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    Summary
    EudraCT Number:2012-005375-14
    Sponsor's Protocol Code Number:TS-104
    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:2013-04-17
    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 number2012-005375-14
    A.3Full title of the trial
    A prospective randomized clinical trial on 90Yttrium trans-arterial
    radio-Embolization (Therasphere) vs. standard of care (sorafenib)
    for the treatment of advanced Hepatocellular carcinoma (HCC)
    with Portal Vein Thrombosis (PVT)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A prospective randomized clinical trial with the medical device Therasphere versus the drug sorafenib for the treatment of liver cancer (HCC) with a clot in the major liver (Portal Vein Thrombosis - PVT)
    A.3.2Name or abbreviated title of the trial where available
    YES-P
    A.4.1Sponsor's protocol code numberTS-104
    A.5.4Other Identifiers
    Name:ClinicalTrials.gov IdentifierNumber:NCT01887717
    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 SponsorBiocompatibles UK Ltd
    B.1.3.4CountryUnited Kingdom
    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 supportBiocompatibles UK Ltd
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationTheorem Clinical Research
    B.5.2Functional name of contact pointProject management
    B.5.3 Address:
    B.5.3.1Street AddressMethuen South, Methuen Park
    B.5.3.2Town/ cityChippenham
    B.5.3.3Post codeSN14 0GT
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number+441353777768
    B.5.5Fax number+441249444189
    B.5.6E-mailrebecca.thompson@theoremclinical.com
    D. IMP Identification
    D.IMP: 1
    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 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.3.4Pharmaceutical form Film-coated tablet
    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 INNSORAFENIB TOSYLATE
    D.3.9.1CAS number 475207-59-1
    D.3.9.4EV Substance CodeSUB22347
    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) 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
    Advanced Hepatocellular Carcinoma (HCC) with Portal Vein Thrombosis (PVT)
    E.1.1.1Medical condition in easily understood language
    Liver cancer
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 17.0
    E.1.2Level LLT
    E.1.2Classification code 10019828
    E.1.2Term Hepatocellular carcinoma non-resectable
    E.1.2System Organ Class 100000004864
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 17.0
    E.1.2Level PT
    E.1.2Classification code 10036206
    E.1.2Term Portal vein thrombosis
    E.1.2System Organ Class 10019805 - Hepatobiliary disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Assess efficacy and safety of TheraSphere in comparison to standard of care therapy (sorafenib) in the treatment of patients with portal vein thrombosis associated with unresectable hepatocellular carcinoma.
    E.2.2Secondary objectives of the trial
    Not applicable
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Patients over 18 years of age, regardless of race or gender
    2. Advanced stage HCC confirmed by histology (mandatory in non cirrhotic patients) or non-invasive criteria (EASL/AASLD) with branch PVT.
    -Either naïve or recurrent HCC after curative treatment (minimum 6 3 months from curative treatment - minor resection or local ablation) is acceptable.
    -Branch PVT classified as Type I, Type II or Type IIIa (see Section 9.2.5).
    3. Unilobar disease as defined in Section 8.1.
    4. Tumor volume ≤ 70% of liver volume (determined by visual estimation)
    5. Child-Pugh A
    6. At least one uni-dimensional HCC target lesion assessable according to the RECIST v1.1 criteria by CT-scan or MRI
    7. No confirmed extrahepatic metastases. Patients with indeterminate hepatic hilar lymph nodes up to 2.5 cm in greatest dimension, or with indeterminate lung nodules (single lesion between 1-1.5cm, or multiple smaller lesions with a total diameter ≤ 2 cm) may be included if metastatic disease is deemed unlikely
    8. No known contraindications to standard-of-care sorafenib including allergic reaction, pill swallowing difficulty, uncontrolled hypertension or history of cardiac disease (according to sorafenib package insert and country-specific policies, may include evidence of severe or uncontrolled systemic diseases, cardiac arrhythmias (requiring anti-arrhythmic therapy or pace maker), congestive cardiac failure >New York Heart Association class 2, myocardial infarct within 6 months, prolonged QT/QTc >450ms), or laboratory finding that in the view of the investigator makes it undesirable for the patient to participate in the trial uncontrolled hypertension or history of cardiac disease, significant GI bleed within 30 days, renal failure requiring dialysis
    9. No evidence of hepatic vein invasion or caval thrombosis
    10. Cancer-related symptoms within the ECOG 0-1 category
    11. PLT ≥ 50 x103/µL
    12. WBC ≥ 1.5 x103/µL
    13. AST/ALT ≤ 5 times the upper limit of normal (U/L)
    14. Creatinine ≤ 2.0 mg /dL
    15. No evidence of pulmonary insufficiency or clinically evident chronic obstructive pulmonary disease.
    16. No indication for any possible curative treatment after multidisciplinary assessment (surgery, ablation, transplantation)
    17. No previous treatment with Sorafenib for more than 4 weeks during the 2 previous months; no prior sorafenib-related toxicity at any dose and/or duration defined as documented sorafenib-related grade 3 or 4 adverse events that led to sorafenib discontinuation
    18. No initiation of any other anti-tumor therapy including chemotherapy, radioembolization (maximum lung shunt of 20% for prior radioembolization) or investigational drug treatment within 30 days before the beginning of the study
    19. In case of patients progressing from an intermediate to an advance stage because of occurrence of PVT, enrolment is allowed if previous conventional or drug eluting TACE was performed at least 6 3 months prior to screening phase
    20. Patients cannot be on a liver transplantation list
    21. No history of organ allograft
    22. No contraindication to angiography or selective visceral catheterization
    23. No history of severe allergy or intolerance to contrast agents, narcotics, sedatives or atropine that cannot be managed medically
    24. No previous external beam radiation treatment to the liver
    25. No evidence of continuing adverse effect of prior therapy
    26. No active GI bleeding and any bleeding diathesis or coagulopathy that is not correctable by usual therapy or haemostatic agents (e.g., closure device)
    27. No evidence of any disease or condition that would place the patient at undue risk and preclude safe use of microspheres (TheraSphere®) treatment
    28. Negative serum pregnancy test in females of child-bearing potential; patients who are breast-feeding cannot participate in this trial
    29. Life expectancy of greater than 3 months
    30. No participation in concurrent interventional clinical trials
    31. Signed informed consent form
    E.4Principal exclusion criteria
    Not applicable
    E.5 End points
    E.5.1Primary end point(s)
    Overall Survival
    E.5.1.1Timepoint(s) of evaluation of this end point
    D0 until patient dies
    E.5.2Secondary end point(s)
    • Time to progression (TTP) based on investigator assessment according to RECIST v 1.1, modified RECIST and EASL response criteria
    • Time to worsening of PVT
    • Time to symptomatic progression (TTSP)
    • Tumor response according to RECIST v 1.1, modified RECIST and EASL response criteria based on investigator evaluations
    • Patient reported outcome (PRO) as assessed by the Functional Assessment of
    Cancer Therapy – Hepatobiliary Questionnaire (FACT-Hep) questionnaire
    • Adverse events
    E.5.2.1Timepoint(s) of evaluation of this end point
    • Time to progression (TTP): D0, W4, W8, W12, W16, W20, W24, WQ8
    • Time to worsening of PVT: D0, W8, W16, W24, WQ8
    • Time to symptomatic progression (TTSP): D0 until ECOG performance status ≥2
    • Tumor response: D-14 to 0, W4, W8, W12, W16, W20, W24, WQ8
    • Patient reported outcome: D-14 to 0, W4, W8, W12, W16, W20, W24, WQ8
    • Adverse events: D-14 to 0, W2, W4, W8, W12, W16, W20, W24, WQ8

    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 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 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 Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    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 No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    Medical device trial with the IMP sorafenib being the comparator
    E.8.2.4Number of treatment arms in the trial2
    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 concerned1
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA21
    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 No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Canada
    Hong Kong
    Korea, Republic of
    Singapore
    Switzerland
    Taiwan
    United States
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months6
    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: 160
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 160
    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 state10
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 318
    F.4.2.2In the whole clinical trial 318
    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)
    None
    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 Decision2013-05-17
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-06-03
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2017-05-23
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