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    The EU Clinical Trials Register currently displays   43974   clinical trials with a EudraCT protocol, of which   7312   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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    Summary
    EudraCT Number:2011-002445-36
    Sponsor's Protocol Code Number:0001
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2011-08-31
    Trial 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 ConcernedNetherlands - Competent Authority
    A.2EudraCT number2011-002445-36
    A.3Full title of the trial
    Neo-adjuvant dovitinib in patients with hepatocellular carcinoma prior to local treatment: a phase II study
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Treatment with dovitinib in patients with liver cancer before local treatment: a phase II study
    A.3.2Name or abbreviated title of the trial where available
    Neo-adjuvant dovitinib in HCC
    A.4.1Sponsor's protocol code number0001
    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 SponsorDepartment of Clinical Oncology, Leiden University Medical Center
    B.1.3.4CountryNetherlands
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportNovartis Pharma Services AG
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationDepartment of Clinical Oncology, Leiden University Medical Center
    B.5.2Functional name of contact pointprof. dr. S. Osanto
    B.5.3 Address:
    B.5.3.1Street AddressAlbinusdreef 2
    B.5.3.2Town/ cityLeiden
    B.5.3.3Post code2333 ZA
    B.5.3.4CountryNetherlands
    B.5.4Telephone number31715263464
    B.5.5Fax number31715266760
    B.5.6E-mails.osanto@lumc.nl
    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 nameTKI258
    D.3.2Product code TKI258
    D.3.4Pharmaceutical form Capsule
    D.3.4.1Specific paediatric formulation No
    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 INNdovitinib
    D.3.9.1CAS number 915769-50-5
    D.3.9.2Current sponsor codeTKI258
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    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) 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 No
    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
    Hepatocellular carcinoma, not metastatic
    E.1.1.1Medical condition in easily understood language
    Liver cancer that has not spread to other parts of the body
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.0
    E.1.2Level LLT
    E.1.2Classification code 10019830
    E.1.2Term Hepatocellular carcinoma resectable
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.0
    E.1.2Level LLT
    E.1.2Classification code 10019828
    E.1.2Term Hepatocellular carcinoma non-resectable
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    1. Toxicity and Safety of TKI 258 (all grades, and grade 3 or 4 toxicities).
    2. Tumor response according to RECIST criteria (version 1.1) after 4 weeks of treatment as determined by CT-imaging and changes in intratumoral blood flow as measured by CT perfusion imaging.
    3. Histopathology of HCC specimens obtained following 4 weeks of treatment with TKI258 (comparison with pre-treatment biopsy, parameters: e.g. tumor necrosis, percentage of vital tumor cells, vascular density).
    E.2.2Secondary objectives of the trial
    1. Progression free survival of local relapse.
    2. Immunohistochemistry: changes in FGFR1, FGFR2, FGFR3, FGFR4, bFGF, FGF19, HGF, PLGF, cleaved caspase-3, Ki-67, CD31, pERK, M30/M65, and correlation with clinical data.
    3. Changes in plasma levels of VEGF, basic FGF, soluble VEGFR1, soluble VEGFR2, FGF2, FGF23, FGF19, HGF, cKit, and inhibition of ERK (extracellular receptor kinase) phosphorylation in PBMC’s (pre-treatment, day 15, day 26, and 1 month after local treatment) and correlation with clinical data.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Histological or cytological confirmed HCC or HCC diagnosed by the Barcelona criteria.
    2. HCC stage A or B according to the Barcelona Clinic Liver Cancer (BCLC) staging classification (appendix 2; Llovet et al, 2008a).
    3. Patients eligible for local therapy, i.e. RF-ablation, chemo-embolization, or surgical resection
    4. ECOG (WHO) performance status 0, 1, or 2
    5. Age ≥ 18 years old
    6. At least one uni-dimensional measurable lesion. Lesions must be measured by CT-scan or MRI-scan
    7. Patients must have adequate bone marrow, liver and renal function as assessed by the following laboratory requirements:
    • Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
    • Platelets ≥ 75 x 109/L
    • Hemoglobin (Hgb) ≥ 6.0 mmol/L
    • Serum total bilirubin: ≤ 1.5 x ULN
    • Child-Pugh score of up to 6 points, i.e. Child-Pugh classe A (appendix 3), with no encephalopathy. Child-Pugh status must be calculated based on clinical findings and laboratory results during the baseline/screening period
    • ALT and AST ≤ 3.0 x ULN (with or without liver metastases)
    • Serum creatinine ≤ 1.5 x ULN or serum creatinine >1.5 – 3 x ULN if calculated creatinine clearance (CrCl) is ≥ 30 mL/min using the Cockroft-Gault equation, see formula below:
    CrCl = [140-age (years)] x weight (kg) / [72 x serum Cr (mg/dL)]
    (if patient is female multiply the above by 0.85)
    8. Life expectancy of at least 3 months
    9. Patients who give a written informed consent obtained according to local guidelines
    E.4Principal exclusion criteria
    1. Patients with brain metastases or who have signs/symptoms attributable to brain metastases and have not been assessed with radiologic imaging to rule out the presence of brain metastases
    2. Patients with another primary malignancy within 3 years prior to starting study drug, with the exception of adequately treated in-situ carcinoma of the uterine cervix, skin cancer (such as basal cell carcinoma, squamous cell carcinoma, or non-melanomatous skin cancer), or superficial bladder tumors (Ta, Tis, and T1)
    3. Patients who have received the last administration of an anticancer therapy including chemotherapy, immunotherapy, hormonal therapy and monoclonal antibodies (but excluding nitrosurea, mitomycin-C, targeted therapy and radiation) ≤ 4 weeks prior to starting study drug, or who have not recovered from the side effects of such therapy
    4. Patients who have received the last administration of nitrosurea or mitomycin-C ≤ 6 weeks prior to starting study drug, or who have not recovered from the side effects of such therapy
    5. Patients who have received targeted therapy (e.g. sunitinib, sorafenib, pazopanib) ≤ 2 weeks prior to starting study drug, or who have not recovered from the side effects of such therapy
    6. Patients who have had radiotherapy ≤ 4 weeks prior to starting study drug, or ≤ 2 weeks prior to starting study drug in the case of localized radiotherapy (e.g. for analgesic purpose or for lytic lesions at risk of fracture), or who have not recovered from radiotherapy toxicities
    7. Patients who have undergone major surgery (e.g. intra-thoracic, intra-abdominal or intra-pelvic), open biopsy or significant traumatic injury ≤ 4 weeks prior to starting study drug, or patients who have had minor procedures, percutaneous biopsies or placement of vascular access device ≤ 1 week prior to starting study drug, or who have not recovered from side effects of such procedure or injury
    8. Patients with any of the following concurrent severe and/or uncontrolled medical conditions which could compromise participation in the study:
    • Impaired cardiac function or clinically significant cardiac diseases, including any of the following:
    a. History or presence of serious uncontrolled ventricular arrhythmias
    b. Clinically significant resting bradycardia
    c. LVEF assessed by 2-D echocardiogram (ECHO) < 50% or lower limit of normal (which ever is higher) or multiple gated acquisition scan (MUGA) < 45% or lower limit of normal (which ever is higher)
    d. Any of the following within 6 months prior to starting study drug: myocardial infarction (MI), severe/unstable angina, Coronary Artery Bypass Graft (CABG), Congestive Heart Failure (CHF), Cerebrovascular Accident (CVA), Transient Ischemic Attack (TIA), Pulmonary Embolism (PE)
    e. Uncontrolled hypertension defined by a SBP ≥ 160 mm Hg and/or DBP ≥ 100 mm Hg, with or without anti-hypertensive medication(s)
    • Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of dovitinib (e.g. ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection)
    • Known diagnosis of human immunodeficiency virus (HIV) infection (HIV testing is not mandatory)
    • Patients who are currently receiving anticoagulation treatment with therapeutic doses of warfarin
    • Other concurrent severe and/or uncontrolled concomitant medical conditions (e.g. active or uncontrolled infection, uncontrolled diabetes) that could cause unacceptable safety risks or compromise compliance with the protocol
    9. Pregnant or breast-feeding women
    10. Women of child-bearing potential, who are biologically able to conceive, not employing two forms of highly effective contraception. Highly effective contraception (e.g. male condom with spermicidal jelly, foam suppository or film, diaphragm with spermicide) must be used by both sexes during the study and must be continued for 8 weeks after the end of study treatment. Oral, implantable, or injectable contraceptives may be affected by cytochrome P450 interactions, and are therefore not considered effective for this study. Women of child-bearing potential, defined as sexually mature women who have not undergone a hysterectomy or who have not been naturally postmenopausal for at least 12 consecutive months (i.e., who has had menses any time in the preceding 12 consecutive months), must have a negative serum pregnancy test ≤ 14 days prior to starting study treatment and must use two forms of highly effective contraception (also applicable to their partners who are biologically able to conceive).
    11. Fertile males not willing to use contraception, as stated above
    12. Patients unwilling or unable to comply with the protocol
    E.5 End points
    E.5.1Primary end point(s)
    1. Toxicity and Safety of TKI258 (all grades, and grade 3 or 4 toxicities).
    2. Tumor response according to RECIST criteria (version 1.1) after 4 weeks of treatment as determined by CT-imaging and changes in intratumoral blood flow as measured by CT perfusion imaging.
    3. Histopathology of HCC specimens obtained following 4 weeks of treatment with TKI258 (comparison with pre-treatment biopsy, parameters: e.g. tumor necrosis, percentage of vital tumor cells, vascular density).
    E.5.1.1Timepoint(s) of evaluation of this end point
    After 4 weeks of treatment with TKI258, at the time of local treatment and one month after local treatment of the hepatocellular carcinoma
    E.5.2Secondary end point(s)
    1. Progression free survival of local relapse.
    2. Immunohistochemistry: changes in FGFR1, FGFR2, FGFR3, FGFR4, bFGF, FGF19, HGF, PLGF, cleaved caspase-3, Ki-67, CD31, pERK, M30/M65, and correlation with clinical data.
    3. Changes in plasma levels of VEGF, basic FGF, soluble VEGFR1, soluble VEGFR2, FGF2, FGF23, FGF19, HGF, cKit, and inhibition of ERK (extracellular receptor kinase) phosphorylation in PBMC’s (pre-treatment, day 15, day 26, and 1 month after local treatment) and correlation with clinical data.
    E.5.2.1Timepoint(s) of evaluation of this end point
    For 1: 1,5 year after inclusion of the first patient into this study.
    For 2 and 3: At the time of local treatment of the hepatocellualr carcinoma.
    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 No
    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 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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open No
    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) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee No
    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
    Last patient last visit
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days1
    E.8.9.2In all countries concerned by the trial years0
    E.8.9.2In all countries concerned by the trial months0
    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: 15
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 5
    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.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)
    Normal treatment of that condition
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2011-08-30
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2011-10-31
    P. End of Trial
    P.End of Trial StatusOngoing
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