E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
hepatocellular carcinoma |
carcinoma epatocellulare |
|
E.1.1.1 | Medical condition in easily understood language |
liver cancer |
carcinoma epatico |
|
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 | LLT |
E.1.2 | Classification code | 10019829 |
E.1.2 | Term | Hepatocellular carcinoma recurrent |
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 the OS of patients with advanced HCC receiving axtitinib + best supportive care (BSC) versus (vs) placebo + BSC following failure of one prior antiangiogenic therapy. |
Confrontare l’OS dei pazienti con HCC avanzato che ricevono axitinib + miglior terapia di supporto (BSC) rispetto a placebo + BSC dopo mancata risposta ad una precedente terapia antiangiogenica. |
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E.2.2 | Secondary objectives of the trial |
•To compare PFS between both arms •To compare TTP between both arms •To compare overall response rate (ORR) between both arms •To evaluate DR within each treatment arm •To compare CBR between both arms •To evaluate the safety and tolerability of axitinib in this patient population •To evaluate the pharmacokinetics of axitinib in this patient population. •To compare patients' health-related quality of life (HRQoL) and health status between both arms. •To evaluate baseline blood VEGF-C level as a potential predictive biomarker of axitinib efficacy. •To evaluate blood soluble protein concentrations and RNA transcripts associated with angiogenesis or tumor growth. |
•Confrontare PFS tra i due bracci •Confrontare TTP tra i due bracci •Confrontare il tasso di risposta complessiva (ORR) tra i due bracci •Valutare la durata della risposta (DR) in ciascun braccio di trattamento •Confrontare la risposta di beneficio clinico (CBR) tra i due bracci •Valutare la sicurezza e la tollerabilità di axitinib in questa popolazione di pazienti •Valutare la farmacocinetica di axitinib in questa popolazione di pazienti •Confrontare la qualità della vita relativa alla salute (HRQoL) dei pazienti e lo stato di salute tra i due bracci •Valutare il livello ematico di VEGF-C basale come potenziale biomarcatore predittivo dell’efficacia di axitinib •Valutare le concentrazioni di proteine solubili nel sangue e trascritti di RNA associati all’angiogenesi o alla crescita del tumore. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Locally advanced or metastatic HCC confirmed by histology or cytology (diagnosis of HCC obtained from a prior tumor biopsy specimen is acceptable) or liver mass confirmed as HCC by one or more imaging modalities, including triphasic contrastenhanced helical CT, triphasic dynamic contrast-enhanced MRI and contrast-enhanced ultrasonography, and not amenable to local therapy. 2. Failure of one prior antiangiogenic therapy (patients must have received at least 4 weeks of prior therapy). Antiangiogenic agents include sorafenib, bevacizumab and brivanib. Failure is defined as either a) documented progressive disease (per RECIST version 1.1) while receiving prior therapy or after the last dose of prior therapy; or b) intolerance to the prior antiangiogenic therapy. Intolerance to prior antiangiogenic therapy (at any dose and/or duration) is defined as documented treatment-related grade 3 or 4 adverse events that led to treatment discontinuation. 3. Presence of either measurable or non-measurable disease according to RECIST (version 1.1). |
1. HCC avanzato o localmente metastatico confermato da esame istologico o citologico (la diagnosi di HCC ottenuta da una precedente biopsia tumorale è accettabile) o massa a livello epatico confermata come HCC da una o più immagini, tra cui trifasico CT contrasto enhanced elicoidale trifasico, MRI con contrasto enhanced dinamico e ultrasonografia con contrasto enhanced e non suscettibili di terapia locale. 2. Fallimento di una precedente terapia antiangiogenica (i pazienti devono avere ricevuto almeno 4 settimane di terapia preventiva). Agenti antiangiogenici comprendono sorafenib, bevacizumab e brivanib. Il fallimento è definito come a) malattia documentata (a seconda dei RECIST versione 1.1) durante la terapia prima o dopo l'ultima dose della terapia precedente, oppure b) intolleranza alla precedente terapia antiangiogenica. Intolleranza a precedente terapia antiangiogenica (a qualsiasi dosaggio, e/o durata) è definito come eventi avversi di grado 3 e 4 documentati e correlati al trattamento che hanno portato alla sospensione del trattamento. 3. Presenza di una malattia misurabile o non misurabile secondo RECIST (versione 1.1). |
|
E.4 | Principal exclusion criteria |
1. Prior treatment of advanced HCC with more than one prior first-line systemic therapy. 2. Any prior local therapy (such as surgery, radiation therapy, hepatic arterial embolization, TACE, hepatic arterial infusion, radiofrequency ablation, percutaneous ethanol injection or cryoablation) within 2 weeks of study screening. 3. Prior history of liver transplant. |
1. precedente trattamento di carcinoma epatico avanzato con più di una precedente terapia sistemica di prima linea. 2. Qualsiasi precedente terapia locale (come la chirurgia, la radioterapia, embolizzazione arteriosa epatica, TACE, infusione arteriosa epatica, ablazione con radiofrequenza, l'iniezione percutanea di etanolo o crioablazione) entro 2 settimane dallo screening. 3. 3. precedente storia di trapianto di fegato. |
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E.5 End points |
E.5.1 | Primary end point(s) |
overall survival. |
sopravvivenza generale. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Randomized Portion: Overall Survival evaluated for 3 years after the last subject is randomized. Non-randomized Portion • Plasma PK (Cmax, AUCinf, AUClast, Tmax, t1/2, CL/F, Vz/F) and tolerability of single-agent axitinib following continuous dosing. Assessed Cycle 1 Day 15 • First-cycle DLT (Child-Pugh Class B, Score 7 population only). • Type, incidence, severity, timing, seriousness, and relatedness of adverse events, laboratory abnormalities based upon the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. will be assessed throughout the study. |
Porzione randomizzata: sopravvivenza complessiva valutata per 3 anni dopo la randomizzazione dell'ultimo soggetto. Porzione non randomizzata: • PK plasmatica (Cmax, AUCinf, AUClast, Tmax, t1/2, CL/F, Vz/F) e tollerabilità di axitinib come agente singolo a seguito di somministrazione continua. Valutazione del giorno 15 del ciclo 1 • Primo ciclo DLT (Child-Pugh B, popolazione con punteggio 7 solamente)• Tipo, incidenza, gravità, tempi, serietà, e relazione degli eventi avversi, anomalie di laboratorio in base al National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 saranno valutati durante lo studio. |
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E.5.2 | Secondary end point(s) |
- PFS - TTP - ORR - DR - CBR - Type, incidence, severity (graded by the National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE], version 3.0), timing, seriousness, and relatedness of adverse events and laboratory abnormalities - Axitinib population PK analysis - Patient Reported Outcome (PRO) of health-related quality of life and disease-related symptoms as measured by the Functional Assessment of Cancer Therapy – Hepatobiliary questionnaire (FACT-Hep) and health status measured by the EuroQol EQ-5D Self-Report Questionnaire (EQ-5D). - Plasma soluble proteins [including but not limited to AFP, VEGF-A, VEGF-C, sVEGFR, HGF, sHGFR] - Plasma RNA transcripts associated with angiogenesis and tumor growth. |
- PFS - TTP - ORR - DR - CBR - Tipo,incidenza, gravità (classificata secondo il National Cancer Institute [NSC] Criteri per la Terminologia comune degli eventi avversi[CTCAE], versione 3.0),tempi,serietà, relazione degli eventi avversi e anomalie di laboratorio - analisi PK della popolazione con Axitinib - risultati (PRO) sulla qualità della vita e sintomi correlati alla malattia misurati scondo la Functional Assessment of Cancer Therapy - questionario epatobiliare (FACT-Hep) e stato di salute misurato con EuroQol EQ-5D Self-Report Questionnaire (EQ-5D). - proteine ​​plasmatiche solubili [compreso ma non limitato ad AFP, VEGF-A,VEGF-C,sVEGFR, HGF, sHGFR] - trascrizione di RNA plasmatico associato ad angiogenesi e crescita tumorale. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
• Tumor assessment including CT/MRI will be required at baseline and every 8 weeks. Response (CR/PR) requires confirmation at least 4 weeks after the response is noted. • Safety assessment (for adverse events) will be carried out throughout the study and at the 28 day follow-up visit. • Axitinib Population PK analysis - assessed Day 1 of Cycle 1, 2 and 3 • Patient Reported Outcome (PRO) of health-related quality of life and disease-related symptoms as well as Health status will be assessed every 4 weeks during the study, end of treatment and at the 28 day follow-up visit. • Plasma soluble proteins will be assessed, at baseline, Cycle 2 Day 1 and end of treatment. • Plasma RNA transcripts will be assessed, at baseline, Cycle 2 Day 1 and end of treatment. |
•valutazione del tumore inclusa TC/RM sarà richiesta al basale e ogni 8 settimane. La risposta (CR/PR) richiede la conferma almeno 4 settimane dopo che la risposta è nota. -valutazione della sicurezza (per eventi avversi) sarà effettuata durante tutto lo studio e il giorno 28 alla visita di follow-up. - Analisi della popolazione PK con Axitinib, valutata al giorno 1 del ciclo 1, 2 e 3 -PRO di qualità di salute e di vita e i sintomi correlati alla malattia, nonché lo stato di salute verranno valutati ogni 4 settimane durante lo studio, alla fine del trattamento e al giorno 28 della visita di follow-up. -Le proteine plasmatiche solubili verranno valutate al basale, Giorno 1 del Ciclo 2 e alla fine del trattamento. -La trascrizione dell’RNA plasmatico sarà valutata al basale |
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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 | 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 | 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 | 10 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 21 |
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 |
China |
Hong Kong |
Japan |
Korea, Democratic People's Republic of |
Korea, Republic of |
Singapore |
Taiwan |
Turkey |
United States |
|
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
|
- Enrolment is completed according to protocol planned sample size, and assessments and requirements are completed as per protocol. - The stated objectives of the trial are achieved. - Recommendation by DMC. |
- Arruolamento completato in base alle dimensioni del campione previste dal protocollo, valutazioni e requisiti completati in accordo al protocollo. - sono raggiunti gli obiettivi dello studio indicati. - raccomandazioni dal DMC. |
|
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 | 19 |
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 | 19 |
E.8.9.2 | In all countries concerned by the trial days | 0 |