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

Multicenter, open-label, randomized phase II/III trial evaluating the efficacity of mitazalimab in combination with mFOLFOX compared to mFOLFOX alone in participant advanced BTC

• mFOLFOX regimen (Drug), also known as Oxaliplatin, folinic acid and 5-FU: oxaliplatin 85 mg/m² intravenous infusion (IV), folinic acid 400 mg/m² IV (or L-folinic acid 200 mg/m²), and fluorouracil (5-FU) 400 mg/m² IV bolus; followed by 5 FU 2400 mg/m² as a 46-hours continuous IV infusion: * every two week (14-day cycles) until disease progression on control arm * at D8 the first cycle and at D1 for subsequent cycles (14-day cycles) until disease progression on experimental arm
• Mitazalimab (Drug), also known as ADC-1013, JNJ-64457107: The first cycle of treatment (21-day cycle): Mitazalimab 900 µg/kg by intravenous infusion (IV) at D1 and D10 Subsequent cycles (14-day cycles): Mitazalimab 900 µg/kg by intravenous infusion (IV) at D3 of each cycle until disease progression

Primary outcomes

• 6 months overall survival rate of participants [From randomisation to 6 months after randomisation]: Proportion of participant still alive 6 months after randomisation

Secondary outcomes

• Safety of the treatments [From inclusion to completion of the study, up to 64 months]: Adverse events will be collected and scored according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) common criteria v 6.0. This scale, divided into 5 grades (1 = "mild", 2 = "moderate", 3 = "severe", 4 = "life-threatening", and 5 = "death") determined by the investigator, will make it possible to assess the severity of the disorders.
• Objective response rate of participants (ORR) [Time from randomisation to disease progression, up to 64 months]: The objective response rate is defined as the percentage of participants with a complete response (CR) or a partial response (PR) on CT-scan for a given treatment
• Disease control rate (DCR) [Time from randomisation to disease progression, up to 64 months]: Proportion of participants with stable disease, or partial response or complete response on CT-Scan
• Progression-free survival (PFS) [Time from randomisation to disease progression or death, up to 64 months]: The Progression free survival is the lengh of time during and after the treatment of a disease that a patient lives with the disease but it does not get worse
• Duration of overall response (DOR) [Time from randomisation to disease progression or death, up to 64 months]: Time from first documented response (compared to baseline measurement taken at randomisation) until the date of disease progression or death from any cause, whichever occurs first
• Overall survival (OS) [From randomisation to death from any cause, up to 64 months]: The overall survival is the length of time from randomization that patients enrolled in the study are still alive.
• Quality of life questionnaire - Core Function 17 (QLQ-F17) [Baseline and every 2 months during the first year after randomisation]: Developed by the EORTC, this self-reported questionnaire assesses the health-related quality of life of cancer patients in clinical trials. The questionnaire contains 15 items organized into five functional scales (physical, everyday activity, cognitive, emotional, and social) and 2 items for health/quality of life overall scale. The 15 items are rated on a four-point Likert-type scale (1 = "not at all", 2 = "a little", 3 = "quite a bit", and 4 = "very much") and are linearly transformed to a 0-100 scale, with higher scores indicating more severe symptoms. The 2 last items for health/quality of life overall are rated on 7 point scale (from 1 = "very poor" to 7 = "excellent")
• Quality of life Questionnaire - Biliary tract cancer module (QLQ-BIL21) [Baseline and every 2 months during the first year after randomisation]: This EORTC cholangiocarcinoma and gallbladder cancer specific questionnaire is intended to supplement the QLQ-C30. The QLQ-BIL21 contains 21 items to assess symptoms. 3 single-item assessments relating to treatment side effects, difficulties with drainage bags/tubes and concerns regarding weight loss, and 18 items grouped into 5 scales: eating symptoms (4 items), jaundice symptoms (3 items), tiredness (3 items), pain symptoms (4 items) and anxiety symptoms (4 items). All items are rated on a four-point Likert-type scale (1 = "not at all", 2 = "a little", 3 = "quite a bit", and 4 = "very much"), and are linearly transformed to a 0-100 scale, with higher scores indicating more severe symptoms.
• The Developed 5-level version of EQ-5D (EQ-5D-5L) questionnaire [At Baseline and every 2 months during the first year after randomisation]: Developed by the EuroQol group, the self-reported questionnaire assesses the health-related quality of life of cancer patients in clinical trials consists of a descriptive system and a visual analogue scale (VAS). The EQ-5D-5L descriptive system comprises five dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression), each dimension has 5 levels (1 = "no problems", 2 = "slight problems", 3 = "moderate problems", 4 = "severe problems", and 5 = "extreme problems"). This questionnaire provide a 5-digit score which generate a health state profile. The VAS records the patient's self-rated health on a vertical visual analogue scale where the score range from 0 (The best health you can image) to 100 (The worst health you can image). The VAS is used as a quantitative measure of health outcome that reflects the patient's own judgement.

Sex: All, ages: 18 Years to any

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.

• Cindy NEUZILLET, Principal investigator, Institut Curie
• Matthieu DELAYE, Principal investigator, Institut Curie