RANDOMIZED PHASE III TRIAL OF MFOLFIRINOX +/- NIVOLUMAB VS. FOLFOX +/- NIVOLUMAB FOR FIRST-LINE TREATMENT OF METASTATIC HER2-NEGATIVE GASTROESOPHAGEAL ADENOCARCINOMA

This phase III trial compares the effect of modified fluorouracil, leucovorin calcium,
oxaliplatin, and irinotecan (mFOLFIRINOX) to modified fluorouracil, leucovorin calcium,
and oxaliplatin (mFOLFOX) for the treatment of advanced, unresectable, or metastatic HER2
negative esophageal, gastroesophageal junction, and gastric adenocarcinoma. The usual
approach for patients is treatment with FOLFOX chemotherapy. Chemotherapy drugs work in
different ways to stop the growth of tumor cells, either by killing the cells, by
stopping them from dividing, or by stopping them from spreading. Fluorouracil stops cells
from making DNA and it may kill tumor cells. Leucovorin is used with fluorouracil to
enhance the effects of the drug. Oxaliplatin works by killing, stopping, or slowing the
growth of tumor cells. Some patients also receive an immunotherapy drug, nivolumab, in
addition to FOLFOX chemotherapy. Immunotherapy may induce changes in body's immune system
and may interfere with the ability of tumor cells to grow and spread. Irinotecan blocks
certain enzymes needed for cell division and DNA repair, and it may kill tumor cells.
Adding irinotecan to the FOLFOX regimen could shrink the cancer and extend the life of
patients with advanced gastroesophageal cancers.

Inclusion Criteria:

- Histologic documentation: HER2 negative adenocarcinoma as defined by American
Society of Clinical Oncology (ASCO) College of American Pathologists (CAP)
guidelines (Bartley et al., Journal of Clinical Oncology [JCO] 2017) with known
PD-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 Response
Evaluation Criteria in Solid Tumors (RECIST) 1.1

- No prior treatment for unresectable or metastatic disease

- Prior neoadjuvant or adjuvant cytotoxic chemotherapy or adjuvant immunotherapy is
allowed 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.) creatinine
clearance >= 30 mL/min

- Total bilirubin =< 1.5 x ULN

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3 x ULN (in
patients with liver metastasis: =< 5 x ULN if clearly attributable to liver
metastases)

- Patients with a prior or concurrent malignancy whose natural history or treatment
does not have the potential to interfere with the safety or efficacy assessment of
the investigational regimen are eligible for this trial

- Patients positive for human immunodeficiency virus (HIV) are eligible only if they
meet all of the following:

- On effective anti-retroviral therapy

- Undetectable HIV viral load by standard clinical assay =< 6 months of
registration

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

- Patients who will receive nivolumab in addition to chemotherapy must not have any
contraindications to immune checkpoint inhibitors

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

- Patients must not have a condition requiring systemic treatment with either
corticosteroids (>10mg/day prednisone equivalents) or other immunosuppressive
medications within 14 days prior to registration. Inhaled or topical steroids
and adrenal replacement doses (=< 10mg/day prednisone equivalent) are permitted

- Patients must not have a history of noninfectious pneumonitis requiring
steroids

- Patients with prior immune mediated adverse events related to immunotherapy
that resulted in permanent treatment discontinuation with these agents are
ineligible

- 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 read
in 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 known
genotoxic, mutagenic and teratogenic effects

* Therefore, for women of childbearing potential only, a negative serum or urine
pregnancy 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 neuromotor
toxicity per CTCAE version (v) 5.0 regardless of causality

- No medical condition such as uncontrolled infection or uncontrolled diabetes
mellitus which, in the opinion of the treating physician, would make this protocol
unreasonably hazardous for the patient

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

- No allogeneic tissue/organ transplant