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The European Union Clinical Trials Register   allows you to search for protocol and results information on:
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    The EU Clinical Trials Register currently displays   44335   clinical trials with a EudraCT protocol, of which   7366   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

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    Summary
    EudraCT Number:2014-005068-13
    Sponsor's Protocol Code Number:I4T-MC-JVDE
    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:2015-04-27
    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 number2014-005068-13
    A.3Full title of the trial
    Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study of Ramucirumab and Best Supportive Care (BSC) Versus Placebo and BSC as Second-Line Treatment in Patients With Hepatocellular Carcinoma and Elevated Baseline Alpha-Fetoprotein (AFP) Following First-Line Therapy With Sorafenib
    Estudio de fase 3, aleatorizado, doble ciego, controlado con placebo, de ramucirumab y las mejores medidas complementarias frente a placebo y las mejores medidas complementarias como tratamiento de segunda línea en pacientes con carcinoma hepatocelular y con la alfafetoproteína (AFP) basal elevada, tras un tratamiento de primera línea con sorafenib
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Study of Ramucirumab (LY3009806) and best supportive care in Participants with Hepatic Cancer
    Estudio con Ramucirumab (LY3009806) y el mejor ciudado de apoyo en pacientes con cancer hepatico
    A.4.1Sponsor's protocol code numberI4T-MC-JVDE
    A.5.3WHO Universal Trial Reference Number (UTRN)U1111-1165-1891
    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 SponsorLilly S.A.
    B.1.3.4CountrySpain
    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 supportEli Lilly and Company
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationLilly S.A.
    B.5.2Functional name of contact pointSite Activation
    B.5.3 Address:
    B.5.3.1Street AddressAvda de la Industria 30
    B.5.3.2Town/ cityAlcobendas Madrid
    B.5.3.3Post code28108
    B.5.3.4CountrySpain
    B.5.4Telephone number34916635327
    B.5.5Fax number34916633481
    B.5.6E-mailalonsoaj@lilly.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 Yes
    D.2.1.1.1Trade name Cyramza
    D.2.1.1.2Name of the Marketing Authorisation holderEli Lilly Nederland B.V.
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/12/1019
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNRamucirumab
    D.3.9.1CAS number 947687-13-0
    D.3.9.3Other descriptive nameRAMUCIRUMAB
    D.3.9.4EV Substance CodeSUB32795
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    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 No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    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 Yes
    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 placeboConcentrate for solution for infusion
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Hepatic Cancer
    Cancer hepatico
    E.1.1.1Medical condition in easily understood language
    Hepatic Cancer
    Cancer Hepatico
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.0
    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
    The primary objective is to compare overall survival (OS) for ramucirumab versus placebo in patients with advanced HCC after intolerance or progression on prior sorafenib treatment
    El objetivo principal de este estudio es comparar la supervivencia global (SG) cuando se administra ramucirumab o placebo, en pacientes con carcinoma hepatocelular (CHC) en estadio avanzado que hayan experimentado intolerancia a un tratamiento previo con sorafenib o progresión de la enfermedad mientras recibían dicho tratamiento.
    E.2.2Secondary objectives of the trial
    The secondary objectives of the study are to evaluate:
    ? Progression-free survival (PFS)
    ? Time to radiographic progression (TTP)
    ? Objective response rate (ORR)
    ? Safety profile of ramucirumab
    ? Ramucirumab pharmacokinetics (PK)
    ? Immunogenicity of ramucirumab
    ? Patient-reported outcome (PRO) measures of disease-specific symptoms and health related quality of life
    Los objetivos secundarios de este estudio son evaluar: la supervivencia sin progresión, el tiempo hasta la progresión radiológica, la tasa de respuestas objetivas (TRO), el perfil de seguridad de ramucirumab, la farmacocinética de ramucirumab, la inmunogenicidad de ramucirumab y los instrumentos de medida de los resultados percibidos por los pacientes (en relación con los síntomas específicos de la enfermedad y la calidad de vida relacionada con la salud).
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    [1] The patient has a diagnosis of HCC based on either:
    a. histopathologic or cytologic findings
    b. in the absence of histologic confirmation, a diagnosis of cirrhosis and HCC with classical imaging characteristics (that is, at least a 3-phase liver protocol CT or MRI and a lesion that demonstrates arterial hyperenhancement and washes out in the venous phase).
    [2] The patient received sorafenib treatment for at least 14 days and discontinued sorafenib treatment ?14 days prior to randomization.
    [3] The patient experienced radiographically confirmed disease progression during or after discontinuation of sorafenib therapy or discontinued sorafenib treatment because of intolerance despite appropriate sorafenib management and supportive care.
    [4] The patient received sorafenib as the only systemic therapeutic intervention for advanced HCC.
    [5] The patient has ?1 measurable lesion per Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1 (Eisenhauer et al. 2009) that has not been previously treated with locoregional therapy.
    [6] The patient is ?18 years of age or of an age acceptable according to local regulations, whichever is older.
    [7] The patient has a Child-Pugh score of <7 (Child-Pugh Class A only).
    [8] The patient has Barcelona Clinic Liver Cancer (BCLC) Stage C disease or BCLC Stage B disease not amenable to locoregional therapy or refractory to locoregional therapy.
    [9] The patient has a baseline AFP ?400 ng/mL, as determined by local laboratory testing.
    [1] Al paciente se le ha diagnosticado CHC, de acuerdo con alguno de los siguientes criterios:
    a. Hallazgos histopatológicos o citológicos
    b. En caso de que el diagnóstico no se haya confirmado histológicamente, diagnóstico de cirrosis y CHC con las características típicas en las pruebas de imagen (es decir, al menos una TAC o una RMN con un protocolo de exploración hepática de 3 fases y la presencia de una lesión con hiperrealce arterial que desaparezca en la fase venosa).
    [2] El paciente ha recibido tratamiento con sorafenib al menos durante 14 días y ha interrumpido dicho tratamiento con sorafenib ? 14 antes de la aleatorización.
    [3] El paciente ha experimentado progresión de la enfermedad (confirmada radiológicamente) durante el tratamiento con sorafenib, o tras haber interrumpido dicho tratamiento, o ha dejado de recibir sorafenib por presentar intolerancia al tratamiento, a pesar de haber realizado los ajustes adecuados al tratamiento con sorafenib y de haber recibido tratamiento complementario.
    [4] El paciente ha recibido sorafenib como la única intervención terapéutica sistémica para el CHC en estadio avanzado.
    [5] El paciente tiene ? 1 lesión mensurable, de acuerdo con los Criterios de evaluación de la respuesta en tumores sólidos (RECIST), versión 1.1 (Eisenhauer et al. 2009), que no ha sido tratada anteriormente con tratamiento locorregional.
    [6] El paciente tiene ? 18 años o una edad aceptable, de acuerdo con la normativa local (la edad que sea superior).
    [7] El paciente tiene una puntuación de Child-Pugh < 7 (únicamente clase A de Child-Pugh) (Child y Turcotte 1964; Pugh et al. 1973; Lucey et al. 1997).
    [8] El paciente presenta enfermedad en estadio C (de acuerdo con los criterios del grupo Barcelona Clinic Liver Cancer [BCLC]) o en estadio B y que no pueda tratarse con tratamiento locorregional o sea resistente a este.
    [9] El paciente tiene una concentración basal de AFP ? 400 ng/ml, de acuerdo con una prueba analítica realizada en un laboratorio local. En el apartado 10.4.1 se incluyen requisitos relativos a la prueba de la AFP.
    E.4Principal exclusion criteria
    [17] The patient has fibrolamellar carcinoma or mixed hepatocellular cholangiocarcinoma.
    [18] The patient had a previous or has concurrent malignancy. Patients with carcinoma in situ of any origin and patients with prior malignancies who are in remission and whose likelihood of recurrence is very low, as judged by the investigator, may be eligible for this study in consultation with and approval by the Lilly CRP.
    [19] The patient has previously documented brain metastases, leptomeningeal disease, or uncontrolled spinal cord compression.
    [20] The patient has a history of or current hepatic encephalopathy (any grade) or clinically meaningful ascites. Clinically meaningful ascites is defined as CTCAE Grade >1 ascites resulting from cirrhosis. Patients who have been on a stable medical regimen (for ?3 months) to manage ascites are eligible if they show no evidence of ascites on clinical exam that would require further intervention.
    [21] The patient has ongoing or recent (?6 months prior to randomization) hepatorenal syndrome.
    [22] The patient had a prior liver transplant.
    [23] The patient received any previous systemic therapy with VEGF inhibitors or VEGF-Receptor inhibitors (including investigational agents) other than sorafenib for treatment of HCC.
    [24] The patient received any hepatic locoregional therapy (including radiation, surgery, hepatic arterial embolization, chemoembolization, radiofrequency ablation, cryoablation, or percutaneous ethanol injection) following sorafenib or within 28 days prior to randomization. Use of locoregional therapy prior to sorafenib is allowed.
    [25] The patient received radiation to any nonhepatic (for example, bone) site within 14 days prior to randomization. Prior radiation to >25% total bone marrow is not allowed.
    [17] El paciente tiene carcinoma fibrolamelar o colangiocarcinoma hepatocelular mixto.
    [18] El paciente ha padecido o padece una neoplasia maligna. Podrán participar en este estudio los pacientes con carcinoma in situ de cualquier origen y los pacientes que anteriormente hayan presentado otras neoplasias malignas, estén en remisión y tengan una probabilidad de recurrencia muy baja, de acuerdo con el criterio del investigador, tras consultar con el CRP de Lilly y contar con su aprobación.
    [19] El paciente ha padecido anteriormente metástasis cerebrales, enfermedad leptomeníngea o compresión medular no controlada, todo ello documentado.
    [20] El paciente tiene antecedentes o padece en la actualidad encefalopatía hepática (de cualquier grado) o ascitis clínicamente significativa. Por ?ascitis clínicamente significativa? se entiende la ascitis de grado > 1 (criterios CTCAE) que se produce como consecuencia de la cirrosis. Los pacientes que hayan recibido un tratamiento farmacológico estable (durante ? 3 meses) para la ascitis se considerarán idóneos si al realizar una exploración clínica no se observen indicios de ascitis que requieran realizar intervenciones adicionales.
    [21] El paciente padece o ha padecido recientemente (? 6 meses antes de la aleatorización) síndrome hepatorrenal.
    [22] El paciente ha recibido anteriormente un trasplante de hígado.
    [23] El paciente ha recibido cualquier tratamiento sistémico con inhibidores del VEGF o con inhibidores del receptor del VEGF (incluidos fármacos en fase de investigación) para el CHC (distintos de sorafenib).
    [24] El paciente ha recibido tratamiento hepático locorregional (incluidas radioterapia, cirugía, embolización de la arteria hepática, quimioembolización, ablación por radiofrecuencia, crioablación o inyección percutánea de etanol) tras el tratamiento con sorafenib o en el transcurso de los 28 días previos a la aleatorización. Se permite la administración de tratamiento locorregional antes del tratamiento con sorafenib.
    [25] El paciente ha recibido radioterapia en cualquier localización extrahepática (por ejemplo, el hueso), en el transcurso de los 14 días previos a la aleatorización. No se permite la administración previa de radioterapia en > 25 % de la médula ósea.
    E.5 End points
    E.5.1Primary end point(s)
    Compare ramucirumab versus placebo in terms of OS in patients with advanced HCC after intolerance or progression on prior sorafenib
    Comparar ramucirumab con placebo en lo que respecta a la supervivencia global, en pacientes con carcinoma hepatocelular en estadio avanzado que hayan experimentado intolerancia a un tratamiento previo con sorafenib
    E.5.1.1Timepoint(s) of evaluation of this end point
    The primary analysis will be performed after approximately 318 deaths have been observed
    El análisis principal se llevará a cabo una vez que se hayan observado aproximadamente 318 muertes
    E.5.2Secondary end point(s)
    The secondary objectives of the study are to evaluate: progression-free survival, time to radiographic progression, objective response rate (ORR), safety profile of ramucirumab, ramucirumab pharmacokinetics, immunogenicity of ramucirumab, and patient-reported outcome measures of disease-specific symptoms and health-related quality of life.
    ? La supervivencia sin progresión (SSP)
    ? El tiempo hasta la progresión (ThP)
    ? La tasa de respuestas objetivas (TRO)
    ? El perfil de seguridad de ramucirumab
    ? La farmacocinética (FC) de ramucirumab
    ? La inmunogenicidad de ramucirumab
    ? Los instrumentos de los resultados percibidos por los pacientes (RPP) en relación con los síntomas específicos de la enfermedad y la calidad de vida relacionada con la salud
    E.5.2.1Timepoint(s) of evaluation of this end point
    Secondary endpoints will be analyzed at the same time as OS and at the same level of significance.
    2 safety interim analyses are planned to be performed when approximately 50 and 150 patients have received 3 cycles of study treatment, died, or discontinued study treatment. Thereafter, safety review will be conducted twice annually, or as requested by the IDMC
    Los criterios secundarios de valoración se analizarán al mismo tiempo que la SG y con el mismo nivel de significación.
    Está previsto que los 2 primeros análisis provisionales de los datos de seguridad se lleven a cabo aproximadamente cuando 50 y 150 pacientes hayan recibido 3 ciclos del tratamiento del estudio, hayan fallecido o hayan dejado de recibir el tratamiento del estudio. Posteriormente, las revisiones de la seguridad se realizarán con una periodicidad bianual, o según requiera el CIMD.
    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 Yes
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Immunogenicity, Health Outcome
    Inmunogenicidad, Resultado de Salud
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    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 concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA51
    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
    Australia
    Austria
    Belgium
    Brazil
    Canada
    China
    Czech Republic
    France
    Germany
    Hong Kong
    Israel
    Italy
    Japan
    Korea, Republic of
    Poland
    Spain
    Switzerland
    Taiwan
    United Kingdom
    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
    LVLS
    Ultima visita ultimo paciente
    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 months10
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    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: 212
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 187
    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 180
    F.4.2.2In the whole clinical trial 399
    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)
    None
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2015-06-19
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-06-05
    P. End of Trial
    P.End of Trial StatusCompleted
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