Durvalumab + Intraductal Radiofrequency Ablation (ID-RFA) in Extrahepatic Cholangiocarcinoma

Inclusion Criteria:

1. Patient* has given written informed consent.

2. Patient is ≥ 18 years of age at time of signing the written informed consent.

3. Patient is willing and able to comply with the protocol for the duration of thestudy including undergoing treatment and scheduled visits and examinations includingfollow up.

4. Patient has been diagnosed with histologically or cytologically confirmed

5. histologically or cytologically confirmed cholangiocarcinoma as adenocarcinomaof pancreatobiliary type

6. unresectable perihilar and/or ductal cholangiocarcinoma with indication forbile duct stenting and palliative systemic therapy as determined by the localmultidisciplinary team (MDT) and already resolved cholestasis due to RFA +stent

7. Patient tolerated RFA prior to inclusion and is eligible for repeat RFA during thestudy (does not have any contraindications) as determined by investigator.

8. Patient is eligible for palliative systemic therapy based on clinical and laboratoryparameters (except hyperbilirubinemia) as determined by the local MDT

9. Patient has a ECOG ≤ 1.

10. Patient has life expectancy of ≥ 12 weeks

11. Patient has body weight > 30 kg

12. Adequate blood count, liver-enzymes, and renal function:

13. ANC > 1,500 cells/μL without the use of hematopoietic growth factors

14. Platelet count ≥ 100 x 109/L (>100,000 per mm3)

15. Hemoglobin ≥ 9 g/dL

16. Serum total bilirubin ≤ 3x upper normal limit (ULN) (biliary drainage isallowed for biliary obstruction; elevated bilirubin should be caused byobstruction not impaired liver function as assessed by albumin and INR values)

17. Albumin levels ≥ 2.8 g/dL

18. Patients not receiving therapeutic anticoagulation must have an INR< 2.0 ULNand PTT < 1.5 ULN within 7 days prior to randomization. The use of full doseanticoagulants is allowed as long as the INR or PTT is within therapeuticlimits (according to the medical standard in the institution) and the patienthas been on a stable dose for anticoagulants for at least three weeks at thetime of inclusion

19. AST (SGOT)/ALT (SGPT) ≤ 2.5 x institutional ULN unless liver metastases arepresent, in which case it must be ≤ 5x ULN

20. Serum Creatinine ≤ 1.5 x ULN and a calculated creatinine clearance rate ≥ 60 mL /min

21. Female patients defined as women of childbearing potential (WOCBP) or male patientswith WOCBP partners must agree to remain abstinent (refrain from heterosexualintercourse) or use contraceptive methods that result in a failure rate of <1% peryear during the treatment period and for at least 6 months after the last dose ofchemotherapy or for at least 3 months after last dose of durvalumab, whateverhappens last. Male patients must refrain from donating sperm during this sameperiod. Male patients with a pregnant partner must agree to remain abstinent or touse a condom for the duration of the pregnancy.

Exclusion Criteria:

1. Patient received previous or simultaneous endobiliary treatment other than RFA (e.g.PDT or brachytherapy)

2. Patient received previous systemic therapy with a PD-1, PD-L1 inhibitor (includingdurvalumab) or CTLA4 inhibitor or classical chemotherapy agents like platinum,fluoropyrimidine or gemcitabine-based regimens.

3. Patient receives any concurrent chemotherapy, investigational product or hormonaltherapy for cancer treatment. Concurrent use of hormonal therapy for non-cancerrelated conditions (e.g., hormone replace therapy) is acceptable.

4. Patient has known hypersensitivity to any component of the durvalumab formulation aswell as a known history of severe allergic, anaphylactic, or other hypersensitivityreactions to chimeric or humanized antibodies or fusion protein and/or any knowncontraindication (including hypersensitivity) to gemcitabine or cisplatin.

5. Patient has history of primary immunodeficiency

6. Patient has stage B cirrhosis according to Child-Pugh criteria (or worse) orcirrhosis (of any grade) with a history of hepatic encephalopathy or clinicallysignificant ascites resulting from cirrhosis. Clinically significant ascites isdefined as ascites resulting from cirrhosis requiring diuretics or paracentesis.

7. Patient has any unresolved NCI CTCAE grade ≥ 2 from previous anticancer therapy withthe exception of alopecia, vitiligo, and laboratory values defined in the inclusioncriteria

8. Patients with grade ≥ 2 neuropathy will be evaluated on a case-by-case basisafter consultation with the Lead Investigator

9. Patients with irreversible toxicity not reasonably expected to be exacerbatedby treatment with durvalumab may be included only after consultation with theLead Investigator.

10. Patient had a prior allogeneic bone marrow transplantation or prior solid organtransplantation.

11. Patient has active or history of autoimmune or inflammatory disorders (including,but not limited to, 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]) . The following areexceptions:

12. Patients with vitiligo or alopecia

13. Patients with hypothyroidism (e.g. following Hashimoto syndrome) stable onhormone replacement

14. Patients with any chronic skin condition that does not require systemic therapy

15. Patients with celiac disease controlled by diet alone

16. Patients without active disease in the last 5 years may be included but onlyafter consultation with the Lead Investigator

17. Uncontrolled intercurrent illness, including but not limited to, ongoing or activeinfection, symptomatic congestive heart failure, uncontrolled hypertension, unstableangina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronicgastrointestinal conditions associated with diarrhea, or psychiatric illness/socialsituations that would limit compliance with study requirement, substantiallyincrease risk of incurring AEs or compromise the ability of the patient to givewritten informed consent