FOLFOX Plus Regorafenib in Patients With Unresectable or Metastatic Esophagogastric Cancer

Inclusion Criteria: * Patient must have histologically or cytologically confirmed metastatic or unresectable esophageal, gastroesophageal junction or gastric adenocarcinoma. * Patient must have disease that can be evaluated radiographically. This may be measurable disease or non-measurable disease. Minimum indicator lesion size = 10 mm by helical CT or = 20 mm by conventional techniques. Pathological nodes must be = 15 mm by the short axis to be considered measurable. * Subject must be able to swallow and retain oral medication * Age 18 years or older. * Karnofsky performance status \> or = to 70% * Peripheral neuropathy ≤ grade 1 * Hematologic (minimal values) White blood cell count \> or = to 3000/mm3© Absolute neutrophil count \> 1500 cells/ mm3 Hemoglobin \> or = to 8.0 g/dl Platelet count \> or = to 90,000 / mm3 Total bilirubin ≤ 1.5 x the upper limits of normal (ULN) * Alanine aminotransferase (ALT) and aspartate amino-transferase (AST) ≤ 2.5 x ULN (≤ 5 x ULN for subjects with liver involvement of their cancer) * Alkaline phosphatase limit ≤ 2.5 x ULN (≤ 5 x ULN for subjects with liver involvement of their cancer). Patients with alkaline phosphatase elevation secondary to the bony metastases rather than liver dysfunction may proceed with treatment on protocol after discussion with the principal investigator. * Serum creatinine ≤ 1.5 x the ULN * Women of childbearing potential must have a negative serum pregnancy test performed within 7 days prior to the start of study drug. Post-menopausal women (defined as no menses for at least 1 year) and surgically sterilized women are not required to undergo a pregnancy test.. * Patients with prior deep vein thrombosis (DVT) or pulmonary embolism (PE) currently on an stable anticoagulation regimen with low molecular weight heparin (LMWH) or rivaroxaban will be permitted. Exclusion Criteria: * Uncontrolled hypertension (systolic pressure \>140 mm Hg or diastolic pressure \> 90 mm Hg on repeated measurement) despite optimal medical management. * Active or clinically significant cardiac disease including: * Congestive heart failure - New York Heart Association (NYHA) \> Class II. * Active coronary artery disease. * Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers or digoxin. * Unstable angina (anginal symptoms at rest), new-onset angina within 3 months before randomization, or myocardial infarction within 6 months before randomization. * Evidence or history of bleeding diathesis or coagulopathy. * Any hemorrhage or bleeding event ≥ NCI CTCAE version 4.0 Grade 3 within 4 weeks prior to start of study medication. * Unwillingness to give written informed consent, unwillingness to participate, or inability to comply with the protocol for the duration of the study. * Active hepatitis B infection, active hepatitis C infection or known HIV carrier. * Patient may not have received prior chemotherapy for metastatic or unresectable disease. * Patients may have received prior adjuvant therapy (chemotherapy and/or chemoradiation) if more than 6 months have elapsed between the end of adjuvant therapy and registration. * Patient may not have received prior 5-Fluorouracil, Leucovorin, Oxaliplatin or regorafenib. Patient may have received prior radiosensitizing doses of 5Fu if more than 6 months have elapsed between the end of adjuvant therapy and registration. * Patient may not have had major surgical procedure within 4 weeks of registration. * Patient may not have had radiation within 2 weeks of registration.