First-line EXL01 With Nivolumab and FOLFOX for PD-L1 CPS ≥5 Metastatic Gastric Cancer

Inclusion Criteria:

The patient is eligible to be included in the study only if all of the following criteria apply:

1. Patients must have dated and signed an approved written informed consent form. Thismust be obtained before the performance of any protocol-related procedures that arenot part of normal patient care.

2. Patients must be willing and able to comply with scheduled visits, treatmentschedule, laboratory tests and other requirements of the study, Target Population

3. Inoperable, advanced, or metastatic gastric cancer or gastroesophageal junction ordistal esophageal carcinoma and histologically confirmed predominant adenocarcinoma,

4. Expression of PD-L1 with a combined positive score (PD-L1 CPS) ≥5, Note: informationmust be available at the time of inclusion, the examination will be performedlocally in the center and secondarily confirmed centrally,

5. No prior systemic cancer treatment given as primary therapy for advancednonresectable or metastatic disease, Nota bene (NB): if patient receivedneoadjuvant/adjuvant therapy, this therapy should be completed at least 6 monthsprior to the diagnosis of metastatic or recurrent disease is made. Palliativeradiotherapy is allowed and must be completed 2 weeks prior to randomization,

6. At least one measurable lesion as assessed by computed tomography (CT)-scan ormagnetic resonance imaging (MRI) according to Response Evaluation Criteria in SolidTumors (RECIST) v 1.1 and feasibility of repeated radiological assessments;radiographic tumor assessment should be performed within 28 days prior torandomization,

7. Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1,

8. Adequate hematologic and end-organ function, defined by the following laboratorytest results, obtained within 14 days prior to randomization of study treatment:

9. White blood cell ≥ 2000/μL;

10. Neutrophils ≥ 2000/μL;

11. Platelets ≥ 100.000/μL;

12. Hemoglobin ≥ 9.0 g/dL;

13. Serum albumin ≥ 30 g/L;

14. Serum creatinine level ≤ 150 μM and calculated creatinine clearance (Cockcroft-Gault) > 50 mL/minute,

15. Total bilirubin ≤ 1.5 x upper normal limit (ULN);

16. Alanine aminotransferase (ALT) ≤ 3.0 x ULN (or ≤ 5.0 x ULN if liver metastasesare present);

17. Aspartame aminotransferase (AST) ≤ 3.0 x ULN (or ≤ 5.0 x ULN if livermetastases are present);

18. Potassium ≥ 1.0 x lower limit of normal (LLN),

19. Magnesium ≥ 1.0 x LLN,

20. Calcium ≥ 1.0 x LLN,

21. Baseline-corrected QT interval ≤ 450 msec for males and ≤ 470 msec for females,

22. Availability of a representative tumor tissue specimen for exploratory translationalresearch; tumor tissue samples, either formalin-fixed paraffin-embedded (FFPE)tissue block or unstained tumor tissue sections (minimum of 20 positively chargedslides) from primary or metastatic site must be submitted to the central laboratory,

23. Registration in a national health care system (PUMa-Protection Universelle Maladieincluded. Age and reproductive status

24. Age ≥ 18 years,

25. Women must not be pregnant, breastfeeding, or expecting to conceive during thestudy,

26. Reproductive status:

27. Women of childbearing potential (WOCBP) must have a negative serum pregnancytest within 72 hours prior to the start of study drug,

28. WOCBP must agree to use an adequate method of contraception or birth controlfor the duration of study treatment and 5 months (nivolumab), 9 months (oxaliplatin), 6 months (5-FU) or at least 1 month (EXL01) of the patient'slast dose of the study drug,

29. Males who are fertile and sexually active with WOCBP must agree to followinstructions for method(s) of contraception for the duration of study treatmentand 6 months (nivolumab, oxaliplatin, or 5-FU) or at least 1 month (EXL01)after the last dose of study treatment. In addition, males must be willing torefrain from sperm donation during this time,

Exclusion Criteria:

The patient is ineligible for the study if any of the following criteria apply:

Target Disease Exceptions

1. Known HER-2 positive status or unknown HER-2 status before inclusion,

2. Active brain metastases or known history of leptomeningeal carcinomatosis,

3. Ascites, which cannot be controlled with appropriate interventions, Exclusion criteria related to medical history and concurrent disease

4. Prior malignancy active within the previous 3 years except for locally curablecancers that have been apparently cured, such as basal or squamous cell skin cancer,superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast,

5. Active, known, or suspected autoimmune disease; type I diabetes mellitus,hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo,psoriasis, or alopecia) not requiring systemic treatment, or conditions not expectedto recur in the absence of an external trigger are permitted,

6. Interstitial lung disease that is symptomatic or may interfere with the detection ormanagement of suspected treatment-related pulmonary toxicity,

7. Prior treatment with an anti-PD(L)1, anti-LAG-3, or anti-CTLA-4 antibody, or anyother antibody or drug specifically targeting T-cell co-stimulation or immunecheckpoint pathways, including prior therapy with anti-tumor vaccines or otherimmuno-stimulatory antitumor agents,

8. Condition requiring systemic treatment with either corticosteroids (>10 mg dailyprednisone equivalent) or other immunosuppressive medications within 14 days (2weeks) of randomization. Inhaled or topical steroids, and adrenal replacementsteroid doses >10 mg daily prednisone equivalent, are permitted prior torandomization in the absence of active autoimmune disease,

9. Persistence of toxicity (The National Cancer Institute Common Terminology Criteriafor Adverse Event [NCI CTCAE] v 5.0) grade >1 related to prior anticancertreatments,

10. Major surgery within 28 days (4 weeks) prior to first dose of study treatment,

11. Concomitant unplanned antitumor therapy (e.g., chemotherapy, molecular targetedtherapy, radiotherapy, immunotherapy), Exclusion criteria related to EXL01

12. GI obstruction, poor oral intake, or difficulty in taking oral medication ordifficulties in swallowing; nasogastric tubes are not permitted,

13. Known GI malabsorption,

14. Is currently participating in or has participated in a study with an investigationalcompound within 28 days prior to the first dose of study treatment, NB: Participantswho have entered the follow-up phase of an investigational study may participate solong as it has been at least 3 months since the last dose of the previousinvestigational agent,

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

16. Fecal microbiota transplant within 3 months prior to screening, Note: Patients musthave recovered adequately from the toxicity and/or complications from the treatmentprior to starting study intervention.

17. Current probiotics administration, or planned probiotics administration duringtreatment course is not allowed, NB: The following therapies should be avoided during the study; however, they arenot prohibited if, in the assessment of the Investigator, they are required forclinical management:

• Nonsteroidal anti-inflammatories,

• Antacids,

• Proton-pump inhibitors.

18. Excessive alcohol intake: moderate consumption, defined as no more than 1 drink perday for women and no more than 2 drinks per day for men, is permitted,

19. Known allergy and/or hypersensitivity to any component or excipients of studytreatments (nivolumab, EXL01), any other live pro-biotherapeutic product, and/or tosoybean or soy-containing products,

20. Known history or newly diagnosed GI parasitic infection within 3 months prior toscreening, NB: Patients must have recovered adequately from the toxicity and/orcomplications from the treatment prior to starting study intervention,

21. Active inflammatory intestinal disease (Crohn disease, Hemorrhagic recto-colitis,coeliac disease) or any serious chronic intestinal disease with uncontrolleddiarrhea, or other inflammatory disease requiring anti-inflammatory medications (according to exclusion criteria n°8), Exclusion criteria related to chemotherapy

22. Active or chronic hepatitis B virus (HBV), hepatitis C virus (HCV) and/or humanimmunodeficiency virus infection (HIV 1/2 antibodies). Participants are eligible ifthey:

• Have controlled HCV load defined as undetectable hepatitis C RNA by polymerasechain reaction either spontaneously or in response to a successful prior courseof anti-hepatitis C therapy,

• Have received HBV vaccination with only anti-HBs positivity and no clinicalsigns of hepatitis,

• Are HBV surface antigen (HBsAg)- and anti- Hepatitis B core antibody (HBc)+ (i.e., those who have cleared HBV after infection),

• Are HBsAg+ with chronic HBV infection (lasting 6 months or longer) and meetconditions below:

• HBV DNA viral load <100 IU/mL,

• Have normal transaminase values, or, if liver metastases are present,abnormal transaminases, with a result of AST/ALT <3 × ULN, which are notattributable to HBV infection,

• Start or maintain antiviral treatment if clinically indicated as per theinvestigator,

23. Any (attenuated) live vaccine use within 28 days (4 weeks) prior to randomization,while in the study; live vaccines include, but are not limited to, the following:yellow fever, varicella, shingles, measles, mumps, rubella, tuberculosis, rotavirus,influenza,

24. Ongoing or concomitant use of the antiviral drug sorivudine or its chemicallyrelated analogs, such as brivudine,

25. Dihydropyrimidine dehydrogenase deficiency (DPD; uracilemia dosage >16 ng/ml),Uracilemia dosing results must be available before inclusion,

26. Any condition that, in the opinion of the investigator, would interfere withevaluation of the investigational product or interpretation of the patient's safetyor study results,

27. Known peripheral sensory neuropathy with functional impairment according exclusioncriteria n°9) prior to first treatment, according to the Summary of productcharacteristics (SmPC) of oxaliplatin,

28. Known potentially serious infection, according to the SmPC of 5-FU

29. Has clinically significant active heart disease or myocardial infarction within 6months given the cardiotoxicity of 5-FU, according to the SmPC of 5-FU,

30. Known history of hypersensitivity to 5-FU, oxaliplatin, or leucovorin, or to any oftheir excipients, according to the Summary of Product Characteristic (SmPCs) ofthese products. Exclusion criteria related to geographical, social, and legal issues

31. Impossibility of submitting to the medical follow-up of the study for geographical,social, or psychiatric illness,

32. Patient under a legal protection regime (guardianship, curatorship, judicialsafeguard) or administrative decision or incapable of giving his/her consent.