The primary purpose of this trial is to define the maximum tolerated and/or recommended phase II dose of the combination of panitumumab, oxaliplatin and capecitabine in patients undergoing radiation therapy for carcinoma of the thoracic esophagus or gastroesophageal junction. An additional primary objective is to describe the frequency and nature of grade III/IV and grade I/II toxicities associated with this regimen. Secondary objectives include describing 1-year disease-free survival and overall survival rates as well as to estimate clinical and pathologic complete response rates associated with this regimen.

This study has a phase I/II design. For this study the administration of panitumumab is considered investigational.

Pretreatment: Part of regular cancer care and disease staging includes Chest/Abdomen CT Scan, upper endoscopic ultrasound, PET scan, J-Tube Placement (if clinically indicated), bronchoscopy (per clinician judgment), ECG, and baseline laboratory studies.

During Treatment Weeks 1-5.5 of Radiation Therapy(RT)/Chemotherapy:

• RT (180 cGy/fx, Mon-Fri) days 1-5, 8-12, 15-19, 22-26, 29-33 and 36-38.
• Panitumumab (per dose level) days 1, 15, 29.
• Oxaliplatin (per dose level) days 1, 8, 15, 22, 29, 36.
• Capecitabine (per dose level M-F) 1-5, 8-12, 15-19, 22-26, 29-33, 36-38.

Inclusion Criteria:

• 18 years of age or older.
• Histologically or cytologically documented squamous cell carcinoma or Siewert's classification adenocarcinoma of the esophagus or proximal stomach T1-4, N0-2, M0-1, for which bimodality treatment with chemotherapy and radiation therapy is indicated.
• Measurable Disease
• ECOG Performance Status 0-1
• Laboratory values must be as follows:
• Absolute neutrophil count > or = 2,000/mm3,
• Platelets > or = 100,000/mm3,
• Hemoglobin > 9.0,
• Total bilirubin <1.5 x institutional upper normal limit,
• Serum creatinine <1.5 x institutional upper normal limit,
• AST or ALT < 3x institutional upper normal limit,
• Magnesium equal or higher than institutional lower limit,
• Creatinine clearance Estimated > 40 ml/min,
• Calcium > lower limit of normal.
• Not pregnant or lactating. Negative pregnancy test within 72 hours prior to registration (female patients of childbearing potential). Postmenopausal woman must have been amenorrheic for at least 12 months to be considered of non-childbearing potential.
• Life expectancy must be >3 months.
• No serious or poorly controlled medical or psychological conditions that could be exacerbated by the treatment or would seriously complicate compliance with the protocol.
• Able to swallow capecitabine (whole or crushed tablet or liquid dispersed) or patients may have a G or J tube.
• No conditions that would significantly compromise intestinal absorption of the study drugs.

Exclusion Criteria:

• Tumors extending above the level of the thoracic inlet or beyond 5 cm below the gastroesophageal junction.
• Patients with radiographic or bronchoscopic evidence of esophageal perforation.
• Patients with known evidence of brain metastases, lymphangitic lung metastases, or carcinomatous meningitis.
• Dementia or significantly altered mental status
• Major surgery within 4 weeks of the start of study treatment
• Prior chemotherapy, radiation therapy, hormonal or biologic therapy within the past 6 months.
• Subjects requiring chronic use of immunosuppressive agents (e.g., methotrexate, cyclosporine, corticosteroids)
• Currently requiring medications that may interact with the metabolism or disposition of capecitabine/5-FU: dipyridamole, folinic acid, allopurinol, trimethoprim, misonidazole, metoclopramide, flucytosine or cimetidine.
• Hypersensitivity to platinum containing compounds or capecitabine or any of the excipients of this product. Prior unanticipated severe reaction to fluoropyrimidine/platinum therapy, or known sensitivity to 5-fluorouracil/platinum containing compounds.
• Serious, uncontrolled, concurrent infection(s).
• History of other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that might affect the interpretation of the results of the study or render the subject at high risk from treatment complications.
• Treatment for other carcinomas within the last five years, except cured non-melanoma skin and treated in-situ cervical cancer.
• Peripheral neuropathy > grade 1
• Any of the following within 24 weeks before randomization: clinically significant cardiovascular disease (including myocardial infarction, unstable angina, symptomatic congestive heart failure, serious uncontrolled cardiac arrhythmia).
• Uncontrolled gastrointestinal ulcer within 28 days of randomization
• History of interstitial pneumonitis or pulmonary fibrosis, or evidence of interstitial pneumonitis or pulmonary fibrosis on baseline chest X-ray or CT-scan
• Preexisting known bleeding diathesis or coagulopathy
• Plans to continue on or use of ketoconazole, phenytoin, phenobarbital, carbamazepine, rifampin, rifabutin or St. John's Wort, 14 days prior to randomization.
• History of hypersensitivity to tetracyclines
• Subject known to be human immunodeficiency virus positive
• Subjects known to have chronic or active hepatitis B or C infection