iSABRT: This phase I/II trial is evaluating the benefits of using a targeted therapy (Durvalumab) in combination with Stereotactic Ablative Body Radiotherapy (SABR) to treat inoperable early-stage non-small-cell lung cancerRandomized Phase I/II Study of Ablative Radiotherapy +/- MEDI 4736 (Durvalumab) for Medically Inoperable Early-Stage Non-Small Cell Lung Cancer

Exclusion

1. ECOG Performance status >1.
2. Patients with metastatic or node positive NSCLC.
3. Patients with prior radiation therapy to the same bronchopulmonary segment.

4. History of automimmune disease including myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematous, rheumatoid arthritis, inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis), vascular thrombosis associated with antiphospholipid syndrome, Wegner's granulomatosis, Sjogren's syndrome, Guillain-Barre syndrome, multiple sclerosis, or glomerulonephritis.

   a. However, patients with type 1 diabetes mellitus, vitiligo, alopecia, hypothyroidism requiring hormone replacement, Graves disease, or skin disorders not requiring systemic treatment are permitted to enroll.

5. Patients with history of idiopathic pulmonary fibrosis, idiopathic pneumonitis, drug induced pneumonitis, or evidence of active pneumonitis on screening chest CT scan.
6. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).
7. Participation in another clinical study with an investigational product during the last 6 months.
8. Any previous treatment with a Programmed Death-1 (PD1) or Programmed Death-Ligand 1(PD-L1) inhibitor, including durvalumab, and therapeutic anticancer vaccine.

9. History of another primary malignancy except for:

   1. Malignancy treated with curative intent and with no known active disease ≥5 years before the first dose of study drug and of low potential risk for recurrence.
   2. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease.
   3. Adequately treated carcinoma in situ without evidence of disease e.g., cervical cancer in situ.
10. Mean QT interval corrected for heart rate (QTc) ≥470 ms calculated from 3 electrocardiograms (ECGs) using Frediricia's Correction.
11. Current or prior use of immunosuppressive medication within 28 days before the first dose of durvalumab, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid.
12. Any unresolved ≥ Grade 2 pulmonary toxicity from previous anti-cancer therapy.
13. Any prior Grade ≥3 immune-related adverse event (irAE) while receiving any previous immunotherapy agent, or any unresolved irAE >Grade 1.
14. History of primary immunodeficiency.
15. History of allogeneic organ transplant.
16. History of hypersensitivity to durvalumab or any excipient.
17. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, active bleeding diatheses including any subject known to have evidence of acute or chronic hepatitis B, hepatitis C or human immunodeficiency virus (HIV), or psychiatric illness/social situations that would limit compliance with study requirements or compromise the ability of the subject to give written informed consent.
18. Known history of previous clinical diagnosis of tuberculosis.
19. History of leptomeningeal carcinomatosis.
20. Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 days of receiving durvalumab.
21. Female subjects who are pregnant, breast-feeding or male or female patients of reproductive potential who are not employing an effective method of birth control.
22. Any condition that, in the opinion of the investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study results.
23. Subjects with uncontrolled seizures.