REGISTRATION TO STEP 1

Patient must be >= 18 years of age

Patient must have histologically confirmed HER2 negative metastatic esophageal or gastric adenocarcinoma (American Joint Committee on Cancer [AJCC] 8th edition) with known PDL1 CPS expression

Patient must have oligometastatic disease at the time of diagnosis of metastatic disease and prior to initiation of induction systemic therapy, which is defined as the following:
* Once to three (1-3) radiologically visible metastatic lesions (not sites), in addition to the primary site. Computed tomography (CT) or magnetic resonance imaging (MRI) scans will be performed for staging purposes. Patients with oligometastatic sites that are only detected with positron emission tomography (PET)/CT will be eligible for participation, as long as radiation planning and administration is feasible after discussion with treating radiation oncologist. Malignant lymph node must be at least 1 cm in size or biopsy proven involved by disease
* Anatomically defined lymphadenopathy will be considered as 1 metastatic lesion. For example, 2 enlarged paraaortic lymph nodes will be considered as one lesion, and 2 additional lesions will be allowed to meet protocol definition of oligometastatic disease. However, if supraclavicular or cervical nodes are involved for distal esophageal tumors or gastric tumors, these are counted separately from intrathoracic nodes. For upper thoracic/cervical esophageal tumors, the involvement of celiac nodes are counted separately from intrathoracic nodes. Intrathoracic nodes, defined as hilar and mediastinal nodes, will be collectively counted as one
* Patients with radiologically evident peritoneal metastasis are not eligible.

Patient must have baseline imaging done within 4 weeks prior to Step 1 registration. For patients registering to Arm S, scans must demonstrate at least stable disease after induction systemic therapy

Patient must not have any contraindications to 5-fluorouracil (5-FU) capecitabine, leucovorin, or oxaliplatin

Patients who receive(d) nivolumab in addition to chemotherapy must not have any contraindications to immune check point inhibitors
* Patient must not have active autoimmune disease that has required systemic treatment within 2 years prior to Step 1 registration. Patients are permitted to receive immunotherapy if they have vitiligo, type I diabetes mellitus, 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)
* Patient must not have a condition requiring systemic treatment with either corticosteroids (> 10 mg/day prednisone equivalents) or other immunosuppressive medications within 14 days prior to Step 1 registration. Inhaled or topical steroids and adrenal replacement doses (=< 10 mg/day prednisone equivalent) are permitted
* Patients with prior immune mediated adverse events related to immunotherapy that resulted in permanent treatment discontinuation with these agents are ineligible

Patient must not have any contraindications to radiation therapy based on consultation with a radiation oncologist. Formal radiation oncology evaluation will be required for eligibility purposes. Prior palliative or definitive radiation or chemoradiation to the primary site is allowed. Palliative treatments must be completed at least 2 weeks prior to registration

Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status 0-1

Patient must not be pregnant or breast-feeding due to the potential harm to unborn fetus and possible risk for adverse events in nursing infants with the treatment regimens being used
* A patient of child bearing potential must have a serum or urine pregnancy test to rule out pregnancy within 14 days prior to Step 1 registration
* A patient of childbearing potential is defined as anyone, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy; or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)

Patients must not expect to conceive or father children by using accepted and effective method(s) of contraception (both double barrier contraception and birth control pills or implants) or by abstaining from sexual intercourse while on protocol treatment (for all patients) and continue for 5 months after the last dose of protocol treatment (for patients of child bearing potential). Investigators must counsel all patients on the importance of pregnancy prevention and the implications of an unexpected pregnancy

Absolute neutrophil count (ANC) >= 1.5 x 10^9/L (obtained within 28 days prior to Step 1 registration)

Hemoglobin >= 8 g/dL (obtained within 28 days prior to Step 1 registration)

Platelets (PLT) >= 100 x 10^9/L (obtained within 28 days prior to Step 1 registration)

Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 3.0 x upper limit of normal (ULN) (obtained within 28 days prior to Step 1 registration)

Bilirubin =< 1.5 x institutional ULN (obtained within 28 days prior to Step 1 registration)

Serum creatinine =< 1.5 x institutional ULN (Cockcroft and Gault formula) (obtained within 28 days prior to Step 1 registration)

Albumin > 2.5 g/dL (obtained within 28 days prior to Step 1 registration)

Patient must be able to understand and willing to sign and date the written voluntary informed consent form prior to any protocol-specific procedures. Patients with impaired decision-making capacity (IDMC) who have a legally authorized representative (LAR) or caregiver and/or family member available will also be considered eligible

Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this protocol and must have CD4 > 200 within 6 months prior to registration
*NOTE: HIV testing is not required for eligibility

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 protocol

Patients who had prior definitive treatment for early stage EGA are eligible for participation as long as recurrent disease developed at least 6 months after completion of all prior therapies

For patients registering to Arms A, B, G, or H, patient must not have had any systemic prior treatment for metastatic disease
* NOTE: Patients previously treated with radiosensitizing doses of 5-FU and oxaliplatin will be eligible for participation as long as adequate time has elapsed from past treatments. If treatments were palliative in nature, 2 week washout is required. For prior definitive treatments with curative intent, recurrent disease must be diagnosed at least 6 months after treatment completion
* NOTE: Patients who received systemic chemotherapy as part of the treatment for their locoregional disease (for example, induction therapy before chemoradiation or adjuvant therapy after resection) are eligible for participation, as long as all definitive therapy has been completed at least 6 months prior to Step 1 registration

For patients registering to Arm S, patient must have completed at least 4 months, but not more than 5 months of systemic induction therapy for advanced disease (with CAPOX, FOLFOX, CAPOX plus nivolumab, or FOLFOX plus nivolumab)

Any major surgery must have been completed >= 4 weeks prior to Step 1 registration

Patients with known central nervous system (CNS) metastasis will be excluded from protocol participation, regardless of the status of the CNS disease

Patient must not have any uncontrolled intercurrent illness including, but not limited to ongoing or active infection requiring treatment, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements

Patient must not have had live vaccines within 4 weeks prior to Step 1 registration. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, chicken pox, yellow fever, rabies, Bacillus Calmette Guerin (BCG), and typhoid (oral) vaccine. Patients are permitted to receive inactivated vaccines and any non-live vaccines including those for the seasonal influenza and coronavirus disease 2019 (COVID-19) (Note: intranasal influenza vaccines, such as Flu-Mist are live attenuated vaccines and are not allowed). If possible, it is recommended to separate study drug administration from vaccine administration by about a week (primarily, in order to minimize an overlap of adverse events)

REGISTRATION TO STEP 2

For patients registered to Arms A, B, G or H on Step 1, the patient must have histologically confirmed HER2 negative metastatic esophageal or gastric adenocarcinoma (AJCC 8th edition) with stable disease after 4 cycles of fluorouracil, leucovorin calcium, and oxaliplatin (FOLFOX) or 6 cycles of CAPOX (Step 1 treatment). For patients registered to Arm S on Step 1, patients must have completed at least 4 months, but not more than 5 months of systemic induction therapy for advanced disease (with CAPOX, FOLFOX, CAPOX plus nivolumab, or FOLFOX plus nivolumab)

Patient must have no evidence of disease progression since systemic induction treatment initiation (all patients on Arms A, B, G, H and S). Imaging must be done within 7 days prior to Step 2 randomization. Patients with complete radiologic response are eligible for Step 2

Patient must have an ECOG performance status 0-1

For patients registered to Arms A, B, G or H on Step 1 must have a serum or urine pregnancy test to rule of pregnancy within 14 days prior to Step 2 randomization

PRIMARY OBJECTIVE:
I. Overall survival (OS), which will be measured from the time of randomization.

SECONDARY OBJECTIVES:
I. Safety and tolerability of consolidative radiation therapy in the treatment of oligometastatic esophageal and gastric adenocarcinoma (EGA).
II. Progression-free survival (PFS) which will be measured from the time of randomization.

OUTLINE:

STEP 1 (INDUCTION PHASE): Patients are assigned to 1 of 5 arms. 

ARM A: Patients receive oxaliplatin intravenously (IV) over 1.5 hours, leucovorin IV over 1.5 hours, and 5-fluorouracil IV over 46-48 hours on days 1 and 15. Treatment repeats every 28 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity.

ARM B: Patients receive oxaliplatin IV over 2 hours on day 1 and capecitabine orally (PO) twice daily (BID) on days 1-14. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.

ARM G: Patients receive treatment as in Arm A. Patients also receive nivolumab IV on day 1 of each cycle. Treatment repeats every 28 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity.

ARM H: Patients receive treatment as in Arm B. Patients also receive nivolumab IV on day one of each cycle. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity.

ARM S: Patients who completed induction therapy prior to study enrollment and have no evidence of disease progression are assigned to Arm S and may proceed directly to Step 2 randomization.

STEP 2 (CONSOLIDATION): Patients on Arms A or S are randomized to either Arms C or D. Patients on Arm B or S are randomized to either Arms E or F. Patients on Arms G or S are randomized to either Arms I or J. Patients on Arms H or S are randomized to Arms K or L.

ARM C: Patients undergo radiation therapy for up to 15 days. Within 2-4 weeks post radiation therapy, patients continue oxaliplatin, leucovorin, and 5-fluorouracil as in Arm A for 2 years in the absence of disease progression or unacceptable toxicity.

ARM D: Patients continue oxaliplatin, leucovorin, and 5-fluorouracil as in Arm A for 2 years in the absence of disease progression or unacceptable toxicity.

ARM E: Patients undergo radiation therapy for up to 15 days. Within 2-4 weeks post radiation therapy, patients continue oxaliplatin and capecitabine as in Arm B for 2 years in the absence of disease progression or unacceptable toxicity.

ARM F: Patients continue oxaliplatin and capecitabine as in Arm B for 2 years in the absence of disease progression or unacceptable toxicity.

ARM I: Patients undergo radiation therapy for up to 15 days. Within 2-4 weeks post radiation therapy, patients continue oxaliplatin, leucovorin, 5-fluorouracil and nivolumab as outlined in Arm G for 2 years in the absence of disease progression or unacceptable toxicity.

ARM J: Patients continue oxaliplatin, leucovorin, 5-fluorouracil, and nivolumab as outlined in Arm G for 2 years in the absence of disease progression or unacceptable toxicity.

ARM K: Patients undergo radiation therapy for up to 15 days. Within 2-4 weeks post radiation therapy, patients continue oxaliplatin, capecitabine, and nivolumab as outlined in Arm H for 2 years in the absence of disease progression or unacceptable toxicity.

ARM L: Patients continue oxaliplatin, capecitabine, and nivolumab as outlined in Arm H for 2 years in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up periodically for up to 5 years from study entry. Patients experiencing disease progression are followed up every 3 months in years 1-2, and then every 6 months for up to 5 years from study entry.