MnSOD (Esophageal Protectant) to Prevent Esophagitis During Radiation/Chemotherapy Treatment for Non-Small Cell Lung Cancer (NSCLC)

• feasibility and safety [ Time Frame: The endpoint will be the proportion of toxicities attributed to administration of MnSOD plasmid liposome. ] [ Designated as safety issue: Yes ]
• Efficacy [ Time Frame: The clinical endpoint will be the proportion of radiation - induced grade III/IV esophageal toxicity. ] [ Designated as safety issue: No ]
• Biologic endpoints [ Time Frame: Characterization of esophageal biopsy specimens by immunohistochemistry, RT-PCR for MnSOD mRNA as a measure of gene transfection and expression levels of inflammatory cytokines ] [ Designated as safety issue: No ]

This is a Phase I-II study evaluating the feasibility, safety, and efficacy of swallowed MnSOD plasmid/liposome (PL) transgene given as protection against radiation-induced esophagitis during concurrent paclitaxel and carboplatin chemotherapy with thoracic radiation in subjects with locally advanced non-small cell lung cancer (NSCLC).

This is a Phase I-II study evaluating the feasibility, safety, and efficacy of swallowed MnSOD plasmid/liposome (PL) transgene given as protection against radiation-induced esophagitis during concurrent paclitaxel and carboplatin chemotherapy with thoracic radiation in subjects with locally advanced non-small cell lung cancer (NSCLC). Phase I of the study will assess the feasibility and safety of MnSOD PL by dose escalation in 3 cohorts of 3 chemoradiotherapy subjects each (Cohort1 = 0.3 mg/dose, Cohort2 = 3 mg/dose, Cohort3 = 30 mg/dose). The highest dose completed (as determined by toxicity monitoring for 8 weeks from initial treatment) will be the starting dose for Phase II. Phase II will examine the efficacy of MnSOD PL by assessing the incidence of Grade 3 or 4 esophagitis in 27 additional chemoradiotherapy subjects. Incidence of esophageal toxicity, as well as clinical response to the combination of chemoradiotherapy with MnSOD PL are the outcomes of interest.

• Esophageal
• Toxicity

Inclusion Criteria:

• Histologically or cytologically documented NSCLC including squamous cell carcinoma, adenocarcinoma (including bronchoalveolar cell), and large cell anaplastic carcinoma (including giant and clear cell carcinomas) and poorly differentiated non-small cell lung cancer. Totally resected tumors are excluded.
• Subjects must be without evidence of M0.
• Subjects with T1 or T2 disease with N2 or tumor stage 3, lymph node metastasis 1-2 ( stage 1) disease (Stage IIIA) are eligible if they are medically inoperable. Subjects with T4 with any N or any T with N3 disease are eligible. Radiographic evidence of mediastinal lymph nodes >2.0 cm in the largest diameter is sufficient to stage N2 or N3 disease. If the largest mediastinal node is < 2.0 cm in diameter and this is the basis for stage III disease, then at least one of the nodes must be proven positive cytologically or histologically.
• Subjects with tumors adjacent to a vertebral body are eligible as long as all gross disease can be encompassed in the radiation boost field. The boost volume must be limited to < 50% of the ipsilateral lung volume.
• Subjects with a pleural effusion that is a transudate, cytologically negative and non-bloody are eligible if the radiation oncologists feel the tumor can still be encompassed within a reasonable field of radiotherapy. Exudative, bloody, or cytologically malignant effusions are ineligible. If a pleural effusion can be seen on the chest CT but not on chest X-ray and is too small to tap, the subject will be eligible.
• Subjects must be deemed a suitable candidate for protocol treatment by both Radiation Oncology and Medical Oncology
• Subjects must have a Performance Status > 70 (Karnofsky Performance Scale).
• Subjects Weight loss < 10% in 3 months prior to diagnosis.
• Subjects must be male or female > 18 years.
• Subjects must have had no prior systemic chemotherapy, radiation therapy to the thorax, or total surgical resection.
• At least 3 weeks since formal exploratory thoracotomy and the subject has recovered from surgery, or 1 week from diagnostic thoracoscopy.
• Laboratory values must be as follows: (See Section 6.1 of the full protocol for required timing): Granulocytes > 2,000/ml, Platelets > 100,000/ml, Hemoglobin* > 8 mg/dl, Bilirubin < 1.5 x normal, Creatinine clearance > 50 ml/n (24 hour or calculated, forced expiratory volume at one second > 800 cc. Note: *Physician can maintain a subject's hemoglobin with the use of Erythropoetin or transfusions prophylactic use of G-CSF (colony stimulating factor, is not permitted).
• Subjects must have a MRI or CT brain scan within 4 weeks prior to study entry to rule out asymptomatic brain metastases.
• Subjects must be informed of the investigational nature of the study and sign an informed consent form and have no serious medical or psychiatric illnesses that would prevent informed consent.
• No history of serious cardiac disease that is not adequately controlled.
• Female subjects must be non-pregnant and non-lactating. Female subjects of childbearing potential must implement an effective method of contraception during the study. All women of childbearing potential must have a pre-study negative serum or urine pregnancy test within 7 days prior to study entry.

Exclusion Criteria

• Inability to meet any of the above eligibility requirements