E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Hepatocellular carcinoma |
Carcinoma epatocellulare |
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E.1.1.1 | Medical condition in easily understood language |
Liver cancer |
Tumore epatico |
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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 | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10073071 |
E.1.2 | Term | Hepatocellular carcinoma |
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 | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To compare recurrence-free survival (RFS) (based on BICR assessment) of nivolumab vs placebo in all randomized participants |
Confrontare la sopravvivenza libera da recidiva (RFS) (in base a valutazione BICR) di nivolumab rispetto a placebo in tutti i partecipanti randomizzati. |
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E.2.2 | Secondary objectives of the trial |
To compare overall survival (OS) of nivolumab vs placebo in all randomized participants. ¿ To evaluate time to recurrence (TTR) (based on BICR assessment) of nivolumab vs placebo in all randomized participants. |
Confrontare la sopravvivenza globale (OS) di nivolumab rispetto a placebo in tutti i partecipanti randomizzati. ¿ Valutare il tempo alla recidiva (TTR) (in base a valutazione BICR) di nivolumab rispetto a placebo in tutti i partecipanti randomizzati.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Males and females, ages 18 or older. 2. Participants must have a first diagnosis of HCC amenable for management with curative intent by resection or local ablation. 3. Participants are eligible to enroll if they have non-viral related-HCC, or if they have HBV-HCC, or HCV-HCC 4. Participants are eligible to enroll if they have undergone: i) Hepatic resection and have the following tumor characteristics: up to three tumors, at least one with a diameter > 5 cm OR none with a diameter > 5 cm but with confirmation of microvascular invasion or poorly /undifferentiated HCC; or more than three tumors, none with a diameter > 5 cm ii) Local ablation [radiofrequency ablation (RFA) or microwave ablation (MWA)] and have the following tumor characteristics: solitary tumor > 3cm but <=5 cm; OR Multiple tumors (up to 4), none with a diameter > 5 cm 5. Participants must have complete resection response, or must have achieved radiologically documented complete resection after local ablation. 6. All participants are required to have imaging studies confirming disease-free status at least 4 weeks after either complete tumor removal after surgical resection or local ablation, and within 4 weeks prior to randomization. 7. Child-Pugh Score 5 or 6 8. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1 |
1. Soggetti di sesso maschile e femminile di età pari o superiore a 18 anni. 2. I partecipanti devono avere una prima diagnosi di carcinoma HCC trattabile con intento curativo mediante resezione o ablazione locale. 3. I partecipanti sono idonei all'arruolamento se hanno HCC non virale, o se hanno HBV-HCC o HCV-HCC 4. I partecipanti sono idonei all’arruolamento se si sono sottoposti a: I) Resezione epatica e presentano le seguenti caratteristiche tumorali: fino a tre tumori, almeno uno con un diametro > 5 cm OPPURE nessuno con un diametro > 5 cm ma con conferma di invasione microvascolare o HCC scarsamente /indifferenziato; o più di tre tumori, nessuno con un diametro > 5 cm ii) ablazione locale [ablazione a radiofrequenza (RFA) o ablazione a microonde (MWA)] ed hanno le seguenti caratteristiche tumorali: tumore solitario > 3cm ma <=5 cm; OPPURE tumori multipli (fino a 4), nessuno con un diametro > 5 cm 5. I partecipanti devono avere risposta completa a resezione o devono avere raggiunto resezione completa documentata radiologicamente a seguito di ablazione locale. 6. Tutti i partecipanti sono tenuti a sottoporsi a studi di diagnostica per immagini che confermino lo stato di ‘libero da malattia’ almeno 4 settimane dopo o la rimozione completa del tumore dopo la resezione chirurgica o l’ablazione locale, e entro 4 settimane prima della randomizzazione. 7. Punteggio di Child-Pugh 5 o 6 8. Performance status (PS) ECOG (Eastern Cooperative Oncology Group) 0 o 1
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E.4 | Principal exclusion criteria |
1. Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC. 2. Prior recurrence of HCC. 3. Any evidence of tumor metastasis or co-existing malignant disease. 4. Participants showing evidence of macrovascular invasion on imaging tests. 5. Participants who have undergone a liver transplant or those who are in the waiting list for liver transplantation. 6. Active co-infection with with both Hepatitis B and C, OR Hepatitis D and B 7. Known history of positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS). 8. Participants with an active, known or suspected autoimmune disease. 9. Participants with a condition requiring systemic treatment with either corticosteroids or other immunosuppressive medications within 14 days of start of study treatment. 10. Prior malignancy active within the previous 3 years except for locally curable cancers that have been apparently cured. 11. Participants previously receiving any prior therapy for HCC, including loco-regional therapies, before or after resection or ablation. 12. Participants receiving or expected to receive IFN-based therapies during the study period. 13. Positive pregnancy test. |
1. Noto HCC fibrolamellare, HCC sarcomatoide, o combinazione di colangiocarcinoma e HCC. 2. Prima recidiva di HCC. 3. Eventuali evidenze di metastasi tumorale o malattia maligna co-esistente. 4. Partecipanti che mostrano evidenze di invasione macrovascolare al test di diagnostica per immagini. 5. Partecipanti che hanno subito un trapianto del fegato o partecipanti in lista di attesa per trapianto del fegato. 6. Co-infezione attiva con epatite sia B che C, o con epatite D e B 7. Nota anamnesi di test positivo per il virus dell'immunodeficienza umana (HIV) o nota sindrome da immunodeficienza acquisita (AIDS). 8. Partecipanti con una malattia autoimmune attiva, nota o sospetta. 9. Partecipanti con una condizione che richiede il trattamento sistemico con corticosteroidi o con altri medicinali immunosoppressori entro 14 giorni dall’inizio del trattamento in studio. 10. Prima neoplasia maligna attiva entro i precedenti 3 anni eccetto per cancri localmente curabili che sono stati apparentemente curati. 11. Partecipanti che in precedenza ricevevano qualsiasi terapia preventiva per HCC, comprese terapie loco-regionali, prima o dopo la resezione o l’ablazione. 12. Partecipanti che ricevono o che ci si aspetta che ricevano terapie a base di IFN durante il periodo dello studio. 13. Test di gravidanza positivo. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Recurrence free survival (RFS), defined as the time from randomization to the first documented disease recurrence or death (by any cause), whichever occurs first |
• Sopravvivenza libera da recidiva (‘Recurrence free survival’, RFS), definita come il tempo trascorso dalla randomizzazione alla prima recidiva di malattia documentata o decesso (per qualsiasi causa), a seconda dell’evento che si verifica per primo |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
RFS will be evaluated on an ongoing basis from randomization until recurrence |
L’RFS, sarà valutata su base continuativa dalla randomizzazione fino alla recidiva |
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E.5.2 | Secondary end point(s) |
¿ OS, defined as the time between the date of randomization and the date of death (by any cause). ¿ Time to Recurrence (TTR), defined as the time from randomization to the first documented disease recurrence |
OS, definita come il tempo tra la data di randomizzazione e la data di decesso (per qualsiasi causa). ¿ Tempo alla recidiva (¿Time to Recurrence ¿, TTR), definito come il tempo trascorso dalla randomizzazione alla prima recidiva di malattia documentata |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
OS: From the beginning of randomization period up to date of event TTR: time from randomization to the first documented disease recurrence |
OS dall'inizio del periodo di randomizzazione fino alla data dell'evento TTR: tempo trascorso dalla randomizzazione alla prima recidiva di malattia documentata |
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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 | Yes |
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 | Yes |
E.6.13.1 | Other scope of the trial description |
Biomarker, immunogenicity analysis and outcome research (OR) QoL questionnaires |
Analisi dei biomarcatori, della immunogenicit¿ e questionari sulla Qualit¿ della vita (QoL) sulla ricerca sugli esiti (¿Outcome Research, ¿OR¿) |
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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.8.2.4 | 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 | 9 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 69 |
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 |
Australia |
Brazil |
Canada |
China |
Hong Kong |
Japan |
Korea, Republic of |
Mexico |
Russian Federation |
Singapore |
Taiwan |
United States |
Austria |
Belgium |
France |
Germany |
Italy |
Poland |
Romania |
Spain |
United Kingdom |
Argentina |
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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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 6 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 27 |
E.8.9.2 | In all countries concerned by the trial years | 6 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 27 |