| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Hepatocellular carcinoma (HCC) |
| Carcinona epatocellulare (HCC) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Hepatocellular carcinoma (HCC) |
| Carcinona epatocellulare (HCC) |
|
| 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) |
|
| 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 estimate in terms of PFS the efficacy of cabozantinib, given as second- or third- line treatment in HCC patients that progress on or are intolerant to immune checkpoint inhibitors. |
| Valutare l’efficacia del cabozantinib in termini di progressione libera da malattia (PFS) quando somministrato come trattamento di seconda o terza linea in paziente affetti da epatocarcinoma (HCC) in progressione o intolleranti a trattamento con immunoterapia. |
|
| E.2.2 | Secondary objectives of the trial |
1) To evaluate objective response rate (ORR) per RECIST 1.1, duration of response, time to treatment failure (TTF), time to progression (TTP), and OS.
2) To evaluate the safety and tolerability of cabozantinib in sequence after immunotherapy, according to NCI-CTCAE.
Exploratory objectives:
• To evaluate the health-related quality of life according to: a) Functional Assessment of Cancer Therapy (FACT) Hepatobiliary Symptom Index-8 (FHSI-8); b) EuroQol 5-Dimension 5-Level (EQ-5D-
5L) Questionnaire delivered at screening, after eight weeks of treatment, and at disease progression;
• To analyze biomarkers possibly related to cabozantinib efficacy and prior immune checkpoint inhibitors. |
1) Valutare l’attività di cabozantinib in termini di percentuale di risposta (ORR) per RECIST 1.1, durata della risposta, tempo al fallimento del trattamento (TTF), tempo alla progressione (TTP) e sopravvivenza (OS).
2) Valutare il profilo di sicurezza e tollerabilità di cabozantinib somministrato dopo trattamento con immunoterapia (in sequenza) in accordo a NCI-CTCAE v.5.
Obiettivi esploratori:
• valutare la qualità di vita tramite la somministrazione di questionari allo screening, dopo 8 settimane di trattamento ed alla progressione: Functional Assessment of Cancer Therapy (FACT) Hepatobiliary
Symptom Index-8 (FHSI-8); EuroQol 5-Dimension 5-Level (EQ-5D-5L) Questionnaire;
• analizzare biomarker potenzialmente correlati all'efficacia del Cabozantinib e del precedente trattamento con immunoterapia. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• Histological or cytological diagnosis of HCC (results of a previous biopsy will be accepted)
• A baseline tumor tissue (newly obtained) available at screening is optional. Patient must have a site of disease amenable to biopsy, and be a candidate for tumor biopsy according to the treating institution’s guidelines and requirements for such procedure. Biopsy cannot be performed less than ten days before treatment start.
• The subject has disease that is not amenable to a locoregional treatment approach (eg, transplant, surgery, radiofrequency ablation, TACE)
• Patients must have documented disease progression following at least 1 and no more than 2 prior systemic regimens for advanced disease (nonresectable or metastatic), the last of which includes immune checkpoint inhibitors. Alternatively, eligible patients may have experienced an immune-related, requiring treatment discontinuation.
• Recovery to = Grade 1 from toxicities related to any prior treatments, unless the adverse events are clinically not significant and/or stable on supportive therapy
• Age = 18 years old on the day of consent
• ECOG performance status of 0 or 1 (See Appendix V)
• Adequate hematologic function, based upon meeting the following laboratory criteria within 7 days before treatment beginning:
• absolute neutrophil count (ANC) = 1200/mm3 (= 1.2 x 109/L)
• platelets = 60,000/mm3 (= 60 x 109/L)
• hemoglobin = 8 g/dL (= 80 g/L)
• Adequate renal function, based upon meeting the following laboratory criteria: serum creatinine = 1.5 × upper limit of normal or calculated creatinine clearance = 40 mL/min (using the Cockroft-Gault equation: (140 – age) x weight (kg)/(serum creatinine × 72 [mg/dL]) for males. (For females multiply by 0.85)
• Child-Pugh Score of A (See Appendix IV)
• Total bilirubin = 2 mg/dL within 7 days before treatment start
• Serum albumin = 2.8 g/dL (= 28 g/L) within 7 days before treatment start
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) = 5.0 upper limit of normal (ULN)
• Antiviral therapy per local standard of care if active hepatitis B (HBV) infection
• Capable of understanding and complying with the protocol requirements and signed informed consent
• Sexually active fertile subjects and their partners must agree to use medically accepted methods of contraception (eg, barrier methods, including male condom, female condom, or diaphragm with spermicidal gel) during the course of the study and for 4 months after the last dose of study treatment
• Female subjects of childbearing potential must not be pregnant at screening. Females of childbearing potential are defined as premenopausal females capable of becoming pregnant (ie, females who have had any evidence of menses in the past 12 months, with the exception of those who had prior hysterectomy). However, women who have been amenorrheic for 12 or more months are still considered to be of childbearing potential if the amenorrhea is possibly due to prior chemotherapy, antiestrogens, ovarian suppression, low body weight, or other reasons |
• Diagnosi istologica o citologica di HCC
• Possibilità di disporre di tessuto tumorale ottenuto prima di iniziare lo studio, dopo la firma del consenso informato. Il paziente deve avere una sede di malattia accessibile per biopsia La procedura bioptica è opzionale e deve esser eseguita non meno di 10 giorni prima dell’avvio del trattamento.
• Malattia non suscettibile di trattamento curativo (trapianto, chirurgia, ablazione radiofrequenza, embolizzazione epatica)
• Progressione in corso di trattamento con immunoterapia somministrata in prima o seconda linea per HCC avanzato (non resecabile o metastatico). In alternativa, sono eleggibili pazienti che hanno riportato tossicità immuno-relate per le quali è stato interrotto il trattamento
• Risoluzione a = G1 delle tossicità da pregresso trattamento, eccetto per eventi avversi clinicamente non significativi e/o trattati con terapia di supporto
• Età = 18 anni alla firma del consenso
• ECOG performance status 0 o 1
• Adeguata funzione midollare, valutata su esami ematici da eseguire 7 giorni prima dell’inizio del trattamento:
• conta assoluta neutrofili = 1200/mm³ (= 1.2 x 10¿/L)
• conta piastrinica = 60,000/mm³ (= 60 x 10¿/L)
• emoglobina = 8 g/dL (= 80 g/L)
• Adeguata funzionalità renale:
• creatinina sierica = 1.5 x il limite superiore del range di normalità del test di laboratorio (ULN) o calcolo della clearance della creatinina = 40 mL/min (con equazione Cockroft-Gault: (140 – età) x peso (Kg) / (creatinina sierica x 72 [mg/dL]) per gli uomini (per le donne moltiplicare per 0.85)
• Calcolo classe di Child-Pugh A
• Bilirubina totale = 2 mg/dl, test eseguito entro 7 giorni dall’avvio del trattamento
• Albumina sierica = 2.8 gr/dl, test eseguito entro 7 giorni dall’avvio del trattamento
• Transaminasi (AST, ALT) = 5 volte il valore superiore del range di normalità previsto dal laboratorio di analisi
• Terapia antivirale in caso di infezione da epatite B (HBV)
• Capacità di comprendere ed aderire al protocollo e di firma consenso informato
• In caso di età fertile il/la paziente ed il/la partner devono utilizzare metodi di contraccezione durante lo studio e nei 4 mesi successivi all’ultima assunzione di dose
• Screening per gravidanza negativo per le pazienti in età fertile |
|
| E.4 | Principal exclusion criteria |
Fibrolamellar carcinoma or mixed hepatocellular cholangiocarcinoma
Child-Pugh score of B or C
Any type of anticancer agent (including investigational) within 2 weeks before treatment start
Radiation therapy within 4 weeks (2 weeks for radiation for bone metastases) or radionuclide treatment (eg, I-131 or Y-90) within 6 weeks of treatment start. Subject is excluded if there are any clinically relevant ongoing complications from prior radiation therapy
Prior cabozantinib treatment
Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery (including radiosurgery) and stable for at least 3 months before treatment start. Eligible subjects must be without corticosteroid treatment at the time of treatment start
Concomitant anticoagulation, at therapeutic doses. Low-dose aspirin for cardioprotection (per local applicable guidelines), low-dose warfarin (= 1 mg/day), and low-dose LMWH are permitted
Significant intercurrent or recent illness including, but not limited to, the following conditions:
Cardiovascular disorders including:Symptomatic congestive heart failure, unstable angina pectoris, or serious cardiac arrhythmias;Uncontrolled hypertension;Stroke (including TIA), myocardial infarction, or other ischemic event within 6 months before treatment start;Thromboembolic event within 3 months before treatment start. Subjects with thromboses of portal/hepatic vasculature attributed to underlying liver disease and/or liver tumor are eligible;
Gastrointestinal (GI) disorders including those associated with a high risk of perforation or fistula formation:Tumors invading the GI tract, active peptic ulcer disease, inflammatory bowel disease (eg, Crohn’s disease), diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, acute pancreatitis or acute obstruction of the pancreatic duct or common bile duct, or gastric outlet obstruction
Abdominal fistula, GI perforation, bowel obstruction, intra-abdominal abscess within 6 months before treatment start.
Major surgery within 2 months before treatment start. Complete healing from major surgery must have occurred 1 month before treatment start. Complete healing from minor surgery (eg, tooth extraction) must have occurred at least 7 days before treatment start.
Cavitating pulmonary lesion(s) or endobronchial disease
Lesion invading a major blood vessel including, but not limited to: inferior vena cava, pulmonary artery, or aorta. Subjects with lesions invading the portal vasculature are eligible
Clinically significant bleeding risk including the following within 3 months of treatment start
Other clinically significant disorders such as:
Active infection requiring systemic treatment, known infection with human immunodeficiency virus (HIV), or known acquired immunodeficiency syndrome (AIDS)-related illness. Subjects with active hepatitis virus infection controlled with antiviral therapy are eligible
Serious non-healing wound/ulcer/bone fracture
Malabsorption syndrome
Uncompensated/symptomatic hypothyroidism
Requirement for hemodialysis or peritoneal dialysis
History of solid organ transplantation
Rare hereditary problems of galactose intolerance.
Subjects with untreated or incompletely treated varices with bleeding or high risk for bleeding. Subjects treated with adequate endoscopic therapy (according to institutional standards) without any episodes of recurrent GI bleeding requiring transfusion or hospitalization for at least 6 months prior to study entry are eligible
Moderate or severe ascites
Corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms.
Inability to swallow tablets
Previously identified allergy or hypersensitivity to components of the study treatment formulations
Pregnant or lactating females
Diagnosis of another malignancy within 2 years before treatment start, except for superficial skin cancers, or localized, low-grade tumors deemed cured and not treated with systemic therapy |
• Carcinoma fibrolamellare o forme miste colangiocarcinoma epatocellulare
• Punteggio classe di Child-Pugh B o C
• Terapia sistemica (inclusi trattamenti sperimentali) nelle due settimane prima della somministazione di cabozantinib. Trattamento palliativo radioterapico nelle 4 settimane antecedenti al trattamento con cabozantinib ( 2 settimane per radioterapia lesioni ossee) o trattamento con radionuclidi (I-131 or Y-90) nelle 6 settimane antecedenti al trattamento. I pazienti sono inoltre esclusi se presentano complicanze persistenti dalla pregressa radioterapia
• Precedente trattamento con cabozantinib
• Metastasi cerebrali o diffusione epidurale se non adeguatamente trattata con radioterapia e/o chirurgia ed evidenza di stabilità negli ultimi 3 mesi. L’impiego di corticosteriori al momento dell’avvio del trattamento costituisce criterio di esclusione
• Farmaci anticoagulanti assunti alla dose terapeutica: warfarin, agenti warfarin-simili, eparina a basso peso molecolare, inibitori della trombina o del fattore X della coagulazione, antiaggreganti piastrinici (es. clopidogrel). Sono permesse basse dosi di cardioaspirina a scopo cardioprotettivo, warfarin a basse dosi (=1 mg/die) e basse dosi di eparina a basso peso molecolare.
• Il paziente è affetto da patologie concomitanti non in fase di compenso:
• Malattie cardiovascolari: cardiopatica congestizia sintomatica, sindrome anginosa, aritmie cardiache, ipertensione arteriosa non controllata, evento ischemico miocardico negli ultimi 6 mesi, evento tromboembolico negli ultimi 3 mesi (i pazienti con trombosi delle vene porta/epatiche sono includibili)
• Malattie gastrointestinali con elevato rischio di perforazione o formazione di fistole: tumore che infiltra il tratto gastrointestinale, ulcera peptica attiva, malattie infiammatorie dell’intestino, diverticolite, colecistite, colangite sintomatica, appendicite, pancreatite acuta, ostruzione acuta dei dotti pancreatico-biliari, ostruzione alte vie digestive, fistola addominale, perforazione gastrointestinale, ostruzione intestinale, ascesso intraddominale negli ultimi 6 mesi (conferma della completa risoluzione dell’ascesso prima dell’avvio del trattamento)
• Intervento di chirurgia maggiore negli ultimi due mesi e guarigione entro un mese prima dell’avvio del trattamento con cabozantinib. Per intervento di chirurgia minore si considerino almeno 7 giorni dalla guarigione
• Lesioni cavitate polmonari o malattia endobronchiale
• Lesioni infiltranti la vena cava inferiore, arteria polmonare e l’aorta
• Rischio significativo di sanguinamento negli ultimi 3 mesi
• Altre condizioni cliniche: infezione HIV o AIDS, ferite/ulcere/fratture ossee non guaribili, sindrome da malassorbimento, ipotiroidismo scompensato/sintomatico, dialisi, trapianto, intolleranza ereditaria al galattosio, deficit della Lapp lattasi o malassorbimento glcosio-galattosio, varici esofagee non trattate o trattate con rischio elevato di sanguinamento, episodio di sanguinamento da varici negli ultimi sei mesi, moderata e/o severa ascite, intervallo QT corretto >500 ms, difficoltà nel deglutire le compresse, nota ipersensibilità ad eccipienti contenuti nella compressa, allattamento o gravidanza, diagnosi di altra patologia oncologica negli ultimi due anni eccetto per tumori cutanei o neoplasie di basso grado a lenta crescita considerate curate senza impiego di terapia sistemica. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| PFS on cabozantinib treatment (considering as PFS events: clinical or radiological progressive disease, per RECIST 1.1, or death). |
| Valutare l’efficacia di cabozantinib in termini di Prossion Free Survival (PFS) (considerando eventi di PFS la progressione radiologica secondo criteri RECIST 1.1 o clinica o evento morte). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Primary Endpoint will be assessed before each additional treatment cycle. |
| L'endpoint primario verrà valutato prima di ogni nuovo ciclo di trattamento. |
|
| E.5.2 | Secondary end point(s) |
Exploratory Endpoint:
Patients' quality of life will be assessed throught the following questionnaires: Functional Assessment of Cancer Therapy (FACT) Hepatobiliary Symptom Index-8 (FHSI-8) e EuroQol 5-Dimension 5-Level (EQ-5D-5L) Questionnaire.; Exploratory Endpoint:
To analyze biomarkers possibly related to Cabozantinib efficacy and prior immune checkpoint inhibitors.; To evaluate the safety and tolerability, according to NCI-CTCAE v.5; Objective Response Rate (ORR) as per RECIST 1.1, duration of response, Treatment Time Failure (TTF), Time to Progression (TTP), and Overall Survival (OS). |
Endpoint esplorativo:
valutare la qualità di vita tramite la somministrazione dei questionari Functional Assessment of Cancer Therapy (FACT) Hepatobiliary Symptom Index-8 (FHSI-8) e EuroQol 5-Dimension 5-Level (EQ-5D-5L) Questionnaire.; Endpoint esplorativo:
Analizzare biomarker potenzialmente correlati all'efficacia del Cabozantinib del precedente trattamento con immunoterapia.; Valutare il profilo di sicurezza e tollerabilità di cabozantinib somministrato dopo trattamento con immunoterapia (in sequenza) in accordo a NCI-CTCAE v.5.; Valutare l’attività di cabozantinib in termini di percentuale di risposta Objective Response Rate (ORR) per RECIST 1.1, durata della risposta, tempo al fallimento del trattamento (TTF), tempo alla progressione (TTP) e sopravvivenza (OS). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Endpoint will be evaluated every 8 weeks of treatment and at disease progression.; Biomarkers will be evaluated at different time points during the Cabozantinib treatment, as described in the study protocol.; Endpoint will be evaluated at each treatment cycle.; ORR will be assessed before each additional treatment cycle.
OS will be evaluated from starting treatment until death or last contact for patients alive.
TTP will be considered from the date of starting treatment until progressive disease. For patients without progression last available assessment will be considered.
TTF will be evaluated as time from starting treatment to discontinuation of treatment for any reason, including disease progression, treatment toxicity, and death. |
L'endpoint verrà valutato ogni 8 settimane di trattamento e alla progressione.; L'analisi sui biomarker verrà effettuata a tempi diversi nel corso del trattamento con Cabozantinib in base a quanto riportato nel protocollo.; L'endpoint verrà valutato ad ogni ciclo di trattamento.; ORR verrrà valutato prima di ogni nuovo ciclo di trattamento.
OS verrà valutato dall'inzio del trattamento fino all'evento morte o all'ultimo contatto con il paziente.
TTP verrà valutato dall'inizio del trattamento fino alla progressione della malattia. Per pazienti senza progressione al fine del TTP verrà considerata l'ultima valutazione effettuata.
TTF verrà valutato dall'inizio del trattamento fino alla sua discontinuazione per qualsiasi ragione, inclusa la progressione di malattia, tossicità ed evento morte |
|
| 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 | 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 | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| 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 | No |
| 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 | 4 |
| 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 | 4 |
| 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 |
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