Neoadjuvant RP2 & Flot Treatment for Advanced Gastroesophageal Adenocarcinoma

Study start date: November 8, 2025

Inclusion Criteria: * Patients must have histologically confirmed and clinically staged T2 or higher or node positive, non-metastatic esophageal, gastroesophageal junction, or gastric adenocarcinoma. * Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 - 1. * Patents must be deemed a surgical candidate by a thoracic surgeon, surgical oncologist, or surgeon who is qualified to perform the appropriate surgical procedure based on patient's primary tumor site. * Patients must have normal organ and bone marrow function, as defined below, less than or equal to 14 days prior to the initiation of study therapy: * Absolute neutrophil count (ANC) ≥ 1,500/microliter * Platelets ≥100,000/microliter * Total bilirubin ≤ the institutional upper limit of normal (ULN). * AST and ALT ≤ 2.5 times the institutional ULN * Serum creatinine ≤ 1.5 times the institutional ULN * Hemoglobin ≥ 9 g/dL Exclusion Criteria * Has received prior chemotherapy, radiation therapy, or immunotherapy (anti-programmed cell death protein-1 (PD-1), anti-programmed death ligand-1 (PD-L1), or anti-cytotoxic T-lymphocyte associated protein 4 (CTLA-4) for the current malignancy. * Per the investigator, has contraindications to receiving chemotherapy with FLOT. * Per the sub-investigator (gastroenterologist) responsible for intra-tumoral injections or the investigator, patient has contraindications to repeated upper endoscopy for intra-tumoral injections. These could include medical conditions that would, per the judgment of the sub-investigator or investigator, inappropriately increase the risk of upper endoscopy. * Conditions in which anticoagulant therapies cannot be safely stopped in the periprocedural period or patients on warfarin with a target international normalized ratio (INR) ≥ 2.5 that cannot be temporarily reversed to INR ≤ 1.7. * Active significant herpetic infections or prior complications of Herpes simplex virus-1 (HSV-1) infection (e.g., herpetic keratitis or encephalitis) or requires intermittent or chronic use of systemic (oral or intravenous \[IV\]) antivirals with known antiherpetic activity (e.g., acyclovir). Note: Patients with sporadic cold sores may be enrolled as long as no active cold sores are present at the time of first dose of study treatment. * Has received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacille Calmette-Guérin (BCG), and typhoid vaccine. Note: Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed, however, intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed. Available COVID-19 vaccines do not contain live virus and are allowed. * Has a condition requiring systemic treatment with corticosteroids (\>10mg/day prednisone equivalents) or other immunosuppressive medications within 14 days of first study treatment administration. * Inhaled or topical steroids and adrenal replacement doses ≤ 10mg/day of prednisone equivalents are permitted. * Prior organ transplantation including allogeneic stem-cell transplantation. * Has a previous or concurrent malignancy. Exceptions include: * Non-melanoma skin cancer, in situ cervical cancer, superficial bladder cancer, or breast cancer in situ OR * Prior malignancy has been completely excised or removed and patient has been continuously disease free for \> 5-years * Has a positive test result for hepatitis B virus surface antigen (HBsAg) or hepatitis C virus ribonucleic acid (HCV RNA) indicating acute or chronic infection with hepatitis B or hepatitis C. Testing will be performed as part of screening on the study. * Patients with a known history of hepatitis B or hepatitis C that have been effectively treated (with negative HBsAg and HCV RNA) will be eligible for enrollment on this criterion. * Has a known history of human immunodeficiency virus (HIV) with detectable viral load. HIV testing will not be performed as part of screening for the study. * Patients with known HIV infection with an undetectable viral load and who are on a stable highly active antiviral regimen per the investigator's assessment will eligible to enroll. * Has a psychiatric illness, substance use, or other social conditions that, in the judgment of the investigator, would limit compliance with study requirements.