Immunotherapy Combined With Y-90 SIRT Therapy in Advanced Stage Intrahepatic Biliary Tract Cancer (BTC)

Inclusion Criteria:

1. Fully-informed written consent and locally required authorization (European Union [EU]: General Data Privacy Regulation (GDPR)) obtained from the patient prior toperforming any protocol-related procedures, including screening evaluations.
2. Age ≥ 18 years.
3. Histologically documented diagnosis of locally-advanced OR limited metasizedintrahepatic BTC not amenable to curative treatment (tumor resection or ablation),specified as

• Tumor being confined to the liver or
• In case of presence of extrahepatic lesions, metastasis must be stable AND oflimited extent* AND patient must have a potential benefit from studyparticipation in comparison to standard of care systemic therapy per local tumorboard evaluation. *Limited extent is defined in this protocol as presence of
• EITHER ≤3 malignant extrahepatic lymph nodes (short axis diameter ≥3cm)
• OR metastatic lesions in one organ other than liver (if only single lesionis present diameter MUST be < 3cm; if up to 3 lesions in one organ eachlesion MUST be ≤ 1cm).
• Presence of peritoneal or brain metastatsis excludes patients from studyparticipation (see exclusion criterion #4)
• Tumor tissue (block or at least 4 slides) is available for translationalresearch.

4. Patients with prior chemotherapy can be enrolled if ONE of the following criteria ismet:

• Capecitabin or gemcitabine+cisplatin in the adjuvant setting
• Experienced progressive disease under gemcitabine+cisplatin therapy in theadvanced setting
• Stable disease after 3 months of gemcitabine+cisplatin treatment

5. Has been considered candidate for standard-of-care Y-90 SIRT therapy per Investigatordecision and after prior consultation with the tumor board if available at site anddoes not display contraindications against SIRT. Contraindications against SIRT would be

• hepatic tumor load > 50%
• any Gastrointestinal deposition that cannot be corrected via angiographictechniques
• irreversibly elevated serum bilirubin
• renal insufficiency
• increased pulmonary shunt fraction being able to deliver > 16.5 mCi to the lungs
• gastrointestinal ulceration
• hepatic dysfunction
• biliary complications
• portal hypertension
• vascular injury and lymphopenia.

6. Performance status (PS) ≤ 1 (ECOG scale).
7. Body weight >30 kg
8. At least one measurable site of disease as defined by RECIST 1.1 criteria.
9. Adequate bone marrow and renal function
10. Adequate hepatic function (with stenting for any obstruction, if required)
11. Female patients with reproductive potential must have a negative urine or serumpregnancy test within 7 days prior to start of trial.
12. Evidence of post-menopausal status or negative urinary or serum pregnancy test forfemale pre-menopausal patients. Women will be considered post-menopausal if they havebeen amenorrheic for 12 months without an alternative medical cause.
13. The patient is willing and able to comply with the protocol for the duration of thestudy, including hospital visits for treatment and scheduled follow-up visits andexaminations.
14. Must have a life expectancy of at least 12 weeks.
15. If patient has concurrent Hepatitis B virus (HBV) or Hepatitis C virus (HCV)infection, meets the following criteria:

• Patients with HBV or HCV infection should be monitored for viral levels duringstudy participation.

• Patients with detectable hepatitis B surface antigen (HBsAg) or detectable HBVDNA should have HBV DNA < 100 IU/ml and should be managed per local treatmentguidelines. Controlled (treated) hepatitis B subjects will be allowed if they started treatment at thetime point of enrollment into the study by the latest and treatment is continued duringstudy participation and for ≥ 6 months after end of study treatment.

• HCV patients with advanced BTC are mostly not treated for their HCV infection. However,patients treated for HCV are considered suitable for inclusion if antiviral therapy hasbeen completed ≥ 30 days prior to first administration of study drug.

Exclusion Criteria:

1. Concurrent enrolment in another clinical study, unless it is an observational (non-interventional) clinical study, or during the follow-up period of aninterventional study.
2. Participation in another clinical study with an investigational product within 21 daysprior to the first dose of the study treatment.
3. Prior immunotherapy or use of other investigational agents, including prior treatmentwith an anti-Programmed Death receptor-1 (PD-1), anti-Programmed Death-1 ligand-1 (PD-L1), anti-PD-L2, or anti-cytotoxic T-lymphocyte associated antigen-4 (anti-CTLA-4)antibody, therapeutic cancer vaccines.
4. Presence of peritoneal carcinomatosis or brain metastases.
5. Any unresolved toxicity NCI CTCAE Grade ≥ 2 from previous anticancer therapy with theexception of alopecia, vitiligo, and the laboratory values defined in the inclusioncriteria
6. Any concurrent chemotherapy, investigational product (IP), biologic, or hormonaltherapy for cancer treatment. Concurrent use of hormonal therapy for non-cancerrelated conditions (eg, hormone replacement therapy) is acceptable.
7. Prior radiotherapy treatment before the first dose of any study drug.
8. Major surgery (as defined by the Investigator) within 4 weeks prior to enrollment intothe study; patients must have recovered from effects of any major surgery. Note: Localnon-major surgery for palliative intent (e.g. surgery of isolated lesions,per-cutaneous biliary drainage or biliary stenting) is acceptable.
9. Active or prior documented autoimmune or inflammatory disorders (includinginflammatory bowel disease [e.g. colitis or Crohn's disease], diverticulitis [with theexception of diverticulosis], celiac disease, systemic lupus erythematosus,Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves'disease, rheumatoid arthritis, hypophysitis, uveitis].
10. Uncontrolled intercurrent illness, including but not limited to, ongoing or activeinfection, symptomatic congestive heart failure, uncontrolled hypertension, unstableangina pectoris, cardiac arrhythmia, , serious active, uncontrolled, gastrointestinalconditions associated with diarrhea, or psychiatric illness/social situations thatwould limit compliance with study requirement, substantially increase risk ofincurring AEs or compromise the ability of the patient to give written informedconsent.
11. History of non-infectious pneumonitis requiring steroids, or patients with Grade ≥ 2pneumonitis.
12. History of another primary malignancy except for:

• Malignancy treated with curative intent and with no known active disease ≥ 5years before the first dose of IP and of low potential risk for recurrence
• Adequately treated non-melanoma skin cancer or lentigo maligna without evidenceof disease
• Adequately treated carcinoma in situ without evidence of disease

13. History of leptomeningeal carcinomatosis
14. Brain metastases or spinal cord compression. Patients with suspected brain metastasesat screening should have a CT/ MRI of the brain prior to study entry.
15. History of active primary immunodeficiency
16. History of allogenic organ transplantation.
17. Active infection including tuberculosis (clinical evaluation that includes clinicalhistory, physical examination and radiographic findings, and TB testing in line withlocal practice), or human immunodeficiency virus (positive HIV 1/2 antibodies) oractive hepatitis B/hepatitis C co-infection.
18. Current or prior use of immunosuppressive medication within 14 days before the firstdose of durvalumab or tremelimumab.
19. Female patients who are pregnant or breastfeeding or male or female patients ofreproductive potential who are not willing to employ highly effective birth controlfrom screening to 180 days after the last dose of durvalumab.
20. Known allergy or hypersensitivity to any of the IMPs or any of the constituents of theproduct.
21. Any co-existing medical condition that in the investigator's judgement willsubstantially increase the risk associated with the patient's participation in thestudy.
22. Patient who has been incarcerated or involuntarily institutionalized by court order orby the authorities § 40 Abs. 1 S. 3 Nr. 4 AMG.
23. Patients who are unable to consent because they do not understand the nature,significance and implications of the clinical trial and therefore cannot form arational intention in the light of the facts [§ 40 Abs. 1 S. 3 Nr. 3a AMG].
24. Receipt of live attenuated vaccine within 30 days prior to the first administration ofany of the IMPs and without need to receive any live attenuated vaccines during studyconduct and for up to 30 days after end of Durvalumab treatment or 90 days after endof Tremelimumab treatment respectively.