Inclusion Criteria:

• Histologically confirmed, unresectable or metastatic stage IV esophageal or gastric adenocarcinoma. Tumors with squamous cell differentiation, including those with a mixture of squamous and adenomatous differentiation, are excluded.
• Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) criteria, greater than or equal to 1 cm (longest diameter) by spiral computed tomography (CT) scan or greater than or equal to 2 cm by other radiographic technique. Disease in an irradiated field as only site of measurable disease is acceptable if there has been a clear progression of the lesion.
• Patients must have at least one paraffin block or twenty unstained slides available for analysis of epidermal growth factor receptor (EGFR) status.
• Treatment with 1-2 prior chemotherapy regimens given in the metastatic setting for unresectable or metastatic esophageal or gastric carcinoma.
• ECOG performance status 0-2.
• Life expectancy greater or equal to 12 weeks.
• Age 18 years or older.
• Ability to sign an informed consent document.
• Neutrophils greater than or equal to 1,000/mm3.
• Platelets greater than or equal to 75,000/mm3.
• Serum bilirubin less than or equal to 2.0 mg/dl.
• Serum creatinine less than or equal to 1.5 mg/dl.
• Aspartate aminotransferase (AST or SGOT) less than or equal to 2.5 x upper institutional normal limit.

Exclusion Criteria:

• Pregnant or lactating women. Women of childbearing potential must have a negative serum or urine pregnancy test within 14 days of initiation of therapy. Men and women of reproductive potential may not participate unless they have agreed to use an effective contraceptive method while in this study.
• Subjects should have no other active malignancy other than non-melanoma skin cancer or in-situ cervical carcinoma. A resected cancer (other than in-situ carcinoma) must have demonstrated no evidence of recurrence for at least 3 years.
• Subjects should not have a significant history of cardiac disease, i.e., uncontrolled hypertension; unstable angina; congestive heart failure; myocardial infarction less than 6 months prior to registration; or serious uncontrolled cardiac arrhythmia.
• Subjects must not have received prior cetuximab or other therapy that specifically and directly targets the EGFR pathway. Prior therapy with bevacizumab is permissible.
• Subjects must not have experienced prior severe infusion reaction to a monoclonal antibody.
• Subjects must not have received any chemotherapy regimen or radiation therapy within 28 days prior to study entry.
• Patients must have completed any major surgery 4 weeks or any minor surgery 2 weeks prior to the first infusion of cetuximab. Patients must have fully recovered from the procedure.
• No concurrent use of chemotherapy, radiation, or other investigational agents is allowed while participating in this study.