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

This study uses durvalumab (MEDI 4736), an experimental type of drug made by Astra Zeneca Pharmaceuticals, (limited partnership) LP, which in early studies has shown to possibly reduce the growth of certain types of lung cancer. The Investigators will enroll up to 105 subjects into the study. After an initial safety sample of 15 individuals receiving durvalumab (MEDI 4736) and Stereotactic Ablative Body Radiotherapy (SABR), if it is shown to be safe to administer this combination of therapies, the next enrolled subjects will be randomized in a 1:1 fashion (each subject with a "50-50 chance" like the flip of a coin) to receive either SABR and durvalumab (MEDI 4736), or SABR alone. Once treatment is completed, all subjects will return to the University of California at Los Angeles (UCLA) for regular follow-up visits to check on their health and outcomes. At visits both prior to and after treatment special blood samples will be drawn to be studied by UCLA scientists to look into the basic science aspects of how durvalumab (MEDI 4736) and radiation work in the body. It is hoped that we will learn more about the basic safety and science of durvalumab (MEDI 4736) combined with Stereotactic Ablative Body Radiotherapy (SABR) vs. SABR alone, while extending the life and quality of life of these subjects.

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.