Neoadjuvant Tremelimumab and Durvalumab With Gem/Cis in Intrahepatic Cholangiocarcinoma

Inclusion Criteria:

1. Patients of age 18 years and older at the time of study entry, both sexes, allethnicities.

2. Patients with histologically proven intrahepatic cholangiocarcinoma, untreated withsystemic therapy.

3. Patients with an absence of extrahepatic metastasis (outside of periportal lymphnode enlargement) or peritoneal carcinomatosis as demonstrated by CT-scan.

4. Patients with a performance status ECOG 0, 1.

5. Patients with an estimated life expectancy > 6 months.

6. Patients with disease that is not readily suitable for resection with curativeintent, as validated by a multidisciplinary committee with at least onehepatobiliary surgeon, defined as stage II and stage III disease, surgicalresectable if there is tumor shrinkage.

7. Patients with at least one measurable lesion according to RECIST 1.1 criteria. Tumorassessment by computed tomography (CT) scan or magnetic resonance imaging (MRI) mustbe performed within 28 days prior to start of study.

8. Patients with platelets ≥ 75,000/mm3, polynuclear neutrophils ≥ 1500/mm3, hemoglobin ≥ 9g/dL.

9. Patients with serum creatinine < 1.5 times institutional upper limit of normal (ULN), measured creatinine clearance > 40 mL/min or Calculated creatinine clearance > 40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24 hoururine collection for determination of creatinine clearance.

10. Patients with serum bilirubin ≤ 1.5 times institutional upper limit of normal (ULN) (after biliary drainage if necessary).

11. Absolute neutrophil count (ANC ≥ 1.0 × 109 /L)

12. Aspartate aminotransferase (AST or SGOT) / alanine transaminase (ALT or SGPT) ≤ 2.5x institutional upper limit of normal unless liver metastases are present, in whichcase it must be ≤5x ULN

13. Patients with a reference CT Scan within 30 days preceding the 1st cycle oftreatment.

14. Patients with US health insurance coverage.

15. Patients are capable of giving signed informed consent which includes compliancewith the requirements and restrictions listed in the informed consent form (ICF) andin this protocol. Written informed consent and any locally required authorization (e.g., Health Insurance Portability and Accountability Act in the US, European Union [EU] Data Privacy Directive in the EU) obtained from the patient/legalrepresentative prior to performing any protocol-related procedures, includingscreening evaluations.

16. Patients are willing and able to comply with the protocol for the duration of thestudy including undergoing treatment and able to comply with the protocol for theduration of the study including undergoing treatment and scheduled visits andexaminations including follow up.

17. Body weight ≥30 kg

Exclusion Criteria:

1. Patients with hilar or distal cholangiocarcinoma or those withhepatocholangiocarcinoma.

2. Patients who are eligible for surgical resection or liver transplantation based ontumor characteristics.

3. Patients who would not be surgical candidates due to reasons unrelated to theircholangiocarcinoma, e.g. Cirrhosis with portal hypertension

4. Patients with extrahepatic metastases beyond periportal lymph node enlargement

5. Patients with a contraindication or grade 3-4 allergy to durvalumab, tremelimumab,gemcitabine, cisplatin, or capecitabine.

6. Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with theexception of alopecia, vitiligo, and the laboratory values defined in the inclusioncriteria

7. Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis afterconsultation with the Study Physician.

8. Patients with irreversible toxicity not reasonably expected to be exacerbated bytreatment with durvalumab or tremelimumab may be included only after consultationwith the Study Physician.

9. Radiotherapy treatment to more than 30% of the bone marrow or with a wide field ofradiation within 4 weeks of the first dose of study drug

10. Major surgical procedure (as defined by the Investigator) within 28 days prior tothe first dose of Investigational Product (IP). Note: Local surgery of isolatedlesions for palliative intent is acceptable

11. Active or prior documented autoimmune or inflammatory disorders (includinginflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [withthe exception of diverticulosis], systemic lupus erythematosus, Sarcoidosissyndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease,rheumatoid arthritis, hypophysitis, uveitis, etc.]). The following are exceptions tothis criterion:

• Patients with vitiligo or alopecia

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

• Any chronic skin condition that does not require systemic therapy

• Patients without active disease in the last 5 years may be included but onlyafter consultation with the study physician

• Patients with celiac disease controlled by diet alone

12. History of leptomeningeal carcinomatosis

13. Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥470 mscalculated from 3 ECGs (within 15 minutes at 5 minutes apart)

14. Prior randomization or treatment in a previous durvalumab and/or tremelimumabclinical study regardless of treatment arm assignment.

15. Patients with an active autoimmune disease that has required systemic treatment inthe past 2 years with the use of disease-modifying agents, corticosteroids, orimmunosuppressive drugs. Exceptions to this criterion include intranasal, inhaled,topical steroids or local steroid injections, systemic corticosteroids atphysiologic doses not to exceed 10mg/day or prednisone or its equivalent, orsteroids as premedication for hypersensitivity reactions.

16. Patients with a history of allogenic organ transplantation.

17. Patients with a history of non-infectious pneumonitis that required steroids or hascurrent pneumonitis.

18. Patients who are recipients of a live attenuated vaccine within 30 days prior to thedose of durvalumab.

19. Patients with poorly controlled diarrhea (grade ≥ 2).

20. Coinfection of hepatitis B virus (HBV) and hepatitis C virus (HCV) as determined byviral load. HBV infection is allowed only if patient is on HBV treatment perinstitutional guideline. HCV infection is allowed.

21. Patients known to have tested positive for human immunodeficiency virus (HIV) (positive HIV 1/2 antibodies) or active tuberculosis infection (clinical evaluationthat may include clinical history, physical examination and radiographic findings,or tuberculosis testing in line with local practice)

22. Patients with a serious, non-stabilized disease, active uncontrolled infection, orother serious underlying disorders that would likely prevent the patient fromreceiving therapy.

23. Patients who are pregnant, breast-feeding, or of child-bearing age with a refusal touse effective contraception.

24. Patients with another cancer, active within the 5 years preceding or at the time ofinclusion in this trial. Note: Patients with early-stage cancer that has beenresected/ablated/radiated, without evidence of disease recurrence or progression,within 2 years may be considered.

25. Patients with legal incapacity.

26. Patients who are deprived of civil liberty.

27. Patients for whom it is impossible to sign the informed consent document or toadhere to medical follow-up of the trial for geographical, social, or psychologicalreasons.

28. Patients who have participation in another clinical study with an investigationalproduct during the last 4 weeks.

29. Patients who are concurrently enrolled in another clinical study, unless it is anobservational (non-interventional) clinical study or during the follow-up period ofan interventional study.

30. Patients who are judged by the investigator that the patient is unsuitable toparticipate in the study and the patient is unlikely to comply with the studyprocedures, restrictions and requirements.