Stereotactic Body Radiation Therapy and Chemotherapy in Treating Patients with Stage IIA-IIIA Non-Small Cell Lung Cancer That Cannot Be Removed by Surgery

PRIMARY OBJECTIVE:

I. Determine the maximum tolerated dose of stereotactic body radiation therapy (SBRT) with sequential chemotherapy for locally-advanced non-small cell lung cancer (NSCLC) without mediastinal lymph node involvement by assessing SBRT related acute toxicities >= grade 4, or persistent >= grade 3 radiation pneumonitis, esophagitis, dermatitis and acute chest wall pain. (Cohort A)

SECONDARY OBJECTIVES:

I. Assess >= grade 4 or persistent grade >= 3 late toxicities (>= 3 months post SBRT) including late cough, dyspnea, esophageal strictures, brachial plexopathy, and chest wall pain. (Cohort A)

II. Perform exploratory immunology studies before and after SBRT on the peripheral blood levels of

IIa. T-cells: activation and memory markers, e.g. activated cluster of differentiation (CD)8+ T-cells, activated ICOS-high CD4+ T-cells, and T regulatory (reg) cells (CD4 + FOXP3+).

IIb. Myeloid-derived suppressor cells, e.g. CD14+ human leukocyte antigen (HLA)-DR low.

IIc. Serology assay: to identify cancer-testis antigen-specific antibody response against e.g. NY-ESO-1, LAGE, MAGE1 and MAGE3. (Cohorts A and B)

III. Assess early intratumoral vascular changes to high-dose SBRT as measured by functional magnetic resonance imaging (MRI). (Cohorts A and B)

IV. Assess local progression-free survival, locoregional control, distant-metastasis-free survival and overall survival. (Cohort A)

V. Assess pre-treatment tumor slides for components of the cGAS-STINg signaling pathway to test whether activation of this pathway as well as its negative regulators can be used to predict radiation response. (Cohorts A and B)

VI. Assess patient’s plasma to try to characterize and validate the HART coronary artery disease (CAD) and HART cardiovascular events (CVE) cardiovascular biomarker panels in patients with lung cancer undergoing contemporary thoracic radiation therapy (RT) and evaluate their associations with radiation dose-volume metrics including mean heart dose (MHD), V5, and V30. (Cohorts A and B)

OUTLINE: This is a dose-escalation study of SBRT. Patients are assigned to 1 of 2 cohorts.

COHORT A:

SBRT: Patients undergo SBRT every other day (3-5 fractions total). Patients are then assigned to 1 of 3 chemotherapy regimens.

PEMETREXED + CISPLATIN OR CARBOPLATIN: Beginning 6-8 weeks after SBRT, patients with non-squamous NSCLC receive pemetrexed disodium intravenously (IV) over 10 minutes and cisplatin IV over 1 hour or carboplatin IV over 30 minutes on day 1. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.

GEMCITABINE + CISPLATIN OR CARBOPLATIN: Beginning 6-8 weeks after SBRT, patients with squamous NSCLC receive gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 and cisplatin IV over 1 hour or carboplatin IV over 30 minutes on day 8. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.

PACLITAXEL + CARBOPLATIN: Beginning 6-8 weeks after SBRT, patients with either histology, with a medical contraindication to the assigned regimen of pemetrexed or gemcitabine, receive paclitaxel IV over 3 hours and carboplatin over 30 minutes on day 1. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.

COHORT B: Patients undergo SBRT every other day (=< 8 fractions total).

All patients receive fludeoxyglucose F-18 (FDG) and undergo positron emission tomography/computed tomography (PET/CT) or CT during screening and during follow up. Patients also undergo magnetic resonance imaging (MRI) throughout the trial as well as blood sample collection on the trial and during follow up.

After completion of study treatment, patients are followed up every 3 months for 1 year.