: beta blockers or endoscopic treatment. Assessment of esophageal varices should be performed by endoscopy within 6 months prior to start of study treatment and within 12 months for patients in whom conventional medical intervention for known esophageal varices is already in place.
    - Patients with seizure disorder requiring medication.
    Excluded prior therapies and medication:
    - Radiotherapy within 4 weeks prior to start of screening. Patients must have recovered from all therapy-related toxicities. The site of previous radiotherapy should have evidence of PD if this is the only site of disease.
    - Systemic anticancer therapy including cytotoxic therapy, signal transduction inhibitors, hormonal therapy and experimental or approved therapies
    - Any drug that targets angiogenesis, especially vascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR).
    - Tyrosine-kinase inhibitors.
    - Major surgery or significant traumatic injury within 4 weeks prior to start of screening.
    - Hematopoietic growth factors, such as granulocyte colony-stimulating factor (G-CSF) or granulocyte-monocyte colony-stimulating factor (GM-CSF), within 3 weeks prior to start of screening (these may be used in the management of acute toxicity such as febrile neutropenia or CTCAE 4.03 grade 3-4 neutropenia at the discretion of the investigator; however they may not be substituted for a required dose reduction).
    - Use of strong inhibitors of CYP3A4 and strong inducers of CYP3A4 should be stopped 2 weeks prior to start of screening
    - Acute steroid therapy or taper for any purpose (chronic steroid therapy is acceptable provided that the dose is stable for 1 month prior to start of screening and thereafter).
    Cáncer tratado<3 años antes de inclusión en ensayo(EC),excepto carcinoma cervicouterino in situ,carcinoma basocelular tratado y tumores vesicales superficiales(estadificación:Ta,Tis yT1).Pacientes candidatos a intervención quirúrgica,trasplante hígado,ablación o quimioembolización transarterial para HCC.Insuficiencia renal que requiere hemodiálisis o diálisis peritoneal.Antecedentes cardiopatía.Insuficiencia cardíaca congestiva clase grado>2 según NHYA.Angina inestable(síntomas anginosos en reposo),angina nueva aparición(últimos 3meses)o infarto miocardio en últimos 6meses antes del inicio de selección.Arritmias cardíacas que requieran tto antiarrítmico.Hipertensión no controlada(PAsistólica>150mmHg o PAdiastólica>90mmHg a pesar del tto médico óptimo).Infección en curso>2 según criterios CTCAE del NCI,v4.03.Pacientes con hepatitisB permitidos si no presentan replicación activa(definida como ALT anormal >2xLSN asociada a ADN del VHB >20 000 UI/ml )(45)y con hepatitisC si no requieren tto antiviral.Infección por el virus de la inmunodeficiencia humana(VIH).Antecedentes o síntomas de tumor cerebral metastásico sintomático o tumores meníngeos(TC o RM craneal en selección para confirmar ausencia de patología del SNC si el paciente presenta síntomas que indiquen o concuerden con enfermedad del SNC).Antecedentes enfermedad pulmonar intersticial(EPI).Antecedentes encefalopatía hepática.Hemorragia GI clínicamente significativa grado>=3 según CTCAE 4.03)en 30días previos a selección.Acontecimientos trombóticos o embólicos,como accidente cerebrovascular(incluidos accidentes isquémicos transitorios)en 6meses anteriores a selección.Antecedentes de alotrasplante de órgano,excepto trasplante de córnea.Consumo de sustancias psicoactivas y trastornos médicos,psicológicos o sociales que puedan interferir en participación del paciente o evaluación de resultados del EC.Hipersensibilidad conocida o sospecha a cualquiera de los fármacos,clases de los fármacos del estudio o componentes incluidos en la formulación proporcionada durante el EC.Embarazadas o en período de lactancia.Mujeres con capacidad reproductora que no empleen método anticonceptivo adecuado.Mujeres fértiles deben dar negativo en prueba de embarazo en suero en 7días previos al inicio de selección y el resultado deberá ser negativo antes de la primera dosis del fármaco del estudio.Atención:mujeres fértiles y hombres incluidos en este EC deberán aceptar el uso de métodos anticonceptivos adecuados(de barrera)desde la firma del CI hasta al menos 3meses después de la última administración del tto del EC.Método anticonceptivo adecuado definido como cualquier método recomendado desde el punto de vista médico(o combinación de métodos),según normas asistenciales.Ascitis no controlada(definida como mal controlada con diuréticos).Antecedentes o signos actuales de oclusión venosa retiniana(OVR) o retinopatía serosa central(RSC).Patología retiniana visible,evaluada en exploración oftalmológica,que se considera un factor de riesgo de OVR o RSC.Herida tórpida,úlcera sin cicatrizar o fractura ósea no consolidada.Pacientes con varices esofágicas grandes con riesgo de hemorragia que no reciban tto con la intervención médica convencional:betabloqueantes o tto endoscópico.Dicha evaluación se realizará por endoscopia en 6meses anteriores al inicio de selección y en 12meses previos en los pacientes tratados con intervención médica convencional.Pacientes con trastornos convulsivos que requieran medicación.Tto y fármacos previos excluidos:Radioterapia en 4semanas anteriores a selección.Los pacientes deben haberse recuperado de todas toxicidades relacionadas con este tto.El lugar de la radioterapia previa deberá mostrar signos de PD si es la única localización de la enfermedad.Tto antineoplásico sistémico incluido tto citotóxico,inhibidores de transducción de señales, tto hormonal y experimental o tto autorizados aprobados.Cualquier fármaco que actúe sobre la angiogénesis,el factor de crecimiento del endotelio vascular(VEGF)y el receptor del VEGF(VEGFR).Inhibidores de la tirosina-cinasa.Intervención de cirugía mayor o lesión traumática significativa en 4semanas anteriores al inicio de selección.Factores de crecimiento hematopoyéticos,como factor estimulante de colonias de granulocitos(G-CSF)o factor estimulante de colonias de granulocitos y monocitos(GM-CSF),en 3semanas previas al inicio de selección(estos factores pueden utilizarse para tto de toxicidad aguda como neutropenia febril o neutropenia de grado 3-4 según CTCAE 4.03,según criterio del investigador;no podrán sustituir la reducción necesaria de la dosis).Deberá interrumpirse la administración de inhibidores potentes de la CYP3A4 y de inductores potentes de la CYP3A4 2semanas antes del inicio de selección.Tto agudo con corticosteroides o reducción gradual por cualquier motivo(se permite tto crónico con corticosteroides siempre que la dosis se mantenga estable durante 1mes antes del inicio de selección y después).
    E.5 End points
    E.5.1Primary end point(s)
    The primary efficacy variable, for both stages of this study, is the central radiological assessment of ORR [confirmed complete response (CR) plus partial response (PR)] according to mRECIST. ORR is defined as the proportion of patients with the best tumor response (confirmed PR or CR) that is achieved during the study.
    Radiologic tumor assessments (central image review and investigators assessment) will be done at Screening and then every 6 weeks during treatment. A further radiologic tumor assessment will be done within 14 days after last study medications intake, not needed if the previous tumor evaluation was performed within 4 weeks. In case of clinical progression, every effort should be made to provide radiological images for central image review to confirm the progression radiologically.

    Analysis will be performed separately for each stage.
    The analysis of the primary efficacy variable of Stage 1 will be performed 12 weeks after the last Stage 1 patient's first treatment. At that timepoint, an exploratory analysis of all other safety and efficacy variables will be performed. If the study is not continued into Stage 2, the final analysis of Stage 1 will be performed 12 months after the last Stage 1 patient's first treatment.

    The primary analysis of the primary efficacy variable of Stage 2 will be performed 12 weeks after the last Stage 2 patient's first treatment. At that time point, an exploratory analysis of all other safety and efficacy variables will be performed.

    Efficacy variables will be analyzed for both the FAS and the PPS. At Stage 1 and Stage 2, the analysis based on the FAS, full-analysis set ( all patients assigned to study treatment) will be considered primary.

    As Stage 1 is exploratory, there will be no statistical testing at the end of Stage 1; all analyses will be descriptive only.

    ORR will be tested at Stage 2 against the null hypothesis that the true ORR is less than or equal to 0.45 at a one-sided type-1 error level of 0.025. A point estimate and the 95% confidence intervals for ORR will be calculated.
    En las dos fases de este ensayo, la variable principal de eficacia es la evaluación radiológica centralizada de la ORR (respuesta completa [CR] confirmada más respuesta parcial [PR]) según los criterios RECISTm. La ORR se define como el porcentaje de pacientes con mejor respuesta tumoral (CR o PR confirmada) que se obtenga durante el ensayo.
    Las evaluaciones radiológicas del tumor (revisión central de las imágenes en tiempo real y evaluación por el investigador) se realizarán en la Selección y, posteriormente, cada 6 semanas durante el periodo de tratamiento. Se realizará una evaluación radiológica adicional del tumor en los 14 días posteriores a la última administración de la medicación del ensayo, aunque no será necesario realizar esta evaluación si se ha efectuado una evaluación del tumor en las 4 semanas previas.

    El análisis de la variable principal de la eficacia de la fase 1 se realizará 12 semanas después del primer tratamiento del último paciente de la fase 1. En ese momento, se realizará un análisis exploratorio de todas las demás variables de seguridad y eficacia. Si no se continúa con la fase 2 del ensayo, el análisis final de la fase 1 se realizará 12 meses después del primer tratamiento del último paciente de la fase 1.

    El análisis principal de la variable principal de la eficacia de la fase 2 se realizará 12 semanas después del primer tratamiento del último paciente de la fase 2. En ese momento, se realizará un análisis exploratorio de todas las demás variables de seguridad y eficacia.

    Las variables de la eficacia se evaluarán en el Grupo completo de análisis (GCA)(Todos los pacientes asignados al tratamiento del estudio) y en el Grupo por protocolo (GPP). En la etapa 1 y en la etapa 2, los análisis basados en el GCA se considerarán principales.

    La etapa 1 es exploratoria, por lo que no se realizará ningún análisis estadístico a su finalización; todos los análisis serán únicamente descriptivos.

    En la fase 2, se evaluará la ORR comparándola con la hipótesis nula de que la ORR real es inferior o igual a 0,45 con un nivel de error de tipo 1 unilateral de 0,025. Se calculará una estimación puntual y los intervalos de confianza del 95 % para la ORR.
    E.5.1.1Timepoint(s) of evaluation of this end point
    The analysis will be performed for both stages approximately 12 weeks after the last patient started study treatment
    El análisis se realizará para ambas fases, unas 12 semanas después de la primera administración del tratamiento del estudio en el último paciente
    E.5.2Secondary end point(s)
    Overall response rate (ORR) by investigator's assessment according to mRECIST and RECIST 1.1
    Overall response rate (ORR) confirmed according to RECIST (Version 1.1)
    Disease control rate (DCR), central and investigator's assessment
    Overall survival (OS)
    Time to radiographic tumor progression (TTP), central and investigator's assessment
    Duration of Response (DOR), central and investigator's assessment
    Time to objective response (CR or PR), central and investigator's assessment
    Change in tumor size, central and investigator's assessment
    Best overall response, central and investigator's assessment
    Progression-free survival (PFS), central and investigator's assessment
    Functional Assessment of Cancer Therapy-Hepatobiliary (FACT-Hep)
    Biomarker analysis
    PK analysis
    Patient Reported Outcome (PRO) / Health Related Quality of Life (HRQoL) at Stage 2 only
    Safety

    Secondary efficacy variables will be evaluated and presented by means of descriptive statistics. Time-to-event variables will be displayed by Kaplan-Meier estimates and corresponding graphs.
    Tasa de respuesta tumoral objetiva (ORR) evaluación por el investigador
    Tasa de respuesta tumoral objetiva (ORR) confirmada según los criterios RECIST (versión 1.1).
    Tasa de control de la enfermedad (DCR)evaluación central y por el investigador
    Supervivencia global (OS)
    Tiempo hasta la progresión radiológica del tumor (TTP) evaluación central y del investigador
    Duración de la respuesta (DOR) evaluación central y del investigador
    Tiempo hasta la respuesta objetiva(CR or PR), evaluación central y del investigador
    Cambio del tamaño del tumor evaluación central y del investigador
    Mejor respuesta global, evaluación central y del investigador
    Supervivencia libre de progresión (PFS), evaluación central y del investigador
    Evaluación funcional del tratamiento oncológico-Hepatobiliar (Cuestionario FACT-Hep)
    Análisis de los biomarcadores
    Análisis de farmacocinética
    Resultados comunicados por el paciente (PRO) / Calidad de vida relacionada con la salud, sólo en la Fase 2.
    E.5.2.1Timepoint(s) of evaluation of this end point
    An exploratory analysis of all other safety and efficacy variables of Stage 1 will be performed 12 weeks after the last Stage 1 patient's first treatment.
    An exploratory analysis of all other safety and efficacy variables of Stage 2 will be performed 12 weeks after the last Stage 2 patient's first treatment.
    The final analysis of all secondary efficacy and safety variables, and an additional exploratory analysis of the primary efficacy variable will be performed when the median time to radiological tumor progression can be determined (i.e. when the majority of patients have experienced progression).
    Se realizará un análisis exploratorio de todas las demás variables de seguridad y eficacia de la fase 1 se realizará 12 semanas después del primer tratamiento del último paciente de la fase 1.
    Se realizará un análisis exploratorio de todas las demás variables de seguridad y eficacia de la fase 2 se realizará 12 semanas después del primer tratamiento del último paciente de la fase 2.
    El análisis final de todas las variables secundarias de eficacia y seguridad y otros análisis exploratorios adicionales de la variable principal de eficacia se realizarán cuando se pueda determinar la mediana del tiempo hasta la progresión radiológica tumoral (es decir, cuando la mayoría de los pacientes hayan experimentado progresión).
    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 Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    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 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) Information not present in EudraCT
    E.8.2.2Placebo Information not present in EudraCT
    E.8.2.3Other Information not present in EudraCT
    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 concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA40
    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
    Austria
    Belgium
    Czech Republic
    France
    Germany
    Hong Kong
    Hungary
    Israel
    Italy
    Japan
    Korea, Democratic People's Republic of
    Singapore
    Spain
    Taiwan
    Thailand
    Turkey
    United Kingdom
    United States
    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
    For each participating EU country, the end of the study according to the EU Clinical Trial Directive will be reached when the last visit of the last patient for all centers in the respective country has occurred.
    The primary completion date for this study according to the Food and Drug Administration (FDA) Amendment Act is specified in a separate document (not part of this Clinical Study ProtocolCSP).
    En cada uno de los países de la UE participantes, y de acuerdo con la Directiva Europea de Ensayos Clínicos, el final del ensayo tendrá lugar cuando se haya realizado la última visita al último paciente en todos los centros del país respectivo.
    La fecha principal de finalización de este ensayo, de acuerdo con la ley Food and Drug Administration (FDA) Amendment Act, se especifica en un documento aparte (no incluido en este Protocolo).
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months10
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months10
    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: 1590
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 1060
    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 state15
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 700
    F.4.2.2In the whole clinical trial 2650
    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)
    Post-study therapy will be at the discretion of the investigator.
    El tratamiento posterior al ensayo quedará a discreción del investigador.
    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 Decision2013-10-04
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-09-09
    P. End of Trial
    P.End of Trial StatusCompleted
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