| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Hepatocellular carcinoma non-resectable |
| Hepatocellular carcinoma non-resectable |
|
| 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 | 14.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10019695 |
| E.1.2 | Term | Hepatic neoplasm |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 |
| The primary objective of this trial is to determine the Progression Free Survival Rate (PFSR) of repeated oral doses of 4SC-201 and of the treatment combination of Sorafenib plus 4SC-201 after 12 weeks. |
| Determinare il tasso di sopravvivenza senza progressione della patologia (PFSR, Progression Free Survival Rate) dopo 12 settimane. |
|
| E.2.2 | Secondary objectives of the trial |
| • To establish the MTD of 4SC-201 in combination with Sorafenib; • To investigate the safety and tolerability of repeated oral doses of 4SC-201 and of the treatment combination of ascending repeated oral doses of 4SC-201 and Sorafenib; • To investigate the Overall Response Rate (ORR) of repeated oral doses of 4SC-201 and of the treatment combination of Sorafenib plus 4SC-201 • To determine Time to Progression (TTP) of repeated oral doses of 4SC-201 and of the treatment combination of Sorafenib plus 4SC-201, including radiological and symptomatic progression; • To assess Overall Survival (OS) in patients getting repeated oral doses of 4SC-201 or the combination of Sorafenib plus 4SC-201; • To determine Progression Free Survival (PFS) of repeated oral doses of 4SC-201 and of the treatment combination of Sorafenib plus 4SC-201, including radiological and symptomatic progression |
- Det. la DMT di 4SC-201 incomb con Sorafenib;
- stabilire la sicur. e la toll di dosi ripetute assunte per via orale di 4SC-201 e dellacomb terapeutica di 4SC-201,assunto per via orale in dosi ripetute e quantità crescenti,con Sorafenib;
- valut il tasso di risp complessivo(ORR,Overall Response Rate)di dosi orali ripetute di 4SC-201 e dellacomb terapeutica di Sorafenib più 4SC-201(sulla base sia dei Criteri di valut della risp in Tumori solidi [RECIST] sia dei criteri del“Panel di esperti AASLD 2008 in sperimentazioni cliniche su progetti sull’epatocarcinoma”,considerati separatamente);
- det. il tempo allaprogr(TTP)di dosi orali ripetute di 4SC-201 e dellacomb terapeutica di Sorafenib più 4SC-201,compresa laprogr radiologica e sintomatica;
- stabilire la Sopravvivenza Complessiva(OS,Overall Survival)dei paz che assumono dosi orali ripetute di 4SC-201 oppure lacomb di Sorafenib più 4SC-201;
ecc. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
| 1. Male or female P 18 years; 2. Written informed consent obtained prior to any trial specific procedure; 3. Advanced stage hepatocellular carcinoma, BCLC class B (intermediate stage, performance status 0, multinodular HCC) or C (advanced stage, performance status-ECOG 1-2, invasive tumor pattern (vascular invasion/extra hepatic spread)), with either histological proven HCC or clinical diagnosis of HCC by AASLD criteria (HCC defined in cirrhotic patients by one imaging technique (CT, MRI or second generation contrast ultrasound) showing a nodule of > 2 cm with contrast uptake in the arterial phase and washout in venous or late phases or two imaging techniques showing this radiological behavior for nodules of 1 to 2 cm in diameter), exhibiting PD under Sorafenib treatment. For patients without cirrhosis, histological confirmation of HCC is mandatory; 4. Exhibiting PD under Sorafenib treatment, as detected by at least one CT/MRI scan within 4 weeks prior to study inclusion. Progressive disease will be confirmed by an independent radiological review; 5. Child-Pugh class A and B. Only patients with Child-Pugh index class B of not more than 7 will be included. Patients with more than slight ascites or hepatic encephalopathy > Grade 1 are excluded (see exclusion criteria); 6. ECOG performance status 0, 1 or 2 (refer to Appendix C for definitions of ECOG grades); 7. Life expectancy of 12 weeks or more; 8. Precedent first-line treatment with Sorafenib minimum dosing of 400 mg per day for at least 8 weeks. Treatment interruptions for any reason must not be more in the sum than 14 days within this 8 week period. Patients have stopped Sorafenib therapy not more than 10 weeks prior to treatment start, but at least 2 weeks prior to treatment start;; 9. Adequate hematological parameters, as demonstrated by: • Hemoglobin P 9.0 g/dl (SI units: 5.6 mmol/l); • White Blood Cells (WBCs) P 3.0 x 109/l; • Absolute neutrophil count P1,500/mm3; • Platelets P 75 x 109/l; • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) T 5 times upper limit of normal range (ULNR); • Bilirubin T 3 mg/dl; • Serum creatinine T 1.5 mg/dl (SI units: 132 Umol/l); • Prothrombin Time (PT) International Normalized Ratio (INR) T 2.3; • Serum potassium, magnesium and calcium within normal range; 10. Safe contraception in females of childbearing potential during the entire study using an established treatment with hormonal contraceptives for at least 2 months prior to start of screening; 11. For females of child bearing potential (without using hormonal contraceptives for at least 2 months prior to start of screening) a double contraception method is requested during the entire study meeting the criteria for an effective method of birth control. That means at least two effective birth control methods such as condoms, diaphragms or intra-uterine devices must be used; 12. Male patients with partners of child bearing potential are requested to use barrier contraception in addition to having their partner use another method of contraception during the trial and for 3 months after the last dose. Male patients will also be advised to abstain from sexual intercourse with pregnant or lactating women, or to use condoms; 13. Completes a period of at least 30 days since ending investigational device or drug trials and have recovered from treatment-related toxicities; 14. Able to comply with all the requirements of the protocol. |
1.uomo o donna di eta' ≥ ai 18 anni;
2.consenso informato scritto da ottenere prima di ogni altro specifico procedimento di sperimentazione clinica;
3.carcinoma epatocellulare allo stadio avanzato, classe B nella stadiazione BCLC (fase intermedia, performance status: 0; epatocarcinoma multinodulare) o classe C (stadio avanzato, performance status ECOG: 1-2, pattern tumorale invasivo (invasione vascolare / diffusione extraepatica)) in pazienti affetti sia da carcinoma epatocellulare provato istologicamente oppure con diagnosi clinica stilata con criteri AASLD (carcinoma epatocellulare definito in pazienti cirrotici tramite una tecnica di imaging (TAC, MRI oppure con mezzi di contrasto a ultrasuoni di seconda generazione) che presentano un nodulo > di 2 cm con captazione del mezzo di contrasto nella fase arteriosa e washout nelle fasi venosa o ultimal, oppure con due tecniche a imaging che dimostrano questo comportamento negli accertamenti radiologici per noduli di 1 max 2 cm di diametro), caratterizzati da patologia progressiva con trattamento a base di Sorafenib. Per pazienti non affetti da cirrosi e' obbligatoria la conferma istologica dell’epatocarcinoma;
4.persone trattate con Sorafenib affette da patologia progressiva risultante da almeno una scansione TAC o MRI effettuata nelle 4 settimane precedenti all’inclusione nello studio. La patologia progressiva sara' confermata con una verifica radiologica indipendente;
5.Classe A e B di Child-Pugh: verranno coinvolti soltanto pazienti appartenenti alla classe B di Child-Pugh non superiore a 7. Saranno esclusi i pazienti con asciti molto lievi o encefalopatie epatiche di grado > 1 (vd. criteri di esclusione);
6.ECOG performance status ECOG 0, 1 o 2 (consultare Appendice C per le definizioni dei gradi ECOG);
7.aspettativa di vita pari o superiore alle 12 settimane;
8.trattamento precedente di prima linea con un dosaggio minimo di Sorafenib di 400 mg al di' per almeno 8 settimane. In tutto, il trattamento non dovra' subire interruzioni per qualsiasi ragione per non piu' di 14 giorni nel corso delle 8 settimane; prima di iniziare il trattamento i pazienti devono aver terminato la terapia con Sorafenib da non oltre 10 settimane e comunque da non meno di 2 settimane;
9.parametri ematologici soddisfacenti, dimostrati da:
•emoglobina ≥ 9,0 g/dl (unita' SI: 5,6 mmol/l);
•globuli bianchi ≥ 3,0 x 109/l;
•conta assoluta dei neutrofili ≥1,500/mm3;
•piastrine ≥ 75 x 109/l;
•alanina aminotransferasi (ALT) e aspartato aminotransferasi (AST) ≤ 5 volte al limite superiore alla norma (ULNR, upper limit of normal range);
•bilirubina ≤ 3 mg/dl;
•creatinina sierica ≤ 1,5 mg/dl (unita' SI: 132 µmol/l);
•tempo di protrombina (PT) nel rapporto INR (International Normalized Ratio, rapporto internazionale normalizzato) ≤ 2.3;
•potassio sierico, magnesio e calcio nei valori normali;
10.contraccezione sicura per le donne in eta' di potenziale gravidanza durante l’intero decorso dello studio per mezzo di un trattamento riconosciuto con contraccettivi ormonali per almeno 2 mesi prima di iniziare la selezione;
11.alle donne in eta' di potenziale gravidanza (che non hanno fatto ricorso a contraccettivi ormonali per almeno 2 mesi prima dell’inizio della selezione) si richiede di adottare un doppio metodo contraccettivo per l’intero svolgimento dello studio che sia riconosciuto come metodo efficace di controllo delle nascite. Cio' significa che si deve ricorrere ad almeno due metodi efficaci di controllo delle nascite, come preservativi, diaframmi oppure dispositivi intrauterini; |
|
| E.4 | Principal exclusion criteria |
| 1. 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 and T1). Any cancer curatively treated > 3 years prior to entry is permitted; 2. Renal failure requiring hemo- or peritoneal dialysis; 3. Known central nervous system (CNS) tumors including symptomatic brain metastasis; 4. Patients with no adequate treatment for gastrointestinal bleeding and esophagus varices within 14 days prior to study entry. IMP administration is scheduled to start within 14 days after adequate treatment. 5. Child-Pugh index class B in combination with more than slight ascites or hepatic encephalopathy > Grade I (see Child-Pugh index, Appendix D); 6. History and current cardiovascular complications, including unstable angina pectoris, uncontrolled hypertension, congestive heart failure (NYHA Class III or IV) related to primary cardiac disease, a condition requiring anti arrhythmic therapy, ischemic or severe valvular heart disease, or a myocardial infarction within 6 months prior to the trial entry; A marked baseline prolongation of QT/QTc interval (e.g., repeated demonstration of a QTc interval >450 milliseconds (ms)); A history of additional risk factors for TdP (e.g., heart failure, hypokalemia, family history of Long QT Syndrome); 7. The use of concomitant medications that prolong the QT/QTc interval (see Appendix B) and treatment with cytokine growth factors; 8. Current evidence of any severe internal, psychiatric or neurologic disease; 9. Altered mental status precluding understanding of the informed consent process and/or completion of the necessary studies; 10. Pregnant or breastfeeding women; 11. Sorafenib intolerance; 12. History of allergic reactions attributed to compounds of similar chemical or biological composition to the study drug; 13. Active alcohol and/or drug abuse; 14. Major surgery within the last 4 weeks; 15. Patients who are employees at the investigational center, relatives or spouse of the investigator. |
| 1. 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 and T1). Any cancer curatively treated > 3 years prior to entry is permitted; 2. Renal failure requiring hemo- or peritoneal dialysis; 3. Known central nervous system (CNS) tumors including symptomatic brain metastasis; 4. Patients with no adequate treatment for gastrointestinal bleeding and esophagus varices within 14 days prior to study entry. IMP administration is scheduled to start within 14 days after adequate treatment. 5. Child-Pugh index class B in combination with more than slight ascites or hepatic encephalopathy > Grade I (see Child-Pugh index, Appendix D); 6. History and current cardiovascular complications, including unstable angina pectoris, uncontrolled hypertension, congestive heart failure (NYHA Class III or IV) related to primary cardiac disease, a condition requiring anti arrhythmic therapy, ischemic or severe valvular heart disease, or a myocardial infarction within 6 months prior to the trial entry; A marked baseline prolongation of QT/QTc interval (e.g., repeated demonstration of a QTc interval >450 milliseconds (ms)); A history of additional risk factors for TdP (e.g., heart failure, hypokalemia, family history of Long QT Syndrome); 7. The use of concomitant medications that prolong the QT/QTc interval (see Appendix B) and treatment with cytokine growth factors; 8. Current evidence of any severe internal, psychiatric or neurologic disease; 9. Altered mental status precluding understanding of the informed consent process and/or completion of the necessary studies; 10. Pregnant or breastfeeding women; 11. Sorafenib intolerance; 12. History of allergic reactions attributed to compounds of similar chemical or biological composition to the study drug; 13. Active alcohol and/or drug abuse; 14. Major surgery within the last 4 weeks; 15. Patients who are employees at the investigational center, relatives or spouse of the investigator. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Progression-free survival at 12 weeks |
| Progression-free survival at 12 weeks |
|
| 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 | No |
| 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 | 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| 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 | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 16 |
| 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 | No |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 11 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 28 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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