Precision Medicine in Patients With Unresectable CholAngiocarcinoma: RadioEmbolization and Combined Biological Therapy

Inclusion Criteria: * Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. Written informed consent and any locally required authorization (European Union \[EU\] Data Privacy Directive) obtained from the patient/legal representative prior to performing any protocol related procedures, including screening evaluations. * Patients with liver predominant intrahepatic cholangiocarcinoma with intermediate/high rate of early recurrence calculated according to https://k-sahara.shinyapps.io/Veryearlyrecurrence/. * Patients aged \> 18 to ≤ 80 at time of study entry; * Body weight \>30kg * Suspicion or biopsy confirmed diagnosis of iCC, not previously treated with systemic or surgical therapies, including not previously enrolled in another clinical study with an investigational product; * Preserved liver function as defined as: Child Pugh Class A; Model for End Stage Liver Disease Score (MELD) \<10; Future Liver Remnant (FLR) uptake function ≥2.7%/min/m2 on technetium- 99m mebrofenin hepatobiliary scintigraphy and FLR volume\> 30% of total functional liver volume for a normal liver, or \> 40% of total functional liver volume if the liver has been damaged by chronic liver disease, cholestasis, steatohepatitis or diabetes; * No technical contraindications to TARE as confirmed by pre-procedural angiographic and scintigraphy; * DNA tests for hepatitis B virus (HBV) and RNA tests for hepatitis C virus (HCV) negative at Screening; * Adequate heart and lung function; * Eastern Cooperative Oncology Group (ECOG) Performance Score 0 or 1; * Adequate renal and hepatic function as indicated by: serum creatinine \<2x upper limit of normal and estimated glomerular filtration rate (eGFR) ≥30ml/min or 1.73m2; measured creatinine clearance (CL) \>40 mL/min or calculated creatinine CL\>40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976\*) or by 24-hour urine collection for determination of creatinine clearance; Alkaline phosphatase (ALP), alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) ≤ 5 times the upper limit of normal (ULN) and total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) (this will not apply to patients with confirmed Gilbert's syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or hepatic pathology), who will be allowed only in consultation with their physician); * Hemoglobin ≥9 g/dL, platelet count ≥75,000/mm3, absolute neutrophil count (ANC) ≥ 1.0 x 109 /L * Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up. * Must have a life expectancy of at least 12 weeks Exclusion Criteria: * Cancer classified as a combined or mixed type (HCC hepatocelular carcinoma and ICC) at screening -histopathological examination; * Child-Pugh class B or more or evidence of severe portal hypertension at screening or at any time up to and including baseline; * History of major gastrointestinal bleeding that required medical intervention within 30 days prior to screening or baseline; * Known hypersensitivity to tumor specific chemotherapy agents used during the study; * Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients; * Previous allogeneic bone marrow transplant, kidney or liver transplant, i.e. - history of allogenic organ transplantation; * Active viral, bacterial or fungal infection, clinically relevant for the assessment of suitability; * Current history or evidence of neuropsychiatric diseases, including depression, schizophrenia,bipolar disorder, impaired cognitive function, dementia, or suicidal tendency; * Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease \[e.g., colitis or Crohn's disease\], diverticulitis \[with the exception of diverticulosis\], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome \[granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis,etc\]). The following are exceptions to this criterion: Patients with vitiligo or alopecia; Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement; Any chronic skin condition that does not require systemic therapy; Patients without active disease in the last 5 years may be included but only after consultation with the study physician; Patients with celiac disease controlled by diet alone; * History of severe cardiovascular disease such as a previous stroke, coronary artery disease requiring surgery, or unresolved arrhythmias within the past 6 months; * Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥470 ms calculated from 3 ECGs (within 15 minutes at 5 minutes apart); * Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring adverse events (AEs) or compromise the ability of the patient to give written informed consent * History of another primary malignancy except for: malignancy treated with curative intent and with no known active disease ≥5 years before the first dose of IP and of low potential risk for recurrence; Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease; Adequately treated carcinoma in situ without evidence of disease * History of leptomeningeal carcinomatosis; * Evidence of any hematological malignancy; * History of active primary immunodeficiency - Positive for human immunodeficiency virus type 1 or 2 (HIV-1, HIV-2) (serum or RNA) - and / or hepatitis B virus surface antigen (HBsAg) positive and/or active Treponema pallidum infection or Mycoplasma (active tuberculosis infection); Known active hepatitis infection, positive hepatitis C virus (HCV) antibody, hepatitis B virus (HBV) surface antigen (HBsAg) or HBV core antibody (anti-HBc), at screening. Participants with a past or resolved HBV infection (defined as the presence of anti-HBc and absence of HBsAg) are eligible. Participants positive for HCV antibody are eligible only if polymerase chain reaction is negative for HCV RNA; * Alcohol abuse in the 2 months prior to study or other substance abuse in the 6 months prior to the study; * Pregnant or breastfeeding women or women planning to become pregnant; * Known bleeding diathesis or history of abnormal bleeding or any other known coagulation abnormality that may contraindicate future surgery or biopsies; * Use of systemic immunosuppressants or steroids (prednisone equivalent\> 10 mg/day); * Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab. The following are exceptions to this criterion: Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection); Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent; Steroids as premedication for hypersensitivity reactions; * Active autoimmune conditions * Patients weighing \<30kg will be excluded from enrolment; * Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients; * Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of Investigational product (IP). Note: Local surgery of isolated lesions for palliative intent is acceptable. * Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note: Patients, if enrolled, should not receive live vaccine whilst receiving IP and up to 90 days after the last dose of IP and up to 90 days after the last dose; * Presence of Hepatopulmonary shunt \>20% at diagnostic angiography/99mTC-MAA. * Prior randomisation or treatment in a previous durvalumab clinical study regardless of treatment arm assignment; * Presence of Hepatopulmonary shunt \>20% at diagnostic angiography/99mTC-MAA; * Concurrent enrolment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study.