IRX-2, Cyclophosphamide, and Pembrolizumab in Treating Participants With Recurrent or Metastatic Gastric or Gastroesophageal Junction Cancer

Inclusion Criteria

• Patients with histologically or cytologically confirmed recurrent or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma progressed or intolerant to >= 2 lines of systemic therapy.
• Patients must have recurrent or metastatic gastric/GEJ adenocarcinoma that are not amenable to local therapy with curative intent (surgery or radiation therapy with or without chemotherapy).
• Willing and able to give informed consent and adhere to protocol therapy; written informed consent and any locally required authorization must be obtained from the patient prior to performing any protocol-related procedures, including screening evaluations.
• No prior exposure to PD-1/PD-L 1 inhibitor therapy.
• Patients are deemed eligible for pembrolizumab therapy with tumors demonstrating PD-L1 expression by the Combined Positive Score (CPS) being >= 1 as per the Food and Drug Administration (FDA)-approved Dako PD-L1 immunohistochemistry (IHC) 22C3 PharmDx assay.
• Eastern Cooperative Oncology Group (ECOG) 0-1.
• Body weight must be > 30 Kg.
• Hemoglobin > 8 g/dL.
• Absolute neutrophil count (ANC) > 1, 200 x 10^9/mL.
• Platelet count > 75 x 10^9/mL.
• Serum bilirubin = 1.5 x ULN.
• Aspartate aminotransferase (AST/serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT/serum glutamate-pyruvate transaminase [SGPT]) = 40 mL/min or calculated creatinine clearance CL > 40 mL/min by the Cockcroft-Gault formula or by 24- hour urine collection for determination of creatinine clearance.
• Palliative radiation therapy is allowed to non-target lesions at the discretion of the treating physician.
• Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) or evaluable disease as outlined in Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
• Life expectancy of greater than 3 months in the opinion of the treating physician.
• Female patients of childbearing potential must have a negative serum pregnancy test within 7 days prior to enrollment.

Exclusion Criteria

• Prior exposure to the IRX-2 regimen and/or PD-1/PD-L1 inhibitors are excluded.
• Radiation therapy with a curable intent within 30 days of first dose of study treatment is excluded. However, radiation therapy with a palliative intent is allowed as long as treatment with study medication occurs >= 14 days after the last dose of radiation.
• Any medical contraindications or previous therapy that would preclude treatment with the IRX-2 regimen or pembrolizumab.
• Known allergies to ciprofloxacin or phytohemagglutin given trace amount of these agents are contained in IRX-2.
• Patients with ongoing chronic myelosuppression, myelodysplasia, or hemorrhagic cystitis which would contraindicate receipt of cyclophosphamide.
• Any unresolved toxicity National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) grade >= 2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria.
• Patients with grade >= 2 neuropathy will be evaluated on a case-by-case basis after consultation with the study physician.
• Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with IRX-2, pembrolizumab may be included only after consultation with the study physician.
• Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc]). The following are exceptions to this criterion:
• Patients with vitiligo or alopecia.
• Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement.
• Any c