E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
histologically proven advanced hepatocellular carcinoma (HCC) not suitable for resection or liver transplantation but without extrahepatic manifestations and without previous treatment for 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 | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Primary objective: – determination of time to progression (TTP)
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E.2.2 | Secondary objectives of the trial |
Secondary objectives: determination of – overall survival (OS) – disease control rate (DCR: CR, PR or SD as best overall response (BOR)) – progression-free survival (PFS) – total number of TACE cycles – safety profile
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
– Patients with histologically confirmed HCC not suitable for resection or liver transplantation (> 3 tumors > 3 cm; one tumor > 5 cm; vascular invasion; corresponding to intermediate stage according to the BCLC staging criteria) – Age >= 18 years –Patients with measurable disease according to RECIST – Performance status ECOG 0-2 – Patients naive to treatment with respect to the HCC – Normal organ and bone marrow function defined as: – Hematopoetic: absolute neutrophil count > 1,500/mm3, platelet count > 100,000/mm3, hemoglobin > 9g/dL – INR < 1.5 ULN and PTT within normal limits – Hepatic: AST or ALT < 5 x ULN, alkaline phosphatase < 4 x ULN – Renal: serum creatinine < 1.5 x ULN – Women of childbearing potential must have a negative serum pregnancy test performed within 7 days prior to the start of treatment – Male or female patients with reproductive potential must use an approved contraceptive method during and for 3 months after the end of treatment with study medication (Approved methods for women are oral contraceptives with estrogen and progesterone, vaginal rings, contraceptive patches, estrogen-free ovulation inhibitors, intrauterine devices with progesterone, 3-month injections with depot progesterone, implants settting free progesterone, abstinence or sterilization (vasectomy) of the male partner. Men must use condomes.) – Written informed consent (including consent to data reporting) |
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E.4 | Principal exclusion criteria |
– Patient is eligible for liver resection or liver transplantation – Extrahepatic tumor manifestation – Thrombosis of the portal vein – > 8 points according to Child Pugh classification – Prior TACE or RFTA or any other local ablative treatment – Prior systemic anticancer chemotherapy or radiotherapy for HCC – Total bilirubin > 4.5 mg/dl – Life expectancy of less than 12 weeks – Esophageal varices grade III (any) or esophageal varices grade II with increased risk for bleeding (red wale signs, cherry spots, red coloration, hematocystic spots) without prophylactic band ligation – Cardiac disease: congestive heart failure > class II NYHA, unstable angina or new onset of angina or myocardial infarction within the past 6 months. Cardiac ventricular arrhythmias requiring antiarrhythmic therapy – Uncontrolled hypertension defined as systolic blood pressure > 150 mm Hg or diastolic pressure > 90 mm Hg, despite optimal management – Known or suspected hyperthyroid state – Known brain metastasis. Patients with symptoms should undergo CT/MRT of the brain to exclude brain metastasis – Patients with seizure disorder requiring medication (such as steroids or antiepileptics) – History of organ allograft – Active clinically serious infections > CTCAE grade 2 – Thrombotic or embolic events including transient ischemic attacks within the past 6 months – Hemorrhage/bleeding event >= CTCAE grade 3 within 4 weeks of first dose of study drug – Acute variceal bleeding within the last 2 weeks – Serious non healing wound, ulcer or bone fracture – Evidence or history of bleeding diathesis or coagulopathy – Therapeutic anticoagulation with vitamin K antagonists such as warfarin, or with heparins or heparinoids. Low dose warfarin is permitted if INR is < 1.5. Low dose aspirin is permitted (<= 100 mg/day) – Chronic daily treatment with aspirin > 100 mg/day – Major surgery, open biopsy or significant traumatic injury within 4 weeks of first dose of study drug – Known or suspected allergies to sorafenib, anthracyclines (including doxorubicin) or lipiodol (containing esters of iodinated fatty acids of poppy oil) or any agent given in the course of this trial – Contraindications to the use of sorafenib, doxorubicin or lipiodol as mentioned in the current summary of product characteristics – Previous cancer that is distinct in primary site or histology from HCC except cervical cancer in situ, treated basal cell carcinoma, superficial bladder tumors or any cancer curatively treated 3 years prior to study entry – Substance abuse, medical or psychological condition that may interfere with the patient´s participation in the study – Participation in another clinical trial with any investigational study drug (whatever the use, curative, prophylactic or diagnostic intent) within 30 days prior to enrollment – Incapability to give valid informed consent (including patients who are dependent on the sponsor or the investigator) – Lactating women |
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E.5 End points |
E.5.1 | Primary end point(s) |
Progression of HCC or patient´s death |
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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 | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
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 | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
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) | Information not present in EudraCT |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | 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.8.4.1 | Number of sites anticipated in Member State concerned | 10 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.7 | Trial 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
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Treatment will be continued until one of the following occurs: - PD - not tolerable toxicity - patient´s wish - other reason according to which continuation of treatment is not in the patient´s best interest |
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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 | 2 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | |