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    Summary
    EudraCT Number:2004-001773-26
    Sponsor's Protocol Code Number:100554
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2005-02-16
    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 ConcernedGermany - BfArM
    A.2EudraCT number2004-001773-26
    A.3Full title of the trial
    A Phase III randomized, placebo-controlled study of sorafenib in patients with advanced hepatocellular carcinoma
    A.4.1Sponsor's protocol code number100554
    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 SponsorBayer HealthCare AG, D-51368 Leverkusen Germany
    B.1.3.4CountryCanada
    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 numberEU/3/06/364
    D.3 Description of the IMP
    D.3.1Product namesorafenib
    D.3.2Product code BAY 43-9006
    D.3.4Pharmaceutical form Film-coated 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.3.9.2Current sponsor codeBAY 43-9006
    D.3.9.3Other descriptive nameBAY 53-9085: sorafenib tosylate
    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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboFilm-coated tablet
    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
    Advanced hepatocellular carcinoma
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 7.1
    E.1.2Level LLT
    E.1.2Classification code 10049010
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Main objective:
    To evaluate safety, efficacy, PRO, and population PK of sorafenib versus placebo in patients with advanced HCC.

    Primary efficacy objectives:
    • Efficacy in patients treated with sorafenib will be compared to that in patients treated with placebo.
    • There are two primary efficacy objectives, which will be assessed independently.
    o Overall survival (OS)
    o Time to symptomatic progression (TTSP)
    If the analysis of either OS or TTSP (or both) is positive, the efficacy of sorafenib in HCC will be considered established.
    E.2.2Secondary objectives of the trial
    Secondary objectives:
    The secondary efficacy objectives are to assess the following variables between patients treated with sorafenib versus placebo:
    • Time to progression (TTP)
    • Overall disease control rate (Proportion of patients who have a best response rating of complete response [CR], PR or SD according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria, that is maintained for at least 28 days from the first demonstration of that rating)
    • Functional Assessment of Cancer Therapy-Hepatobiliary (FACT-Hep) response rate
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Primary diagnosis
    Patients with advanced HCC, ECOG PS 0, 1, or 2, Child-Pugh status A, who have not received prior systemic anti-cancer treatment for HCC.

    Inclusion Criteria:
    •Male or female patients > 18 years of age
    •Patients who have a life expectancy of at least 12 weeks
    •Patients with advanced HCC
    •Patients with histologically or cytologically documented HCC (original biopsy at first diagnosis is acceptable)
    •Patients must have at least one tumor lesion that meets both of the following criteria:
     The lesion can be accurately measured in at least one dimension according to RECIST
     The lesion has not been previously treated with local therapy (such as surgery, radiation therapy, hepatic arterial therapy, chemoembolization, radiofrequency ablation, percutaneous ethanol injection or cryoablation)
    •Patients who have received local therapy, such as surgery, radiation therapy, hepatic arterial embolization, chemoembolization, radiofrequency ablation, percutaneous ethanol injection or cryoablation are eligible. Previously treated lesions will not be selected as target lesions. Local therapy must be completed at least 4 weeks prior to the baseline scan.
    •Patients who have an ECOG PS of 0, 1, or 2
    •Cirrhotic status of Child-Pugh class A only. Child-Pugh assessment is to be carried out during the screening period.
    The following laboratory parameters:
     Platelet count >= 60 x 109/L
     Hemoglobin >= 8.5 g/dL
     Total bilirubin <= 3 mg/dL
     Albumin >= 2.8 g/dL
     Alanine transaminase (ALT) and AST <= 5 x upper limit of normal
     Amylase and lipase <=1.5 x the upper limit of normal
     Serum creatinine <= 1.5 x the upper limit of normal
     Prothrombin time (PT)-international normalized ratio (INR) <= 2.3 or PT <= 6 seconds above control. Patients who are being therapeutically anticoagulated with an agent such as Coumadin or heparin will be allowed to participate provided that no prior evidence of underlying abnormality in these parameters exists.
    • Patients who give written informed consent prior to any study specific screening procedures with the understanding that the patient has the right to withdraw from the study at any time, without prejudice.

    Extension with Crossover Phase
    The inclusion criteria required for this segment of the study are the following:
    •Patients must provide written informed consent prior to any study specific screening procedures with the understanding that the patient has the right to withdraw from the study at any time, without prejudice.
    •Patients must either be currently participating in the double-blind portion of the study, or are currently in follow-up.
    •A patient who had previously discontinued double-blind therapy due to a drug related toxicity and after unblinding was determined to have been on sorafenib, must be re-assessed by the investigator who must judge whether the patient may derive benefit from re-starting sorafenib treatment. The toxicity responsible for treatment discontinuation must resolve or improve to a level that allows re-initiation of sorafenib therapy.
    •Prior use of systemic anti-cancer therapy is allowed but concomitant systemic anti-cancer therapy is not allowed.
    E.4Principal exclusion criteria
    • Previous or concurrent cancer that is distinct in primary site or histology from HCC, EXCEPT cervical carcinoma in situ, treated basal cell carcinoma, superficial bladder tumors (Ta, Tis & T1). Any cancer curatively treated > 3 years prior to entry is permitted.
    • Renal failure requiring hemo- or peritoneal dialysis
    • History of cardiac disease: congestive heart failure > New York Heart Association (NYHA) class 2; active coronary artery disease (CAD); cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers or digoxin), or uncontrolled hypertension. Myocardial infarction more than 6 months prior to study entry is permitted.
    • Active clinically serious infections (> grade 2 National Cancer Institute [NCI]-Common Terminology Criteria for Adverse Events [CTCAE] version 3.0)
    • Known history of human immunodeficiency virus (HIV) infection
    • Known Central Nervous System tumors including metastatic brain disease
    • Patients with clinically significant gastrointestinal bleeding within 30 days prior to study entry
    • History of organ allograft
    • Substance abuse, medical, psychological or social conditions that may interfere with the patient’s participation in the study or evaluation of the study results
    • Known or suspected allergy to the investigational agent or any agent given in association with this trial
    • Patients unable to swallow oral medications
    • Any condition that is unstable or which could jeopardize the safety of the patient and his/her compliance in the study
    • Pregnant or breast-feeding patients. Women of childbearing potential must have a negative pregnancy test performed within seven days prior to the start of study drug. Both men and women enrolled in this trial must use adequate barrier birth control measures during the course of the trial.

    Excluded therapies and medications, previous and concomitant
    • Prior use of any systemic anti-cancer chemotherapy for HCC
    • Prior use of systemic investigational agents for HCC
    • Prior use of Raf-kinase inhibitors (RKI), VEGF inhibitors, MEK inhibitors or Farnesyl transferase inhibitors
    • Major surgery within 4 weeks of start of study drug
    • Radiotherapy during study or within 3 weeks prior to start of study drug. (Palliative radiotherapy will be allowed as described in Prior and Concomitant Therapy)
    • Use of biologic response modifiers, such as granulocyte colony-stimulating factor (G-CSF), within 3 weeks prior to study entry. (G-CSF and other hematopoietic growth factors may be used in the management of acute toxicity such as febrile neutropenia when clinically indicated or at the discretion of the investigator; however they may not be substituted for a required dose reduction). Patients taking chronic erythropoietin are permitted provided no dose adjustment is undertaken within 1 month prior to the study or during the study.
    • Autologous bone marrow transplant or stem cell rescue within four months of start of study drug
    • Concomitant treatment with rifampin and St John’s wort

    Extension with Crossover Phase
    The exclusion criterion required for this segment of the study is the following:
    •Pregnant or breast-feeding patients. Women of childbearing potential must have a negative pregnancy test performed within seven days prior to enrolling in this portion of the study.
    E.5 End points
    E.5.1Primary end point(s)
    Primary efficacy variables
    • Overall Survival (OS)
    • Time to symptomatic progression (TTSP)
    Secondary efficacy variables
    • Time to progression (TTP)
    • Disease control rate
    • Patient Reported Outcomes (PRO) as measured by total score on FACT-Hep
    • Tertiary efficacy variables
    • Overall response rate
    • Overall response duration
    • Time to response
    • Patient Reported Outcomes (PRO) as measured by Physical and Functional Well-Being subscales of the FACT-Hep
    Other variables
    • Population PK parameters
    • Correlation between the following baseline characteristics (in order of priority) and key clinical endpoints (ie, response, TTP, TTSP, and OS): tumor pERK, phospho VEGF-R2 concentration, plasma proteomics, and gene expression profiling of blood cells and tumor biopsies
    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 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 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.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA72
    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 the trial is dependant on Overall Survival. Overall survival data will be considered mature and the final analysis will be performed when approximately 424 events (deaths) are observed.
    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 months26
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial months26
    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 state
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 208
    F.4.2.2In the whole clinical trial 560
    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 Decision2005-03-23
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2005-05-03
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2008-11-21
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