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    Summary
    EudraCT Number:2011-002843-92
    Sponsor's Protocol Code Number:BA2011/03/04
    National Competent Authority:Austria - BASG
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2013-07-03
    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 ConcernedAustria - BASG
    A.2EudraCT number2011-002843-92
    A.3Full title of the trial
    Multicentre, randomised, controlled, open-label, study comparing the efficacy and safety of slow repeated intravenous infusions of 2 doses of Doxorubicin Transdrug™ (DT) (20 mg/m² or 30 mg/m²) to those of best standard of care (BSC) in patients with advanced hepatocellular carcinoma (HCC) after failure or intolerance to sorafenib - ReLive Study
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study comparing the efficacy and safety of doxorubicin Transdrug™ administered intravenously to the best available treatment in patient suffering from liver cancer after treatment with sorafenib.
    A.3.2Name or abbreviated title of the trial where available
    ReLive
    A.4.1Sponsor's protocol code numberBA2011/03/04
    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 SponsorOnxeo
    B.1.3.4CountryFrance
    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 supportOnxeo
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationOnxeo
    B.5.2Functional name of contact pointClinical Director
    B.5.3 Address:
    B.5.3.1Street Address49 boulevard du Général Martial Valin
    B.5.3.2Town/ cityParis
    B.5.3.3Post code75015
    B.5.3.4CountryFrance
    B.5.4Telephone number33145587600
    B.5.5Fax number33145580881
    B.5.6E-mailclinicaltrials@onxeo.com
    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/3/04/229
    D.3 Description of the IMP
    D.3.1Product nameDoxorubicin Transdrug
    D.3.2Product code BA003
    D.3.4Pharmaceutical form Powder for suspension for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous drip use (Noncurrent)
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNdoxorubicin
    D.3.9.1CAS number 25316-40-9
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number9 to 11
    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)
    E.1.1.1Medical condition in easily understood language
    Hepatic cancer
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To compare the overall survival (OS) of repeated slow IV infusions of 20 or 30 mg/m2 DT to the Best Standard of Care (BSC) in patients with advanced HCC after failure or intolerance to Sorafenib.
    E.2.2Secondary objectives of the trial
    - To compare additional efficacy parameters as progression free-survival (PFS) and objective reponse rate
    - To determine the optimal dose of DT infusions;
    - To evaluate the safety of DT;
    - To assess PK parameters of DT at the doses of 20 and 30 mg/m2;
    - To evaluate pharmacodynamics parameters and predictive factors of safety and efficacy: relationship between efficacy and safety (clinical, biological…) parameters, concentrations of doxorubicin and blood biomarkers.
    - To measure QoL (Quality of Life) using a generic health-related questionnaire
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Male or non-pregnant, non-breast feeding female;
    2. Aged ≥ 18 years;
    3. Patients with
    - advanced HCC (BCLC-C according to BCLC staging classification) having progressed under Sorafenib therapy or intolerant to Sorafenib, or
    - intermediate HCC (BCLC-B) non eligible or non responders to transarterial chemoembolization (TACE), and having progressed under or intolerant to Sorafenib therapy;
    4. Patients with porta hepatis lymph nodes, extrahepatic metastases, or portal/suprahepatic vein thrombosis without extension in inferior/superior vena cava, are eligible;
    5. HCC diagnosed according to the AASLD and/or EASL criteria:
    - Radiological Criteria applicable in cirrhotic liver:
    - Nodule ≥ 10 mm: one imaging technique among MRI and CT-scan showing typical appearances for HCC defined as arterial enhancement and rapid washout in portal venous or delayed phase;
    - If appearance not typical for HCC on initial imaging: second contrast enhanced study (CT or MRI) showing typical appearances for HCC defined as arterial enhancement and rapid wash-out in portal venous or delayed phase;
    - And/Or cyto-histology criteria (e.g. in case of atypical lesions for HCC at imaging, absence of cirrhosis);
    6. Without cirrhosis or with a non decompensated cirrhosis (Child-Pugh score from A5 to B7 included);
    7. ECOG Performance Status 0 or 1;
    8. Adequate laboratory tests, in particular with:
    - Platelets ≥ 50,000 /mm3
    - Neutrophil count ≥ 1000 /mm3
    - Hemoglobin ≥ 10g/dL
    - Serum transaminases < 5 ULN (NCI/CTC grades 0, 1, or 2)
    - Alkaline phosphatases < 5 ULN (NCI/CTC grades 0, 1, or 2)
    - Serum bilirubin < 35 µM/L (or 2.0 mg/dL);
    9. Signed and dated written informed consent form.
    E.4Principal exclusion criteria
    1. Cirrhosis with a Child-Pugh score B8-C15;
    2. Untreated chronic hepatitis B (in case of chronic hepatitis B, an efficacious antiviral treatment should have been started before randomisation to be included in the study);
    3. Patients eligible for curative treatments (transplantation, surgical resection, percutaneous treatment);
    4. Patients eligible for palliative treatments with demonstrated efficacy: TACE, Sorafenib; Patients who failed to Sorafenib treatment or intolerant to Sorafenib are eligible and can be included if Sorafenib has been stopped at least 2 weeks before randomization;
    5. Other prior malignancy without complete remission in the last five years with the exception of adequately treated basal cell carcinoma or in situ cervical cancer. In case of other prior malignancy, the diagnosis of HCC has to be histologically proven;
    6. HCC developed on transplanted liver;
    7. Known HIV infection;
    8. Risk of variceal bleeding - i.e. patients with stage 2-3 varices with fragility signs (patients at risk for variceal bleeding may be included after a preventive treatment (oesophageal varices ligation, beta blockers)) has been administered; DT will not be administered in case of digestive bleeding in the 4 previous weeks;
    9. SaO2 < 95%;
    10. Presence of a significant acute or chronic respiratory disease defined as NCI /CTCAE > grade 2;
    11. Presence of recent (< 6 months) or current cardiac failure (class II, III or IV NYHA classification), baseline LVEF < LLN by either cardiac ultrasound or cardiac scintigraphy; recent (< 6 months) acute coronary syndrome, clinically significant ECG abnormalities or recent (less than 6 months) acute vascular diseases (stroke, MI…);
    12. Prior cumulative dose of 300 mg/m² of doxorubicin or equivalent;
    13. Patients currently treated with immunosuppressive agents that cannot be stopped;
    14. Patients whose medical or surgical conditions are unstable and may not allow the study completion or compliance, and especially patients with uncontrolled diabetes;
    15. Uncontrolled systemic infection;
    16. Patients with a life expectancy of less than 2 months;
    17. Patients who have received an experimental drug in another clinical trial in the last 30 days prior to randomization in the present clinical trial;
    18. Women of child-bearing age who are unwilling or unable to use an effective contraception method (oral contraception or intra-uterine device for woman) during the study treatment period and for 6 months after the last administration of study drug, and their male partner(s) refusing to use a condom (if applicable),
    Men who are unwilling or unable to use a condom during the study treatment period and for 6 months after the last administration of study drug, and their female partner(s) refusing to use one of the appropriate effective contraception methods (if applicable);
    19. Patients unwilling or unable to comply with protocol requirements and scheduled visits.
    E.5 End points
    E.5.1Primary end point(s)
    Overall survival (OS)
    E.5.1.1Timepoint(s) of evaluation of this end point
    At each visit and until death
    After the study treatment period, the survival status of all patients (including patients prematurely withdrawn) will be collected every 3 months until death with the follow-up contact.
    E.5.2Secondary end point(s)
    Secondary efficacy endpoints:
    - Progression-free survival (PFS) by the Independent Radiological Review according to RECIST 1.1;
    - Objective Response Rate (ORR) by the Independent Radiological Review according to RECIST 1.1

    Exploratory efficacy endpoints*:
    - Progression-free survival by the investigator’s evaluation according to RECIST 1.1;
    - Objective Response Rate by the investigator’s evaluation according to RECIST 1.1;
    - Time To Progression (TTP), Best Overall Response and Disease Control Rate;
    - Time to Objective Response and Duration of Response;
    - Evolution in serum Alpha-foetoprotein levels (AFP).
    *PFS and ORR will be analyzed by the investigator evaluation according to RECIST 1.1 and according to modified RECIST for HCC (if possible), and by the Independent Radiological Review according to the modified RECIST for HCC (if possible). TTP, Best Overall Response, Disease Control Rate, time to objective response and
    duration of response will be analyzed by the Investigator Evaluation and by the Independent Radiological Review, according to RECIST 1.1 and according to modified RECIST for HCC (if possible).

    Safety endpoints:
    Respiratory:
    - Incidence and duration of reduction of SaO2 during DT infusion (in DT arms);
    - Incidence and severity of respiratory events;
    Cardiac:
    - Incidence and severity of cardiovascular events (including BP and HR);
    - ECG and LVEF change;
    Overall:
    - Incidence and severity of all TEAEs and SAEs according to NCI-CTCAE v4.0 scale;
    - Biological (haematology and biochemistry analyses, and particularly AST/ALT, WBC).
    - Child Pugh Score deterioration from baseline

    Pharmacokinetic endpoints (in selected sites for PK):
    - Pharmacokinetic profile of Doxorubicin and its metabolites;
    - Relationship between efficacy and safety (e.g., clinical, biological) parameters, concentrations of total and free doxorubicin and doxorubicinol and blood biomarkers

    Quality of Life:
    - EuroQoL EQ-5D questionnaire to be completed by patients during the study treatment period: at baseline, then every 2 cycles and finally, at progression or at the latest, if treatment is stopped for
    other-than-progression reasons (e.g., end of study visit)
    E.5.2.1Timepoint(s) of evaluation of this end point
    - Efficacy evaluation every 2 months
    - Safety evaluation during 2 days after the infusion, and at each visit.
    - Optional and limited pharmacokinetic sampling, in selected PK sites, at several timepoints in cycle 1 and 3, then every two cycles starting from cycle 4 (for patients who have more than 3 treatment cycles)
    - QoL evaluation at baseline, then every two cycles and upon the end of treatment
    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 Yes
    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) 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
    Best standard of care
    E.8.2.4Number of treatment arms in the trial3
    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 concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA90
    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
    Austria
    Belgium
    Egypt
    France
    Germany
    Hungary
    Italy
    Lebanon
    Spain
    Turkey
    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
    End of overall survival follow-up period, defined as 2 years after Last Patient In
    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 months9
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years5
    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: 112
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 203
    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 315
    F.4.2.2In the whole clinical trial 390
    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)
    There are no plans for treatment of care after the subject has ended the participation in the trial.
    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 Decision2013-08-08
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-06-12
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2019-02-25
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