E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Advanced hepatocellular carcinoma |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 7.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10049010 |
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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 |
Main objective: To evaluate safety, efficacy, PRO, and population PK of sorafenib versus placebo in patients with advanced HCC.
Primary efficacy objectives: • Efficacy in patients treated with sorafenib will be compared to that in patients treated with placebo. • There are two primary efficacy objectives, which will be assessed independently. o Overall survival (OS) o Time to symptomatic progression (TTSP) If the analysis of either OS or TTSP (or both) is positive, the efficacy of sorafenib in HCC will be considered established.
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E.2.2 | Secondary objectives of the trial |
Secondary objectives: The secondary efficacy objectives are to assess the following variables between patients treated with sorafenib versus placebo: • Time to progression (TTP) • Overall disease control rate (Proportion of patients who have a best response rating of complete response [CR], PR or SD according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria, that is maintained for at least 28 days from the first demonstration of that rating) • Functional Assessment of Cancer Therapy-Hepatobiliary (FACT-Hep) response rate |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Primary diagnosis Patients with advanced HCC, ECOG PS 0, 1, or 2, Child-Pugh status A, who have not received prior systemic anti-cancer treatment for HCC.
Inclusion Criteria: •Male or female patients > 18 years of age •Patients who have a life expectancy of at least 12 weeks •Patients with advanced HCC •Patients with histologically or cytologically documented HCC (original biopsy at first diagnosis is acceptable) •Patients must have at least one tumor lesion that meets both of the following criteria: The lesion can be accurately measured in at least one dimension according to RECIST The lesion has not been previously treated with local therapy (such as surgery, radiation therapy, hepatic arterial therapy, chemoembolization, radiofrequency ablation, percutaneous ethanol injection or cryoablation) •Patients who have received local therapy, such as surgery, radiation therapy, hepatic arterial embolization, chemoembolization, radiofrequency ablation, percutaneous ethanol injection or cryoablation are eligible. Previously treated lesions will not be selected as target lesions. Local therapy must be completed at least 4 weeks prior to the baseline scan. •Patients who have an ECOG PS of 0, 1, or 2 •Cirrhotic status of Child-Pugh class A only. Child-Pugh assessment is to be carried out during the screening period. The following laboratory parameters: Platelet count >= 60 x 109/L Hemoglobin >= 8.5 g/dL Total bilirubin <= 3 mg/dL Albumin >= 2.8 g/dL Alanine transaminase (ALT) and AST <= 5 x upper limit of normal Amylase and lipase <=1.5 x the upper limit of normal Serum creatinine <= 1.5 x the upper limit of normal Prothrombin time (PT)-international normalized ratio (INR) <= 2.3 or PT <= 6 seconds above control. 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 who give written informed consent prior to any study specific screening procedures with the understanding that the patient has the right to withdraw from the study at any time, without prejudice.
Extension with Crossover Phase The inclusion criteria required for this segment of the study are the following: •Patients must provide written informed consent prior to any study specific screening procedures with the understanding that the patient has the right to withdraw from the study at any time, without prejudice. •Patients must either be currently participating in the double-blind portion of the study, or are currently in follow-up. •A patient who had previously discontinued double-blind therapy due to a drug related toxicity and after unblinding was determined to have been on sorafenib, must be re-assessed by the investigator who must judge whether the patient may derive benefit from re-starting sorafenib treatment. The toxicity responsible for treatment discontinuation must resolve or improve to a level that allows re-initiation of sorafenib therapy. •Prior use of systemic anti-cancer therapy is allowed but concomitant systemic anti-cancer therapy is not allowed. |
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E.4 | Principal exclusion criteria |
• 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. • Renal failure requiring hemo- or peritoneal dialysis • History of cardiac disease: congestive heart failure > New York Heart Association (NYHA) class 2; active coronary artery disease (CAD); cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers or digoxin), or uncontrolled hypertension. Myocardial infarction more than 6 months prior to study entry is permitted. • Active clinically serious infections (> grade 2 National Cancer Institute [NCI]-Common Terminology Criteria for Adverse Events [CTCAE] version 3.0) • Known history of human immunodeficiency virus (HIV) infection • Known Central Nervous System tumors including metastatic brain disease • Patients with clinically significant gastrointestinal bleeding within 30 days prior to study entry • History of organ allograft • Substance abuse, medical, psychological or social conditions that may interfere with the patient’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 • Patients unable to swallow oral medications • Any condition that is unstable or which could jeopardize the safety of the patient and his/her compliance in the study • Pregnant or breast-feeding patients. Women of childbearing potential must have a negative pregnancy test performed within seven days prior to the start of study drug. Both men and women enrolled in this trial must use adequate barrier birth control measures during the course of the trial.
Excluded therapies and medications, previous and concomitant • Prior use of any systemic anti-cancer chemotherapy for HCC • Prior use of systemic investigational agents for HCC • Prior use of Raf-kinase inhibitors (RKI), VEGF inhibitors, MEK inhibitors or Farnesyl transferase inhibitors • Major surgery within 4 weeks of start of study drug • Radiotherapy during study or within 3 weeks prior to start of study drug. (Palliative radiotherapy will be allowed as described in Prior and Concomitant Therapy) • Use of biologic response modifiers, such as granulocyte colony-stimulating factor (G-CSF), within 3 weeks prior to study entry. (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). Patients 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 four months of start of study drug • Concomitant treatment with rifampin and St John’s wort
Extension with Crossover Phase The exclusion criterion required for this segment of the study is the following: •Pregnant or breast-feeding patients. Women of childbearing potential must have a negative pregnancy test performed within seven days prior to enrolling in this portion of the study.
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary efficacy variables • Overall Survival (OS) • Time to symptomatic progression (TTSP) Secondary efficacy variables • Time to progression (TTP) • Disease control rate • Patient Reported Outcomes (PRO) as measured by total score on FACT-Hep • Tertiary efficacy variables • Overall response rate • Overall response duration • Time to response • Patient Reported Outcomes (PRO) as measured by Physical and Functional Well-Being subscales of the FACT-Hep Other variables • Population PK parameters • Correlation between the following baseline characteristics (in order of priority) and key clinical endpoints (ie, response, TTP, TTSP, and OS): tumor pERK, phospho VEGF-R2 concentration, plasma proteomics, and gene expression profiling of blood cells and tumor biopsies
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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 | Yes |
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 | 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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
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 | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
Extension with cross-over Phase |
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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 | 6 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 72 |
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 trial is dependant on Overall Survival. Overall survival data will be considered mature and the final analysis will be performed when approximately 424 events (deaths) are observed. |
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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 | |
E.8.9.1 | In the Member State concerned months | 26 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial months | 26 |