E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with Hepatocellular carcinoma (liver-predominant disease) |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10019829 |
E.1.2 | Term | Hepatocellular carcinoma recurrent |
E.1.2 | System Organ Class | 100000004864 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10019828 |
E.1.2 | Term | Hepatocellular carcinoma non-resectable |
E.1.2 | System Organ Class | 100000004864 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10049010 |
E.1.2 | Term | Carcinoma hepatocellular |
E.1.2 | System Organ Class | 100000004864 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10019830 |
E.1.2 | Term | Hepatocellular carcinoma resectable |
E.1.2 | System Organ Class | 100000004864 |
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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 |
1. In patients in whom local ablation therapy is appropriate (local ablation group), to determine if the sorafenib in combination with radiofrequency ablation (RFA) prolongs the time-to-recurrence (TTR) in comparison with RFA + placebo.
2. In patients in whom RFA is NOT appropriate (palliative treatment group), to determine if the combination of yttrium-90 microspheres (SIRT) + sorafenib improves the overall survival (OS) in comparison to sorafenib alone.
3. To confirm in a 2-step procedure that Primovist-enhanced MRI is non-inferior (first step) or superior (second step) compared with contrast-enhanced multislice CT for stratification of patients to a palliative vs. local ablation treatment strategy.
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E.2.2 | Secondary objectives of the trial |
• to assess health-related quality of life • to compare the number of detected lesions and the diagnostic confidence in Primovist-enhanced MRI with contrast-enhanced CT • to compare Primovist-enhanced MRI with contrast-enhanced CT regarding the detection of recurrence (patients in the local ablation group only) • to assess the safety of the combination of RFA + sorafenib in comparison to RFA + placebo • to assess the safety of the combination of SIR-Spheres therapy and sorafenib in comparison to sorafenib alone • to assess in the palliative study group overall survival separately for patients with and without portal thrombosis
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Age: 18-85 years 2. Hepatocellular carcinoma 3. If extrahepatic metastases: liver-dominant disease 4. Stage BCLC A, B, or C 5. Child-Pugh A, Child-Pugh B up to 7 points 6. Willing to comply with all study procedures 7. Has voluntarily given written informed consent
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E.4 | Principal exclusion criteria |
1. If female, pregnant or breast feeding (females of child-bearing potential must use adequate contraception and must have a negative pregnancy test performed within 7 days prior to inclusion into this study) 2. If male, not using adequate birth control measures 3. One or more of the following: - Hemoglobin <10g/dL, - WBC <2,500 cells/mm3, - ANC <1,500 cells/mm3, - platelets <50,000/mm3, - ECOG performance status >2 4. Life expectancy <16 weeks or medically unstable 5. Pulmonary metastases 6. Patients with known GFR <30 mL/min/1.73m2 7. PT-INR/PTT >1.5 times the upper limit of normal 8. uncontrolled infections at the time of microtherapy 9. Child-Pugh score >7 points; 10. Uncontrolled ascites 11. tumor load of the whole liver >70% 12. Contraindications for study medications according to product labeling or procedures 13. Having undergone surgical procedures with resection of the sphincter of Oddi 14. Significant cardiovascular disease; e.g., myocardial infarction within 6 months of inclusion, chronic heart failure (New York Heart Association class III or IV), unstable coronary artery disease 15. Uncontrolled hypertension 16. Thrombotic or embolic events including transient ischemic attacks within the past 6 months (tumor-related portal vein thrombosis allowed in the palliative part of the trial) 17. History of GI bleeding within 30 days before inclusion into this study 18. History of esophageal varices bleeding which has not been controlled by effective therapy and/or therapy to prevent bleeding recurrence 19. Previous malignancy other than carcinoma in situ of the skin or the cervix uteri within 5 years prior to inclusion 20. History of organ transplant (including prior liver transplantation) 21. HIV, congenital immune defect, any immunosuppressive therapy for autoimmune disease (rheumatoid arthritis) or inflammatory bowel disease 22. Mental conditions rendering the subject incapable to understand the nature, scope, and consequences of the trial 23. Close affiliation with the investigational site; e.g. first-degree relative of the investigator. 24. Participating in another therapeutic clinical trial or has completed study participation in another therapeutic clinical trial within 30 days of enrolment into this trial 25. Having been previously enrolled in this clinical trial |
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E.5 End points |
E.5.1 | Primary end point(s) |
• TTR (local ablation group) • Overall Survival (palliative treatment group) • number of correct assignments to a local ablation / palliative treatment strategy (diagnostic part of the study) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
• to assess health-related quality of life • to compare the number of detected lesions and the diagnostic confidence in Primovist-enhanced MRI with contrast-enhanced CT • to compare Primovist-enhanced MRI with contrast-enhanced CT regarding the detection of recurrence (patients in the local ablation group only) • to assess the safety of the combination of RFA + sorafenib in comparison to RFA + placebo • to assess the safety of the combination of SIR-Spheres therapy and sorafenib in comparison to sorafenib alone • to assess in the palliative study group overall survival separately for patients with and without portal thrombosis
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | Yes |
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 | Yes |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
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 | Yes |
E.8.1.7.1 | Other trial design description |
randomised, double blinded for sorafenib in local ablation arm; randomised, open for palliative arm |
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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 | Yes |
E.8.2.3.1 | Comparator description |
contrast-enhanced computed tomography |
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E.8.2.4 | Number of treatment arms in the trial | 2 |
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 | 1 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 35 |
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 | No |
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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Last visit of the last patient |
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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 |