MFOLFIRINOX Versus MFOLFOX with or Without Nivolumab for the Treatment of Advanced, Unresectable, or Metastatic HER2 Negative Esophageal, Gastroesophageal Junction, and Gastric Adenocarcinoma

Inclusion Criteria:

• Histologic documentation: HER2 negative adenocarcinoma as defined by AmericanSociety of Clinical Oncology (ASCO) College of American Pathologists (CAP)guidelines (Bartley et al., Journal of Clinical Oncology [JCO] 2017) with knownPD-L1 CPS (Any CPS is allowed, but should be known prior to registration)

• Stage: unresectable or metastatic

• Tumor site: esophagus, gastroesophageal junction, or stomach

• Measurable disease or non-measurable but evaluable disease as defined by ResponseEvaluation Criteria in Solid Tumors (RECIST) 1.1

• No prior treatment for unresectable or metastatic disease

• Prior neoadjuvant or adjuvant cytotoxic chemotherapy or adjuvant immunotherapy isallowed as long as it was completed at least 1 year prior to registration

• Age >= 18 years

• Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1

• Absolute neutrophil count (ANC) >= 1,500/mm^3

• Platelet count >= 100,000/mm^3

• Creatinine =< 1.5 x upper limit of normal (ULN) OR calculated (calc.) creatinineclearance >= 30 mL/min

• Total bilirubin =< 1.5 x ULN

• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3 x ULN (inpatients with liver metastasis: =< 5 x ULN if clearly attributable to livermetastases)

• Patients with a prior or concurrent malignancy whose natural history or treatmentdoes not have the potential to interfere with the safety or efficacy assessment ofthe investigational regimen are eligible for this trial

• Patients positive for human immunodeficiency virus (HIV) are eligible only if theymeet all of the following:

• On effective anti-retroviral therapy

• Undetectable HIV viral load by standard clinical assay =< 6 months ofregistration

• Patients with known history or current symptoms of cardiac disease, or history oftreatment with cardiotoxic agents, should have a clinical risk assessment of cardiacfunction using the New York Heart Association Functional Classification. To beeligible for this trial, patients should be class 2B or better

• Patients who will receive nivolumab in addition to chemotherapy must not have anycontraindications to immune checkpoint inhibitors

• Patients must not have active autoimmune disease that has required systemictreatment within 6 months prior to registration. Patients are permitted toreceive immunotherapy if they have vitiligo, type I diabetes, residualhypothyroidism due to autoimmune condition only requiring hormone replacement,psoriasis not requiring systemic treatment, or conditions not expected to recurin the absence of an external trigger (precipitating event)

• Patients must not have a condition requiring systemic treatment with eithercorticosteroids (>10mg/day prednisone equivalents) or other immunosuppressivemedications within 14 days prior to registration. Inhaled or topical steroidsand adrenal replacement doses (=< 10mg/day prednisone equivalent) are permitted

• Patients must not have a history of noninfectious pneumonitis requiringsteroids

• Patients with prior immune mediated adverse events related to immunotherapythat resulted in permanent treatment discontinuation with these agents areineligible

• This study includes the use of the mandatory patient completed measure, PRO-CTCAE.For this study the PRO-CTCAE is available in English, Spanish, Korean, Chinese (Simplified), and Russian, hence patients must be able to speak, understand and readin these languages. Ad-hoc translation of patient-reported measures is not permitted

Exclusion Criteria:

• Not pregnant and not nursing, because this study involves an agent that has knowngenotoxic, mutagenic and teratogenic effects

• Therefore, for women of childbearing potential only, a negative serum or urinepregnancy test done =< 7 days prior to registration is required

• No known Gilbert's syndrome or known homozygosity for UGAT1A1*28 polymorphism

• No baseline grade >= 2 peripheral neuropathy, neurosensory toxicity, or neuromotortoxicity per CTCAE version (v) 5.0 regardless of causality

• No medical condition such as uncontrolled infection or uncontrolled diabetesmellitus which, in the opinion of the treating physician, would make this protocolunreasonably hazardous for the patient

• No untreated, symptomatic brain metastasis. Patients with treated brain metastasesare eligible if the following criteria are met: 1) follow-up brain imaging done atleast in 4 weeks after central nervous system (CNS)-directed therapy shows noevidence of progression and 2) the patient no longer requires steroids, or is on astable steroid dose for more than four weeks

• No allogeneic tissue/organ transplant