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    Summary
    EudraCT Number:2009-010196-25
    Sponsor's Protocol Code Number:CRAD001O2301
    National Competent Authority:Belgium - FPS Health-DGM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2010-02-16
    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 ConcernedBelgium - FPS Health-DGM
    A.2EudraCT number2009-010196-25
    A.3Full title of the trial
    A randomized phase III, double-blind, placebo-controlled, multi-center study to evaluate the efficacy and safety of everolimus (RAD001) in adult patients with advanced Hepatocellular Carcinoma after failure of sorafenib treatment – The EVOLVE-1 Study
    A.4.1Sponsor's protocol code numberCRAD001O2301
    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 SponsorNovartis Pharma Service AG
    B.1.3.4CountrySwitzerland
    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.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    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 INNeverolimus
    D.3.9.1CAS number 159351-69-6
    D.3.9.3Other descriptive nameEVEROLIMUS
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2.5
    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) 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 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
    hepatocellular cancer (2nd/3rd line)
    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 of this study is to compare overall survival between the combination treatment of everolimus plus BSC to placebo plus BSC in patients with advanced HCC whose disease progressed while on or after sorafenib treatment or who are intolerant to sorafenib
    E.2.2Secondary objectives of the trial
    Key Secondary Objective:
    The key secondary objective of this study is to compare time to tumor progression (TTP) between the combination treatment of everolimus plus BSC to placebo plus BSC in patients with advanced HCC whose disease progressed while on or after sorafenib treatment or who are intolerant to sorafenib.

    Other Secondary Objectives, please refer to protocol section 3.2
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Male or female patients ≥ 18 years old
    2. Diagnosis of advanced HCC according to the AASLD Guidelines (Bruix and Sherman 2005)
    3. HCC stage B or C according to the Barcelona Clinic Liver Cancer (BCLC) staging classification (Llovet et al. 2008a)
    4. Prior systemic treatment with sorafenib for advanced HCC and for whom their disease progressed during or after sorafenib treatment, or were intolerant to sorafenib treatment. Specifically, this can be defined as:
    • Documented radiological confirmation (radiology scans or report) of disease progression during or after sorafenib treatment (For France only: patients must have received at least 8 weeks of prior sorafenib treatment).
    • Intolerance to sorafenib (at any dose and/or duration) is defined as documented sorafenib-related grade 3 or 4 adverse events that led to sorafenib discontinuation.
    NOTE:
    • Sorafenib must be the last antineoplastic treatment before randomization
    • Prior local and/or hormonal therapy (e.g., tamoxifen) before sorafenib is allowed
    • One systemic chemotherapy regimen for advanced HCC is allowed before sorafenib treatment
    5. Current cirrhotic status of Child-Pugh class A (5-6 points), with no encephalopathy (although ascites controlled by diuretics is permitted in this study). Child-Pugh status must be calculated based on clinical findings and laboratory results during the screening period
    6. ECOG performance status of ≤ 2
    7. Adequate bone marrow function as shown by:
    • Absolute neutrophil count (ANC) ≥ 1.2 x 109/L (1200/mm3)
    • Platelets ≥ 100 x 109/L (100,000/mm3)
    • Hemoglobin (Hgb) ≥ 8.5 g/dL (5.3mmol/L)
    8. Adequate liver function as shown by:
    • Serum alanine aminotransferase (ALT) ≤ 5 x upper limit of normal (ULN)
    • Bilirubin ≤ 2 mg/dL
    9. Adequate renal function as shown by:
    • Serum creatinine ≤ 1.5 x ULN
    10. Written informed consent according to local guidelines and the ability to follow the visit schedule.
    E.4Principal exclusion criteria
    1. Any local antineoplastic therapy and/or investigational drugs within 28 days prior to randomization
    2. Active bleeding within 28 days prior to Screening Visit 1 including variceal bleeding (esophageal varices should be treated according to standard practice e.g. ligation or banding and procedure completed 28 days prior to Visit 1)
    3. Prior therapy with mTOR inhibitors (e.g., sirolimus, temsirolimus, everolimus)
    4. Known previous/current malignancy within the last 3 years except for cervical carcinoma in situ, basal cell carcinoma or superficial bladder carcinoma
    5. Prior liver or other organ transplantation which mandates systemic immunosuppression
    6. Known history of human immunodeficiency virus (HIV) seropositivity (HIV testing is not mandatory)
    7. Clinically significant third space fluid accumulation (i.e., ascites requiring tapping (despite use of diuretics) or pleural effusion that either requires tapping or is associated with shortness of breath
    8. Any severe and/or uncontrolled medical conditions including:
    • Unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction ≤ 6 months prior to randomization, serious uncontrolled cardiac arrhythmia, uncontrolled hypertension
    • Previous Transient Ischemic Attack (TIA), Cerebrovascular Accident (CVA), symptomatic Peripheral Vascular Disease (PVD) within last 6 months prior to randomization
    • Uncontrolled diabetes as defined by glycosylated hemoglobin (HbA1c) > 8 %
    • Acute and chronic, active infectious disorders, including fungal infections, and non-malignant medical illnesses that are uncontrolled or whose control may be jeopardized by the complications of this study therapy, in the opinion of the investigator, except chronic HBV or HCV infection
    • Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of study drugs (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome)
    • Other concurrent severe and/or uncontrolled medical conditions (e.g., chronic obstructive or chronic restrictive pulmonary disease including dyspnea at rest from any cause) that could cause unacceptable safety risks or compromise compliance with the protocol.
    9. Patients with an active alcohol intake of 80 grams or more per day.
    10. Patients receiving chronic treatment with corticosteroids (except for intermittent topical, local injection, eye drops or systemic aldosterone) or another immunosuppressive agent
    11. Female patients who are pregnant or breast feeding, or adults of reproductive potential who are not using effective birth control methods. Adequate contraceptives must be used throughout the trial and for 8 weeks after last study drug administration in both sexes. Women of child-bearing potential must have a negative serum pregnancy test within 7 days prior to first administration of study drug.
    12. Patients who have undergone major surgery ≤ 3 weeks prior to starting study drug or who have not recovered from surgery.
    E.5 End points
    E.5.1Primary end point(s)
    The primary efficacy endpoint is this study is overall survival (OS). OS is defined as the time from date of randomization to the date of death from any cause. If a patient is not known to have died at the date of analysis cut-off, the OS will be censored at the last date of contact.
    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 No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic No
    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.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 No
    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 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
    LPLV
    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 months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months4
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero Information not present in EudraCT
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) Information not present in EudraCT
    F.1.1.3Newborns (0-27 days) Information not present in EudraCT
    F.1.1.4Infants and toddlers (28 days-23 months) Information not present in EudraCT
    F.1.1.5Children (2-11years) Information not present in EudraCT
    F.1.1.6Adolescents (12-17 years) Information not present in EudraCT
    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 Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Please refer to the protocol, section 11.3 Informed Consent
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 180
    F.4.2.2In the whole clinical trial 531
    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)
    up to 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 Decision2010-03-22
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2010-04-29
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2013-10-08
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