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    Summary
    EudraCT Number:2010-019318-26
    Sponsor's Protocol Code Number:IMCL CP12-0919
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2010-11-08
    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 ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2010-019318-26
    A.3Full title of the trial
    A multicenter, Randomized, Double-Bind, Phase 3 Study of Ramucirumab (IMC-1121B) Drug Product and Best Supportive Care (BSC) Versus Placebo and BSC as Second-Line Treatment in Patients With Hepatocellular Carcinoma Following First-Line Therapy With Sorafenib
    A.3.2Name or abbreviated title of the trial where available
    ND
    A.4.1Sponsor's protocol code numberIMCL CP12-0919
    A.5.1ISRCTN (International Standard Randomised Controlled Trial) NumberND
    A.7Trial is part of a Paediatric Investigation Plan Information not present in EudraCT
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorIMCLONE LLC
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    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 nameIMC-1121B
    D.3.2Product code IMC-1121B
    D.3.4Pharmaceutical form Solution for infusion
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.1CAS number 947687-13-0
    D.3.9.2Current sponsor codeIMC-1121B
    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) Information not present in EudraCT
    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 Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    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 Information not present in EudraCT
    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 Yes
    D.3.11.13.1Other medicinal product typemonoclonal AB
    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 placeboSolution 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
    Hepatocellular Carcinoma
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 9.1
    E.1.2Level LLT
    E.1.2Classification code 10019828
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective is to compare the overall survival (OS; time from randomization to death) in patients with hepatocellular carcinoma (HCC) who had disease progression during or following sorafenib therapy, or were intolerant to this agent. Patients will receive either ramucirumab (IMC-1121B) drug product (hereafter referred to as ramucirumab DP) plus best supportive care (BSC) or placebo plus BSC.
    E.2.2Secondary objectives of the trial
    Secondary objectives are to evaluate: -Progression-free survival (PFS) -Best objective response rate (ORR) -Time to radiographic progression -Patient-reported outcome (PRO) measures of disease-specific symptoms and health-related quality of life -Safety profile of ramucirumab DP -Ramucirumab serum concentrations -Pharmacodynamics of ramucirumab -Immunogenicity of ramucirumab
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. The patient has provided signed informed consent and is amenable to compliance with protocol schedules and testing. 2. The patient is at least 18 years of age. 3. The patient has an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1. 4. The patient has a Child-Pugh score of < 9 (Child-Pugh A or B [B7 or B8]). 5. The patient has a Barcelona Clinic Liver Cancer (BCLC) stage C at randomization. A patient with BCLC stage B may be eligible if he/she has disease that is not amenable to locoregional therapy or is refractory to locoregional therapy (examples include very large or diffusely infiltrative tumors and intrahepatic tumors that are refractory to transarterial chemoembolization [TACE] or not amenable to TACE). 6. The patient has a diagnosis of HCC (excluding fibrolamellar carcinoma) based on histopathologic or cytologic findings; or in the absence of histologic confirmation, all of the following are present (at the time of study entry): a. There are either clinical, laboratory, or radiographic findings consistent with a diagnosis of liver cirrhosis, b. The patient has a liver mass measuring at least 2 cm with characteristic vascularization (intense inhomogeneous enhancement seen in the hepatic arterial-dominant phase and contrast washout in the late portal venous phase) seen on either triphasic computed tomography (CT) scan or magnetic resonance imaging (MRI) with gadolinium, c. The patient has a serum alpha-fetoprotein (AFP) concentration greater than the institutional upper limit of normal (ULN). For the complete list of inclusion criteria please refer to the Protocol
    E.4Principal exclusion criteria
    1. The patient (P) has undergone major surgery within 28 days prior to randomization, or subcutaneous venous access device placement within 7 days prior to randomization. 2. Hepatic locoregional therapy (including radiation, surgery, hepatic arterial embolization, chemoembolization, radiofrequency ablation, cryoablation, or percutaneous ethanol injection) within 28 days prior to randomization 3. Radiation to any nonhepatic site within 14 days prior to randomization 4. Sorafenib within 14 days prior to randomization 5. Any investigational therapy within 28 days prior to randomization 6. Any previous systemic therapy with vascular endothelial growth factor inhibitors or vascular endothelial growth factor receptor inhibitors (including investigational agents) other than sorafenib for treatment of HCC. For the complete list of exclusion criteria please refer to the Protocol
    E.5 End points
    E.5.1Primary end point(s)
    Primary Efficacy Endpoint: Overall Survival Overall survival is defined as the time from the date of randomization to the date of death from any cause. If the patient is alive at the end of the follow-up period or is lost to follow-up, OS data will be censored on the last date the patient is known to be alive. Overall survival will be evaluated by the Kaplan-Meier method, and a 95% confidence interval will be provided for the median OS in each treatment arm. The primary analysis will compare the observed OS under the combination therapy ramucirumab DP plus BSC versus placebo plus BSC. The comparison will use the log-rank test, stratified at randomization by geographic region (North America vs Europe vs East Asia), etiology of liver disease (hepatitis B vs hepatitis C vs other etiologies), and Child-Pugh score (Child-Pugh A vs B [B7 or B8]). An additional analysis with an unstratified log-rank test will also be performed. The estimation of the survival curves for the 2 treatment groups will be generated using the Kaplan-Meier methodology. A stratified Cox proportional hazards regression model to compare the treatments within the clusters defined by the stratifying variables will also be performed to generate the hazard ratio (HR). An additional unstratified Cox regression model will be employed to explore the effects of prognostic variables, including the stratification variables and additional factors (eg, Child-Pugh score, presence of macrovascular invasion, extrahepatic spread, BCLC stage, presence vs absence of histologic confirmation of diagnosis, and prior treatment with sorafenib [including duration of treatment and reasons for discontinuation]), on treatment efficacy. Safety Endpoints The safety and tolerability of ramucirumab DP are determined by reported SAEs, AEs, physical examinations, vital sign measurements, and clinical laboratory evaluations. Patients who receive any quantity of ramucirumab DP or placebo are considered evaluable for safety. Adverse events will be summarized by MedDRA System Organ Class and preferred term, classified from verbatim terms. The incidence and percentage of patients with at least 1 occurrence of a preferred term will be included, according to the most severe NCI-CTCAE v 4.02 grade. Causality (relationship to study therapy), will be separately summarized. Duration of AE will be determined and included in the listings, along with action taken and outcome. Adverse events leading to treatment discontinuation will also be listed. Laboratory results will be classified according to NCI-CTCAE v 4.02. Incidence of laboratory abnormalities will be summarized. Laboratory results not corresponding to an NCI-CTCAE v 4.02 term will not be graded. Pretreatment and posttreatment immunogenicity samples will be assayed using a double antigen radiometric assay. A sample will be considered positive for anti-ramucirumab antibodies if it exhibits a posttreatment antibody level that exceeds the positive upper cut point determined from the anti-ramucirumab level seen in healthy untreated individuals. A patient will be considered to have an anti-ramucirumab response if there are 2 consecutive positive samples or if the final sample tested is positive.
    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 No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    immunogenicity
    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.8.3 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 concerned15
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA90
    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 Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    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
    • All patients have completed an End-of-Study visit.
    • The study is discontinues due to safety considerations.
    • The Steering Committee (SC) discontinues the study in response to a recommendation from the IDMC, or
    because of safety concerns.
    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 months3
    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 months3
    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.1.3Elderly (>=65 years) Yes
    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 state50
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 337
    F.4.2.2In the whole clinical trial 544
    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 Decision2010-10-29
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2010-09-16
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2015-03-17
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