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    Summary
    EudraCT Number:2009-010760-42
    Sponsor's Protocol Code Number:4SC-201-1-2009
    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:2009-04-03
    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 number2009-010760-42
    A.3Full title of the trial
    A proof-of-concept Phase II study to evaluate efficacy, safety and pharmacokinetics of 4SC-201 and the treatment combination of Sorafenib plus 4SC-201 in patients with hepatocellular carcinoma exhibiting progressive disease under Sorafenib treatment
    A.3.2Name or abbreviated title of the trial where available
    SHELTER
    A.4.1Sponsor's protocol code number4SC-201-1-2009
    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 Sponsor4SC AG
    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 No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameResminostat
    D.3.2Product code 4SC-201
    D.3.4Pharmaceutical form Capsule, hard
    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.3.9.1CAS number 864814-88-0
    D.3.9.2Current sponsor code4SC-201
    D.3.9.3Other descriptive nameBYK408740 (old substance code)
    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.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 Yes
    D.2.1.1.1Trade name Nexavar
    D.2.1.1.2Name of the Marketing Authorisation holderBayer Healthcare 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.3.4Pharmaceutical 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.3.9.1CAS number L01XE05
    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
    Patients aged ≥ 18, of both gender, with advanced stage hepatocellular carcinoma, BCLC class B (intermediate stage, performance status-ECOG 0, multinodular HCC) or C (advanced stage, performance status-ECOG 1-2, invasive tumor pattern (vascular invasion/extra hepatic spread)), with either histological proven HCC or clinical diagnosis of HCC by AASLD criteria. For patients without cirrhosis, histological confirmation of HCC is mandatory.
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    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
    To determine Progression Free Survival Rate (PFSR) after 12 weeks.
    E.2.2Secondary objectives of the trial
    To establish the MTD of 4SC-201 in combination with Sorafenib;

    To investigate safety and tolerability of repeated oral doses of 4SC-201 and of the treatment combination of ascending repeated oral doses of 4SC-201 and Sorafenib;

    To investigate Overall Response Rate (ORR) of repeated oral doses of 4SC-201 and of treatment combination of Sorafenib plus 4SC-201;

    To determine Time to Progression (TTP) of repeated oral doses of 4SC-201 and of treatment combination of Sorafenib plus 4SC 201, including radiological and symptomatic progression;

    To assess Overall Survival (OS) in patients getting repeated oral doses of 4SC-201 or the combination of Sorafenib plus 4SC-201;

    To determine Progression Free Survival (PFS) of repeated oral doses of 4SC-201 and of treatment combination of Sorafenib plus 4SC 201, including radiological and symptomatic progression;

    To determine PFSR after 6 weeks (C5D1 [Day 43]) and 20 weeks;
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Male or female ≥ 18 years;
    2. Written informed consent obtained prior to any trial specific procedure;
    3. Advanced stage hepatocellular carcinoma, BCLC class B (intermediate stage, performance status 0, multinodular HCC) or C (advanced stage, performance status-ECOG 1-2, invasive tumor pattern (vascular invasion/extra hepatic spread)), with either histological proven HCC or clinical diagnosis of HCC by AASLD criteria (HCC defined in cirrhotic patients by one imaging technique (CT, MRI or second generation contrast ultrasound) showing a nodule of > 2 cm with contrast uptake in the arterial phase and washout in venous or late phases or two imaging techniques showing this radiological behavior for nodules of 1 to 2 cm in diameter), exhibiting PD under Sorafenib treatment. For patients without cirrhosis, histological confirmation of HCC is mandatory;
    4. Exhibiting PD under Sorafenib treatment, as detected by at least one CT/MRI scan within 4 weeks prior to study inclusion. PD will be confirmed by an independent radiological review;
    5. Child-Pugh class A and B. Only patients with Child-Pugh index class B of not more than 7 will be included. Patients with more than slight ascites or hepatic encephalopathy > Grade 1 are excluded (see exclusion criteria);
    6. ECOG performance status 0, 1 or 2 (refer to Appendix C for definitions of ECOG grades);
    7. Life expectancy of 12 weeks or more;
    8. Precedent first-line treatment with Sorafenib minimum dosing of 400 mg per day for at least 8 weeks. Treatment interruptions for any reason must not be more in the sum than 14 days within this 8 week period. Patients have stopped Sorafenib therapy not more than 10 weeks prior to treatment start, but at least 2 weeks prior to treatment start
    9. Adequate hematological parameters, as demonstrated by:
    • Hemoglobin ≥ 9.0 g/dl (SI units: 5.6 mmol/l);
    • WBC ≥ 3.0 x 109/l;
    • Absolute neutrophil count ≥1,500/mm3;
    • Platelets ≥ 75 x 109/l;
    • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 7.5 times upper limit of normal range (ULNR);
    • Bilirubin ≤ 5 mg/dl;
    • Serum creatinine ≤ 1.5 mg/dl (SI units: 132 µmol/l);
    • Partial Thromboplastin Time (PTT) International Normalized Ratio (INR) ≤ 2.3
    • Serum potassium, magnesium and calcium within normal range
    10. Safe contraception in females of childbearing potential during the entire study using an established treatment with hormonal contraceptives for at least 2 months prior to start of screening;
    11. For females of child bearing potential (without using hormonal contraceptives for at least 2 months prior to start of screening) a double contraception method is requested during the entire study meeting the criteria for an effective method of birth control. That means at least two effective birth control methods such as condoms, diaphragms or intra-uterine devices must be used;
    12. Male patients with partners of child bearing potential are requested to use barrier contraception in addition to having their partner use another method of contraception during the trial and for 3 months after the last dose. Male patients will also be advised to abstain from sexual intercourse with pregnant or lactating women, or to use condoms;
    13. Completes a period of at least 30 days since ending investigational device or drug trials and have recovered from treatment-related toxicities;
    14. Able to comply with all the requirements of the protocol.
    E.4Principal exclusion criteria
    1. 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 and T1). Any cancer curatively treated > 3 years prior to entry is permitted;
    2. Renal failure requiring hemo- or peritoneal dialysis;
    3. Known central nervous system (CNS) tumors including symptomatic brain metastasis;
    4. Patients with no adequate treatment for gastrointestinal bleeding and esophagus varices within 14 days prior to study entry. IMP administration is scheduled to start within 14 days after adequate treatment.
    5. Child-Pugh index class B in combination with more than slight ascites or hepatic encephalopathy > Grade I (see Child-Pugh index, Appendix D);
    6. History and current cardiovascular complications, including unstable angina pectoris, uncontrolled hypertension, congestive heart failure (NYHA Class III or IV) related to primary cardiac disease, a condition requiring anti arrhythmic therapy, ischemic or severe valvular heart disease, or a myocardial infarction within 6 months prior to the trial entry; A marked baseline prolongation of QT/QTc interval, e.g., repeated demonstration of a QTc interval > 500 msec; Long QT Syndrome; the required use of concomitant medication on 4SC-201 dosing days that may substantially increase the risk of Torsade de Pointes (see Appendix B);
    7. Concurrent treatment with drugs that can prolong the QT interval (see Appendix B) and treatment with cytokine growth factors;
    8. Current evidence of any severe internal, psychiatric or neurologic disease;
    9. Altered mental status precluding understanding of the informed consent process and/or completion of the necessary studies;
    10. Pregnant or breastfeeding women;
    11. Sorafenib intolerance;
    12. History of allergic reactions attributed to compounds of similar chemical or biological composition to the study drug;
    13. Active alcohol and/or drug abuse;
    14. Major surgery within the last 4 weeks;
    15. Patients who are employees at the investigational center, relatives or spouse of the investigator.
    E.5 End points
    E.5.1Primary end point(s)
    Progression-free survival at 12 weeks.
    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 No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    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 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) Yes
    E.7.3Therapeutic confirmatory (Phase III) Information not present in EudraCT
    E.7.4Therapeutic use (Phase IV) Information not present in EudraCT
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised Information not present in EudraCT
    E.8.1.2Open Information not present in EudraCT
    E.8.1.3Single blind Information not present in EudraCT
    E.8.1.4Double blind Information not present in EudraCT
    E.8.1.5Parallel group Information not present in EudraCT
    E.8.1.6Cross over Information not present in EudraCT
    E.8.1.7Other Information not present in EudraCT
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Information not present in EudraCT
    E.8.2.2Placebo Information not present in EudraCT
    E.8.2.3Other Information not present in EudraCT
    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 concerned8
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA14
    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 Information not present in EudraCT
    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
    The total treatment duration is not limited given the patient shows no PD or persisting non-acceptable toxicity effects.
    July 2009 (First-Patient-In [FPI]) to May 2012(Last-Patient-In [LPI]).
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months11
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months11
    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 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 state74
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 74
    F.4.2.2In the whole clinical trial 74
    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 Decision2009-06-19
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2009-06-09
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2013-06-18
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