Astra Zeneca (Immuno Stereotactic Ablative Body Radiotherapy) ISABR Study: Randomized Phase I/II Study of Stereotactic Body Radiotherapy

This is a single center, prospective, randomized phase II study with a phase I safety lead in. Patients in this study will undergo radiation therapy alone or in combination with durvalumab (MEDI 4736). Patients eligible for treatment must be diagnosed with node negative, non-metastatic, biopsy- proven early-stage NSCLC and be ineligible for surgical resection or refuse surgical resection. Enrollment will begin with a phase I lead in evaluating radiation therapy with durvalumab (MEDI 4736). (Regimen A) to ensure general safety of this combination and specifically relating to pulmonary toxicity (pneumonitis), cardiac toxicity (pericarditis) and gastrointestinal toxicity (esophagitis, gastritis, enterocolitis). Following initial demonstration of safety, enrollment to the phase II component with 1:1 randomization to radiation therapy and durvalumab (MEDI 4736), (Regimen A) or radiation therapy alone (Regimen B) will be performed with stratification only based on T-stage (Tumor) (T1 versus T2). A total of 90 patients will be randomized in the phase II component. Regimen A: Durvalumab (MEDI 4736), at 1500 mg via IV infusion will be delivered on day -5 of therapy. Radiation therapy will start on Day 0 ±5 from the first infusion of durvalumab (MEDI 4736) and patients will receive 3, 4, or 10 fractions of radiation therapy to a total dose of 54 Grays (Gy), 50Gy, or 65Gy, respectively. Starting on day 23 (28 days post first durvalumab (MEDI 4736), infusion), durvalumab (MEDI 4736), 1500mg IV q4weeks will be delivered for up to 4 additional cycles or until progression, toxicity or withdrawal from study. Regimen B: Patients will receive radiation therapy alone of 3, 4, or 10 fractions to a total dose of 54Gy, 50Gy, or 65Gy, respectively. Regimen B patients will not receive durvalumab (MEDI 4736) and will only receive radiation therapy. Safety review will continue to occur on an ongoing basis. Should the rates of grade 3 treatment-related pulmonary toxicity (defined as pneumonitis), cardiac toxicity (defined as pericarditis) or gastrointestinal toxicity (defined as esophagitis, gastritis or enter colitis) be observed at a frequency greater than 15%, accrual will be halted and study will be re-evaluated. Should any patient have ≥ grade 4 treatment-related adverse effects, accrual will be halted and study will be re-evaluated Follow-up Routine surveillance computerized axial tomography (CT) imaging of the chest, abdomen, and pelvis will be performed starting at 12 weeks after completion of radiation in both treatment groups to allow for primary endpoint assessment. Routine CT imaging surveillance will continue per standard of care. Patients will also be followed clinically with history and physical examinations, vitals signs, and laboratory examinations as indicated.