This is a Phase 1/ 2, open-label, single-center study of preoperative chemoradiotherapy and AT-101 in patients with locally advanced esophageal or gastroesophageal junction cancer.

Inclusion Criteria:

• Male or female patients age ≥18 years
• Histologically confirmed primary (non-recurrent) adenocarcinoma (AC) or squamous cell carcinoma of the esophagus or AC of the gastroesophageal (GE) junction.
• For Phase 1: Phase 1 patients must have unresectable disease (Stage II to IVa). A patient can be unresectable for medical reasons or technical reasons but eligible for chemoradiation.
• For Phase 2: Phase 2 patients must have resectable cancer defined as: T2, T3, N0; OR T1-3, N+
• Patients must have archived tumor tissue to correlate tumor biomarker expression with clinical response. Availability of tumor specimens in paraffin blocks or at least two unstained slides must be confirmed prior to study entry. Results will not be used to determine patient eligibility for the study.
• ECOG performance status 0-1
• Adequate hematologic function
• Adequate liver and renal function
• Ability to swallow and retain oral medication.

Exclusion Criteria:

• Patients with distant metastasis, including M1b lymph node status. (M1b status allowed on Phase I only for patients appropriate for chemoradation). Lymph nodes suspicious of M1b status by diagnostic imaging must be verified by fine-needle aspiration cytology. (Phase 2 only)
• For Phase 2: Patients with positive pleural, pericardial, or peritoneal cytology.
• For Phase 2: Patients with carcinoma of the cervical esophagus.
• For Phase 2: Patients with clinical evidence of metastasis to cervical or supraclavicular lymph nodes.
• Prior chemotherapy or radiotherapy for esophageal or gastroesophageal junction cancer. Phase 1 patients with prior chemotherapy are permitted to enter.
• Prior radiotherapy that would overlap the anticipated study treatment fields or radiotherapy to >30% of the marrow cavity (no prior chest irradiation).
• Patients with malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel are excluded. Subjects with ulcerative colitis, inflammatory bowel disease, or partial or complete small bowel obstruction are also excluded.
• Pregnant or nursing females. Fertile patients (male and female) must use effective contraception.