Clinical Trials Comparing Immunotherapy Plus Stereotactic Ablative Radiotherapy (I-SABR) Versus SABR Alone for Stage I, Selected Stage IIa or Isolated Lung Parenchymal Recurrent Non-Small Cell Lung Cancer: I-SABR

Study Groups:

If you are found to be eligible to take part in this study, you will be randomly assigned (as
in the flip of a coin) to receive either SABR alone (Group 1) or SABR and nivolumab (Group
2). This is done because no one knows if one study group is better, the same, or worse than
the other group.

You will have an equal chance (50/50) of being assigned to either group. Both you and the
doctor will know which treatment you are receiving.

Study Drug Administration:

You will receive SABR as part of your standard care. The study doctor will discuss with you
how SABR will be administered and how often you will receive it.

If you are in Group 2, you will also receive nivolumab by vein over about 30 minutes within
36 hours before or after your SABR treatment and then every 4 weeks after that for a total of
4 doses (about 3 months).

Length of Study Participation:

You will receive SABR over about 1-2 weeks. If you are in Group 2, you may receive nivolumab
for up to 4 doses. You will no longer be able to take the study drug if the disease gets
worse, if intolerable side effects occur, or if you are unable to follow study directions.

Your participation in this study will be over after you have completed follow up.

Follow-Up:

After you complete SABR therapy, you will be followed every 3 months for 2 years, then every
6 months for up to 3 years, and then 1 time every year after that. At each follow-up visit:

- You will have a physical exam.

- You will have a CT scan.

- At Month 9, you may have a PET-CT scan. The doctor will tell you if you will have this
scan.

- At Month 12 you will have a lung function test and EKG.

Inclusion Criteria:

1. Histological confirmation of NSCLC by either biopsy or cytology will be is required
for the primary diagnosis and is recommended for recurrent disease. The following
primary cancer types are eligible: squamous cell carcinoma, adenocarcinoma (with or
without bronchioloalveolar carcinoma features), large cell carcinoma (with or without
neuroendocrine features), neuroendocrine carcinoma (either NSCLC with neuroendocrine
features or atypical carcinoids, but not small cell lung carcinoma),
bronchioloalveolar cell carcinoma, or non-small cell carcinoma not otherwise
specified.

2. Stage I or selected stage IIa according to the 7th version of the IASLC system: stage
I (T1 or T2a [tumor size 5 cm but N0M0).

3. Patients with multiple primary lung tumors (defined below) are eligible: a)
synchronous tumors (diagnosed within 6 months [mo]), *different histology, *same
histology, *second tumor in different lobed or lung; b) metachronous tumors (diagnosed
>6 mo apart), *different histology, *same histology, **second tumor in different lobe
or lung, **tumor-free interval of at least 4 years (y).

4. Patients with isolated lung parenchymal recurrent/persistent NSCLC (histology as
defined in eligibility criterion 1) after prior definitive surgery or
radiotherapy/chemotherapy, when the lesion or lesions are suitable for SABR, are also
eligible. Patients with a single metastatic focus in the lung parenchyma with no other
lesions are also eligible, because this presentation is challenging to distinguish
from recurrent disease. Recurrent disease can be in the same lobe or a different lobe
but should not invade critical structures (esophagus, brachial plexus, major vessels,
heart, spinal cord); should not involve any lymph node; and should not include any
other suspicious lesions in the lung or any other locations. Any prior therapy
(surgery, radiotherapy, or systemic) must have been completed at least 12 weeks before
administration of the study drug.

5. cont'd from inclusion #4: Tumors should be (CT) imaging in the lung window setting) with N0M0; positron emission tomography (PET)
imaging is required for restaging (per eligibility criterion 5 below) and any lymph
node suspected of harboring tumor should be confirmed by biopsy (per eligibility
criterion 6 below).

6. A PET/CT scan is required within 12 weeks (plus/minus 1 week) of study registration.
Any lymph node suspected of harboring disease based on its shape, size, or PET SUV
should be discussed by treating physician and diagnostic radiologist.

7. Patients with medically inoperable stage I disease (T1 or T2a [tumor size N0M0) or selected stage IIa disease (T2 [tumor size >5 cm but poor lung function or other significant cardiovascular or other comorbidity such as
diabetes are eligible. Patients with operable disease who choose to have SABR are also
eligible. The standard justification for medical inoperability is based on pulmonary
function and can include any of the following: baseline FEV1 <50% of predicted value;
diffusion capacity <50% of predicted value; baseline hypoxemia or hypercapnia;
exercise oxygen consumption <50% of predicted value; severe pulmonary hypertension;
severe cerebral, cardiac, or peripheral vascular disease; and severe chronic heart
disease.

8. Patients must be >/= 18 years of age.

9. Patients must have a Zubrod performance status score of 0-2 (2 is included here
because such patients are typically >70 years old and cannot tolerate surgery).

10. The following mandatory staging studies must be done within 12 weeks before study
registration: *PET/CT scans of both lungs, the mediastinum, adrenal glands and rest of
the body; primary tumor dimension will be measured on diagnostic CT and again on
simulation CT using the lung window setting. *Mediastinoscopy or endobronchial
ultrasound -guided biopsy of the mediastinal lymph nodes is recommended and required
for any patients with PET/CT or CT findings suggesting lymph node involvement. *Brain
MRI or CT scan if symptoms or signs suggest brain metastases. *Invasive mediastinal
staging: For all patients with CT or PET evidence of hilar involvement (level 10) or
with mediastinal lymph nodes >1.0 cm in the shortest diameter or clinically suspicious
by treating physician and/or radiologist, disease must be staged by cervical
mediastinoscopy, esophageal endoscopic ultrasound-guided biopsy, or endobronchial
ultrasound-guided biopsy.

11. For patients with left-sided tumors and enlarged nodes (>1.0 cm in the shortest
diameter) on the aortopulmonary window setting, the aortopulmonary nodes must be
biopsied by extended mediastinoscopy, Chamberlain procedure, video-assisted
thoracoscopic surgery (VATS) approach, or ultrasound-guided biopsy to ensure that the
patient does not have N2 disease. At the time of cervical mediastinoscopy, esophageal
endoscopic ultrasound-guided biopsy, or endobronchial ultrasound-guided biopsy, the
following nodal stations must be examined and biopsied, if present: *ipsilateral nodal
station 4 *contralateral nodal station level 4, and *subcarinal nodes (level 7). For
left-sided tumors, any lymph node in the superior or anterior mediastinum >1.0 cm in
the shortest axis on CT or positive on PET must be identified and biopsied.
Eligibility requires that any PET-positive mediastinal or distant sites must be
biopsy-negative.

12. However, if the treating physician and diagnostic radiologist strongly suspect PET
positivity, the patient should not be enrolled even if the biopsy is negative (to
exclude patients with false-negative biopsy).

13. All patients must sign a study-specific consent form

14. All patients (men & women) of childbearing potential should use a method of birth
control that is effective for them throughout their participation in this study. Women
of childbearing potential should use an adequate contraceptive method to avoid
pregnancy for 5 months (30 days plus the time required for nivolumab to undergo five
half-lives) after the last dose of investigational drug; must have a negative serum or
urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human
chorionic gonadotropin [HCG]) within 24 hours before the start of nivolumab; and must
not be breastfeeding. Men who are sexually active with women of childbearing potential
must use a contraceptive method with a failure rate of less than 1% per year; men
receiving nivolumab will be instructed to use contraception for 7 months after the
last dose of nivolumab. Women who are not of childbearing potential (i.e are
postmenopausal or surgically sterile) & azoospermic men do not require contraception.

15. All patients must have adequate organ function as defined below. All screening lab
tests should be done within 30 days before study registration. WBC >=2000/uL; Neuts
>=1500/uL; PLT >=100x10^3/uL; HGB >9.0g/dL; Serum creatinine <=2xULN or creatinine
clearance (calculated with the Cockcroft-Gault formula below) >=30 mL/min: Men:
([l40-age in years] x weight in kg) / (72 x serum creatinine in mg/dL) Women:
([l40-age in years] x weight in kg) / (72 x serum creatinine in mg/dL) x 0.85; AST/ALT
<=3xULN; Bili T <=1.5xULN (although patients with Gilbert syndrome can have total
bilirubin <3.0 mg/dL)

16. All patients must sign a study-specific consent form.

17. All patients (men & women) of childbearing potential should use method of birth
control that is effective for them throughout their participation in this study. Women
of childbearing potential should use an adequate contraceptive method to avoid
pregnancy for 5 months (30 days plus the time required for nivolumab to undergo five
half-lives) after last dose of investigational drug; must have a negative serum or
urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human
chorionic gonadotropin [HCG]) within 24 hours before the start of nivolumab; and must
not be breastfeeding. Men who are sexually active with women of childbearing potential
must use a contraceptive method with a failure rate of less than 1% per year; men
receiving nivolumab will be instructed to use contraception for 7 months after the
last dose of nivolumab. Women who are not of childbearing potential (i.e., are
postmenopausal or surgically sterile) and azoospermic men do not require
contraception.

18. All patients must have adequate organ function as defined below. All screening lab
tests should be done within 30 days before study registration. *WBC >/= 2000/uL; *
Neutrophils >/= 1500/uL; *Platelets >/= 100 x10^3/uL; *Hemoglobin > 9.0 g/dL; *Serum
creatinine formula below) >/= 40 mL/min: Men ([140 - age in years] x weight in kg)/ (72 x serum
creatinine in mg/dL) *Women: ([140 - age in years] x weight in kg) / (72 x serum
creatinine in mg/dL) x 0.85 *AST/ALT (although patients with Gilbert syndrome can have total bilirubin <3.0 mg/dL)

Exclusion Criteria:

1. Patients with tumors >7 cm or tumors involving the main bronchus or associated vessels
or tumors that invade any critical structures (such as esophagus, brachial plexus,
heart, mediastinal major vessels) are not suitable for SABR.

2. Patients with direct evidence of regional or distant metastases after appropriate
staging studies, or with synchronous non-lung primary or prior non-lung malignancy
(other than nonmelanomatous skin cancer or in situ cancer) diagnosed within the past 3
years are not eligible. Patients with a history of curable non-lung cancer up to 3
years before registration and have been cancer-free for 2 years are eligible.

3. Patients who have received previous immunotherapy with PD1 or CTLA4 antibodies are not
eligible.

4. Patients with plans to receive other concomitant local therapy (including standard
fractionated radiotherapy and surgery) or other systemic therapy (including
chemotherapy, target therapy and other type of immunotherapy or investigative agents)
while on this protocol, except at disease progression, are not eligible.

5. Female patients who are pregnant or lactating are not eligible (because treatment
involves unforeseeable risks to the embryo or fetus).

6. Patients for whom SABR plans cannot meet the minimum requirement of target coverage
and dose-volume constraints of critical structures (see SABR treatment planning
section) are not eligible.

7. Patients who have active, known, or suspected autoimmune disease are not eligible.
However, patients with vitiligo, type I diabetes mellitus, residual hypothyroidism due
to an autoimmune condition that requires only hormone replacement, psoriasis not
requiring systemic treatment, or conditions not expected to recur in the absence of an
external trigger are permitted to enroll.

8. Patients with a known history of antibodies to human immunodeficiency virus (HIV) -1
or -2 are not eligible. Patients with live vaccines.

9. Patients with a known positive test for hepatitis B virus surface antigen (HBV sAg) or
hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic
infection are not eligible.

10. Patients who have a condition requiring systemic treatment with corticosteroids (>10
mg daily prednisone equivalents) or other immunosuppressive medications within 14 days
of study drug administration are not eligible. However, inhaled or topical steroids,
adrenal replacement doses, and >10 mg daily prednisone equivalents are permitted in
the absence of active autoimmune disease.

11. Patients with allergies or adverse drug reactions to the following are not eligible:
*History of allergy to study drug components; *History of severe hypersensitivity
reaction to any monoclonal antibody.

12. Patients who have had prior treatment with an anti-PD1, anti-PDL1, anti-PDL2,
anti-CTLA4 antibody, or any other antibody or drug specifically targeting T-cell
costimulation or immune checkpoint pathways are not eligible.

13. Patients are known to have contraindications to radiotherapy.