E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
To evaluate the clinical benefit of sorafenib vs placebo as adjuvant treatment in subjects with HCC who received potentially curative treatment (surgical resection or local ablation). |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10019830 |
E.1.2 | Term | Hepatocellular carcinoma resectable |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 |
The Primary efficacy objective is to compare Recurrence Free Survival (RFS) in the patients treated with sorafenib vs placebo after receiving potentially curative treatment with surgical resection or local ablation. |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives are Time to Recurrence (TTR) and overall survival (OS).
Other objectives are Patient-Reported Outcome (PRO) as assessed by FACT-Hep and EQ 5D questionnaire, and evaluation of biomarkers and pharmacokinetics. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Informed consent
• Confirmation of diagnosis of HCC:
- for subjects undergoing surgical resection histological confirmation is mandatory (a post surgery pathology report is required for both histological confirmation and risk stratification).
- for subjects undergoing local ablation either histological confirmation or clinical diagnosis by AASLD criteria in cirrhotic subjects is required. For subjects without cirrhosis histological confirmation is mandatory.
Prior to curative treatment, confirmation of a maximum tumor load of:
- single lesion any size for surgical resection, or
single lesion ≤ 5cm (largest diameter, unidimensional measurement) for local ablation
- 2-3 lesions, each ≤ 3 cm in size (largest diameter, unidimensional measurement)
• Subjects who have undergone surgical resection or local ablation (PEI or percutaneous or intraoperative RFA) for treatment of HCC with curative intent within 4 months from staging to potentially curative treatment. A maximum of 2 local ablation courses may be administered during this time period.
• At least 3 weeks (21 days) but not more than 7 weeks (49 days), from resection or last local ablation course, to CT/MRI scan date. A timeframe of 4 weeks after surgical resection or last ablation is recommended.
• Male or female subjects ≥ 18 years of age
•Confirmation of CR (absence of residual tumor after curative treatment), on the eligibility scan by independent radiological review.
•For subjects undergoing surgical resection pathology proven complete removal of tumor.
• Intermediate or High Risk of recurrence as assessed by tumor characteristics.
• Child-Pugh score 5 -7 points. A Child-Pugh score of 7 points is allowed only in the absence of ascites.
• ECOG Performance Status of 0.
• Adequate bone marrow, liver and renal function as assessed by central lab by means of the following laboratory requirements from samples within 14 days prior to randomization:
• Alpha fetoprotein < 400 ng/mL
• Women of childbearing potential must have a negative serum pregnancy test performed within 14 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 two weeks after the completion of trial.
• No more than 4 weeks (28 days ± 7 days) from the eligibility scan date (CT or MRI) to randomization.
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E.4 | Principal exclusion criteria |
• Recurrent HCC
• Child-Pugh score 7 points with presence of ascites.
• The following tumor characteristics:
a) Low risk of recurrence after curative treatment defined as any of the following:
for local ablation patients: single lesions < 2 cm
for surgical resection patients: single lesions < 2 cm without microscopic vascular invasion, without tumor satellites and histologically well differentiated.
b) > 3 lesions or 2-3 lesions of which any are > 3 cm in size (largest diameter, unidimensional measurement) prior curative treatment (surgical resection or local ablation)
c) single lesion > 5 cm (largest diameter, unidimensional measurement) in size prior local ablation.
d) Macrovascular invasion
e) Extrahepatic spread (including regional lymph nodes and invasion into adjacent structures)
• History of cardiovascular disease:
• History of HIV infection
• Active clinically serious infections (> grade 2 NCI-CTCAE version 3.0)
• Subjects with seizure disorder requiring medication (such as steroids or anti-epileptics)
• History of organ allograft
• Subjects with evidence or history of bleeding diathesis
• Subjects undergoing renal dialysis
• Previous or concurrent cancer that is distinct in primary site or histology from the cancer being evaluated in this study EXCEPT cervical carcinoma in situ, treated basal cell carcinoma, superficial bladder tumors [Ta, Tis & T1] or any cancer curatively treated > 3 years prior to study entry as defined by the signing of informed consent.
• Uncontrolled ascites (defined as not easily controlled with diuretic treatment)
• Encephalopathy
• History of GI bleeding within 30 days of randomization.
• Subjects with a history of esophageal varices bleeding which has not been followed by effective therapy and/or treatment to prevent bleeding recurrence.
• Prior anti cancer therapy for treatment of HCC (including sorafenib or any other molecular therapy) is excluded.
• Major surgery within 4 weeks of start of study as defined by the signing of informed consent, except for surgical resection or local ablation of HCC.
• Autologous bone marrow transplant or stem cell rescue within 4 months of study entry as defined by the signing of informed consent.
• Use of biologic response modifiers, such as G-CSF, within 3 week of study entry, as defined by the signing of informed consent.
• Investigational drug therapy outside of this trial during or within 4 weeks of study entry, as defined by the signing of informed consent.
• Pregnant or breast-feeding subjects.
•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 sorafenib.
• Any condition that is unstable or could jeopardize the safety of the subject and their compliance in the study
• Subjects unable to swallow oral medications. This applies to subjects with severe obstruction of the upper GI tract that require gavage.
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary efficacy objective: Recurrence Free Survival (RFS)
Secondary efficacy objectives: Time to Recurrence (TTR).
Overall Survival (OS)
Other objectives:
• Patient-Reported Outcome (PRO) as assessed by FACT-Hep and EQ-5D questionnaire.
• Evaluation of biomarkers.
• Evaluation of pharmacokinetics.
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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 | No |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | Yes |
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 | 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.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 80 |
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 overall end of the study for regulatory purposes is the date the last subject completes the end of study visit or records disease recurrence/death, whichever comes later |
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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 | 7 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 7 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |