The purpose of this study is to determine the safety and effectiveness of a combination of chemotherapy, capecitabine and oxaliplatin, plus the antibodies bevacizumab and trastuzumab. Trastuzumab (also called Herceptin) is an antibody that attacks HER2 protein in tumor cells. Bevacizumab (also called Avastin) works by slowing or stopping the growth of cells in cancer tumors by decreasing the blood supply of the tumors. If blood supply is decreased, oxygen and nutrients that are needed for tumor growth are decreased. The chemotherapy used in this trial is called CAPOX, which is an abbreviation of capecitabine and oxaliplatin.

• We recommend that the participants have a vascular access device, more commonly known as a PORT, inserted prior to starting chemotherapy. A port is a small device that is inserted under the skin (usually near the collar bone) by a minor surgical procedure and is then connected to one of the large veins inside the chest. The port will be used to give the intravenous medications.
• During the first cycle, the participant will receive trastuzumab intravenously on Day 1. Cycle 2 will then start one week later. On this day, bevacizumab will be given intravenously first followed by trastuzumab and then oxaliplatin. The participant will then start taking capecitabine tablets orally twice a day for 14 days. Each treatment cycle is 21 days long.
• Participants will have the following tests and procedures at specific time points during study treatment; physical exam, blood tests, CT scan, MUGA scan or echocardiogram, and urine test.

Inclusion Criteria:

• Confirmed HER2-positive esophageal, GE junction or gastric adenocarcinoma that is metastatic or unresectable.
• All patients must have available tumor sample (either paraffin block or 15 freshly cut, unstained slides) prior to study entry.

Part II: Patient must have primary esophagogastric tumor in place or other tumor that is accessible for mandatory biopsy.

• Measurable disease, defined in RECIST 1.1
• 18 years of age or older
• Life expectancy of greater than 12 weeks
• ECOG performance status of 0 or 1
• Organ and marrow function as outlined in the protocol
• Women of child-bearing potential and men must agree to use adequate contraception during study participation and for 30 days from the date of the last study drug administration.
• Part II only: Participant agrees to undergo mandatory pre and post loading dose of trastuzumab biopsy for correlative science.

Exclusion Criteria:

• Prior therapy with any of the following; capecitabine, oxaliplatin, bevacizumab or trastuzumab is not allowed. May have received and completed adjuvant therapy at least 6 months prior to study entry or one prior therapy for metastatic disease as long as it did not include any of the above agents.
• Chemotherapy or radiotherapy to greater then 25% of bone marrow within 4 weeks prior to entering the study.
• Palliative radiation therapy to isolated bone metastasis within 2 weeks of initiating therapy.
• Major surgery, open biopsy, significant traumatic injury within 4 weeks prior to study entry,.
• Minor surgery, including placement of vascular access device within 7 days prior to the first dose of bevacizumab.
• Residual toxicity from prior chemotherapy and/or radiation therapy of Grade 2 or greater.
• Participants may not be receiving any concurrent investigational agents
• Active brain or other CNS metastasis by history or clinical examination.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to capecitabine, bevacizumab or trastuzumab. No known allergy or hypersensitivity to Chinese hamster ovary, or any of the study agents. No known DPD deficiency.
• Warfarin is prohibited; anticoagulation using low molecular weight heparin is allowed.
• Uncontrolled, intercurrent illness
• Patients with a history of other malignancy are not eligible except for the following circumstances: disease-free for at least 3 years and are deemed to be at low risk for recurrence of that malignancy; cervical cancer in situ, basal cell or squamous cell carcinoma of the skin that was treated with curative intent within the past 5 years.
• Known HIV seropositivity, hepatitis C, acute or chronic hepatitis B or other serious active infection
• LVEF less than 50% as determined by MUGA scan or echocardiogram within 28 days prior to initiation of therapy
• Inadequately controlled hypertension
• History of prior hypertensive crisis or hypertensive encephalopathy
• History of any arterial thrombosis, CVA, TIA, MI or unstable angina in past 6 months.
• Evidence of bleeding diathesis or coagulopathy
• Serious, unhealed wounds, bone fractures or skin ulcers
• Pregnant or breast feeding
• Greater than grade 1 peripheral neuropathy at baseline
• Lack of physical integrity of the upper gastrointestinal tract or malabsorption syndrome.

All adverse events experienced by participants will be collected from the time of the first dose of study treatment, throughout the study, and until the final study visit. Participants continuing to experience toxicity at the off-study visit may be contacted for additional assessments until the toxicity has resolved or is deemed irreversible. (10 years and 7 months)

Maximum grade toxicity by type was first calculated. Serious AEs were defined as events with treatment attribution of possibly, probably or definitely and grade 3 or higher per CTCAEv4. All remaining events regardless of treatment attribution were classified as Other AEs. Per the source vocabulary (CTCAEv4.0) there is a category "Other, specify" for each system organ class. No further data is available to specify classification beyond this general term.