E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
This study will evaluate the efficacy and safety of TACE (transarterial chemoembolization) performed with DC Bead and doxorubicin plus sorafenib versus TACE performed with DC Bead and doxorubicin plus placebo for the treatment of intermediate stage HCC. |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10019828 |
E.1.2 | Term | Hepatocellular carcinoma non-resectable |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To demonstrate the superiority of sorafenib over placebo with regard to Time To Progression (TTP) in patients with intermediate stage HCC receiving TACE performed with DC Bead |
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E.2.2 | Secondary objectives of the trial |
• Overall Survival (OS) • Time to untreatable progression (TTUP) • Time to vascular invasion / extrahepatic spread • Safety • Patient-Reported Outcome (PRO) as assessed by FACT-Hep and EQ-5D questionnaire • Evaluation of biomarkers • Response Rate (RECIST Amendment)
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Prior informed consent • Unresectable, multinodular asymptomatic tumor (no vascular invasion or extrahepatic spread) • Confirmed Diagnosis of HCC: - Cirrhotic subjects: Clinical diagnosis by AASLD criteria: HCC can be defined in cirrhotic subjects by one imaging technique (CT scan, MRI, or second generation contrast ultrasound) showing a nodule larger than 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 1-2 cm in diameter. Cytohistological confirmation is required for subjects who do not fulfill these eligibility criteria. - Non-cirrhotic subjects: For subjects without cirrhosis, histological confirmation is mandatory. Documentation of original biopsy for diagnosis is acceptable • Child Pugh class A • ECOG Performance Status of 0 (see appendix 10.9) • At least one uni-dimensional lesion measurable according to the RECIST criteria (see appendix 10.8) by CT-scan or MRI • Male or female subjects ≥ 18 years of age • Ability to swallow oral medications • Life expectancy of at least 12 weeks • Women of childbearing potential must have a negative serum pregnancy test performed within 7 days prior to the start of treatment (assessed centrally) • Both men and women enrolled in this trial must use adequate barrier birth control measures during the course of the trial and 4 weeks after the completion of trial • Adequate bone marrow, liver and renal function as assessed by central lab from samples approximately 7 days prior to randomization.
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E.4 | Principal exclusion criteria |
• Diffuse HCC or presence of vascular invasion (including segmental portal obstruction), extrahepatic spread • Advanced liver disease: Child Pugh B and C, Active gastrointestinal bleeding, Encephalopathy or clinically relevant ascites • Any contraindications for hepatic embolization procedures: Known Hepatofugal blood flow, Known Porto-systemic shunt, Impaired clotting test (platelet count < 60000/mm3, prothrombin activity < 50%), Renal failure / insufficiency requiring haemo-or peritoneal dialysis, Known severe atheromatosis • Target lesion having previously been treated with local therapy such as resection of HCC, radiofrequency ablation (RFA), percutaneous ethanol injection (PEI) or cryoablation. Subjects who have received local treatment prior to TACE are only eligible if performed on a different lesion to the one targeted in this study • Local therapies ongoing or completed < 4 weeks prior to the baseline scan • Any ≥ CTC AE grade 2 acute toxic effects of any prior local treatment • History of cardiac disease: Congestive heart failure >New York Heart Association (NYHA) class 2, Active coronary artery disease (CAD) (myocardial infarction more than 6 months prior to study entry is allowed), Cardiac arrhythmias (>Grade 2 NCI-CTCAE Version 3.0) which are poorly controlled with anti-arrhythmic therapy or requiring pace maker, Uncontrolled hypertension • Known history of HIV infection • Active clinically serious infections (> grade 2 NCI-CTCAE Version 3.0), except for HBV and HCV infection • Clinically significant gastrointestinal bleeding within 4 weeks prior to start of study drug • Thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism within the 6 months prior to the first dose of study drug • 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 • Substance abuse, medical, psychological or social conditions that may interfere with the subject’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 • Any contraindication for sorafenib or doxorubicin administration • Pregnant or breast-feeding subjects • Any disease which could affect the evaluation of the study drug • Any condition that is unstable or could jeopardize the safety of the subject and their compliance in the study • Gastrointestinal disease which could affect the absorption or pharmacokinetics of the study drug • Subjects unable to swallow oral medications. This includes subjects with severe obstruction of the upper GI tract that require gavage • Investigational drug or device therapy outside of this trial during or within 4 weeks of study entry (signing informed consent) • Prior transarterial embolization (with or without chemotherapy) • Prior use of Raf-kinase inhibitors (RKI), VEGF inhibitors, MEK inhibitors or farnesyl transferase inhibitors • Prior use of anthracyclines (e.g. doxorubicin) • Major surgery within 4 weeks prior to start of study drug (e.g. thoracolaparotomy is not allowed, but noninvasive surgery, e.g. biopsy, is allowed) • Radiotherapy for HCC during study or before start of study drug • Use of biologic response modifiers, such as G-CSF, within 3 weeks prior to start of study drug. (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). Subjects 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 1 year prior to start of study drug • History of organ allograft • Any agents which could affect the absorption or pharmacokinetics of the study drug and doxorubicin
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary efficacy objective: Time to progression (TTP) - defined as the time from randomization to radiological disease progression.
Secondary Objectives: •Overall survival (OS) - defined as the time from randomization to death due to any cause. OS of subjects alive at the time of analysis will be censored at their last data of follow-up. •Time to untreatable progression (TTUP) - defined as the time from randomization to untreatable progression defined by at least one of the following: - Failure to achieve objective response after at least 2 TACE sessions in the treated tumor nodule. - Appearance of contraindications according to selection criteria: this includes vascular invasion, extrahepatic spread and evolution to sustained ascites development (not merely after therapy or coinciding with any adverse event) or to Child Pugh B. - Clinical progression to ECOG Performance Status > 2 • Time to vascular invasion/extrahepatic spread is defined as time from randomization to the radiological evidence of vascular invasion/extrahepatic spread confirmed by CT/MRI scan. • Response rate is defined as the percentage of subjects achieving either a confirmed complete or partial tumor response according to RECIST amendment.
Other Objectives: • Patient reported outcome (PRO) as measured by FACT-Hep and EQ-5D • Evaluation of Biomarkers
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
Patient Reported Outcomes |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | 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.8.4.1 | Number of sites anticipated in Member State concerned | 9 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 52 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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E.8.7 | Trial 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
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The end of the study for regulatory purposes will be considered to be when the last subject has completed their end of study visit (LPLV). Patients will continue to be followed up for long term survival information following the completion of the end of the study visit until the above timepoint. They will be contacted by telephone on a 3 monthly basis by the investiagtor or research nurse. This is for information only and does not involve any study related intervention. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 8 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 8 |
E.8.9.2 | In all countries concerned by the trial days | 0 |