Ivonescimab in Comb. With FOLFOX in Advanced HER2 Neg. GEA

Inclusion Criteria:

* Patients must have a pathologically confirmed diagnosis of adenocarcinoma of the esophagus, gastroesophageal junction, stomach. Squamous cell tumors are excluded. Patients with locally tested HER2 positive tumors (HER2+) tumors are excluded.
* Participants must have disease that can be evaluated radiographically. This includes disease that may be measurable or non-measurable as per RECIST version 1.1.
* Patients may not have received prior therapy for Stage IV disease. Patients may have received prior adjuvant therapy if more than 6 months have elapsed between the end of adjuvant therapy and registration.
* Age ≥18 years old. Because there is no dosing or adverse event data for ivonescimab with FOLFOX in participants \<18 years of age, children are excluded from this study.
* ECOG Performance status of 0-2
* Participants must meet the following organ and marrow function as defined below:

  1. absolute neutrophil count ≥1,500/mcL
  2. hemoglobin \> 9.0 g/dL
  3. platelets ≥100,000/mcL
  4. total bilirubin ≤ 1.5x institutional upper limit of normal (ULN). For patients with liver metastases or confirmed/suspected Gilbert syndrome, TBIL ≤3 × ULN
  5. AST(SGOT)/ALT(SGPT) ≤2.5 × institutional ULN. For patients with liver metastases, AST and ALT ≤ 5 × ULN
  6. Creatinine ≤ institutional ULN OR glomerular filtration rate (GFR) ≥50 mL/min.
  7. Urine protein \< 2+ or 24-hour protein quantification \< 1.0 grams.
  8. Coagulation: prothrombin time (PT) or international normalized ratio (INR) ≤ 1.5 × ULN, and partial prothrombin time (PTT) or activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN (unless abnormalities are unrelated to coagulopathy) This applies only to patients who are not on therapeutic anti-coagulation. Patients receiving therapeutic anti-coagulation should be on a stable dose.
* For participants with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.
* Participants with a history of hepatitis C virus (HCV) infection must have been treated and cured. For participants with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.
* Participants with brain metastases (active brain metastases) or leptomeningeal disease are not eligible. Patients with treated brain metastases who are off systemic steroids \> 2 weeks and have documented radiographic stability over 4 weeks since initial brain metastasis diagnosis may be considered in discussion with the overall principal investigator.
* Participants 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 trial.
* The effects of ivonescimab on the developing human fetus are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she must inform her treating physician immediately. Contraception must continue for 9 months from the last dose of any study medication.
* Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 9 months after completion of ivonescimab administration.
* Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

* Prior treatment with a PD-1 or PD-L1 inhibitor is exclusionary unless this therapy was completed \> 6 months prior to the time of enrollment as part of adjuvant therapy.
* Major surgical procedures or serious trauma within 4 weeks prior to enrollment, or plans for major surgical procedures within 4 weeks after the first dose (as determined by the investigator). Minor local procedures (excluding central venous catheterization and port implantation) within 3 days prior to registration.
* Participants who have not recovered from adverse events due to prior adjuvant anti-cancer therapy except for alopecia or peripheral neuropathy grade 1 or less.
* Participants who are receiving any other investigational agents for this condition are not eligible.
* History of allergic reactions attributed to compounds of similar chemical or biologic composition to ivonescimab. Patients with prior oxaliplatin and/or 5FU allergic reactions during adjuvant therapy are allowed if they have undergone prior desensitization with allergy and documented tolerance at standard dosing after desensitization.
* Pregnant women are excluded from this study because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother, breastfeeding must be discontinued if the mother is treated with ivonescimab. These potential risks may also apply to other agents used in this study.
* History of perforation of the gastrointestinal tract and/or fistula, history of gastrointestinal obstruction (including incomplete intestinal obstruction requiring parenteral nutrition), extensive bowel resection (partial colectomy or extensive small bowel resection) within 6 months prior to resgistration.
* Clinically significant hypertension with systolic blood pressure ≥ 150 mmHg or diastolic blood pressure ≥ 100 mmHg after oral antihypertensive therapy.
* History of any grade arterial thromboembolic event, venous thromboembolic event of Grade 3 and above as specified in National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) 5.0, transient ischemic attack, cerebrovascular accident, hypertensive crisis, or hypertensive encephalopathy within 12 months prior to registration.
* Participants with a documented history of impaired wound healing are excluded.
* Participants with a history of allogeneic organ transplantation or allogeneic hematopoietic stem cell transplantation.
* Participants with uncontrolled intercurrent illness that would interfere with ability to participate in the opinion of the treating investigator.
* Participants with psychiatric illness/social situations that would limit compliance with study requirements.
* Unstable angina, myocardial infarction, congestive heart failure (New York Heart Association \[NYHA\] classification ≥ grade 2) or unstable vascular disease (eg, aortic aneurysm at risk of rupture, Moyamoya disease) that required hospitalization within 12 months prior to registration, or other cardiac impairment that may affect the safety evaluation of the study drug (eg, poorly controlled arrhythmias, myocardial ischemia).
* Subjects with any condition requiring systemic treatment with either corticosteroids (\>2mg daily dexamethasone equivalent) or other immunosuppressive medications within 14 days of treatment. Premedication for hypersensitivity reactions (e.g. to contrast for CT or gadolinium for MRI) is allowed.
* Active systemic infection requiring intravenous antibiotics or intravenous monoclonal antibody treatments within 7 days of cycle 1 day 1.
* Participants with a known history of Human Immunodeficiency Virus (HIV) infection are excluded unless they meet all of the following criteria:

  * Stable antiretroviral therapy (ART) for at least 12 weeks prior to enrollment
  * No history of AIDS-defining conditions.
  * CD4+ T-cell count ≥ 350 cells/mm³ at screening
  * HIV viral load ≤ 50 copies/mL at screening.
  * No significant comorbidities associated with HIV infection that could interfere with the safety or efficacy of the investigational treatment.
  * No concurrent use of prohibited medications that may interfere with the study drug or cancer therapy
* History of bleeding tendencies or coagulopathy and/or clinically significant bleeding symptoms or risk within 4 weeks prior to registration, including but not limited to:

  * Hemoptysis (defined as coughing up ≥ 0.5 teaspoon of fresh blood or small blood clots). Note: transient hemoptysis associated with diagnostic bronchoscopy is allowed.
  * Nasal bleeding /epistaxis (bloody nasal discharge is allowed)
  * Current use of prophylactic or full-dose anticoagulants or anti-platelet agents for therapeutic purposes that is not stable prior to registration is not allowed. The use of full-dose anticoagulants is permitted as long as the international normalized ratio (INR) or activated partial thromboplastin time (aPTT) is within therapeutic limits according to the medical standard of the enrolling institution.
* History of non-infectious pneumonitis requiring therapy within 4 weeks of registration.