Nivolumab for the Reversal of Squamous Dysplasia in High Risk Current and Former Smokers

This is a single-institution, open-label, single-arm, two-stage, phase II study of the PD-1
inhibitor nivolumab in patients at high risk for lung cancer. Simon's two-stage design will
be used. In the first stage, 18 subjects will be enrolled. If at least 7 subjects respond to
nivolumab, then an additional 24 subjects will be enrolled for a total of 42 subjects. The
central hypothesis to be tested by this trial is that immune evasion contributes to malignant
transformation of premalignant bronchial dysplastic lesions into invasive lung cancers, and
that blocking PD-1 will allow the immune system to target and eradicate premalignant
bronchial dysplastic lesions, thereby preventing the development of lung cancer.

Nivolumab 240 mg IV will be administered every two weeks for a total of four doses (8 weeks).
Participants will undergo bronchoscopy with endobronchial biopsy at study entry, 2 months,
and 6 months. The primary endpoint will be change in bronchial dysplasia between study entry
and the 6 month timepoint. Secondary endpoints include safety and tolerability of nivolumab
in patients with bronchial dysplastic lesions, and additional endobronchial histology
endpoints. Exploratory endpoints will be used to identify predictive markers of response to
nivolumab.

Inclusion Criteria:

In order to be eligible to participate in this study, an individual must meet all of the
following criteria:

1. Provision of signed and dated informed consent form

2. Stated willingness to comply with all study procedures and availability for the
duration of the study

3. Male or female, aged > 18 years

4. A current or ex-smoker with a > 30 pack-year history of smoking and mild or worse
sputum cytologic atypia, (an ex-smoker is defined as no tobacco use in the prior 12
months) OR History of non-small cell lung cancer (stage I, II, or IIIA) with > 10
pack-year history of smoking and no evidence of active disease at least 1 year after
definitive treatment, OR History of head and neck cancer (stage I, II, III, or IVA)
with > 10 pack-year history of smoking and no evidence of active disease at least 1
year after definitive treatment.

5. Endobronchial dysplasia (score > 4) on screening bronchoscopy

6. Total granulocyte count > 1500

7. Platelet count > 100,000

8. Serum creatinine < 1.5 mg/dL

9. Total bilirubin < 2.0 mg/dL

10. Transaminases and alkaline phosphatase < 2.5x upper limit of normal (ULN)

11. Albumin > 2.5 mg/dL

12. ECOG performance status ≤ 1 (Appendix 1)

13. Participants must be able and willing to undergo three bronchoscopies: before, after
four doses of nivolumab (8 weeks), and after 6 months

Exclusion Criteria:

An individual who meets any of the following criteria will be excluded from participation
in this study:

1. Participants may not be currently receiving immune checkpoint inhibitor treatment or
have been treated with immune checkpoint inhibitors in the past (including
anti-programmed cell death receptor [PD]-1, anti-programmed death ligand 1 [PD-L1],
and anti-cytotoxic T-lymphocyte associated protein 4 [CTLA4] monoclonal antibodies)

2. Patients cannot receive any other investigational anti-cancer agents while
participating in the study

3. Participants cannot have used any other investigational agents within the previous six
months

4. History of allergic reactions attributed to compounds of similar chemical or biologic
composition to nivolumab

5. Clinically apparent bleeding diathesis (i.e., bleeding that is spontaneous, excessive,
or delayed in onset following tissue injury results from a localized pathologic
process or a disorder of the hemostatic process, involving a complex interplay among
vascular integrity, platelet number and function, coagulation factors, and
fibrinolysis)

6. Cardiac dysrhythmia that is potentially life-threatening, such as ventricular
tachycardia, multifocal premature ventricular contractions or supraventricular
tachycardias with a rapid ventricular response. Well-controlled atrial fibrillation or
rare (< 2 minute) premature ventricular contractions are not exclusionary

7. History of coronary artery disease, including myocardial infarction, congestive heart
failure (LV ejection fraction <50% or clinically significant diastolic dysfunction),
or any serious medical condition which would preclude a patient from undergoing a
bronchoscopy or would jeopardize the goals of the study

8. Individuals who are HIV-positive will be considered on a case-by-case basis, but will
be required to meet criteria related to patient safety and data integrity, as assessed
by the study investigators

9. History of hepatitis B or hepatitis C infection that is untreated and/or with a
detectable viral load

10. Hypoxemia (less than 90% saturation with supplemental oxygen)

11. Severe obstructive lung disease (GOLD Stage III or IV, FEV1<30% predicted)

12. Prior chemotherapy or thoracic radiation within the past 1 year

13. Participants with findings on CT chest suspicious for lung cancer (Lung-RADS category
4) will not be allowed to enroll until they have undergone additional evaluation for
malignancy and an alternative (i.e., non-malignant) diagnosis has been established

14. Current malignancy, with the exception of non-melanoma (i.e., basal cell or squamous
cell) skin cancer. Patients with lung carcinoma in situ found during the study biopsy
are also excluded.

15. History of a malignancy except for adequately treated non-melanoma (i.e., basal cell
or squamous cell) skin cancer or in situ cervical cancer for which the subject has not
been disease-free for 5 years. Patients with a history of non-small cell lung cancer
(stage I, II, or IIIA) or head and neck cancer (stage I, II, III, or IVA) must have no
evidence of active disease at least 1 year after definitive treatment.

16. History of stage IIIA NSCLC for which the only treatment was chemoradiation without
surgery

17. Known or suspected autoimmune disease; subjects with type I diabetes mellitus,
hypothyroidism requiring hormone replacement, or skin disorders not requiring systemic
treatment are permitted to enroll

18. Conditions requiring systemic corticosteroids equivalent to > 10 mg prednisone per day
or other immunosuppressive medications within 2 weeks of enrollment

19. Known interstitial lung disease that is symptomatic or may interfere with the
detection or management of suspected drug-related pulmonary toxicity

20. History of interstitial pneumonitis requiring treatment with systemic corticosteroids
or other immunosuppressive agents (e.g., mycophenolate, azathioprine)

21. Life expectancy of < 1 year

22. Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy
test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 4 weeks prior to
the start of nivolumab

23. Women must not be breastfeeding

24. Inability to give informed consent

25. Pneumonia or acute bronchitis for at least 2 weeks prior to enrollment