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    Summary
    EudraCT Number:2010-019318-26
    Sponsor's Protocol Code Number:IMCL_CP12-0919_(I4T-IE-JVBF)
    National Competent Authority:Czechia - SUKL
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2010-07-02
    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 ConcernedCzechia - SUKL
    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
    Randomizovaná, multicentrická, dvojitě zaslepená studie fáze III, hodnotící léčivý přípravek ramucirumab (IMC-1121B) s nejlepší podpůrnou léčbou (BSC- Best Supportive Care) v porovnání s placebem a BSC v léčbě druhé linie u pacientů s hepatocelulárním karcinomem, kteří podstoupili léčbu první linie sorafenibem.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Study of Ramucirumab and Best Supportive Care versus Placebo and Best Supportive care in patients with second line treatment advanced liver cancer after treatment with Sorafenib.
    A.3.2Name or abbreviated title of the trial where available
    REACH
    A.4.1Sponsor's protocol code numberIMCL_CP12-0919_(I4T-IE-JVBF)
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT01140347
    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 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 supportImClone Systems Corporation, a wholly-owned subsidiary
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationElil Lilly and Company
    B.5.2Functional name of contact pointClinical Trial Information
    B.5.3 Address:
    B.5.3.1Street AddressErl Wood Manor, Sunninghill Road
    B.5.3.2Town/ cityWindlesham, Surrey
    B.5.3.3Post codeGU20 6PH
    B.5.3.4CountryUnited Kingdom
    B.5.6E-mailEU_Lilly_Clinical_Trials@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 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 nameramucirumab
    D.3.2Product code IMC-1121B, LY3009806
    D.3.4Pharmaceutical form 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 947 687-13-0
    D.3.9.2Current sponsor codeIMC-1121B, LY3009806
    D.3.9.3Other descriptive namerecombinant human IgG1 monoclonal antibody
    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 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
    E.1.1.1Medical condition in easily understood language
    Advanced liver cancer
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 16.1
    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 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.

    E.2.2Secondary objectives of the trial
    Secondary objectives are to evaluate:
    - Progression-free survival (PFS)
    - 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 pharmacokinetics
    - Immunogenicity of ramucirumab.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    * ECOG PS of 0 or 1.
    * Child-Pugh score of < 7 (Child-Pugh Class A only).
    * BCLC stage C or BCLC stage B not amenable to locoregional therapy or refractory to locoregional therapy.
    * diagnosis of HCC (excluding fibrolamellar carcinoma) in the absence of histologic or cytologic confirmation
    * There are either clinical, laboratory, or radiographic findings consistent with a diagnosis of liver cirrhosis.
    * The patient has a liver mass measuring at least 2 cm with characteristic vascularization seen on either triphasic computed tomography (CT) scan or magnetic resonance imaging (MRI) with gadolinium.
    * The patient has a serum alpha-fetoprotein (AFP) concentration greater than the institutional upper limit of normal (ULN).
    * 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.
    * Previously treated with sorafenib and has discontinued sorafenib treatment at least 14 days prior to randomization. Patients may have experienced:
    * Radiographically documented disease progression during sorafenib therapy or after discontinuation of sorafenib therapy, or
    * Discontinuation of sorafenib due to an adverse drug reaction, despite dose reduction by 1 level and BSC.
    * The patient has received sorafenib as the only systemic therapeutic intervention for advanced HCC. Any hepatic locoregional therapy that has been
    administered prior to sorafenib is allowed, but not following sorafenib. Radiation to metastatic sites (eg, bone) following sorafenib therapy is permitted.
    * Except where otherwise noted in the eligibility criteria, the patient has a resolution to grade ≤ 1 by the NCI-CTCAE v. 4.0 of all clinically significant toxic effects of prior locoregional therapy, surgery, chemoembolization or sorafenib.
    Adequate organ function defined as:
    * Total bilirubin < 3.0 mg/dL (51.3 μmol/L), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 5 × ULN;
    * Serum creatinine ≤ 1.2 × ULN or calculated creatinine clearance > 50 mL/minute;
    * Absolute neutrophil count (ANC) ≥ 1.0 × 10exp3/μL (1.0 × 10exp9/L), hemoglobin ≥ 9 g/dL (5.58 mmol/L), and platelets ≥ 75 × 10exp3/μL (75 × 10exp9/L);
    * International Normalized Ratio (INR) ≤ 1.5. Patients receiving prophylactic low dose anticoagulant therapy are eligible provided that INR ≤ 1.5 and PTT ≤ 5 seconds above the upper limit of normal (ULN).
    * 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.
    E.4Principal exclusion criteria
    * Major surgery within 28 days prior to randomization, or central venous access device placement within 7 days prior to randomization.
    * Hepatic locoregional therapy within 28 days prior to randomization.
    * Radiation to any nonhepatic (eg, bone) site within 14 days prior to randomization.
    * Sorafenib within 14 days prior to randomization.
    * Received any investigational therapy or non-approved drug within 28 days prior to randomization or is concurrently enrolled in any other type of medical research judged not to
    be scientifically or medically compatible with this study.
    * Received any previous systemic therapy with vascular endothelial growth factor (VEGF) inhibitors or vascular endothelial growth factor receptor (VEGFR) inhibitors (including investigational agents) other than sorafenib for treatment of HCC.
    * Fibrolamellar carcinoma.
    * Received any transfusion, blood component preparation, erythropoietin, albumin preparation, or granulocyte colony-stimulating factors (G-CSF) within 14 days prior to randomization.
    * 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 and PTT ≤ 5 seconds above the upper limit of normal (ULN)) are met.
    * Receiving ongoing therapy with nonsteroidal anti-inflammatory agents (NSAIDs, eg, indomethacin, ibuprofen, naproxen, nimesulide, celecoxib, etoricoxib, or similar agents) or other antiplatelet agents (eg, clopidogrel, ticlopidine, prasugrel, dipyridamole, picotamide, indobufen, anagrelide, triflusal).Aspirin (ASA) at doses up to 100 mg/day is permitted.
    * Symptomatic congestive heart failure, unstable angina pectoris, or symptomatic or poorly controlled cardiac arrhythmia.
    * Any arterial thrombotic event, including myocardial infarction, unstable angina, cerebrovascular accident, or transient ischemic attack, within 6 months prior to randomization.
    * Uncontrolled arterial hypertension ≥ 150 / ≥ 90 mm Hg despite standard medical management.
    * 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).
    * Esophageal or gastric varices that require immediate intervention (eg, banding, sclerotherapy) or represent a high bleeding risk. Patients with evidence of portal hypertension (including splenomegaly) or any prior history of variceal bleeding must have had endoscopic evaluation within the 3 months immediately prior to randomization. Patients 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, these eligible patients must receive supportive therapy (eg, beta blocker therapy) according to institutional standards and clinical guidelines during study participation.
    * Central nervous system (CNS) metastases or carcinomatous meningitis.
    * History of or current hepatic encephalopathy or current clinically meaningful ascites. Clinically meaningful ascites is defined as ascites resulting from cirrhosis and requiring ongoing treatment with diuretics and/or paracentesis.
    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.
    E.5.1.1Timepoint(s) of evaluation of this end point
    • The first interim analysis will occur when 25% (109) deaths have been observed.
    • The second interim analysis will be conducted when 50% (219) deaths have been observed.
    • The third interim analysis will be conducted when 75% (328) deaths have been observed.
    • The final OS analysis will be conducted when 100% (438) deaths have been observed. It will be a 1-sided test with a nominal significance level of 0.0241 to preserve the planned 0.025 overall significance level. Based on the assumptions, the expected time to observe this many events is 43 months from the enrollment of the first patient.
    E.5.2Secondary end point(s)
    The secondary efficacy endpoints to be analyzed are:
    • Progression-free survival
    • ORR
    • Time to radiographic progression
    • Patient-reported outcomes
    The analyses of the secondary endpoints will be adjusted by the stratification factors. An additional unstratified analysis will also be performed. The sequential order of the confirmatory testing after
    OS will be: PFS, ORR, and TTP. Tests will continue in this order so long as the previous test is significant.
    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. If the difference in OS is statistically significant at the 1-sided 0.005 level at the interim efficacy analysis, the secondary efficacy endpoints will be analyzed at that time also with a 1-sided significance level of 0.005. However, if statistical significance at the 0.005 level is not observed for OS at the interim analysis, the secondary efficacy endpoints will be analyzed at the end of the study with the same level of significance as OS ( 1-sided 0.0241), provided that OS is significant.
    There may be additional exploratory efficacy analyses regarding response data, if deemed necessary.
    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.8.2.4Number 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 EEA101
    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
    Belgium
    Bulgaria
    Canada
    China
    France
    Italy
    Japan
    Austria
    Netherlands
    New Zealand
    Norway
    Portugal
    Romania
    Sweden
    Australia
    Brazil
    Czech Republic
    Finland
    Germany
    Hong Kong
    Hungary
    Indonesia
    Korea, Republic of
    Malaysia
    Spain
    Thailand
    Israel
    Philippines
    Switzerland
    Taiwan
    Turkey
    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
    Study completion when 438 events observed and analysis of OS performed and fully interpreted as determined by Sponsor. End of trial occurs when Study completion occurred and last patient discontinued study treatment and completed 30-day safety followup visit (and any AE serious or considered related to study treatment or that caused discontinuation of treatment followed until the event has resolved,stabilized,returned to baseline,been deemed irreversible,or otherwise explained).
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months7
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months7
    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: 416
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 208
    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 state18
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 314
    F.4.2.2In the whole clinical trial 624
    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)
    Patients will be assigned to further treatments after discontinuation from the study at the discretion of the investigator.
    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 Decision2010-08-26
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2010-09-02
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2015-03-17
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