PRODIGE 111 – DOMZIGAST A randomized phase II study evaluating FOLFIRI vs FOLFIRI plus Domvanalimab (anti-TIGIT) and Zimberelimab (anti-PD1) in patients with advanced gastric or gastro-oesophageal junction adenocarcinoma with progression during or after peri-operative chemotherapy.

Prior treatment

• Concurrent enrolment in another clinical study – unless it is an observational study or during the follow-up period of an interventional study
• Prior treatment by immune checkpoint inhibitor
• Current or prior use of immunosuppressive medication within 14 days before the first dose of study drugs (excepted: intranasal, inhaled, topical steroids or local steroid injection –at physiological dose that does not exceed 10 mg/day of prednisone or its equivalent – steroids as premedication for hypersensitivity reactions)
• Known untreated, symptomatic or actively progressing central nervous system (CNS) or leptomeningeal metastases (participants with treated brain metastases who are clinically stable and do not require steroid therapy for at least 14 days prior to the first dose of study intervention will not be excluded)
• Clinically significant cardiovascular disease, cerebrovascular accident within 3 months prior to randomization, unstable angina or new onset angina within 3 months prior to randomization, myocardial infarction within 6 months prior to randomization or unstable arrhythmia within 3 months prior to randomization
• Treatment with sorivudine and others analogues as brivudine (irreversibly inhibits the enzyme dihydropyrimidine dehydrogenase) within 4 weeks prior the first dose of treatment
• Pregnant or breastfeeding woman, woman of childbearing potential not having had a negative pregnancy test ≤72hours prior to initiate the treatment,
• Prior treatment by irinotecan
• Radiotherapy within 4 weeks prior to the first dose of treatment
• Known hypersensitivity to any investigational product (IP), or any excipient contained in the formulations of the study drugs
• Treatment with phenytoin within 7 days prior the first dose of treatment
• Dihydropyrimidine Dehydrogenase (DPD) deficiency defined by uracilemia level ≥ 16 ng/mL, if not previously done, blood uracil level must be performed at screening. Uracilemia dosing result is mandatory prior inclusion.
• Strong inducers of CYP3A4 and/or UGT1A1 and strong inhibitor of CYP3A4 within 7 days prior the first dose of treatment or known Gilbert disease: Strong inducers of CYP3A4 (treatment with St John’s Wort (Hypericum perforatum), fampicin, phenobarbital, primidone, phenytoin and carbamazepine (Appendix 12). Strong inhibitors of CYP3A4, continuous use of azole antifungals (posaconazole, voriconazole, itraconazole, isavuconazole), ritonavir, verapamil, diltiazem, grapefruit juice (equivalent to half a fresh grapefruit/day) (Appendix 12).
• Any unresolved significant toxicity NCI CTCAE v5.0 ≥ grade 2 from previous anticancer therapy (excepted neuropathy and alopecia)
• History of trauma or major surgery within 28 days prior to randomization (placement of central venous access catheter is not considered a major surgical procedure)
• Active or prior documented serious autoimmune or inflammatory disorders that required systemic treatment in the past 2 years (e.g., with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs), except for vitiligo or resolved childhood asthma/atopy or inflammatory disorders. Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment as listed above
• Vaccinations with live vaccine within 28 days prior to the start of treatment

Other illness

• History of idiopathic pulmonary fibrosis, interstitial lung disease, including history of interstitial lung disease or non-infectious pneumonitis, drug-induced pneumonitis, organizing pneumonia or evidence of active pneumonitis on screening chest CT-scan)
• Active hepatitis B or C and active tuberculosis (in case of if positive viral load is detected)
• Prior malignancy active within the previous 2 years except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the cervix, breast, or prostate cancer
• Known Uridine Diphosphate Glucuronyltransferase (UGT1A1) deficiency or known Gilbert disease
• History of anterior organ transplant, including stem cell allograft
• History of chronic inflammatory bowel disease (IBD) or intestinal obstruction
• Active viral, bacterial or fungal infections requiring parenteral treatment within 14 days of randomization. Prophylactic antibiotic treatment (e.g., to prevent a urinary tract infection) is allowed

Lab values

• Known immunodeficiency or HIV infection with HIV viral load ≥200 copies/mL or CD4+ T-cell count <350 cells/μL or taking medications that may interfere with metabolism of study drugs
• QTc interval > 480 msec

Other

• Poor nutritional status (weight loss of more than 10% during the last month)
• Person deprived of liberty or under guardianship or incapable of giving consent
• Inability to undergo the medical follow-up of the trial for geographical, social or psychological reasons
• HER2 2+

• Age ≥ 18 years
• pMMR (immunohistochemistry of the 4 MMR protein) and/or MSS (PCR or NGS test) status
• Known PD-L1 CPS (patients are eligible whatever the CPS score and CPS must be performed on the most recent tumor sample)
• Available tumor sample (before or after peri-operative treatment, archival or new tumor sample)
• Participation to all ancillary studies is mandatory
• Progression during or within 6 months after pre-operative, peri-operative or post-operative platinum-based therapy (i.e., FLOT, 5FU cisplatin or FOLFOX regimen) alone or combined with radiation
• Eligible for a treatment with irinotecan and 5-FU
• Patients must not be eligible for an approuved treatment with a combination of conjugated antibody drugs plus chemotherapy or immunotherapy plus chemotherapy
• At least one measurable lesion as assessed by CT-scan or MRI according to RECIST 1.1 criteria
• World Health Organization (WHO) performance status 0-1
• Adequate organ and marrow function, as defined by the following laboratory values: Neutrophils ≥ 1.5 x 109/L, Platelets ≥ 100 x 109/L, Hemoglobin ≥ 9.0 g/dL, Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3x upper limit of normal (ULN) if there is no hepatic metastasis; ≤ 5x ULN with hepatic metastases, Alkaline phosphatase ≤ 5x ULN, Total bilirubin ≤ 1.5 ULN, Creatinine clearance ≥ 50 mL/min according to the CDK-EPI formula, Albumin > 28g/L
• Individuals of childbearing potential must agree to use two medically acceptable contraception methods—one for themselves and one for their partner—during the study and for six months following the last treatment dose intake
• Patient is able to understand, sign, and date the written informed consent form at the screening visit prior to any protocol-specific procedures
• Patient who is a beneficiary of the social security system
• Histologically proven locally advanced unresectable or metastatic gastric, esophagogastric junction (GEJ) or esophageal adenocarcinoma
• HER2 negative tumor