E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Unresectable intrahepatic cholangiocarcinoma |
Colangiocarcinoma intraepatico non resecabile |
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E.1.1.1 | Medical condition in easily understood language |
Cholangiocarcionoma - bile duct cancer - that forms in the bile ducts inside the liver and that cannot be surgically removed. |
Colangiocarcinoma - tumore delle vie biliari - che si sviluppa nelle cellule dei dotti biliari all'interno del fegato e che non è operabile. |
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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 | LLT |
E.1.2 | Classification code | 10073077 |
E.1.2 | Term | Intrahepatic cholangiocarcinoma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 | 10008593 |
E.1.2 | Term | Cholangiocarcinoma |
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 | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Assess efficacy-defined as overall response rate - of radioembolization (TARE) followed by a combination of standard of care chemotherapy with cisplatin and gemcitabine plus durvalumab in patients with liver predominant unresectable intrahepatic cholangiocarcinoma and assess the safety of the therapeutic scheme. This study will administer durvalumab out of its current indication (indication for first-line treatment of adults with unresectable or metastatic biliary tract cancer (BTC) approved by the FDA on September 2, 202; positive opinion given by EMA's Committee for Medicinal Products for Human Use (CHMP) for the same indication awaiting European Commission Approval). Radioembolization will be performed using SIR-Spheres® resin Microspheres (loaded with yttrium-90 ) code SIR-Y001; an approved class II medical device device (145685IR) outside its indication for use for which a request to initiate an investigation will be sent to the Ministry of Health. |
Valutare l'efficacia-definita come overall response rate-dell'associazione di trattamento locoregionale-radioembolizzazione (TARE) seguito da trattamento sistemico i.e. combinazione di cisplatino e gemcitabina con durvalumab e valutarne la sicurezza. ll durvalumab sarà somministrato fuori dalla sua corrente indicazione (indicazione dell'uso del durvalumab in associazione con cisplatino e gemcitabina come trattamento di prima linea in pazienti con tumori delle vie biliari non resecabili o metastatici approvata dal FDA il 2 settembre 2022;parere positivo del Committee for Medicinal Products for Human Use(CHMP) EMA il 10 novembre 2022 per la stessa indicazione (attesa approvazione Comm. Europea). La radioembolizzazione avverrà tramite l'utilizzo di microsfere in resina SIR-Spheres® caricate con ittrio-90 codice codice SIR-Y001; dispositivo medico (145685IR) al di fuori della sua corrente indicazione per l'uso per la quale verra inviata richiesta di avvio indagine al Ministero della Salute |
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E.2.2 | Secondary objectives of the trial |
Describe tumor biological aspects; Investigate the relationship between tumor circulating markers, tumor tissue based markers,quantitative non-invasive imaging and radiomics-based parameters, genetic markers in tissue and biological substrates; Evaluate tumor mutational burden, immunological landscape in responders and non-responders to treatment at given time points and among time points; Quantitative imaging based parameters in responders and non-responders at given time points and among time points; Interim assessment of efficacy of treatment regimen. |
Descrivere gli aspetti biologici tumorali; Valutare la relazione tra marcatori circolanti tumorali, marcatori tumorali tessutali, parametri quantitativi non-invasivi di imaging inclusi la radiomica; marcatori genetici tissutali e in substrati biologici; valutare il tasso mutazionale del tumore, microambiente in termini immunologico nei "responder" e "non responder" al trattamento ai vari tempi e tra i diversi tempi di valutazione; Parametri di imaging quantitativi nei "responder" e "non responder" al trattamento ai vari tempi e tra i diversi tempi di valutazione; valutazione interim dell'efficacia dei regimi di trattamento. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Suspected or biopsy-confirmed diagnosis of intrahepatic cholangiocarcinoma (ICC), not previously treated with systemic or surgical therapies; - Preserved liver function, defined as: Child Pugh Class A; MELD score (Model forEnd Stage Liver Disease Score} <10; - No technical contraindication to TARE, confirmed by pre-procedural angiography and scintigraphy; - Hepatitis B virus (HBV} DNA test and Hepatitis C virus (HCV} RNA test negative at screening; - Adequate heart and lung function; - ECOG Performance Score O or 1; - Adequate renal and hepatic function, as indicated by: serum creatinine <2x the upper limit of normal and estimated glomerular filtration rate (eGFR) >30ml/min or 1.73m/2; alkaline phosphatase (ALP}, alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST} s 5 times the upper limit of normal (ULN) and total bilirubin s 2.0 mg/dl; - Hemoglobin greater than or equal to10 g/dL, platelet count greater than or equal to 70,000/mm3, absolute neutrophil count >1500/mm3. - Ability and willingness to provide written informed consent and to comply with study protocol and procedures |
- Sospetto o diagnosi confermata da biopsia di colangiocarcinoma intraepatico (ICC), non precedentemente trattato con terapie sistemiche o chirurgiche; - Funzione epatica conservata, definita come: Classe A di Child Pugh; punteggio MELD (Model for End Stage Liver Disease Score} <10; - Nessuna controindicazione tecnica alla TARE, confermata dall'angiografia e dalla scintigrafia pre procedurali; - Test per ii virus dell'epatite B (HBV} e test dell'RNA per ii virus dell'epatite C (HCV} negativi allo screening; - Funzionalità cardiaca e polmonare adeguata; - ECOG Performance Score O o 1; - Funzionalità renale ed epatica adeguata, come indicate da: creatinina sierica <2x ii limite superiore della norma e velocità di filtrazione glomerulare stimata (eGFR) >30ml/min o 1,73m2; fosfatasi alcalina (ALP}, alanina aminotransferasi (ALT) e/o aspartato aminotransferasi (AST} s 5 volte ii limite superiore della norma (ULN) e bilirubina totale s 2,0 mg/dl; - Emoglobina maggiore o uguale a 10 g/dL, conta piastrinica maggiore o uguale a 70.000/mm3, conta assoluta dei neutrofili > 1500/mm3. - Capace e disponibile a fornire ii consenso informato scritto e a rispettare ii protocollo e le procedure dello studio |
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E.4 | Principal exclusion criteria |
• Pregnant or breastfeeding women; - Uncorrectable coagulopathies - Extensive disease extrahepatic or extrarenal - Tumor classified as combined or mixed type (HCC and ICC} at screening - Child-Pugh Class B or higher or evidence of severe portal hypertension at screening or at any time up to and including baseline; - History of major gastrointestinal bleeding requiring medical attention within 30 days prior to screening or at baseline; - Known hypersensitivity to the specific chemotherapy agents used during the study; - Any oral or parenteral chemotherapy or immunotherapy treatment within 2 years prior to screening; - Previous allogeneic bone marrow transplant, kidney or legacy transplant; - Active viral, bacterial or fungal infections, clinically relevant to the assessment of fitness; - Current history or evidence of neuropsychiatric illness, including depression, schizophrenia, bipolar disorder, impaired cognition, dementia, or suicidal tendencies; - History of serious cardiovascular disease, such as a previous stroke, coronary artery disease requiring surgery, or unresolved arrhythmias within the last 6 months. - Evidence of any hematologic malignancy; - Positive to human immunodeficiency virus type 1 or 2 (HIV-1, HIV-2) (serum or RNA} and/or hepatitis B virus surface antigen (HBsAg} and/or active infection with Treponema Pallidum or Mycoplasma; - Abuse of alcohol in the 2 months prior to the study or abuse of any substance in the 6 months prior to the study; - Known bleeding diathesis or history of abnormal bleeding or any other known coagulation abnormality that may contraindicate future surgery or biopsies; - Use of immunosuppressant steroids (prednisone equivalent > 10 mg/day}; - Presence of hepatopulmonary shunt >20% or other contraindications to arterial radioembolization |
- Donne in gravidanza o in allattamento; -Coagulopatie non corregibili -Malattia estesa in sede extraepatica o extrarenale- Tumore classificato ccme tipo combinato o misto (HCC e ICC} allo screening; -Classe Child-Pugh B o superiore o evidenza di ipertensione portale grave allo screening o in qualsiasi momenta fino al basale incluso; -Storia di emorragia gastrointestinale importante che ha richiesto un intervento medico nei 30 giorni precedenti lo screening o al basale; - lpersensibilità nota agli agenti chemioterapici specifici utilizzati durante lo studio; - Qualsiasi trattamento chemioterapicoo immunoterapico orale o parenterale nei 2 anni precedenti lo screening; • Precedente trapianto allogenico di midollo osseo, trapianto di rene o di legato; • lnfezioni virali, batteriche o fungine attive, clinicamente rilevanti per la valutazione dell'idoneita; • Anamnesi attuale o evidenza di malattie neuropsichiatriche, tra cui depressione, schizofrenia, disturbo bipolare, compromissione della funzione cognitiva, demenza o tendenza al suicidio; • Storia di gravi malattie cardiovascolari, come un precedente ictus, una malattia coronarica che richiede un intervento chirurgico o aritmie non risolte negli ultimi 6 mesi. • Evidenza di qualsiasi neoplasia ematologica; • positivita al virus dell'immunodeficienza umana di tipo 1 o 2 (HIV-1, HIV-2) (siero o RNA} e/o all'antigene di superficie del virus dell'epatite B (HBsAg} e/o infezione attiva da Treponema Pallidum o Mycoplasma; • Abuse di alcol nei 2 mesi precedenti lo studio o abuse di allre sostanze nei 6 mesi precedenti lo studio; • Diatesi emorragica nota o anamnesi di sanguinamento anomalo o qualsiasi altra anomalia della coagulazione nota che possa controindicare fuluri interventi chirurgici o biopsie; • Uso di immunosoppressorio steroidi (prednisone equivalente> 10 mg/die}; • Presenza di shunt epatopolmonare >20% o altre controindicazioni alla radioembolizzazione arteriosa |
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E.5 End points |
E.5.1 | Primary end point(s) |
Efficacy: Overall response rate (ORR) according to mRECIST 1.1 criteria on imaging Safety: Evaluate adverse events, laboratory findings, vital signs and other diagnostic evaluation alterations |
Efficacia: risposta al trattamento definito come overall response rate (ORR) secondo i criteri mRECIST 1.1 su imaging Sicurezza: Valuatre eventi avversi, alterazioni delle varie valutazione diagnostiche (valori di laboratorio, segni vitali, tra le altre) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Efficacy: at six (6) months after radioembolization (TARE). Safety: throughout the study |
Efficacia: a sei (6) mesi dalla radioembolizzazione (TARE) Sicurezza: durante tutto lo studio |
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E.5.2 | Secondary end point(s) |
Describe tumor biological aspects: Investigate the relationship between tumor circulating markers, tumor tissue based markers; quantitative non-invasive imaging and radiomics-based parameters; genetic markers in tissue and biological substrates; Describe the tumor microenvironment (tissue and circulating biomarkers, quantitative imaging, immune response) correlate these with response to treatment; distinguish characteristics of responders vs non-responders;; Efficacy: interim evaluation of treatment response defined as overall response rate according to mRECIST 1.1 e RECIST |
Descrivere il microambiente tumorale: valutare la relazione tra i marcatori tumorali circolanti, marcatori tumorali tissutali; valutazione dei parametri quantitativi non invasivi estratti dall'imaging e dalla valutazione radiomica; marcatori genetici tissutali e valutazione dei substrati biologici; Descrivere il micro-ambiente tumorale (biomarcatori tessutali e circolanti, quantitativi su imaging, risposta immunitaria) e correlato con la risposta al trattamento; distinguere caratteristiche di responder vs i non responder;; Efficacia: valutazione ad interim della risposta al trattamento definita come overall response response rate secondo criteri mRECIST 1.1 e RECIST |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Serial blood sampling; cytokine profiling - baseline, at approximately one month ( pre-systemic treatment), at three months post TARE Biopsy prior to and following treatment - baseline and at three months post TARE Imaging: protocol defined imaging time points basal, at one month, three months, six months post TARE and at imaging time points during follow up; Data collected during the study; evaluation against imaging at 3 and 6 months - overall evaluation at the end of the treatment period; Imaging at three months after radioembolizzation (TARE) |
Valutazione su sangue periferico: al basale, a un mese circa (pre-trattamento sisemico) e e sei mesi post TARE Biopsia tessuto tumorale: al baslae e a tre mesi post TARE Imaging: alle tempistiche descritte da protocollo; basle, 1 mese, 3 mesi, 6 mesi post TARE e imaging al follow-up; Dati raccolti durante lo studio; valutazione effettuata 3 e 6 mesi dalla TARE - valutazione a fine studio; Imaging a tre (3) mesi dalla radioembolizzazione (TARE) |
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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 | 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 | Yes |
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 | Yes |
E.8.1.7.1 | Other trial design description |
braccio singolo |
Single arm |
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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 |
nessun comparatore - studio a braccio singolo |
no comparator - single arm study |
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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
| 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 | 4 |
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
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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 | 2 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
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 | 0 |