A Study of Nivolumab Combined With FOLFOX and Regorafenib in People Who Have HER2-Negative Esophagogastric Cancer

Inclusion Criteria:

* Patients must have histologically or cytologically confirmed metastatic esophageal, gastric, or gastroesophageal junction adenocarcinoma
* Patients must have disease that can be evaluated radiographically within 28 days of the start of study treatment. This may be measurable disease or non-measurable disease per RECIST 1.1.
* Age 18 years or older
* ECOG performance status 0 to 1
* Peripheral neuropathy grade ≤1
* Available archival tissue for correlative analysis (biopsy is required if no archival tissue is available)
* Adequate organ function as below:

  * Absolute neutrophil count ≥1500/mcL
  * Platelets ≥100,000/mcL
  * Hemoglobin ≥9 g/dL
  * Serum creatinine ≤1.5X ULN
  * Serum total bilirubin ≤1.5X ULN OR Direct bilirubin ≤ULN for s ubjects with total bilirubin levels \>1.5X ULN, except patients with Gilbert's disease (≤3X ULN)
  * AST and ALT ≤2.5X ULN
  * Albumin ≥3 mg/dL
  * ALT, alanine aminotransferase; AST, aminotransferase; ULN, upper limit of normal.

Exclusion Criteria:

* Confirmed HER2-positive disease (IHC 3+ or 2+, fluorescence in situ hybridization HER2:CEP17 ratio ≥2)

  ° Note: Participants that are IHC 2+ but negative by FSH w ill be considered HER2- negative and eligible for trial.
* Inability to swallow oral pills
* Prior chemotherapy for metastatic disease. Patients with metastatic disease after treatment for localized esophagogastric cancer may have received prior adjuvant therapy (chemotherapy and/or chemoradiation) if \>6 months have elapsed between the end of adjuvant therapy and registration
* Currently participating in a study and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment
* Underwent major surgical procedure within 4 weeks of registration
* Underwent radiation within 2 weeks of registration
* Received prior therapy with regorafenib
* Received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent
* Diagnosis of immunodeficiency or receipt of systemic steroid therapy or any other form of immunosuppressive therapy within 7 days before the first dose of trial treatment
* A known history of active Bacillus tuberculosis
* A known active central nervous system metastases and/or carcinomatous meningitis
* A known history of or any evidence of active, noninfectious pneumonitis
* An active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease, systemic lupus erythematosus, Wegener syndrome \[granulomatosis with polyangiitis\], myasthenia gravis, Grave's disease, rheumatoid arthritis, hypophysitis, uveitis) within the 3 years before the start of treatment. The following are exceptions to this criterion:

  * Subjects with vitiligo or alopecia
  * Subjects with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement or psoriasis not requiring systemic treatment
* A known history of human immunodeficiency virus (HIV 1/2 antibodies)
* Known active hepatitis B (e.g., HBsAg reactive) or hepatitis C (e.g., HCV RNA \[qualitative\] is detected). Patients with HBsAg reactive on entecavir may be eligible after consultation with hepatologist and study team.
* Received a live vaccine within 30 days of planned start of study therapy
* Active or clinically significant cardiac disease, including congestive heart failure-New York Heart Association class \>II, active coronary artery disease, cardiac arrhythmias requiring antiarrhythmic therapy other than beta blockers or digoxin, unstable angina (anginal symptoms at rest), new-onset angina within 3 months before initiation, or myocardial infarction within 6 months before initiation
* Uncontrolled hypertension (systolic pressure \>140 mm Hg or diastolic pressure \>90 mm Hg on repeated measurement) despite optimal medical management
* Evidence or history of bleeding diathesis or coagulopathy
* Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
* Pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the trial, starting with the prescreening or screening visit through 120 days after the last dose of trial treatment
* Unwilling to give written, informed consent, unwilling to participate, or unable to comply with the protocol for the duration of the study