E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
HCC epatocellular carcinoma |
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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 | HLT |
E.1.2 | Classification code | 10025577 |
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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 |
To assess whether perfusion changes in one target HCC lesion assessed quantitatively by CE-US at week 2 and 4 of Sorafenib therapy can predict progression of disease at week 8 assessed by CE-MDCT/MRI, using standard RECIST criteria. |
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E.2.2 | Secondary objectives of the trial |
1.To determine if perfusion changes in one target HCC lesion assessed quantitatively by CE-US at wk 2 and 4 of Sorafenib therapy: a)can predict progression of disease at wk 8 with CE-MDCT/MRI, using Llovet crit. b)correlate with OS c)correlate with TTP using RECIST/Llovet crit. d)can predict progression of the same lesion at wk 8 assessed with CE-MDCT/MRI,using Llovet crit. 5.In responder subj. at wk 8, to determine if perfusion changes in the target HCC lesion assessed quantitatively by CE-US at wk > 8 can identify earlier than CE-MDCT/MRI, HCC progression after wk 8. 6.To assess if progression of the target HCC lesion determined by the investigator based on qualitative evaluation of CE-US findings at wk 2 and 4 of Sorafenib therapy predict progression of disease at wk 8 assessed by CE-MDCT/MRI,using RECIST crit. 7.to compare diagnosis of qualitative evaluation of CE-US vs the best quantitative one for predict 1resistance to sorafenib 8. to assess safety of SonoVue |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Adult (age > or = 18 years) male or female; Providing written informed consent and willing to comply with protocol requirements; Confirmed diagnosis of advanced HCC either based on histology or based on AASDL criteria,as follows: -nodule < or = 1 cm in maximum diameter: histology. -nodule of 1-2 cm in diameter: two imaging procedures (CE-CT and CE-MRI or CE-US) showing coincidental typical vascular pattern for HCC (contrast uptake in the arterial phase and washout in venous or late phases). -nodule >2 cm in maximum diameter: one imaging procedure (CE-CT or CE-MRI or CE-US) showing typical vascular pattern for HCC (contrast uptake in the arterial phase and washout in venous or late phases). Candidate to start sorafenib as monotherapy. At least one liver lesion, measurable according to RECIST criteria1 and evaluable by CE-US defined as: -Acoustic window sufficient for adequate US examination of the liver (all target HCC borders should be correctly visualized by B-mode and lesions adjacent to diaphragmatic border should be avoided). -Not previously treated -Diameter of 2 cm or more -Perfused area &#8805; 50% of the total volume. At least 4 weeks since prior surgery/treatment with resolution of all acute toxic effects. |
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E.4 | Principal exclusion criteria |
Has any clinically unstable cardiac condition prior to SonoVue&#61666; administration such as: -evolving or ongoing myocardial infarction, -a history of acute myocardial infarction or percutaneous coronary interventions (PCI) within the previous 3 months, -worsening of typical angina at rest within the previous 7 days, -significant worsening of cardiac symptoms within the previous 7 days, -recent coronary artery intervention or other factors suggesting clinical instability (e.g., recent deterioration of ECG, laboratory or clinical findings), -cardiac failure Class III/IV in accordance to the New York Heart Association , -severe cardiac rhythm disorders (ventricular tachycardia sustained and not sustained in combination with symptoms, flutter fibrillation, ventricular premature complexes occurring close to the preceding T-wave, multifocal complexes). Has respiratory failure or a known history of pulmonary hypertension. Known allergy to one or more of the ingredients of the investigational product. Known allergy to iodinated contrast agents and MRI contrast agents. Any other contraindication to one of the imaging examinations (US, CT or MRI) e.g. implants, claustrophobia, inadequate medical conditions etc. Any contraindication to sorafenib Has received an investigational compound within 30 days before admission into this study. Has any medical condition or other circumstances which would significantly decrease the chances of obtaining reliable data, achieving study objectives, or completing the study and/or post dose follow-up examinations. Subject clinically unsuitable for the study as per Investigators judgment. Pregnant and lactating women. A pregnancy test (serum &#946;HCG or urine stick) should be carried out within 24 hours prior to the administration of the investigational product to exclude pregnancy in women of child bearing potential. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Perfusion changes will be evaluated by CE-US using a dedicated quantification software (SONOTUMOR) that allows calculation of several functional quantitative parameters including parameters related to blood volume (area under curve, perfusion index, maximum intensity, relative perfused area, perfused area) and parameters related to perfusion dynamics (mean transit time, time to peak, wash-in rate and wash-out rate, rise time). The primary quantitative parameter for evaluation of subject outcome based on CE-US cannot be selected a priori as no validated parameter and no validated response criteria are available yet. Thus, the predictiveness of the variations (% changes and absolute changes) of each of the parameters calculated by the software will be explored with the intent to select the most suitable one for prediction of subject outcome. Thus, the best parameter(s), its relevant threshold value(s), and the best time for identification of non responding subjects will be identified a posteriori.For the purpose of the analysis, overall tumor response at week 8 of therapy based on RECIST criteria and RECIST modified according to Llovet et al. will be grouped in two categories, as follows: Non Responders = progressive disease [PD]; Responders = complete response [CR] + partial response [PR] + stable disease [SD] Primary end-point: to correlate the variations (% change and absolute change vs. baseline) of functional quantitative parameters assessed by CE-US in one target HCC at week 2 and 4 of sorafenib therapy in comparison to baseline vs. progression of disease as assessed by CE-MDCT/MRI at week 8 using RECIST criteria. |
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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 | No |
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 | 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 | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
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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 | 22 |
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 | 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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 9 |