Sponsor decision and challenges in finding eligible participants

The goal of this clinical trial is to test feasibility and safety of the combination of tremelimumab and durvalumab plus gemcitabine and cisplatin as a neoadjuvant treatment bridge patients to a curative resection in treatment naïve borderline resectable, or resectable with high risk for recurrence intrahepatic cholangiocarcinoma patients. The main question[s] it aims to answer are:

• What is the rate of conversion of unresectable tumor to resectable cancer?
• What are the side effects of this treatment combination?

Participants will undergo an initial tumor biopsy, imaging and laboratory studies prior to starting treatment with durvalumab, tremelimumab, gemcitabine and cisplatin. Participants will continue for 4 cycles and if the tumor is found to be resectable then they will undergo surgical resection. If the tumor is unresectable (can't be surgically removed) after 4 cycles, then participants will receive 4 more cycles and repeated imaging. If the tumor remains unresectable then the participant will be treated with capecitabine for up to 8 cycles and durvalumab for up to 12 months.

Inclusion Criteria:

1. Patients of age 18 years and older at the time of study entry, both sexes, all ethnicities.
2. Patients with histologically proven intrahepatic cholangiocarcinoma, untreated with systemic therapy.
3. Patients with an absence of extrahepatic metastasis (outside of periportal lymph node 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 curative intent, as validated by a multidisciplinary committee with at least one hepatobiliary surgeon, defined as stage II and stage III disease, surgical resectable if there is tumor shrinkage.
7. Patients with at least one measurable lesion according to RECIST 1.1 criteria. Tumor assessment by computed tomography (CT) scan or magnetic resonance imaging (MRI) must be 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 hour urine 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) ≤ 2.5 x institutional upper limit of normal unless liver metastases are present, in which case it must be ≤5x ULN
13. Patients with a reference CT Scan within 30 days preceding the 1st cycle of treatment.
14. Patients with US health insurance coverage.
15. Patients are 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 (e.g., Health Insurance Portability and Accountability Act in the US, European Union [EU] Data Privacy Directive in the EU) obtained from the patient/legal representative prior to performing any protocol-related procedures, including screening evaluations.
16. Patients are willing and able to comply with the protocol for the duration of the study including undergoing treatment and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up.
17. Body weight ≥30 kg

Exclusion Criteria:

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

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

3. Patients who would not be surgical candidates due to reasons unrelated to their cholangiocarcinoma, 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 the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria

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

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

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

10. 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

11. 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

12. History of leptomeningeal carcinomatosis

13. 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)

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

15. Patients with an active autoimmune disease that has required systemic treatment in the past 2 years with the use of disease-modifying agents, corticosteroids, or immunosuppressive drugs. Exceptions to this criterion include intranasal, inhaled, topical steroids or local steroid injections, systemic corticosteroids at physiologic doses not to exceed 10mg/day or prednisone or its equivalent, or steroids 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 has current pneumonitis.

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

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

20. Coinfection of hepatitis B virus (HBV) and hepatitis C virus (HCV) as determined by viral load. HBV infection is allowed only if patient is on HBV treatment per institutional 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 evaluation that 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, or other serious underlying disorders that would likely prevent the patient from receiving therapy.

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

24. Patients with another cancer, active within the 5 years preceding or at the time of inclusion in this trial. Note: Patients with early-stage cancer that has been resected/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 to adhere to medical follow-up of the trial for geographical, social, or psychological reasons.

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

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

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