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    EudraCT Number:2012-003308-10
    Sponsor's Protocol Code Number:ARQ197-A-U303
    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:2013-02-04
    Trial results View results
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    A. Protocol Information
    A.1Member State ConcernedSpain - AEMPS
    A.2EudraCT number2012-003308-10
    A.3Full title of the trial
    Estudio clínico de fase III, aleatorizado, doble ciego, de tivantinib (ARQ 197) en pacientes con carcinoma hepatocelular (CHC) inoperable con valores altos de MET tratados con una terapia sistémica
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Clinical study to determine whether tivantinib is safe and effective in the treatment of liver cancer.
    Un Ensayo Clinico para determinar si Tivantinib es seguro y efectivo en el tratamiento de cancer hepático.
    A.4.1Sponsor's protocol code numberARQ197-A-U303
    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 SponsorDaiichi Sankyo Development Limited
    B.1.3.4CountryUnited Kingdom
    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 supportArQule, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationDaiichi Sankyo Development Limited
    B.5.2Functional name of contact pointClinical Trial Information
    B.5.3 Address:
    B.5.3.1Street AddressChiltern Place, Chalfont Park
    B.5.3.2Town/ cityGerrards Cross, Buckinghamshire
    B.5.3.3Post codeSL9 0BG
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number+441753 482800
    B.5.5Fax number+441753 899107
    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 nameTivantinib
    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 INNTivantinib
    D.3.9.2Current sponsor codeARQ 197
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number120
    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. cell therapy medicinal product No
    D. therapy medical product No
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. 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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboTablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    MET Diagnostic-High Inoperable Hepatocellular Carcinoma (HCC)
    Carcinoma hepatocelular (CHC) inoperable con valores altos de MET
    E.1.1.1Medical condition in easily understood language
    Advanced Liver Cancer
    Cáncer hepático avanzado.
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 15.1
    E.1.2Level LLT
    E.1.2Classification code 10019828
    E.1.2Term Hepatocellular carcinoma non-resectable
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Evaluate overall survival (OS) among all subjects in the intent-to-treat (ITT) population compared to placebo.
    Evaluar la supervivencia global (SG) de todos los pacientes de la población por intención de tratar (IT) en comparación con un placebo.
    E.2.2Secondary objectives of the trial
    Evaluate progression free survival (PFS) by central, independent radiology review among all subjects in the intent-to-treat (ITT) population compared to placebo.

    Evaluate safety of tivantinib in the treated HCC subjects.
    Evaluar mediante revisión radiológica independiente central la supervivencia sin progresión de todos los pacientes de la población por intención de tratar (IT) en comparación con un placebo.
    ? Evaluar la seguridad del tivantinib en los pacientes con CHC tratados.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Written informed consent granted prior to initiation of any study-specific screening procedures
    2. 18 years of age or older
    3. Histologically confirmed HCC that is inoperable (where surgery is not indicated due to disease extension, co-morbidities, or other technical reasons) and not eligible for local therapy
    4. MET Diagnostic-High tissue reported by the central authorized laboratory using archival or recent biopsy tumor samples (see lab manual and Section 6.1 of protocol for tissue preparation details).
    5. Received at least 4 weeks of one prior sorafenib containing systemic therapy and then experienced documented radiographic disease progression; or inability to tolerate prior therapy received for at least a minimum period of time. For the purpose of this study, intolerance to sorafenib is determined as follows:
    ? The subject must have tried to take sorafenib for a period of at least 28 days (even intermittently)
    ? The subject must have tried to dose reduce sorafenib at ?50% of the full dose for a period of at least 14 days (even intermittently) and still have a documented Grade ?2 toxicity
    ? A period of even less than 14 days on sorafenib is acceptable in case of:
    i. Uncontrolled Grade 3 - 4 arterial hypertension
    ii. Pancreatitis, cardiac event, encephalopathy related to sorafenib
    iii. ? Grade 2 Hand-foot syndrome triggered even at 50% of the sorafenib dose
    6. Discontinued prior systemic treatment or any investigational drug for at least 2 weeks (14 days) or for at least 3 weeks for IV anti-cancer drugs, prior to the study randomization
    7. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ? 1 (Appendix 17.2)
    8. Local or loco-regional therapy (i.e., surgery, radiation therapy, hepatic arterial embolization, chemoembolization, radiofrequency ablation, percutaneous ethanol injection, or cryoablation) must have been completed ? 4 weeks prior to randomization and are allowed.
    9. Measurable disease as defined by the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Tumor lesions previously treated with local therapy should demonstrate clear dimensional increase by radiographic assessment in order to be selected as target lesion(s) at baseline. Baseline radiographic assessment needs to be done within 21 days prior to randomization.
    10. Adequate bone marrow, liver, and renal functions at Screening Visit, defined as: platelet count ? 60 × 109/L; hemoglobin ? 9.0 g/dL; absolute neutrophil count (ANC) ? 1.5 × 109/L; total bilirubin ? 2 mg/dL; Alanine transaminase (ALT) and aspartate aminotransferase (AST) ? 5 × upper limit of normal (ULN); serum creatinine ? 1.5 × ULN; albumin ? 2.8 g/dL; international normalized ratio (INR) 0.8 to ULN or ? 3 for subjects receiving anticoagulant such as coumadin or heparin. Subjects who are therapeutically anticoagulated are allowed to participate provided that prior to anticoagulant therapy no evidence of underlying defect in coagulation exists
    11. Women of childbearing potential must have a negative serum pregnancy test performed within 14 days prior to the randomization (where demanded by local regulations, test may be required within 72 hours prior to randomization)
    12. Male and female subjects of child-bearing potential must agree to use double-barrier contraceptive measures, oral contraception, or avoidance of intercourse during the study and for 90 days after last study drug dose received
    13. Life expectancy of at least 12 weeks
    1. Obtención del consentimiento informado por escrito antes del inicio de cualquier procedimiento de selección específico del estudio
    2. Edad igual o superior a 18 años
    3. CHC confirmado histológicamente que sea inoperable (en el que no esté indicada la cirugía por la extensión de la enfermedad, enfermedades concomitantes u otros motivos técnicos) y no elegible para tratamiento local
    4. Informe del laboratorio central autorizado de valor diagnóstico alto de MET en tejido de muestras de archivo o de biopsia tumoral reciente (para detalles de la preparación del tejido, véanse el manual del laboratorio y la sección 6.1 del protocolo).
    5. Haber recibido al menos 4 semanas de un tratamiento sistémico que incluya sorafenib y haber sufrido luego progresión radiológica de la enfermedad comprobada; o incapacidad de tolerar el tratamiento previo recibido durante al menos un período mínimo. A efectos de este estudio, la intolerancia al sorafenib se determina como sigue:
    ? El sujeto deberá haber intentado tomar sorafenib durante un período mínimo de 28 días (incluso de forma intermitente)
    ? El sujeto deberá haber intentado reducir la dosis de sorafenib a ?50 % de la dosis completa durante un período mínimo de 14 días (incluso de forma intermitente) y seguir teniendo una toxicidad documentada de grado ?2
    ? Es aceptable un período incluso inferior a 14 días recibiendo sorafenib en caso de:
    i. Hipertensión arterial de grado 3 4 no controlada
    ii. Pancreatitis, episodio cardíaco o encefalopatía relacionada con el sorafenib
    iii. Aparición de síndrome palmoplantar de grado ? 2 incluso con el 50 % de la dosis de sorafenib
    6. Suspensión del tratamiento sistémico previo o de cualquier fármaco en investigación durante al menos 2 semanas (14 días), o al menos 3 semanas en el caso de los fármacos antineoplásicos IV, antes de la aleatorización
    7. Estado funcional (EF) del Eastern Cooperative Oncology Group (ECOG) ? 1 (véase el apéndice 17.2)
    8. El tratamiento local o locorregional (es decir, cirugía, radioterapia, embolización arterial hepática, quimioembolización, ablación por radiofrecuencia, inyección percutánea de etanol o crioablación) deberá haberse completado ? 4 semanas antes de la aleatorización.
    9. Enfermedad mensurable, definida por los Criterios de evaluación de la respuesta en tumores sólidos (RECIST) versión 1.1.
    10.Función adecuada de la médula ósea, el hígado y los riñones en la visita de selección, definida como: recuento de plaquetas ? 60 x 109/l; hemoglobina ? 9,0 g/dl; recuento absoluto de neutrófilos (RAN) ? 1,5 x 109/l; bilirrubina total ?
    2 mg/dl; alanina transaminasa (ALT) y aspartato aminotransferasa (AST) ? 5 x límite superior normal (LSN); creatinina sérica ? 1,5 x LSN; albúmina ? 2,8 g/dl; cociente internacional normalizado (CIN) 0,8 x LSN o ? 3 en pacientes que reciban anticoagulantes como warfarina o heparina. Se permite participar a los pacientes con tratamiento anticoagulante siempre que antes de él no haya indicios de defecto subyacente de la coagulación
    11. Las mujeres en edad fértil deberán dar negativo en una prueba de embarazo en suero en los 14 días previos a la aleatorización (cuando lo exija la normativa local, la prueba puede ser necesaria en las 72 horas previas a la aleatorización)
    12. Los varones y las mujeres en edad fértil deberán acceder a usar un método anticonceptivo de doble barrera, anticonceptivos orales o abstinencia sexual durante el estudio y en los 90 días siguientes a la última dosis de fármaco en investigación
    13. Esperanza de vida de al menos 12 semanas.
    E.4Principal exclusion criteria
    1. >1 prior systemic regimen (prior MET inhibitors/antibodies are not allowed; experimental systemic therapy for inoperable HCC given before or after sorafenib counts as separate regimen and is not allowed)
    2. Child-Pugh B-C cirrhotic status based on clinical findings and laboratory results during screening period (see Appendix 17.4 for Child-Pugh Classification and interpretation of ascites at physical examination and Prothrombin Time (PT)/ International Normalized Ratio (INR))
    3. Previous or concurrent cancer that is distinct from HCC in primary site or histology, EXCEPT cervical carcinoma in situ, treated basal cell carcinoma, and superficial bladder tumors (Ta, Tis & T1). Any cancer curatively treated > 3 years prior to enrollment is permitted.
    4. History of congestive heart failure defined as Class II to IV per New York Heart Association (NYHA) classification (see Appendix 17.5) within 6 months prior to study entry; active coronary artery disease (CAD); clinically significant bradycardia or other uncontrolled, cardiac arrhythmia defined as ? Grade 3 according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.03, or uncontrolled hypertension; myocardial infarction occurring within 6 months prior to study entry (myocardial infarction occurring > 6 months prior to study entry is permitted)
    5. Active clinically serious infections defined as ? Grade 3 according to NCI CTCAE, version 4.03
    6. Any medical, psychological, or social conditions, particularly if unstable, including substance abuse, that may, in the opinion of the Investigator, interfere with the subject?s safety or participation in the study, protocol compliance, or evaluation of the study results
    7. Known human immunodeficiency virus (HIV) infection
    8. Blood or albumin transfusion within 5 days prior to the blood draw being used to confirm eligibility
    9. Concomitant interferon therapy or therapies for active Hepatitis C Virus (HCV) infection
    10. Pregnancy or breast-feeding
    11. History of liver transplant
    12. Inability to swallow oral medications
    13. Clinically significant gastrointestinal bleeding occurring ? 4 weeks prior to randomization
    1. >1 tratamiento sistémico previo (no se permiten los inhibidores/anticuerpos de MET; el tratamiento sistémico experimental del CHC inoperable administrado antes o después del sorafenib cuenta como régimen independiente y no se permite)
    2. Estado cirrótico de Child Pugh B C según los hallazgos clínicos y analíticos durante el período de selección (véase en el apéndice 17.4 la clasificación de Child Pugh y la interpretación de la ascitis en la exploración física y el TP/CIN)
    3. Cáncer previo o concomitante con localización primaria o características histológicas distintas de las del CHC, EXCEPTO carcinoma del cuello uterino in situ, carcinoma basocelular tratado y tumores vesicales superficiales (Ta, Tis y T1). Se permite cualquier cáncer tratado con fines curativos > 3 años antes del reclutamiento.
    4. Antecedentes de insuficiencia cardíaca congestiva de clase II a IV según la clasificación de la New York Heart Association (NYHA) (véase el apéndice 17.5) en los 6 meses previos a la entrada en el estudio; arteriopatía coronaria (AC) activa; bradicardia de importancia clínica u otra arritmia cardíaca no controlada definida como de grado ? 3 según los Criterios Terminológicos Comunes para Acontecimientos Adversos (CTCAE) del National Cancer Institute (NCI), versión 4.03, o hipertensión no controlada; infarto de miocardio ocurrido en los 6 meses previos a la entrada en el estudio (se permite el infarto de miocardio ocurrido > 6 meses antes de la entrada en el estudio)
    5. Infecciones graves clínicamente activas definidas como de grado 3 ? según los CTCAE del NCI, versión 4.03
    6. Cualquier proceso médico, psicológico o social, sobre todo si es inestable, incluido el abuso de sustancias, que pueda interferir en la seguridad o la participación del pacientes en el estudio, en el cumplimiento del protocolo del estudio o en la evaluación de sus resultados, en opinión del investigador
    7. Infección conocida por el virus de la inmunodeficiencia humana (VIH).
    8. Transfusión de sangre o albúmina en los 5 días previos a la extracción de sangre utilizada para confirmar la elegibilidad
    9. Tratamiento concomitante con interferón o tratamientos para la infección activa por el VHC
    10. Embarazo o lactancia
    11. Antecedentes de trasplante hepático
    12. Imposibilidad de tragar la medicación oral
    13. Hemorragia digestiva de importancia clínica ocurrida ? 4 semanas antes de la aleatorización
    E.5 End points
    E.5.1Primary end point(s)
    Overall survival (OS) in ITT population
    Supervivencia global (SG) en la población IT
    E.5.1.1Timepoint(s) of evaluation of this end point
    38 months
    38 meses
    E.5.2Secondary end point(s)
    Progression free survival (PFS) by central, independent radiology review

    ?Supervivencia sin progresión (SSP) según la revisión radiológica independiente central
    E.5.2.1Timepoint(s) of evaluation of this end point
    38 months
    38 meses
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic Yes
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E. trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised No
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    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 Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned13
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA131
    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
    New Zealand
    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
    Please refer to protocol
    Véase Protocolo
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months38
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial months38
    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: 303
    F.1.3Elderly (>=65 years) No
    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 state30
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 195
    F.4.2.2In the whole clinical trial 303
    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)
    Please refer to protocol
    véase protocolo.
    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 Decision2013-02-22
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-01-18
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2017-03-02
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