Study of TNFerade™ Gene Therapy, Radiation, 5-FU and Cisplatin in Esophageal Cancer

The primary purpose of this study is to assess the safety and feasibility of giving TNFerade™ with 5-FU, Cisplatin and radiation therapy to patients with locally advanced, esophageal cancer prior to surgical resection. TNFerade™ is a replication deficient (E1, E3 and E4 deleted) adenovirus vector containing the gene for TNF-alpha controlled by a radiation inducible promoter. This allows the expression of TNF-alpha to be greatest in the area receiving radiation. TNF-alpha is a potent cytokine that has been shown to have potent anti-cancer activities but, due to systemic toxicity, could not be delivered at effective doses. TNFerade™ is a novel way of selective delivery of TNF-alpha to tumor cells.

TNFerade™ will be delivered once a week for five weeks by direct intratumoral injection by using endoscopy or Endoscopic Ultrasound. 5-FU (1000 mg/m2/day) will be delivered via continuous infusion for 96 hours during weeks 1 and 4. Cisplatin (75 mg/m2) will be delivered on Day 1 and Day 29 intravenously. The dose of radiation delivered will be 45 Gy in 1.8 Gy fractions for 5 weeks.

Inclusion criteria:

• 18-75 years for age;
• Patients with biopsy proven locally advanced adenocarcinoma or squamous cell carcinoma of the esophagus, stage II, III, who have not received previous treatment and are considered to have resectable carcinoma;
• Informed consent;
• Karnofsky performance status ≥ 70%;
• Life expectancy greater than 6 months.

Exclusion criteria:

• Diagnosis of lymphoma of the esophagus;
• History of other malignancy in the past 2 years except carcinoma in situ of the cervix or bladder, non-melanomatous skin cancer or localized early stage prostate cancer with patients continuously disease-free;
• Previous chemotherapy or radiation for esophageal cancer or previous radiation therapy to the target field;
• T4 disease, metastatic (stage IV) disease or confirmed invasion of the bronchial tree;
• Extension beyond 2 cm into stomach;
• Liver enzymes >2.0 x ULN (ALT, AST, bilirubin, alkaline phosphatase);
• Coagulopathy (INR >1.5, PTT ratio >1.5);
• Renal insufficiency (creatinine >2.0 mg/dL; calculated creatinine clearance <50 ml/min);
• Significant anemia (hematocrit <28% or hemoglobin <9 g/dL) (may have RBC transfusion), or thrombocytopenia (platelet count <100,000/μL)l or leukopenia (WBC <3,000/µL; ANC <1,500 μL);
• Contraindication to endoscopic or EUS-guided delivery including obstructive lesions that can not be dilated to pass endoscope;
• Clinical evidence of active infection of any type, including hepatitis B or C virus;
• Due to the embryotoxic effects of chemotherapy, pregnant or lactating women, or men unable or unwilling to practice contraception are excluded;
• Experimental medications within the last four weeks prior to Day 1;
• Chronic systemic corticosteriod use (orally or parenterally administered);
• Significant concurrent medical or psychiatric illness as defined by the investigator.