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.

Inclusion Criteria:

For inclusion in the study subjects must fulfill all of the following criteria:

1. Written informed consent obtained from the patient/legal representative prior to
performing any protocol-related procedures, including screening evaluation.

2. Newly diagnosed, untreated, biopsy proven non-small cell lung cancer.

3. Medically inoperable or patient refusal to surgery as defined by any single of the
following criteria: a. Determined unfit for surgery by thoracic surgeon or radiation
oncologist as documented in the medical record b. Pulmonary function test (PFTS)
showing Forced Expiratory Volume in the first second (FEV1) ≤ 1.2 L or diffusing Lung
Capacity (DLC) <60%, c. Poor exercise tolerance or failed pre-operative cardiac
work-up, d. Patient refusal to undergo definitive surgery as documented in clinical
note by a surgeon, pulmonologist, medical oncologist, or radiation oncologist.

4. Clinically stage I disease by American Joint Committee on Cancer (AJCC) 7th edition.
(N0, M0, T stages T1-T2a) or patients with stage T2bN0M0 (clinical stage IIA) disease
who are medically unfit for standard of care chemotherapy as documented by a medical
oncologist or radiation oncologist, or who refuse standard of care chemotherapy as
documented by a medical oncologist or radiation oncologist.

5. Age > 18 years at time of study entry.

6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 - 1.

7. Adequate normal organ and marrow function as defined below:

- Haemoglobin ≥ 9.0 g/dL.

- Absolute neutrophil count (ANC) ≥ 1.5 x 109/L (> 1500 per mm3).

- Platelet count ≥ 100 x 109/L (>100,000 per mm3).

- Serum bilirubin ≤ 1.5 x institutional upper limit of normal (ULN). < not apply to subjects with confirmed Gilbert's syndrome (persistent or recurrent
hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis
or hepatic pathology), who will be allowed only in consultation with their
physician.>>

- aspartate aminotransferase (AST) serum glutamic oxaloacetic transaminase (SGOT)/
alanine aminotransferase (ALT) serum glutamic pyruvic transaminase (SGPT) ≤ 2.5 x
institutional upper limit of normal unless liver metastases are present, in which
case it must be ≤ 5x ULN.

- Serum creatinine creatinine clearance (CL) >40 mL/min by the Cockcroft-Gault
formula (Cockcroft and

Gault 1976) or by 24-hour urine collection for determination of creatinine clearance:

Males:

Creatinine CL (mL/min)

= Weight (kg) x (140 - Age) . 72 x serum creatinine (mg/dL)

Females:

Creatinine CL (mL/min)

= Weight (kg) x (140 - Age) x 0.85 72 x serum creatinine (mg/dL)

8. Female subjects must either be of non-reproductive potential (i.e. post-menopausal by
history: ≥60 years old and no menses for ≥1 year without an alternative medical cause;
OR history of hysterectomy, OR history of bilateral tubal ligation, OR history of
bilateral oophorectomy) or must have a negative serum pregnancy test upon study entry.

9. Subject is willing and able to comply with the protocol for the duration of the study
including undergoing treatment and scheduled visits and examinations including follow
up.

Exclusion Criteria:

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. -