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    Summary
    EudraCT Number:2009-013435-38
    Sponsor's Protocol Code Number:M10-963
    National Competent Authority:Greece - EOF
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2010-01-19
    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 ConcernedGreece - EOF
    A.2EudraCT number2009-013435-38
    A.3Full title of the trial
    An Open-label, Randomized Phase 3 Study of the Efficacy and Tolerability of Linifanib (ABT-869) versus Sorafenib in Subjects with Advanced Hepatocellular Carcinoma (HCC)
    A.4.1Sponsor's protocol code numberM10-963
    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 SponsorAbbott GmbH & Co. KG
    B.1.3.4CountryGermany
    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 Yes
    D.2.5.1Orphan drug designation numberEMEA/OD/090/07
    D.3 Description of the IMP
    D.3.1Product nameLinifanib
    D.3.2Product code ABT-869
    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 INNLinifanib
    D.3.9.1CAS number 796967-16-3
    D.3.9.2Current sponsor codeABT-869
    D.3.9.3Other descriptive nameA-741439.0
    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.IMP: 2
    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 Yes
    D.2.5.1Orphan drug designation numberEMEA/OD/090/07
    D.3 Description of the IMP
    D.3.1Product nameLinifanib
    D.3.2Product code ABT-869
    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 INNLinifanib
    D.3.9.1CAS number 796967-16-3
    D.3.9.2Current sponsor codeABT-869
    D.3.9.3Other descriptive nameA-741439.0
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    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 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.IMP: 3
    D.1.2 and D.1.3IMP RoleComparator
    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 Nexavar
    D.2.1.1.2Name of the Marketing Authorisation holderBayer Schering Pharma AG
    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/3/06/364
    D.3 Description of the IMP
    D.3.1Product namesorafenib
    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 INNSORAFENIB
    D.3.9.1CAS number 284461-73-0
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Advanced Hepatocellular Carcinoma (HCC)
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 12.0
    E.1.2Level LLT
    E.1.2Classification code 10019828
    E.1.2Term Hepatocellular carcinoma non-resectable
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 12.0
    E.1.2Level LLT
    E.1.2Classification code 10019829
    E.1.2Term Hepatocellular carcinoma recurrent
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the overall survival of oral linifanib given as monotherapy daily compared to sorafenib given twice daily as standard of care in subjects with advanced or metastatic HCC.
    E.2.2Secondary objectives of the trial
    To evaluate time to progression and objective response rate in those subjects treated with linifanib compared with sorafenib.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Subjects will have the option to participate in the folllowing substudies:

    a) Tissue sample collection: Subjects may consent to providing archived tissue samples taken from a biopsy that was performed at the time of their hepatocellular carcinoma diagnosis. These tissue samples may be used to develop a diagnostic test to identify patients most likely to respond to the drug.

    b) Genetic sub-study: Subjects may consent to an additional blood draw that will be used for genetic testing to help determine why some hepatocellular carcinoma patients may benefit from taking ABT-869 more than others do.

    c) ECG Collection: At approximately 1 to 4 study sites, triplicate ECGs (defined as first ECG after 5 minutes supine, second ECG approximately 60 seconds after the first ECG and third ECG approximately 60 seconds after the second ECG) will be obtained for a cohort of approximately 30 evaluable subjects (who consent) randomized to receive linifanib. An exposure-response analysis will be explored to characterize the effect of linifanib on QTcF intervals.
    E.3Principal inclusion criteria
    1. Subject must be an adult ≥ 18 years of age.
    2. Subject must be diagnosed with unresectable or metastatic HCC defined by:
    ● Histologic or cytologic diagnosis OR
    ● European Association for the Study of Liver Criteria
    o Radiological criteria: two coincident imaging techniques (Four techniques
    considered: ultrasound, spiral computed tomography (CT), magnetic
    resonance imaging (MRI) and angiography)
    o Focal lesion > 2 cm with arterial hypervascularization
    o Combined criteria: one imaging technique associated with AFP (alpha
    fetoprotein) > 400 ng/mL
    3. Subjects must have a measurable lesion by RECIST (version 1.1) on CT scan in at
    least one site which has not received prior radiotherapy.
    4. Subjects must show signs of progression (i.e., new lesion per RECIST version 1.1)
    if prior liver-directed therapy was received.
    5. Subject has an Eastern Cooperative Oncology Group (ECOG) Performance status
    of 0 to 1.
    6. Subject must have the following laboratory values:
    ● Total Bilirubin ≤ 3.0 mg/dL or equivalent
    ● AST/ALT ≤ 5 × ULN
    ● PTT ≤ 1.5 × ULN and INR < 1.5
    ● ANC ≥ 1.0 × 109/L
    ● Platelet count ≥ 50 × 109/L if splenomegaly; if splenomegaly is not present,
    platelet count ≥ 75 × 109/L
    ● Serum Creatinine ≤ 1.5 × ULN
    ● Serum Albumin ≥ 2.8 g/dL
    ● PT ≤ 6 seconds prolonged
    7. Women of childbearing potential and men must agree to use adequate
    contraception (one of the following listed below) prior to study entry, for the
    duration of study participation and for 90 days following completion of therapy.
    Women of childbearing potential must have a negative urine pregnancy test within
    7 days prior to initiation of treatment and/or post-menopausal women must be
    amenorrheic for at least 12 months to be considered of non-childbearing potential.
    ● Total abstinence from sexual intercourse (for minimum of one complete
    menstrual cycle prior to study drug administration),
    ● Vasectomized male subjects or vasectomized partner of female subjects,
    ● Hormonal contraceptives (oral, parenteral or transdermal) for at least
    3 months prior to study drug administration,
    ● Double-barrier method (condoms, contraceptive sponge, diaphragm or vaginal
    ring with spermicidal jellies or cream),
    ● Intra-Uterine Device,
    ● Additionally, male subjects (including those who are vasectomized) whose
    partners are pregnant or might be pregnant must agree to use condoms for the
    duration of the study and for 90 days following completion of therapy.
    8. Subject is capable of understanding and complying with parameters as outlined in
    the protocol and able to sign informed consent, approved by an Independent Ethic
    Committee (IEC)/Institutional Review Board (IRB) prior to the initiation of any
    screening or study-specific procedures, and in the opinion of the Study
    Investigator with agreement by the subject, currently no other treatment options
    exist that will provide benefit to the subject and/or the subject is willing to receive
    (e.g., transcatheter arterial chemoembolization).
    E.4Principal exclusion criteria
    1. Subject has received prior systemic (administered intravenously or orally rather
    than locoregionally) treatment for HCC.
    2. Subject has Child-Pugh grade Class B or C hepatic impairment.
    3. Subject has received prior local therapy (including liver-directed therapy) within
    4 weeks prior to study drug administration. Local therapies include but are not
    limited to: surgery, radiation therapy, hepatic arterial embolization, hepatic
    intra-arterial chemotherapy, chemoembolization, radiofrequency ablation,
    percutaneous ethanol injection or cryoablation. In addition, subject has not
    recovered to ≤ Grade 1 clinically significant adverse effects/toxicities of previous
    therapy.
    4. Subject has untreated brain or meningeal metastases. CT scans are not required to
    rule out brain or meningeal metastases unless there is a clinical suspicion of central
    nervous system disease. Subjects with treated brain metastases that are
    radiographically or clinically stable (for at least 4 weeks after therapy) and have no
    evidence of cavitation or hemorrhage in the brain lesion, are eligible provided that
    they are asymptomatic and do not require corticosteroids (must have discontinued
    steroids at least 1 week prior to Study Day 1).
    5. Subject has previous or concurrent cancer that is distinct in primary site or
    histology from HCC except cervical carcinoma in situ, non-melanoma carcinoma
    of the skin or in situ carcinoma of the bladder. Any cancer curatively treated
    greater than 3 years prior to entry is permitted.
    6. Subject has proteinuria defined by the National Cancer Institute Common
    Terminology Criteria for Adverse Events (NCI CTCAE) grade > 1 at baseline as
    measured by a urine dipstick (2+ or greater) and confirmed by a 24 hour urine collection (> 1 g/24 hrs). Subjects may be re-screened if proteinuria is shown to
    be controlled with or without intervention.
    7. Subject currently exhibits symptomatic or persistent, uncontrolled hypertension
    defined as diastolic blood pressure > 90 mmHg or systolic blood pressure
    > 140 mmHg. Subjects may be re-screened if blood pressure is shown to be
    controlled with or without intervention.
    8. Subject has a documented Left Ventricular Ejection Fraction < 50%.
    9. Subject is receiving therapeutic anticoagulation therapy. Low dose
    anti-coagulation (e.g., low dose warfarin) for catheter prophylaxis only will be
    permitted. No low molecular weight heparin (LMW) is allowed.
    10. Subject is receiving anti-retroviral therapy for Human Immunodeficiency Virus
    (HIV). Prophylactic antiviral therapy to prevent Hepatitis B virus (HBV)
    reactivation is allowed.
    11. Female subjects who are pregnant or breast feeding.
    12. Presence of > grade 2 encephalopathy by NCI CTCAE criteria.
    13. Presence of ≥ grade 2 ascites by NCI CTCAE criteria.
    14. Clinically significant uncontrolled condition(s) including but not limited to:
    ● Active uncontrolled infection
    ● Class III or IV heart failure as defined by the New York Heart Association
    functional classification system
    ● Unstable angina pectoris or cardiac arrhythmia
    ● Myocardial infarction within last 6 months
    ● History of adrenal insufficiency
    ● History of cerebral vascular accident within last 6 months
    ● Active ulcerative colitis, Crohn's disease, celiac disease or any other
    conditions that interfere with absorption
    ● History of autoimmune disease with kidney involvement
    ● History of overt bleeding (> 30 mL bleeding/episode) within 3 months of
    study drug administration
    ● Psychiatric illness/social situation that would limit compliance with study
    requirements
    ● Any medical condition, which in the opinion of the study investigator places
    the subject at an unacceptably high risk for toxicities.
    E.5 End points
    E.5.1Primary end point(s)
    Overall survival.
    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 No
    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 No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Quality of life, health economics and outcomes research
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans Information not present in EudraCT
    E.7.1.2Bioequivalence study Information not present in EudraCT
    E.7.1.3Other Information not present in EudraCT
    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 Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    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) Yes
    E.8.2.2Placebo No
    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 concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA55
    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
    The end of study is defined as the date of the last subject's last visit or date of last follow-up contact, whichever is later.
    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 months29
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial months29
    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 No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state20
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 200
    F.4.2.2In the whole clinical trial 900
    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)
    Each subject will be treated per the Investigator's best clinical judgement. In addition, for subjects randomized to receive linifanib, Abbott and the investigator will develop a plan to provide linifanib. As sorafenib is commercially available, Abbott will not provide sorafenib once the entire study is discontinued.
    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 Decision2010-03-05
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2010-06-15
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2012-07-30
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