Bevacizumab and Combination Chemotherapy Before Surgery in Treating Patients With Locally Advanced Esophageal or Stomach Cancer

PRIMARY OBJECTIVES:

I. To investigate two-year disease-free survival in patients with resectable esophageal and
gastroesophageal (GE) junction cancer treated with perioperative bevacizumab and leucovorin
calcium, fluorouracil, and oxaliplatin (FOLFOX).

SECONDARY OBJECTIVES:

I. To assess, by pathological examination after surgical resection, complete and partial
response to neoadjuvant therapy.

II. To characterize overall and progression free survival. III. To compare baseline and
post-chemotherapy/bevacizumab tissues for biomarkers predicting response or resistance to
this approach.

IV. To investigate safety in this setting.

OUTLINE:

NEOADJUVANT THERAPY: Patients receive bevacizumab intravenously (IV) over 30-90 minutes on
day 1. Patients also receive FOLFOX chemotherapy comprising oxaliplatin IV over 2 hours and
leucovorin calcium IV over 2 hours on day 1, and fluorouracil IV continuously over 46 hours
on days 1-2. Treatment with bevacizumab repeats every 2 weeks for 4 courses and treatment
with FOLFOX repeats every 2 weeks for 6 courses in the absence of disease progression or
unacceptable toxicity.

SURGERY: Patients then undergo planned surgical resection 4-6 weeks after 6 courses of
chemotherapy and at least 8 weeks since the last dose of bevacizumab.

ADJUVANT THERAPY: Beginning 8-10 weeks after surgery, patients receive bevacizumab IV,
oxaliplatin IV, leucovorin calcium IV, and fluorouracil IV as in neoadjuvant therapy.
Treatment repeats every 2 weeks for 6 courses in the absence of disease progression or
unacceptable toxicity.

After completion of study treatment, patients are followed up every 4 months for 1 year,
every 6 months for 2 years, and then annually thereafter.

Inclusion Criteria:

- Patients must have biopsy proven adenocarcinoma, squamous cell carcinoma or
undifferentiated carcinoma of the esophagus, GE junction and/or gastric cardia

- Patients must have potentially resectable disease by the thoracic, minimally invasive
or transhiatal approach

- No portion of the lesion may be within 5 cm of the cricopharyngeus

- Patient must be considered medically fit for surgery with average or below
average risk

- T1-3 or T4 with local invasion confined to diaphragm, pleura or pericardium

- No myocardial infarction within 12 months of enrollment

- Patients must have Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1

- White blood cells (WBC) >= 3,500/mm^3

- Platelet count >= 100,000/mm^3

- Serum creatinine (Cr) =< 1.5 mg and/or creatinine clearance >= 60 cc/min

- Bilirubin must be < upper limit of normal (ULN) unless the patient has a chronic grade
1 bilirubin elevation due to Gilbert's disease or similar syndrome due to slow
conjugation of bilirubin

- Alkaline phosphatase must be < ULN

- Aspartate aminotransferase (AST) & alanine aminotransferase (ALT) must be < ULN

- Urine protein/creatinine (UPC) ratio of < 1.0 or dipstick for protein of < 2+, Common
Terminology Criteria for Adverse Events version 4.0 (CTCAE v 4) grade < 2; patients
with a UPC ratio >= 1.0 or dipstick of 2+ must undergo a 24-hour urine collection and
must demonstrate < 1 gm of protein in order to participate

- Patients must give written informed consent and Health Insurance Portability and
Accountability Act (HIPAA) consent

Exclusion Criteria:

- Patients with prior chemotherapy for any malignant disorder, thoracic radiotherapy or
prior surgical resection of an esophageal tumor are ineligible

- Patients with biopsy-proven invasion of the tracheobronchial tree or
tracheo-esophageal fistula are ineligible

- Patients with a history of a curatively treated malignancy must be disease-free for at
least two years and have a survival prognosis that is greater than five years

- Eligible patients of reproductive potential (both sexes) must agree to use an accepted
and effective method of contraceptive during study therapy and for at least 6 months
after the completion of bevacizumab; women must not be pregnant or breast-feeding
because the study drugs administered may cause harm to an unborn fetus or
breastfeeding child; all females of childbearing potential must have a serum pregnancy
test to rule out pregnancy within 7 days prior to registration

- Patients with a history of hypertension must measure < 150/90 mmHg and be on a stable
regimen of anti-hypertensive therapy; patients with a history of hypertension who have
a blood pressure of 150/90 mmHg, or greater are not eligible; patients with a history
of hypertension who have a blood pressure of < 150/90 mmHg but are not on a stable
regimen of anti-hypertensive therapy, are not eligible

- Any prior history of hypertensive crisis or hypertensive encephalopathy

- New York Association (NYHA) grade II or greater congestive heart failure

- Patients must not have a serious or non-healing wound, skin ulcers or unhealed bone
fracture, or known human immunodeficiency virus (HIV) infection

- Patients with >= grade 2 neuropathy are not eligible

- Patients must not have had significant traumatic injury within 28 days prior to
randomization

- Patients with PT (INR) > 1.5 are not eligible; the patient may not be receiving
full-dose anticoagulation; prophylactic or full dose anticoagulation are permitted
post-resection or for treatment of an intercurrent thrombotic event

- Patients with non-malignant systemic disease (cardiovascular, renal, hepatic, etc.)
that would preclude any of the study therapy drugs are not eligible; specifically
excluded are the following conditions: current symptomatic arrhythmia, symptomatic
peripheral vascular disease

- Patients with a history of the following within 12 months of study entry are not
eligible: arterial thromboembolic events, unstable angina

- Any history of stroke or transient ischemic attack

- Significant vascular disease (i.e. aortic dissection, aortic aneurysm)

- Patients with psychiatric or addictive disorders or other conditions that, in the
opinion of the investigator, would preclude them from meeting the study requirements
are not eligible

- Distant metastases

- History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess
within 6 months prior to study enrollment

- Known hypersensitivity to any component of bevacizumab