CAPOX, Bevacizumab and Trastuzumab for Patients With HER2-Positive Metastatic Esophagogastric Cancer

- 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.