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    The EU Clinical Trials Register currently displays   43974   clinical trials with a EudraCT protocol, of which   7311   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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    EudraCT Number:2010-019318-26
    Sponsor's Protocol Code Number:IMCL CP12-0919
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2010-07-12
    Trial results View results
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    A. Protocol Information
    A.1Member State ConcernedFrance - ANSM
    A.2EudraCT number2010-019318-26
    A.3Full title of the trial
    A Multicenter, Randomized, Double-Blind, 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
    A.4.1Sponsor's protocol code numberIMCL CP12-0919
    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.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.3.8INN - Proposed INNRamucirumab
    D.3.9.1CAS number 947 687-13-0
    D.3.9.2Current sponsor codeIMC-1121B
    D.3.9.3Other descriptive namerecombinant human IgG1 monoclonal antibody (MAb) targeted to VEGFR-2
    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. cell therapy medicinal product No
    D. therapy medical product No
    D. Engineered Product Information not present in EudraCT
    D. ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D. 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. 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 12.1
    E.1.2Level LLT
    E.1.2Classification code 10019828
    E.1.2Term Hepatocellular carcinoma non-resectable
    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).
    7. The patient has at least 1 measurable or evaluable lesion that is viable (ie, is vascularized), and has not been previously treated with locoregional therapy. A lesion that has been previously treated will qualify as a measurable or evaluable lesion if there was demonstrable progression following locoregional therapy.
    8. The patient has previously been treated with sorafenib and has discontinued sorafenib treatment at least 14 days prior to randomization. This will include patients who have experienced:
    a. Radiographically documented disease progression during sorafenib therapy or after discontinuation of sorafenib therapy, or
    b. Discontinuation of sorafenib due to an adverse drug reaction (fatigue, hand-foot syndrome, desquamation/rash, diarrhea, reversible liver dysfunction, abdominal pain, anorexia, or leukopenia), despite dose reduction by 1 level and BSC.
    9. The patient has received sorafenib as the most recent systemic therapeutic intervention. Any hepatic locoregional therapy (including radiation, surgery, hepatic arterial embolization, chemoembolization, radiofrequency ablation, cryoablation, percutaneous ethanol injection) that has been administered prior to sorafenib is allowed, but not following sorafenib. Radiation to metastatic sites (eg, bone) following sorafenib therapy is permitted.
    10. The patient has resolution to Grade ≤ 1 by the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.02 (NCI-CTCAE v 4.02) of all clinically significant toxic effects of prior locoregional therapy, surgery, chemoembolization, or other anticancer therapy, including sorafenib.
    11. The patient has adequate organ function defined as:
    a. Total bilirubin < 3.0 mg/dL (51.3 μmol/L), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 5 × ULN;
    b. Serum creatinine ≤ 1.2 × ULN or calculated creatinine clearance > 50 mL/minute;
    c. Absolute neutrophil count (ANC) ≥ 1.0 × 10 exp3/μL (1.0 × 10 exp9/L), hemoglobin ≥ 9 g/dL (5.58 mmol/L), and platelets ≥ 75 × 10 exp3/μL (75 × 10 exp9/L);
    d. International Normalized Ratio (INR) ≤ 1.5. Patients receiving prophylactic low-dose anticoagulant therapy are eligible provided that INR ≤ 1.5.
    12. The patient’s urinary protein is ≤ 1+ on dipstick or routine urinalysis. If urine dipstick or routine analysis indicates ≥ 2+ proteinuria, then a 24-hour urine must be collected and must demonstrate < 1000 mg of protein in 24 hours to allow participation in the study.
    13. The patient, if sexually active, is postmenopausal, surgically sterile, or using effective contraception (hormonal or barrier methods).
    14. Female patients of childbearing potential must have a negative serum pregnancy test within 7 days prior to randomization.
    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
    7. Fibrolamellar carcinoma
    8. Any transfusion, blood component preparation, erythropoietin, albumin preparation, or granulocyte colony-stimulating factors within 14 days prior to randomization
    9. P is receiving therapeutic anticoagulation with warfarin, low-molecular-weight heparin, or similar agents. Patients receiving prophylactic, low-dose anticoagulation therapy are eligible provided that the coagulation parameters defined in the inclusion criteria (INR ≤ 1.5) are met.
    10. P is receiving ongoing therapy with nonsteroidal anti-inflammatory agents (NSAIDs, eg, indomethacin, ibuprofen, naproxen, or similar agents) or other antiplatelet agents (eg, clopidogrel, ticlopidine, dipyridamole, anagrelide). Aspirin at doses of 325 mg/day or below is permitted.
    11. Symptomatic congestive heart failure, unstable angina pectoris, or symptomatic or poorly controlled cardiac arrhythmia.
    12. Any arterial thrombotic event, including myocardial infarction, unstable angina, cerebrovascular accident, or transient ischemic attack, within 6 months prior to randomization.
    13. Uncontrolled arterial hypertension ≥ 150 / ≥ 90 mm Hg despite standard medical management
    14. Any Grade 3-4 gastrointestinal bleeding or any variceal bleeding episode in the 3 months prior to randomization requiring transfusion, endoscopic or operative intervention (patients with any bleeding episode considered life-threatening during the 3 months prior to randomization are excluded, regardless of transfusion or intervention status)
    15. Esophageal or gastric varices that require immediate intervention (eg, banding, sclerotherapy) or represent a high bleeding risk in the opinion of the investigator or consulting gastroenterologist or hepatologist. P.s with evidence of portal hypertension (defined as splenomegaly, platelets < 100 × 10 exp3/μL [100 × 10 exp9/L], or any prior history of variceal bleeding) must have had endoscopic evaluation within the 3 months immediately prior to randomization.
    P.s with evidence of portal hypertension are eligible for study participation if endoscopic evaluation does not indicate esophageal or gastric varices that require immediate intervention or represent a high bleeding risk; however, they must receive supportive therapy (eg, beta blocker therapy) according to institutional standards and clinical guidelines during study participation. Additional endoscopic assessments during study participation should be performed at the discretion of the consulting gastroenterologist or hepatologist, as clinically indicated.
    16. CNS metastases or carcinomatous meningitis
    17. Serious illness or medical condition(s), including but not limited to the following:
    a. Known HIV infection or AIDS-related illness
    b. Active or uncontrolled clinically serious infection (patients with chronic viral hepatitis are eligible)
    c. Clinical signs of acute hepatitis
    d. Other acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study therapy administration, or may interfere with the interpretation of study results, and in the judgment of the investigator would make the patient ineligible for entry into this study
    e. Uncontrolled thrombotic or hemorrhagic disorder
    f. Elective or planned major surgery to be performed during the course of the clinical trial
    g. Serious or nonhealing wound, ulcer, or bone fracture within 28 days prior to randomization
    h. Known allergy or hypersensitivity to MAb treatment or any components used in the ramucirumab DP preparation
    i. Any other serious uncontrolled medical disorders in the opinion of the investigator
    18. Pregnancy (confirmed by serum β-HCG test) or lactating
    19. Previous or concurrent malignancy except for basal or squamous cell skin cancer and/or in situ carcinoma of the cervix, or other solid tumors treated curatively, and is with evidence of recurrence for at least 2 years prior to randomization
    20. Prior liver transplant
    21. Ascites or encephalopathy refractory to medical management
    22. Participation in another interventional clinical trial. Participation in surveys or observational studies is allowed.
    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
    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 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 concerned8
    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
    This study will be considered complete when 1 or more of the following is met:
    • All patients have completed an End-of-Study visit.
    • The IRB/aEC, ImClone, or a regulatory authority discontinues the study due to safety considerations.
    • The Steering Committee (SC) discontinues the study in response to a recommendation from the IDMC, or because of safety concerns.
    • The SC defines an administrative or clinical cut-off date.
    • ImClone defines an administrative or clinical cut-off date.
    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 state30
    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 Decision2010-08-10
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2010-08-25
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2015-03-17
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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