Use of High Dose Radiation Followed by Chemotherapy and Radiation to Treat Locally Advanced NSCLC

This study's primary objective is to assess the efficacy of a treatment regimen involving
Stereotactic Body Radiation Therapy (SBRT) delivered to the primary tumor followed by
concurrent mediastinal chemoradiation by evaluating the proportion of subjects with
locally-advanced non-small cell lung cancer (NSCLC) stage II/III who are alive and
progression free at 12 months, and to compare to relevant historical controls. Additionally,
the treatment regimen will be evaluated based on progression free survival, overall survival,
radiologic clinical complete response rate following completion of therapy, objective
response rate as defined by RECIST v 1.1, local and locoregional control, patterns of
failure, and quality of life. Safety and exploratory objectives will include the rate of
grade 2+ radiation pneumonitis and grade 3+ pulmonary events, while PFS, OS, QOL and
toxicities will be compared between subjects receiving proton or photon mediastinal
radiotherapy. Differential expression of cytokines and chemokines associated with radiation
therapy will be determined.

Inclusion Criteria

Subjects must meet all the following criteria:

- Histologic or cytologic documentation of NSCLC (all histologies allowed)

- Stage II or III disease (AJCC 7th Edition). Stage II disease includes only subjects
with medically inoperable N1 disease otherwise meeting eligibility criteria

- Appropriate stage for protocol entry including no distant metastases based upon the
following minimum diagnostic workup: History and physical examination within 30 days
prior to enrollment. FDG-PET/CT scan for staging within 90 days prior to enrollment.
Chest CT with contrast within 90 days prior to enrollment. MRI scan of the brain
(preferred) or CT scan of the brain within 90 days prior to enrollment. Contrast is
preferred for all neuroimaging. Primary tumor ≤ 7 cm

- Subjects with non-malignant pleural effusion identified on CT scan are eligible
provided the effusion is not known or demonstrated to be an exudative effusion. If a
pleural effusion is present, the following criteria must be met to exclude malignant
involvement: A pleuracentesis is required if pleural fluid is present and visible on
both CT scan and chest x-ray. Pleural fluid cytology must be negative for malignancy.
Effusions that are minimal and too small for pleuracentesis as determined by the
investigator will be eligible for enrollment.

- FEV1 ≥ 1.0 Liter or ≥ 40% predicted with or without bronchodilator within six months
prior to initiation of study treatment. Subjects who meet the criterion without O2,
but who need acute (started within 10 days prior to enrollment) supplemental oxygen
due to tumor-caused obstruction/hypoxia are eligible, provided the amount of the O2
needed has been stable.

- Age ≥18 years.

- ECOG performance status ≤ 2

- Subjects must have normal organ and marrow function as defined: Leukocytes ≥4,000/mcL;
Absolute neutrophil count ≥1,500/mcL; Platelets ≥100,000/mcL; Total bilirubin ≤1.5
times the upper limit of normal; Creatinine clearance ≥25 mL/min/1.73 m2

- Negative serum or urine pregnancy test within 14 days prior to enrollment for women of
childbearing age and potential.The effects of radiation on the developing human fetus
are not well described. For this reason, women of child-bearing potential and
non-sterilized men who are sexually active with a woman of child-bearing potential
must agree to use adequate contraception (hormonal or barrier method of birth control;
abstinence) prior to study entry and for the duration of study treatment. Should a
woman become pregnant or suspect she is pregnant while she or her partner is
participating in this study, she should inform her treating physician immediately.

- Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria

Subjects must not meet any of the following criteria.

- Subjects who have had prior systemic therapy for lung cancer

- Subjects who have had prior radiation to the region of the chest that would result in
overlap of radiation therapy fields and determined by the treating physician to impede
the treatment of the study malignancy.

- Subjects who are actively being treated on any other interventional research study.

- Prior invasive malignancy unless disease free for a minimum of 3 years from
enrollment. However, non-melanoma skin cancer, low risk prostate cancer, well
differentiated thyroid cancers, in situ carcinomas of the breast, oral cavity, cervix,
and other organs, and tumors that are not thought to impact the life expectancy of the
subject according to the treating investigator is permissible.

- Centrally located primary tumor < 2 cm from involved nodal disease which would result
in significant overlap of radiation dose. Centrally located is defined as within or
touching the zone of the proximal bronchial tree, which is a volume 2 cm in all
directions around the proximal bronchial tree (carina, right and left main bronchi,
right and left upper lobe bronchi, intermedius bronchus, right middle lobe bronchus,
lingular bronchus right and left lower lobe bronchi).