A Study of agenT-797 in Combination With Botensilimab, Balstilimab, Ramucirumab, and Paclitaxel for People With Esophageal, Gastric, or Gastro-esophageal Junction Cancer

Inclusion Criteria:

• Metastatic or advanced unresectable adenocarcinoma of esophageal, gastric, orgastroesophageal junction

• Disease progression on one prior line of therapy for metastatic disease. Patientswith previously untreated advanced unresectable or metastatic disease may beincluded if disease progressed or recurred during neoadjuvant or adjuvant therapy orwithin 6 months of completion of those treatments.

• Patients must have histologically or cytologically confirmed esophageal, gastric, orgastroesophageal junction adenocarcinoma

• Patients must have measurable or evaluable disease as defined by RECIST v1.1criteria. Patients with evaluable disease must be eligible to begin with aninduction cycle

• Age 18 years or older

• ECOG performance status 0 to 1

• Adequate organ function as defined in Table 2

Table 2. Organ function requirements for eligibility Hematological Absolute neutrophil count: ≥1000/mcL Platelets: ≥90,000/mcL Hemoglobin: ≥8 g/dL Renal Serum creatinine: ≤1.5X ULN Hepatic Serum total bilirubin: ≤1.5X ULN OR Direct bilirubin ≤ULN for subjects 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

Exclusion Criteria:

• Received prior therapy with ramucirumab at any time

• Received paclitaxel or docetaxel-based therapy within 6 month of study enrollment

• Had a prior grade >3 immune related adverse event due to anti-PD-1, anti-PD-L1,anti-PD-L2, or anti-CTLA4 therapy at any time

• Diagnosis of immunodeficiency or receipt of systemic steroid therapy or any otherform of immunosuppressive therapy within 7 days before the first dose of trialtreatment. Replacement therapy (ie physiologic corticosteroid replacement therapyfor adrenal or pituitary insufficiency) is not considered a form of systemicimmunosuppressive therapy and is allowed.

• History of gastrointestinal perforation or fistulae

• A known history of active Bacillus tuberculosis

• Known active central nervous system metastases and/or carcinomatous meningitis

• History of or any evidence of active, non-infectious, immune-mediated pneumonitis.Patients with radiation-induced pneumonitis who are asymptomatic are permitted onstudy.

• Peripheral neuropathy limiting ADLs

• 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 beeligible after consultation with hepatologist and study team.

• Received a live vaccine within 30 days of planned start of study therapy

• Known psychiatric or substance abuse disorders that would interfere with cooperationwith the requirements of the trial

• Pregnant or breastfeeding or expecting to conceive or father children within theprojected duration of the trial, starting with the prescreening or screening visitthrough 5 months after the last dose of trial treatment

• Unwilling to give written, informed consent, unwilling to participate, or unable tocomply with the protocol for the duration of the study