MP0317 in Combination With Chemoimmunotherapy in First Line Treatment for Patients With Advanced Biliary Tract Carcinoma

Inclusion Criteria:

1. Signed and dated informed consent

2. Histologically confirmed biliary tract carcinoma: intra/extrahepaticcholangiocarcinoma (note that gallbladder carcinoma are not eligible)

3. Locally advanced unresectable or metastatic

4. Patient who had not previously received systemic anti-cancer treatment (adjuvanttreatment with Capecitabine is allowed if the end of the chemotherapy was at least 6months ago)

5. Age ≥ 18 years

6. Measurable disease defined according to RECIST v1.1 (Response Evaluation Criteria InSolid Tumours) guidelines Note: Previously irradiated lesions can be considered asmeasurable disease only if disease progression has been unequivocally documented atthat site since radiation.

7. Patients who have received previous chemoembolization, radioembolization and/orradiotherapy should have recovered from any treatment related toxicity, to a levelof ≤ grade 1 according to National Cancer Institute [NCI] common terminologycriteria for adverse events, version 5 (CTCAE v5); with the exception of Grade 2alopecia

8. Performance status ECOG-PS < 2 (Eastern Cooperative Oncology Group)

9. Females must be using highly effective contraceptive measures, and have a negativepregnancy test prior to the start of dosing if of childbearing potential, and duringtreatment and at least 7 months after the end of the treatment with cisplatin, 6months after the end of the treatment with gemcitabine, 3 months after the end ofthe treatment with durvalumab, or must have evidence of non-childbearing potentialby fulfilling one of the following criteria at screening:

10. Post-menopausal is defined as aged more than 50 years and amenorrhoeic for atleast 12 months following cessation of all exogenous hormonal treatments.

11. Women under the age of 50 years would be considered postmenopausal if they havebeen amenorrhoeic for 12 months or more following cessation of exogenoushormonal treatments and with luteinizing hormone and follicle stimulatinghormone levels in the post-menopausal range for the institution.

12. Women with documentation of irreversible surgical sterilisation byhysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tuballigation.

13. Male patients with a female partner of childbearing potential should be willingto use barrier contraception during the study and at least: 4 months after theend of the treatment with cisplatin and 3 months after the end of the treatmentwith gemcitabine. Patients should refrain from donating sperm from the start ofdosing until 4 months after discontinuing study treatment.

14. Documented virology status of hepatitis, as confirmed by screening HBV and HCVtests:

15. For patients with active HBV: HBV DNA <500 IU/ml (International unit)duringscreening, initiation of anti-HBV treatment at least 14 days prior torandomization and willingness to continue anti-HBV treatment during the study (per local standard of care; e.g., entecavir)

16. Patients with HCV, either with resolved infection (as evidenced by detectableantibody) or chronic infection (as evidence by detectable HCV RNA), areeligible

17. Patient affiliated to or beneficiary of French social security system

18. Ability to comply with the study protocol, in the Investigator's judgment.

Exclusion Criteria:

For patients whose tumors present a genetic alteration of IDH1, FGFR2 or BRAF as well as an amplification of HER2, the investigators of the TACTIC study recommend, if possible, the orientation for preferential inclusion in the SAFIR ABC10 study".

1. Patients previously exposed to anti-tumor immunotherapy such as anti-PD-1,anti-PD-L1, or anti-CTLA4 (cytotoxic T-lymphocyte-associated protein 4) agent or anyimmune therapy

2. Diagnosis of additional malignancy within 3 years prior to the inclusion with theexception of curatively treated basal cell carcinoma of the skin and/or curativelyresected in situ cervical or breast cancer

3. Patient with any medical or psychiatric condition or disease, which would make thepatient inappropriate for entry into this study

4. Current participation in a study of an investigational agent or in the period ofexclusion

5. Patient under guardianship, curatorship or under the protection of justice

6. Other liver malignancy: hepatocellular carcinoma and hepato-cholangiocarcinoma

7. Uncontrolled pleural effusion, pericardial effusion, ascites or symptomatic fistula

8. Uncontrolled tumor-related pain: exposing patients to risk of exposure to corticoidsor iterative hospitalizations. Symptomatic lesions amenable to palliativeradiotherapy should be treated prior to inclusion. Patients should be recovered fromthe effects of radiation. There is no required minimum recovery period

9. Known active central nervous system metastases and/or carcinomatous meningitis.

10. History of angiocholitis, liver abscess, or acute pancreatitis within 4 weeks priorto initiation of study treatment

11. Inadequate organ functions: known cardiac failure of unstable coronaropathy,respiratory failure, or uncontrolled infection or another life-risk condition.Patients requiring oxygen therapy or with LEVF<40% (Left ventricular ejectionfraction).

12. HIV (human immunodeficiency virus) positive (HIV 1/2 antibodies patients), or aknown history of active Tuberculosis bacillus

13. Any immunosuppressive therapy (i.e. corticosteroids >10 mg of hydrocortisone orequivalent dose) within 14 days before the planned start of study therapy

14. Active autoimmune disease that has required a systemic treatment in the past 2 years (i.e. corticosteroids or immunosuppressive drugs). Replacement therapy (e.g.thyroxine, insulin) is allowed. Active or history of autoimmune disease or immunedeficiency, including, but not limited to, myasthenia gravis, myositis, autoimmunehepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory boweldisease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjögrensyndrome, Guillain-Barré syndrome, or multiple sclerosis, with the followingexceptions:

15. Patients with a history of autoimmune-related hypothyroidism who are on thyroidreplacement hormone are eligible for the study

16. Patients with controlled Type 1 diabetes mellitus who are on an insulin regimenare eligible for the study

17. Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo withdermatologic manifestations only (e.g., patients with psoriatic arthritis areexcluded) are eligible for the study provided all of following conditions aremet:

• Rash must cover < 10% of body surface area,
• Disease is well controlled at baseline and requires only low-potencytopical corticosteroids,
• No occurrence of acute exacerbations of the underlying condition requiringpsoralen plus ultraviolet A radiation, methotrexate, retinoids, biologicagents, oral calcineurin inhibitors, or high potency or oralcorticosteroids within the previous 12 months,

15. Prior allogeneic bone marrow transplantation or prior solid organ transplantation

16. History of severe allergic, anaphylactic, or other hypersensitivity reactions tochimeric or humanized antibodies or fusion proteins

17. Known hypersensitivity or allergy to Chinese hamster ovary cell products or anycomponent of durvalumab

18. Receipt of a live, attenuated vaccine within 30 days prior to inclusion oranticipation that such a live, attenuated vaccine will be required during the studyNote: Patients must agree not to receive live, attenuated influenza vaccine within 28 days prior to randomization, during treatment or within 5 months following thelast dose of durvalumab

19. Inadequate hematology function: Lymphocyte count at baseline < 700/mm3; neutrophilcount < 1 500/mm3, platelets < 10 0000/mm3 (without transfusion), Hemoglobin < 9g/dL (patients may be transfused to meet this criterion).

20. Inadequate hepatic function: bilirubin >2 fold ULN (upper limit of normal), AST/ALT >3 fold ULN, International normalized thromboplastin time ratio >2

21. Creatinine clearance (CrCl) < 60 ml/min (by the Modification of Diet in RenalDisease [MDRD], Cockroft formula, or chronic kidney disease [CKD] formula])

22. Serum albumin < 28 g/L

23. Surgery within 4 weeks previously the initiation of the study treatment

24. Radiotherapy within 2 weeks previously the initiation of the study treatment

25. Patient with weight < 36 kg.

26. Pregnant or breastfeeding woman

27. Known hypersensitivity to components of MP0317, for exemple, histidine buffer or theTween diluent, according to section 7.2 " Contraindications " of the Investigator'sbrochure of MP0317

28. Hypersensitivity to gemcitabine or to cisplatin, or to any of their excipients,according to the SmPCs of these products

29. According to the SmPC of cisplatin: hearing problem, in case of combination withphenytoin with prophylactic aim, patients with neuropathy caused by cisplatin, incase of cardiorespiratory pathology in particular, which forbids a hyperhydration