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

Study Overview
=================
Brief Summary
-----------------
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).

Detailed Description
-----------------
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.

Official Title
-----------------
Chemotherapy (Paclitaxel and Carboplatin)and Thoracic Radiotherapy With Swallowed Manganese Superoxide Dismutase (MnSOD) Plasmid Liposome Protection in Patients With Locally Advanced Stage III Non-Small Cell Lung Cancer: A Phase I-II Study

Conditions
-----------------
Esophageal, Toxicity

Intervention / Treatment
-----------------
* Genetic: Manganese Superoxide Dismutase Plasmid Liposome
* Drug: carboplatin
* Drug: paclitaxel
* Radiation: Radiation Therapy


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Radiation + MnSOD PL + Paclitaxel + Carboplatin<br>MnSOD PL (0.3, 3, or 30 mg) + (Paclitaxel + Carboplatin (45mg/m^2)) + Radiation 1.9-2.1 Gy daily 5 times per week (4-6 hr after the first MnSOD PL dose). The total dose planned at 77.0 Gy with a range of 69-84Gy in 34-38 fractions over 7-8 weeks. | Genetic: Manganese Superoxide Dismutase Plasmid Liposome<br>* 15 ml of liquid that contains either 0.3 mg, 3.0 mg or 30.0 mg (depending on which cohort is open when the subject is entered) of MnSOD PL This will be given on Day 1 and 3 of each week of the experimental treatment for a total of 14 doses.<br>* Other names: MnSOD/PL;Drug: carboplatin<br>* Chemotherapy to stop the growth of tumor cells.<br>* Other names: Paraplatin;Drug: paclitaxel<br>* Chemotherapy to stop the growth of tumor cells. This drug kills tumor cells by inducing multipolar divisions. Cells entering mitosis in the presence of concentrations of paclitaxel equivalent to those in human breast tumors form abnormal spindles that contain additional spindle poles.<br>* Other names: Taxol;Radiation: Radiation Therapy<br>* 1.9-2.1 Gy daily 5 times per week (4-6 hr after the first MnSOD PL dose). The total dose planned at 77.0 Gy with a range of 69-84Gy in 34-38 fractions over 7-8 weeks.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determination of Recommended Phase II Dose of MnSOD/Plasmid DNA | The maximally tolerated dose (milligrams) defined as the highest dose with fewer than one-third of patients experiencing a dose-limiting toxicity (DLT) per CTCAE v3.0 due to MnSOD. (Three patients treated at each at three tiers of 0.3, 3, and 30mg of MnSOD/plasmid DNA. If no DLTs (grade III/IV toxicity due to MnSOD PL) observed, the dose of MnSOD PL escalated to the next tier. If one DLT observed, the cohort is expanded to six patients. If two of six patients experienced a DLT, dose escalation stops and the next lowest dose declared maximum tolerated dose (MTD). If none of three or one of six patients experience DLT at the 30-mg tier, that dose is defined as the starting dose for the efficacy phase and the MTD would be undefined). | Every 8 weeks, up to 2 years | 
| Radiation-induced Esophageal Toxicity | Number of patients experiencing grade III/IV esophageal toxicity per CTCAE v3.0. | Up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall (Objective) Response | Clinical Response per Response Evaluation Criteria in Solid Tumors (RECIST). Per RECIST v1.0: Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (target or non-target) with reduction in short axis to <10 mm. Partial Response (PR): ≥30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Stable Disease: Neither sufficient shrinkage (compared to baseline) to qualify for partial or complete response (CR or PR) nor sufficient increase (taking as reference the smallest sum of diameters at baseline or while on study, whichever is smallest) to qualify for progressive disease (PD). Progressive Disease (PD): At least a 20%increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. | Up to 2 years | 
| Overall Survival (OS) | The length of time from start of treatment that diagnosed patients remain alive. | Up to 5 years | 
| Time to Disease Progression | The length of time from start of treatment until patients first disease recurrence/progression. Per RECIST v1.0: Progressive Disease (PD): At least a 20%increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. | Up to 5 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
NSCLC, lung cancer, chemotherapy, radiation therapy, radiation toxicity