Testing Mitazalimab in Combination With Standard Chemotherapy in Immunotherapy Resistant Advanced Biliary Tract Cancers

Inclusion Criteria: 1. Age ≥18 years 2. Histologically-proven intrahepatic cholangiocarcinoma, extrahepatic (perihilar/distal) cholangiocarcinoma, or gallbladder carcinoma (ampullary carcinoma excluded) 3. Measurable tumor according to RECIST v1.1 classification 4. Non-resectable or metastatic disease or recurrent after surgery (if recurrence more than 6 months after adjuvant treatment stop) 5. Participants having received a standard first-line treatment (CISGEM + durvalumab or pembrolizumab) and eligible for second- or third-line treatment with FOLFOX. Participant could have received a previous targeted therapy in case of targetable alteration, but only one line of chemotherapy is permitted. 6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 7. Adequate bone marrow reserve, normal renal and liver functions: * Neutrophil count ≥ 1500/mm³ * Platelet count ≥ 150 000/mm³ * Hemoglobin ≥ 10 g/dl * Estimated glomerular filtration rate (eGFR) value ≥50 mL/min using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation * Total bilirubin \< 1.5 x ULN (after biliary stent placement in case of biliary obstruction) 8. No dihydropyrimidine dehydrogenase deficiency, as assessed by pre-treatment uracil blood level ≤ 16 ng/mL 9. Women of childbearing potential must have a negative serum or urine pregnancy test done within 7 days before randomization. 10. Participants must agree to use adequate contraception methods for the duration of study treatment and for within 15 months for women and 12 months for men after completing treatment. 11. Participants must be affiliated to a Social Security System (or equivalent). 12. Participant must have signed a written informed consent prior to any trial specific procedures. When the participant is physically unable to give their written consent, a trusted person of their choice, independent from the investigator or the sponsor, can confirm in writing the participant's consent. 13. Participants must be willing and able to comply with the protocol for the duration of the study including scheduled visits, treatment plan, laboratory tests and other study procedures. 14. Have archival tumor tissue sample that has been identified and confirmed as available 15. Participant having consented for a new tumor biopsy at inclusion for ancillary studies (participants with non-contributory new biopsy may still be included in the study). Exclusion Criteria: 1. Participants having received previous treatment with fluoropyrimidine, oxaliplatin or CD40 agonist, except for capecitabine given as adjuvant treatment (if last administered \> 6 months). 2. Concurrent malignancy (other than BTC), with the exception of adequately treated cone-biopsied in situ carcinoma of the cervix uteri and basal or squamous cell carcinoma of the skin. Cancer survivors, who have undergone potentially curative therapy for a prior malignancy, have no evidence of that disease for 3 years or more and are deemed at negligible risk for recurrence, are eligible for the trial 3. Known CNS metastases or carcinomatous meningitis 4. History of chronic diarrhea, inflammatory disease of the colon or rectum, or unresolved partial or complete intestinal obstruction 5. History of myocardial infarction within 12 months of the first administration of mitazalimab, uncontrolled angina pectoris, unstable cardiac arrhythmias, or congestive heart failure of New York Heart Association class II or greater 6. QTc \>450 msec 7. Known history of HIV, hepatitis B or active hepatitis C infection 8. Toxicities from first-line treatment not resolved to Grade ≤ 1 (according to NCI-CTCAE v6.0) before randomization with the exception of alopecia 9. Contraindication to mitazalimab or to FOLFOX regimen, or their excipients 10. Prior toxicities of grade ≥ 3 with durvalumab or pembrolizumab (except from vitiligo, alopecia, hypothyroidism, adrenal insufficiency and diabetes) or other immune-related toxicities that led to definitive discontinuation 11. Has received attenuated vaccine within 28 days before the first dose of study treatment 12. Any condition which in the Investigator's opinion makes it undesirable for the participant to participate in the trial or which would jeopardize compliance with the protocol (including uncontrolled comorbidities, active infections or untreated central nervous system metastases) 13. Participation in another therapeutic trial within the 30 days prior to randomization 14. Pregnant women or women who are breast-feeding 15. Participant unwilling or unable to comply with the medical follow-up required by the trial because of geographic, familial, social, or psychological reasons 16. Individual deprived of liberty or placed under protective custody or guardianship.