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    Summary
    EudraCT Number:2013-002625-35
    Sponsor's Protocol Code Number:CALGB80802
    National Competent Authority:Ireland - HPRA
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2013-06-14
    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 ConcernedIreland - HPRA
    A.2EudraCT number2013-002625-35
    A.3Full title of the trial
    Phase III Randomized Study Of Sorafenib Plus Doxorubicin Versus Sorafenib In Patients With Advanced Hepatocellular Carcinoma (HCC)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Sorafenib with or without doxorubicin for treating patients with advanced or metastatic liver cancer
    A.3.2Name or abbreviated title of the trial where available
    Sorafenib and Doxorubicin in Advanced HCC
    A.4.1Sponsor's protocol code numberCALGB80802
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT01015833
    A.5.4Other Identifiers
    Name:ICORG Study NumberNumber:ICORG 13-08
    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 SponsorAll Ireland Co-operative Oncology Research Group (ICORG)
    B.1.3.4CountryIreland
    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 supportEastern Co-operative Oncology Group (ECOG)
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAll Ireland Co-operative Oncology Research Group (ICORG)
    B.5.2Functional name of contact pointKathleen Scott
    B.5.3 Address:
    B.5.3.1Street Address60 Fitzwilliam Square
    B.5.3.2Town/ cityDublin
    B.5.3.3Post code2
    B.5.3.4CountryIreland
    B.5.4Telephone number35316677211
    B.5.5Fax number35316697869
    B.5.6E-mailKathleen.Scott@icorg.ie
    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 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 AuthorisationGermany
    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.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    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.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 Doxorubicin
    D.2.1.1.2Name of the Marketing Authorisation holderActavis Group PTC ehf.
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    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 nameDoxorubicin Hydrochloride
    D.3.4Pharmaceutical form Infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    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 or Metastatic Hepatocellular Carcinoma
    E.1.1.1Medical condition in easily understood language
    Advanced liver 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
    Compare overall survival (OS) of patients treated with sorafenib and doxorubicin to that of those treated with sorafenib.
    E.2.2Secondary objectives of the trial
    1. Compare time to progression (TTP) of patients treated with sorafenib and doxorubicin to that of those treated with sorafenib.
    2. Compare progression-free-survival (PFS) of patients treated with sorafenib and doxorubicin to that of those treated with sorafenib.
    3. Compare tumor response using RECIST criteria of patients treated with sorafenib and doxorubicin to that of those treated with sorafenib.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    1. Sub-study CALGB 580901: The Evaluation of Tumor Necrotic Areas using a New Volumetric Method of Assessing Non-viable Tumor as a Correlate for Response
    Objective: To correlate outcome based on OS, PFS, and response by RECIST with tumor necrosis as estimated by N/T ratio.
    2. Sub-study CALGB 150902: Correlative Science Studies in CALGB 80802
    a. Evaluation of Circulating Biomarkers
    -To determine if the serum biomarkers GP73, fucosylated hemopexin, fucosylated fetuin-A and fucosylated kininogen correlate with treatment outcome following therapy with sorafenib plus doxorubicin or in patients with sorafenib alone.
    -To examine additional plasma markers of interest, including VEGF, soluble sVEGFR-2, sVEGFR-3, sc-Kit, HGF, Ras p21, and pERK, a tumor biomarker related to sorafenib’s mechanism of action to identify predictors of survival or clinical correlates with sorafenib treatment responses.
    b. Evaluation of Viral Titers in Patients with HBV and/or HCV
    -To determine the proportion of patients with undetectable viral load with <50 copies/mL at 15 weeks.
    -To assess and compare the HCV antiviral effect, if any, of sorafenib or sorafenib plus doxorubicin at 6, 9 and 15 weeks.
    -To study and compare patients’ rate of undetectable viral load (< 50 copies per mL), 2 log decline in viral load, and a continuum of viral load at 6, 9 and 15 weeks, and any association with OS of the whole study population, and patients treated with sorafenib or sorafenib plus doxorubicin.
    -To study and compare patients with detectable versus undetectable viral load (< 50 copies per mL) at 6, 9 and 15 weeks, and any association with PFS of the whole study population, and patients treated with sorafenib or sorafenib plus doxorubicin.
    -To study and compare patients with detectable versus undetectable viral load (<50 copies per mL) at 6, 9 and 15 weeks, and any association with response rate as defined by RECIST criteria of the whole study population, and patients treated with sorafenib or sorafenib plus doxorubicin.
    -To assess retesting of genotype changes.
    -To assess quasi-species in patients with virologic failure defined as reversing from undetectable (<50 copies per mL) to detectable viral load, or increase in 2 logs above nadir, at any point in time.
    Sub-study CALGB 60901: Pharmacogenomic Studies in CALGB 80802
    a. Candidate Marker Study
    -to investigate the association between IL17F (rs763780) and overall survival (OS) in the Caucasian population.
    b. Genome-wide Association Study (GWAS)
    -to identify single-nucleotide polymorphphisms (SNPs) associated with overall survival (OS).
    E.3Principal inclusion criteria
    1. Patients must have pathologically or cytologically proven hepatocelluar carcinoma. Known mixed histology (e.g. hepatocellular carcinoma plus cholangiocarcinoma) or fibrolamellar variant is not allowed.
    2. Patients must have locally advanced or metastatic disease. Locally advanced disease is defined as disease deemed to be unresectable or non-eligible for transplant without distant metastases.
    3. Patients must have Measurable Disease.
    Lesions must be accurately measurable in at least one dimension (longest diameter to be recorded) as ≥2 cm with conventional techniques or as ≥1 cm with spiral CT scan.
    4. Age: ≥ 18 years of age
    5. ECOG Performance Status: 0-2
    6. Required Initial Laboratory Values:
    Granulocytes ≥1,500/μL
    Hemoglobin ≥8.5 g/dL*
    Platelets ≥75,000/μL
    Creatinine ≤1.5 x ULN (or Creatinine Clearance calculated ≥60 cc/minute)
    Child-Pugh score A (Appendix II)**
    Bilirubin≤3 mg/dL
    ALT and AST ≤5 x ULN
    PT-INR ≤1.7
    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 with recent or ongoing gastrointestinal bleed may not be transfused to reach the entry hemoglobin of 8.5 g/dL. Physicians should ensure patients requiring transfusion prior to registration do not have an occult or clinically apparent gastrointestinal bleed.
    **Patients must have a Child-Pugh score of A and meet all laboratory value requirements.
    E.4Principal exclusion criteria
    1. No prior adjuvant sorafenib or other Raf/VEGF inhibitors. Other prior adjuvant therapy is allowed if completed >6 months prior to registration with documented recurrence of HCC.
    2. Patients may have been treated with loco regional therapies provided that they either have:
    • a target lesion that has not been subjected to local therapy or
    • the target lesion(s) within the field of the local therapy has shown an increase of ≥ 20% in the size since last treatment.
    Such therapy must be completed at least 4 weeks prior to registration. Patients that have received palliative radiation therapy to the bone need not wait 4 weeks to begin protocol therapy.
    Prior therapies allowed include the following:
    • bland embolization, radiation, radioactive microspheres, etc
    • chemoembolization using any chemotherapy (except, see “D”, below)
    • chemoembolization drug-eluting beads using doxorubicin
    • prior therapy with chemoembolization using doxorubicin in the non drug eluting beads form is NOT allowed.
    3. No prior systemic therapy for metastatic disease.
    4. No prior exposure to systemic doxorubicin administered intravenously.
    5. Antiviral treatment is allowed, however interferon therapy must be stopped at least 4 weeks prior to registration.
    6. Allografts are not allowed: No prior history of any allograft, including but not limited to liver and bone marrow transplants.
    7. Patients must have completed any major surgery ≥4 weeks from registration.
    8. Concomitant treatment with Rifampin or St John’s Wort is not allowed. Patients should discontinue these drugs at least 4 weeks prior to registration.
    9. No known CNS tumors including brain metastases.
    10. No clinically significant gastrointestinal bleeding events requiring intervention, transfusion, or admission to hospital within 30 days prior to registration.
    11. Patients with a history of hypertension should be well controlled (< 140/90 mmHg) on a regimen of anti-hypertensive therapy.
    12. Significant history of cardiac disease is not allowed:
    • Congestive heart failure > Class II New York Heart Assocation (NYHA)
    • Myocardial infarction within 6 months prior to registration
    • Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers or digoxin
    • Serious myocardial dysfunction, defined as scintigraphically (MUGA, myocardial scintigram) determined absolute left ventricular ejection fraction (LVEF) below 45% or an LVEF below the normal limit at the individual institution.
    13. No history of bleeding diathesis.
    14. Patients receiving combination anti-retroviral therapy for human immunodeficiency virus (HIV) are excluded from the study because of possible pharmacokinetic interactions with sorafenib.
    15. The effects of sorafenib on the developing fetus at the recommended therapeutic dose are unknown and may be teratogenic. Thus, women who are pregnant should not go on study. Women should not breastfeed while participating in this study.
    E.5 End points
    E.5.1Primary end point(s)
    Overall survival (OS).

    E.5.1.1Timepoint(s) of evaluation of this end point
    After disease progression, patients are followed up every 6 months until 3 years after registration to report survival data.
    E.5.2Secondary end point(s)
    -Time to progression (TTP).
    -Progression-free-survival (PFS).
    -Tumor response using RECIST criteria.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Following baseline disease measurements, patients are evaluated for disease/tumour response every 2 cycles during treatment. If treatment ends for reasons other than disease progression, patients are evaluated every 3 months for 1 year, then every 6 months until 3 years after registration.
    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 Yes
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Correlative Science Studies
    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 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) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    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 concerned6
    E.8.5The trial involves multiple Member States No
    E.8.5.1Number of sites anticipated in the EEA6
    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
    Ireland
    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 years7
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years10
    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: 180
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 300
    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 No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    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 state50
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 50
    F.4.2.2In the whole clinical trial 480
    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
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation All Ireland Co-operative Oncology Research Group (ICORG)
    G.4.3.4Network Country Ireland
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2013-08-09
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-09-23
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2015-05-21
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