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

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.