PD-1 Immune Checkpoint Inhibition for the Reversal of Squamous Dysplasia in High Risk Current and Former Smokers With or Without a History of Lung Cancer
Phase: PHASE2
Conditions: Bronchial Dysplasia, Tobacco Smoking, History of Non-Small Cell Lung Cancer, History of Head and Neck Cancer
Sponsor: University of Colorado, Denver

  
PD-1 Immune Checkpoint Inhibition for the Reversal of Squamous 
Dysplasia in High Risk Current and Former Smokers with or without a 
History of Lung Cancer 
COMIRB Protocol Number: 17-1492 
National Clinical Trial (NCT) Identified Number:  03347838 
Principal Investigators: Robert Keith, M.D. 
Funded by: Bristol-Myers Squibb (BMS) 
BMS Protocol Number: CA209-890 
Version Date: November 19, 2021 
 
 
 
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Table of Contents 
1 
PROTOCOL SUMMARY ............................................................................................................................... 1 
1.1 
Synopsis ................................................................................................................................................ 1 
1.2 
Schema ................................................................................................................................................. 4 
2 
INTRODUCTION ............................................................................................................................................ 5 
2.1 
Study Rationale .................................................................................................................................... 5 
2.2 
Background........................................................................................................................................... 5 
2.2.1 
Rationale for Lung Cancer Prevention Studies ........................................................... 5 
2.2.2 
Prior Lung Cancer Chemoprevention Studies ............................................................. 5 
2.2.3 
Lung Cancer Risk Assessment and Patient Selection ............................................... 6 
2.2.4 
The Role of Nivolumab in the Treatment of Lung Cancer ......................................... 7 
2.2.5 
Rationale for Using Nivolumab to Prevent Lung Cancer............................................ 9 
2.3 
Risk/Benefit Assessment .................................................................................................................... 9 
2.3.1 
Known Potential Risks ..................................................................................................... 9 
2.3.2 
Known Potential Benefits .............................................................................................. 12 
2.3.3 
Overall Risk/Benefit Assessment................................................................................. 13 
3 
OBJECTIVES AND ENDPOINTS .............................................................................................................. 14 
3.1 
Objectives ........................................................................................................................................... 14 
3.1.1 
Primary Objective ........................................................................................................... 14 
3.1.2 
Secondary Objective ..................................................................................................... 14 
3.1.3 
Exploratory Objectives .................................................................................................. 14 
3.2 
Endpoints ............................................................................................................................................ 14 
3.2.1 
Primary Endpoint: Improvement in Endobronchial Histology .................................. 14 
3.2.2 
Secondary Endpoints .................................................................................................... 15 
3.2.3 
Exploratory Endpoints ................................................................................................... 16 
4 
STUDY DESIGN ........................................................................................................................................... 20 
4.1 
Overall Design .................................................................................................................................... 20 
4.2 
Scientific Rationale for Study Design.............................................................................................. 20 
4.3 
Justification for Dose ......................................................................................................................... 21 
4.4 
End of Study Definition ..................................................................................................................... 21 
5 
STUDY POPULATION ................................................................................................................................ 21 
5.1 
Inclusion Criteria ................................................................................................................................ 21 
5.2 
Exclusion Criteria ............................................................................................................................... 22 
5.3 
Reproductive Status .......................................................................................................................... 23 
5.4 
Recruitment Plan ............................................................................................................................... 24 
6 
STUDY INTERVENTION ............................................................................................................................ 25 
6.1 
Study Intervention(s) Administration ............................................................................................... 25 
6.1.1 
Study Intervention Description ..................................................................................... 25 
6.1.2 
Dosing and Administration ............................................................................................ 25 
6.2 
Preparation/Handling/Storage/Accountability ................................................................................ 26 
6.2.1 
Acquisition and accountability ...................................................................................... 26 
6.2.2 
Formulation, Appearance, Packaging, and Labeling ................................................ 26 
6.2.3 
Product Storage and Stability ....................................................................................... 27 
6.2.4 
Preparation ...................................................................................................................... 27 
6.2.5 
Destruction of Study Drug ............................................................................................. 27 

  
6.2.6 
Return of Study Drug ..................................................................................................... 28 
6.3 
Measures to Minimize Bias: Randomization and Blinding ........................................................... 28 
6.4 
Study Intervention Compliance ........................................................................................................ 28 
6.5 
Concomitant Therapy ........................................................................................................................ 28 
6.5.1 
Prohibited and/or Restricted Treatments .................................................................... 29 
6.5.2 
Other Restrictions and Precautions ............................................................................. 29 
6.5.3 
Permitted Therapy ......................................................................................................... 29 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL .................................................................................................................... 29 
7.1 
Delay or Discontinuation of Study Intervention ............................................................................. 29 
7.1.1 
Dose Delay Criteria ........................................................................................................ 29 
7.1.2 
Dose Reductions ............................................................................................................ 30 
7.1.3 
Criteria to Resume Treatment with Nivolumab .......................................................... 30 
7.1.4 
Discontinuation Criteria ................................................................................................. 31 
7.1.5 
Adverse Event Management Algorithms .................................................................... 32 
7.1.6 
Treatment of Nivolumab Related Infusion Reactions ............................................... 32 
7.1.7 
Stopping Rules for Toxicity ........................................................................................... 33 
7.2 
Participant Discontinuation/Withdrawal from the Study ............................................................... 33 
7.3 
Lost to Follow-Up ............................................................................................................................... 33 
8 
STUDY ASSESSMENTS AND PROCEDURES ..................................................................................... 35 
8.1 
Schedule of Activities (SoA) ............................................................................................................. 35 
8.2 
Efficacy Assessments ....................................................................................................................... 36 
8.3 
Safety Assessments .......................................................................................................................... 37 
8.4 
Exploratory Assessments ................................................................................................................. 38 
8.5 
Adverse Events and Serious Adverse Events ............................................................................... 40 
8.5.1 
Adverse Events (AE) ..................................................................................................... 40 
8.5.2 
Classification of an Adverse Event .............................................................................. 40 
8.5.3 
Serious Adverse Events (SAE) .................................................................................... 41 
8.5.4 
NON-serious Adverse Events ...................................................................................... 43 
8.5.5 
Laboratory Test Abnormalities ..................................................................................... 43 
8.5.6 
Potential Drug Induced Liver Injury (DILI) .................................................................. 43 
8.5.7 
Pregnancy ....................................................................................................................... 44 
8.5.8 
Overdose ......................................................................................................................... 44 
8.5.9 
Other Safety Considerations ........................................................................................ 44 
9 
STATISTICAL CONSIDERATIONS .......................................................................................................... 45 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .............................. 46 
10.1 
Ethical Considerations ...................................................................................................................... 46 
10.1.1 
Good Clinical Practice ................................................................................................... 46 
10.1.2 
Institutional Review Board/Independent Ethics Committee ..................................... 46 
10.1.3 
Informed Consent ........................................................................................................... 46 
10.2 
Study Management ........................................................................................................................... 48 
10.2.1 
Compliance ..................................................................................................................... 48 
10.2.2 
Records 50 
10.2.3 
Publications ..................................................................................................................... 51 
11 
ABBREVIATIONS ........................................................................................................................................ 51 
12 
REFERENCES ............................................................................................................................................. 54 
13 
APPENDICES ............................................................................................................................................... 58 
13.1 
Appendix 1 – ECOG Performance Status ...................................................................................... 58 

  
13.2 
Appendix 2 – Adverse Event Management Algorithms................................................................ 59 
13.3 
Appendix 3 – Bronchoscopy Patient Communication Log .......................................................... 67 
13.4 
Appendix 4 – Sputum Collection Patient Instruction Sheet ......................................................... 68 
13.5 
Appendix 5 – Nivolumab Follow-up Script ..................................................................................... 69 
 

PD-1 Immune Checkpoint Inhibition for the Prevention of Lung Cancer in High Risk Current and Former Smokers  
Protocol COMIRB#17-1492 
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1 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS  
Title: 
PD-1 Immune Checkpoint Inhibition for the Reversal of Squamous 
Dysplasia in High Risk Current and Former Smokers with or without a 
History of Lung Cancer 
Study Description: 
The goal of this clinical research study is to determine whether the PD-1 
inhibitor nivolumab improves premalignant bronchial dysplastic lesions in 
subjects that are at high risk for the development of lung cancer, including 
those with a prior smoking history, or history of lung cancer or head and 
neck cancer. The safety and tolerability of nivolumab will also be studied.  
Objectives: 
 
Primary Objective: 
To determine whether immune checkpoint blockade using nivolumab can 
reverse premalignant histological changes in the bronchial epithelium of 
subjects at high risk for developing lung cancer as defined by moderate or 
worse bronchial dysplasia; and either 30 pack-years of tobacco exposure, 
or history of early-stage lung or early-stage head and neck cancer at least 
one year after definitive treatment.  
 
Secondary Objective: 
To assess the safety and tolerability of nivolumab in patients with 
bronchial dysplastic lesions. 

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Endpoints: 
Primary Endpoint: 
The primary endpoint is the dichotomous endpoint of whether a subject 
responds to immune checkpoint blockade using nivolumab. Response to 
treatment will be based on the 6-month change (difference between 6-
month score and baseline score) in worst (i.e., maximum) histologic 
classification score, using the 2004 World Health Organization (WHO) 
classification scale for endobronchial dysplasia.  
 
Secondary Endpoints: 
1. Safety and tolerability of nivolumab in patients with bronchial 
dysplastic lesions. 
2. Additional endobronchial histology endpoints 
a. 2-month change (difference between 2-month score and 
baseline score) in worst (i.e., maximum) histologic 
classification score 
b. Using all dysplastic (i.e., histology score ≥ 4.0) baseline 
biopsy pairs, the change in average histology and dysplasia 
index 
c. Using all matched biopsies, the change in worst histology, 
average histology, and dysplasia index 
d. Using all matched biopsies from reference sites, the 
change in worst histology, average histology, and dysplasia 
index 
e. Response to treatment of completers, based on worst 
histology 
 
Exploratory Endpoints: 
An important aspect of this trial is to identify novel prognostic and 
predictive markers present at the time of diagnosis. As such, radiologic 
data and blood will also be collected throughout the study period. The 
markers to be assessed will be determined according to the best scientific 
knowledge and technology available. Correlative studies will be 
interpreted as hypothesis-generating data, to be validated in subsequent 
trials. Candidate markers to be evaluated include: 
1. Expression levels of programmed death receptor 1 (PD-1) on T 
lymphocytes associated with bronchial dysplastic lesions at 
baseline and following treatment with nivolumab. 
2. Expression levels of programmed death ligand 1 (PD-L1) on 
macrophages and epithelial cells associated with bronchial 
dysplastic lesions at baseline and following treatment with 
nivolumab. 
3. Characterization of inflammatory infiltrates (i.e., T lymphocyte and 
macrophage subsets) in bronchial dysplastic lesions at baseline 
and following treatment with nivolumab. 
4. Total mutational burden of bronchial dysplastic lesions as 
measured by whole exome sequencing 

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5. Changes in systemic inflammatory signatures at baseline and 
during treatment with nivolumab as measured by mass cytometry 
(CyTOF) 
Study Population: 
Sample size: This study will use a Simon 2-stage design. The null 
hypothesis that the true response rate is 0.30 will be tested against a 1-
sided alternative. In the first stage, 18 subjects will be enrolled. If there are 
6 or fewer responses in these 18 subjects, the study will be stopped. 
Otherwise, 24 additional subjects will be enrolled for a total of 42 
evaluable subjects. If 17 or fewer subjects are responders at the end of the 
trial, no further investigation of the drug is warranted. The null hypothesis 
will be rejected if 18 or more responses are observed in the 42 total 
subjects. This design has 80.2% power to reject the null hypothesis when 
the true response rate is 0.50, controlling the type I error rate at 0.05 
(actual  = 0.044).  Up to 240 subjects may be consented to the pre-
screening portion of this study.  We plan to enroll up to 60 participants in 
the main/treatment potion of this study for a total of 42 evaluable 
subjects. 
 
Gender: Male and female 
 
Age: Adults ≥ 18 years of age 
 
Demographic group: Subjects at high risk for developing lung cancer as 
defined by endobronchial dysplasia; and either 30 pack years of tobacco 
exposure and sputum cytologic atypia, or history of early-stage lung or 
head and neck cancer at least one year after definitive treatment. 
 
General health status: ECOG 0-1 
 
Geographic location: United States 
Phase: 
2 
Description of 
Sites/Facilities Enrolling 
Participants: 
Academic medical center 
Description of Study 
Intervention: 
Nivolumab 240 mg IV every 2 weeks for 4 doses 
Study Duration: 
5 years 
Participant Duration: 
1 year 
 
 

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1.2 
SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Recruitment 
High risk current or former smokers (≥ 30 pack years) with mild or worse 
sputum cytologic atypia or known bronchial dysplasia 
OR 
History of lung cancer (stage I, II, or IIIA) or head and neck cancer (stage I, 
II, III, or IVA) 
f
d f
Nivolumab 240 mg IV every 2 weeks for 4 
doses 
Total evaluable subjects: 42 
Screening bronchoscopy 
Endobronchial dysplasia (histologic score ≥ 4) present 
Bronchoscopy at 8 weeks and 6 months 
Study end points 
Primary: Change in worst endobronchial histology at 
6 months 
Secondary:  
1. Safety 
2. Additional endobronchial histology endpoints 
3. Biomarkers for response to nivolumab 

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2 
 
INTRODUCTION 
 
2.1 
STUDY RATIONALE  
This study is a phase 2, single-arm, open-label trial of nivolumab in subjects with endobronchial 
dysplasia; and either 30 pack years of tobacco exposure and either mild or worse sputum cytologic 
atypia or known bronchial dysplasia, or history of early-stage lung or head and neck cancer (greater than 
1 year after definitive treatment). The central question of interest is to determine whether nivolumab 
improves bronchial dysplastic lesions and prevents the histologic progression of premalignant central 
airway lesions in subjects that are at high risk for the development of lung cancer. The safety and 
tolerability of nivolumab will also be studied. Exploratory endpoints will include potential predictive 
biomarkers of nivolumab efficacy in subjects at high risk for the development of lung cancer. 
 
2.2 
BACKGROUND  
2.2.1 RATIONALE FOR LUNG CANCER PREVENTION STUDIES 
Lung cancer is the leading cause of cancer death in both men and women in the United States with a 
dismal 5-year survival rate of approximately 16% (1). Although the National Lung Screening Trial (NLST) 
has shown that yearly low dose chest CT scans can decrease lung cancer mortality by 20% (2), currently 
less than 25% of patients present with surgically curable disease (stages I and II) (1). Cigarette smoking 
accounts for 85-87% of all new lung cancer cases and the increased risk of lung cancer persists for more 
than 20 years after smoking cessation. In the US, the majority of new lung cancer cases are diagnosed in 
former smokers (3). Therefore, improved success in decreasing lung cancer mortality rates will rely not 
only on smoking prevention/cessation and CT scanning of high risk populations, but also on effective 
preventive strategies. 
2.2.2 PRIOR LUNG CANCER CHEMOPREVENTION STUDIES 
 
 Table 1: Lung Cancer Prevention Trials  
 
There have been a limited number of 
chemoprevention studies in lung cancer. 
Early trials were based on epidemiological 
data, which suggested that diets high in 
vitamin A reduced the risk of lung cancer. 
Several large randomized primary and 
secondary lung cancer prevention trials 
have been conducted (summarized in 
Table 1) (4-9). Three large trials in primary 
prevention evaluated -carotene plus 
retinol, -carotene and/or α-tocopherol, or 
-carotene alone, while three trials 
investigating secondary prevention 
strategies administered retinyl palmitate, 
retinyl palmitate and/or N-acetylcysteine 
(NAC) or 13-cis retinoic acid. 
Unfortunately, the results from these trials 

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were disappointing.  No protective effect against lung cancer was observed, and two trials suggested 
these agents could increase the risk of lung cancer in the smoking population. Thus, high doses of a 
single antioxidant vitamin do not appear to be a viable strategy. In addition, these trials were based only 
on epidemiologic data and required thousands of subjects and years to decades to complete. A study 
exploring the association of supplemental multivitamins, vitamin C, vitamin E, and folate in a large 
cohort failed to find a decrease in lung cancer risk (10). In fact, the researchers found a small increased 
risk associated with supplemental vitamin E. The most recent lung cancer tertiary chemoprevention trial 
examined the ability of selenium to prevent second primary tumors also failed to show any clinical 
benefit. 
Due to the length and considerable cost to conduct trials with lung cancer incidence as the endpoint, 
more recent studies have focused on intermediate endpoints (endobronchial dysplasia) that are 
precursors for invasive squamous cell lung cancer. The World Health Organization (WHO) classification 
for lung cancer recognizes distinct histological lesions that are precursors of lung cancer (11). Our group 
at the University of Colorado Anschutz Medical Campus and Denver VA Medical Center showed that 
bronchial dysplastic lesions can be reproducibly graded, and that persistence of bronchial dysplasia (BD) 
is associated with the development of invasive squamous cell lung cancer (12). Our group also showed 
that the oral prostacyclin analog iloprost significantly improves BD in former smokers (13), which 
suggests that targeted agents such as prostacyclin analogs may prevent the development of lung cancer 
in former smokers. Unfortunately, oral iloprost is currently unavailable, although we currently have a 
phase I trial that evaluates the effects of inhaled iloprost. Moreover, agents that prevent the 
development of lung cancer in active smokers have not been identified. Smaller trials with intermediate 
endpoints in high-risk subjects are urgently needed. 
2.2.3 LUNG CANCER RISK ASSESSMENT AND PATIENT SELECTION 
It is critical to define entry criteria for lung cancer prevention trials carefully. Study subjects must be of 
high enough risk that either lung cancer or intermediate endpoints will be found as frequently as 
possible. Over the past 25 years, investigators at the Denver VA Medical Center and the University of 
Colorado SPORE in Lung Cancer have focused on defining risk factors for both the development of lung 
cancer and the determination of intermediate endpoint biomarkers. The group at highest absolute risk 
for the development of lung cancer is comprised of survivors of previous lung cancer or head and neck 
cancer (14). The risk of developing new primary lung cancer in these patients is approximately 1-2% per 
patient per year. 
Interestingly, bronchial 
dysplasia is the most common 
premalignant lesion in lung 
specimens from patients who 
underwent resection for 
invasive lung cancer (15). Our 
group at the University of 
Colorado Cancer Center has 
recruited subjects with 
previous lung cancer to 
clinical trials involving sputum 
collection and serial 
bronchoscopies. Although not statistically significant, bronchial dysplasia was more frequent in subjects 
Table 2: Frequency of bronchial dysplasia in bronchoscopic specimens 

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with a history of prior lung cancer (81.3%) than in high-risk former and current smokers with sputum 
atypia who did not have a history of lung cancer (72.7%, Table 2). The presence of BD at multiple sites 
(two or more) was also slightly more common in subjects with a history of lung cancer (62.5%) than in 
high-risk former and current smokers with sputum atypia (56.8%, Table 2). 
Sputum cytologic atypia is also common in subjects with a history of prior lung cancer. Out of 14 
subjects with a history of prior lung cancer, 11 (78.6%) showed dysplastic changes in sputa prior to their 
initial bronchoscopy. Out of the three subjects that had no significant epithelial abnormalities at pre-
bronchoscopy sputum evaluation, two demonstrated mild dysplasia in a subsequent sputum sample. Of 
note, nine out of 14 subjects (64.3%) showed high grade atypia in their sputum, indicating that subjects 
with a history of prior lung cancer continue to harbor advanced premalignant lesions after definitive 
treatment. Although survivors of previous lung cancer or head and neck cancer are at the highest risk for 
developing lung cancer, tobacco smoking is the most common risk factor. However, prevention trials 
that assess intermediate endpoint biomarkers must further refine entry criteria. Subjects with tobacco 
smoke exposure and sputum cytologic atypia have rates of lung cancer greater than 1% yearly and are a 
high-risk group in which lung cancer prevention may have utility (16). Our group has shown that high-
risk current and former smokers (≥ 30 pack year smoking history with sputum cytologic atypia) contain 
premalignant central airway dysplastic lesions that can progress to invasive squamous cell lung cancer 
(12). Unfortunately, bronchial dysplastic lesions are difficult to visualize during routine white light 
bronchoscopy. In order to address this limitation, advanced techniques such as LIFE (Laser Induced 
Fluorescence Endoscopy) and narrow-band imaging (NBI) bronchoscopy have been developed. 
University of Colorado investigators participated in the first multicenter trial to evaluate LIFE 
bronchoscopy for the detection of premalignant dysplasia in which LIFE bronchoscopy was shown to 
have an approximately six-fold increase in sensitivity for detecting moderate or greater dysplasia, 
compared to white-light bronchoscopy (17). In order to further evaluate the efficacy of LIFE 
bronchoscopy and to eliminate potential biases related to order of examination (white-light or LIFE first) 
or bronchoscopist prejudice, we conducted a two-bronchoscopist trial in which the order of examination 
and the identity of the bronchoscopist for each modality was determined randomly. This trial confirmed 
the superiority of LIFE for the detection of premalignant dysplasia. Similarly, NBI is superior to white-
light bronchoscopy, with 96% sensitivity, 84% specificity, 131 diagnostic odds ratio, and 94% area under 
the receiver-operating characteristic curve (18). Using our criteria for patient selection (≥ 30 pack years, 
sputum cytologic atypia, and age) and our techniques for white light bronchoscopy combined with LIFE 
or NBI, we have been able to detect mild or greater dysplasia on bronchial biopsy in approximately 2/3 
of study participants, a rate that is not equaled by any other center. During our more recent oral iloprost 
and pioglitazone trials, approximately 75% of enrolled subjects had at least one area of mild dysplasia 
identified during the initial bronchoscopy.  
Thus, smoking history (current or former smokers with ≥ 30 pack years) with sputum cytologic atypia, 
and a prior history of lung cancer or a tobacco related aerodigestive cancer (specifically head and neck) 
are two of the strongest risk factors for developing lung cancer. As a result, these are the populations 
we have selected for our trial. 
2.2.4 THE ROLE OF NIVOLUMAB IN THE TREATMENT OF LUNG CANCER 
The immune system plays a dual role in cancer progression. It suppresses tumor growth by eliminating 
cancer cells, but also promotes tumor growth by selecting for cancer cells that can evade 
immunosurveillance. Cancer immunoediting has been proposed to occur in three phases: elimination, 
equilibrium, and escape, which involve the activation of innate and adaptive immune mechanisms 

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(19,20). In the elimination phase, transformed cells are destroyed by a competent immune system. 
Cancer cells that survive immunosurveillance enter the equilibrium phase. Equilibrium represents a 
functional state of dormancy in which tumor outgrowth is controlled by adaptive immunity. Tumor cells 
that acquire the ability to circumvent immune recognition will become clinically apparent. Moreover, 
tumor cells that escape immunosurveillance induce an immunosuppressive state through production of 
cytokines and growth factors such as VEGF and TGF, as well as by recruiting regulatory T cells (Tregs) 
and myeloid-derived suppressor cells. 
Immune checkpoints refer to inhibitory pathways crucial for maintaining self-tolerance. However, 
tumors use certain checkpoint pathways to escape immune surveillance (21). Inhibitory ligands and 
receptors that regulate T cell effector functions are commonly overexpressed in tumor cells or in the 
tumor microenvironment (TME). The blockade of immune checkpoints results in tumor-specific T cell 
responses. The most studied immune checkpoint receptor in NSCLC is programmed death receptor 1 
(PD-1). PD-1 mediates immune resistance in the TME by downregulating the activity of effector T cells in 
peripheral tissues in the setting of an inflammatory response (22). PD-1 is expressed on tumor-
infiltrating lymphocytes (TILs), and upon binding to its ligands PD-L1 and PD-L2, PD-1 inhibits kinases 
that are involved in T cell activation (23,24). PD-1 is also highly expressed on Tregs and may enhance 
their proliferation (25). PD-1 ligands are frequently upregulated in human cancer, including NSCLC (26). 
Inhibition of the PD-1 pathway has been shown to enhance intratumoral immune responses in 
preclinical studies (27), and blockade of PD-1 has introduced a new era in lung cancer treatment. 
Nivolumab (OPDIVOTM) is a full human monoclonal immunoglobulin G4 antibody that binds to PD-1. 
Among patients with advanced, previously treated NSCLC, overall survival, response rate, and 
progression-free survival were significantly better with nivolumab than with docetaxel (28,29). As a 
result, the US FDA approved nivolumab for the treatment of locally advanced or metastatic NSCLC after 
prior chemotherapy in adults. Some of the responses with these agents have proven to be prolonged 
(30). Even more encouraging than the objective response rate (ORR) with nivolumab in early-phase 
testing was the durability of the responses, with a median progression free survival (PFS) of 17 months 
(31). Not surprisingly, these durable responses led to promising overall survival, with 42% and 24% of 
patients alive after 1 year and 2 years, respectively. The durable responses seen with nivolumab suggest 
the generation of long-lasting memory T cells that can self-renew, providing a sustained and durable 
response upon re-exposure to the target tumor antigen. These encouraging clinical results have 
rightfully placed PD-1/PD-L1 immunotherapy at the forefront of oncological practice. Unfortunately, the 
overall response rate to PD-1/PD-L1 immune checkpoint inhibition is only modest for patients with 
advanced NSCLC, ranging from 14-24% (29,32-36). 
A large meta-analysis study on the prognostic influence of TILs demonstrated TIL density was associated 
with favorable clinical outcome across different cancer types, supporting the protective role of host anti-
tumor immune response (37). However, the protective impact of TILs faded in later stage cancers, 
suggesting that the tumor microenvironment in advanced cancers is more immunosuppressive. PD-
1/PD-L1 immune checkpoint blockade may therefore have greater responses in patients with early-stage 
NSCLC, and this area of research is under active investigation. At the 2016 ESMO Congress, Forde and 
colleagues reported data from 16 patients with Stage I-IIIA NSCLC who received two doses of nivolumab 
at four and two weeks prior to surgical resection (38). The investigators found that 12 of 15 patients 
(80%) had regression of their tumors, including six of 15 patients (40%) demonstrating major 
pathological regression (<10% residual viable tumor) following nivolumab. Although the sample size in 
this study was small, the response rate to nivolumab observed in patients with early-stage NSCLC (80%) 
is significantly higher than the response rate observed in patients with advanced NSCLC (~20%). 

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2.2.5 RATIONALE FOR USING NIVOLUMAB TO PREVENT LUNG CANCER 
An alternative approach to cancer immunotherapy that has been proposed is the treatment of 
premalignant lesions with immune checkpoint inhibitors to prevent progression to cancer. Premalignant 
lesions are tissues that are not yet invasive but can progress to become malignant. Examples of these 
precancerous tissues include bronchial squamous dysplasia and atypical adenomatous hyperplasia of 
the lung. It is not uncommon for multiple premalignant lesions to develop at various times due to the 
field effect of areas exposed to carcinogens (39). A mouse model of premalignant lung adenomas 
showed infiltration by immature macrophage-lineage cells that support the premalignant cells and 
produce inhibitory mediators such as TGF- (40). Similarly, an immune inhibitory state was 
demonstrated within HPV-associated respiratory papillomas in patients, as demonstrated by increased 
levels of Tregs with suppressive activity and an increased Th2-like milieu (41). This study also showed 
increased expression of the PD-1/PD-L1 inhibitory axis and indications of immune exhaustion. Our 
preliminary data have shown that PD-L1 expression is up-regulated in bronchial dysplastic lesions from 
high risk former or active smokers (Figure 3 in Exploratory Endpoints section below). It has also recently 
been shown that tumor-specific T cell dysfunction is initiated early during tumorigenesis (42). Taken 
together, these data provide the basis for our primary hypotheses: immune evasion contributes to 
malignant transformation of premalignant bronchial dysplastic lesions into invasive lung cancers. We 
further hypothesize that blocking PD-1 with nivolumab will allow the immune system to target and 
eradicate premalignant bronchial dysplastic lesions, thereby preventing the development of lung 
cancer. 
We propose to test the ability of the PD-1 checkpoint inhibitor nivolumab to improve bronchial 
dysplastic lesions in subjects who are at high risk for developing lung cancer. High risk subjects will 
include previously resected lung cancer patients, previously treated head and neck cancer patients, and 
subjects with heavy smoking history (≥ 30 pack-years) and sputum atypia. We have used these criteria in 
our previous studies (13), because subjects with tobacco smoke exposure and sputum cytologic atypia 
have rates of lung cancer greater than 1%/year (43,44) and represent a high risk group in which 
pharmacologic prevention may have the greatest utility. Moreover, subjects with a prior cancer history 
develop new primary lung tumors at a rate of 2% yearly (45). Interestingly, whole-exome sequencing of 
NSCLC samples from patients treated with a PD-1 inhibitor showed that clinical efficacy of nivolumab in 
NSCLC patients correlated with a molecular smoking signature, which was associated with mutation 
burden (46). We therefore hypothesize that high risk current or former smokers will be more likely to 
respond to PD-1 immune checkpoint inhibitors than never smokers, similar to what has been seen in 
NSCLC treatment trials (31). Unlike other pharmacologic agents whose effects may be lost upon 
discontinuation of therapy, PD-1 inhibitors may have durable responses by generating memory T cells 
that will have persistent antitumor activity.  
2.3 
RISK/BENEFIT ASSESSMENT 
 
2.3.1 KNOWN POTENTIAL RISKS  
2.3.1.1 RISK OF NIVOLUMAB 
The overall safety experience with nivolumab, as a monotherapy or in combination with other 
therapeutics, is based on experience in approximately 70 clinical studies. Across those studies, 
approximately 12,300 subjects have received nivolumab monotherapy in single- or multiple-dose Phase 

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1/2/3 studies or studies with nivolumab in combination with other therapeutics, including ipilimumab, 
cytotoxic chemotherapy, anti-angiogenics, and targeted therapies. All available data suggest that 
nivolumab monotherapy has a consistent adverse event (AE) profile across tumor types. The only 
exception is pulmonary inflammation AEs, which may be numerically greater in subjects with NSCLC, 
possibly because in some cases, it can be difficult to distinguish between nivolumab-related and 
unrelated causes of pulmonary symptoms and radiographic changes. The safety profile is generally 
consistent across completed and ongoing clinical trials, with no maximum tolerated dose reached at any 
monotherapy dose tested up to 10 mg/kg. There was no pattern in the incidence, severity, or causality 
of AEs to nivolumab dose level. Most related AEs are thought to be due to the effects of inflammatory 
cells on specific tissues. The most frequently reported treatment-related AE is fatigue, which is almost 
always of low grade. Across all studies conducted to date, drug-related AEs have included pulmonary 
toxicity, renal toxicity (including acute renal failure), endocrine abnormalities, GI toxicity, dermatologic 
toxicity (including rash), and hepatotoxicity. For nivolumab monotherapy, the majority of these AEs have 
been managed successfully with supportive care and, in more severe cases, a combination of dose delay, 
permanent discontinuation, and/or use of corticosteroids or hormone replacement therapy (for 
endocrinopathies). 
The safety of nivolumab was evaluated in CheckMate 057 (28), a randomized, open-label, multicenter 
trial in patients with metastatic non-squamous NSCLC and progression on or after one prior platinum 
doublet-based chemotherapy regimen. Patients received 3 mg/kg of nivolumab (n=287) administered 
intravenously over 60 minutes every 2 weeks or docetaxel (n=268) administered intravenously at 75 
mg/m2 every 3 weeks. The median duration of therapy was 2.6 months (range: 0 to 24+ months) in 
nivolumab-treated patients. In this trial, 30% of patients received nivolumab for greater than 6 months 
and 20% of patients received nivolumab for greater than 1 year. This trial excluded patients with active 
autoimmune disease, medical conditions requiring systemic immunosuppression, or with symptomatic 
interstitial lung disease. The median age of all randomized patients was 62 years (range: 21 to 85); 37% 
of patients in the nivolumab group were ≥65 years of age, 55% were male, and 92% were white. Twelve 
percent of patients had brain metastases and ECOG performance status was 0 (31%) or 1 (69%). 
In CheckMate 057, nivolumab was discontinued in 13% of patients, and was delayed in 29% of patients 
for an adverse reaction. Serious adverse reactions occurred in 47% of patients receiving nivolumab. The 
most frequent serious adverse reactions reported in at least 2% of patients receiving nivolumab were 
pneumonia, pulmonary embolism, dyspnea, pleural effusion, and respiratory failure. In the nivolumab 
arm, seven deaths were due to infection including one case of Pneumocystis jirovecii pneumonia, four 
were due to pulmonary embolism, and one death was due to limbic encephalitis. The most common 
adverse reactions (reported in at least 20% of patients) were fatigue, musculoskeletal pain, cough, 
decreased appetite, and constipation. Table 3 summarizes selected adverse reactions occurring in at 
least 10% of nivolumab-treated patients and more frequently than in docetaxel-treated patients. Table 4 
summarizes selected laboratory abnormalities worsening from baseline occurring in at least 10% of 
nivolumab-treated patients and more frequently than in docetaxel-treated patients. Table 5 summarizes 
immune-mediated adverse reactions occurring in nivolumab-treated patients. 
Table 3: Selected Adverse Reactions Occurring in ≥10% of Nivolumab-Treated Patients and at a Higher 
Incidence than Docetaxel (28) 
Adverse Reaction 
All Grades (% of Patients) 
Grades 3-4 (% of Patients) 
Cough 
30 
0.3 
Decreased appetite 
29 
1.7 
Constipation 
23 
0.7 
Pruritis 
11 
0 

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Toxicity was graded per NCI CTCAE v4. 
Table 4:  Selected Laboratory Abnormalities Worsening from Baseline Occurring in ≥10% of 
Nivolumab-Treated Patients for all NCI CTCAE Grades and at a Higher Incidence than Docetaxel (28) 
Chemistry Test 
All Grades (% of Patients with 
Worsening Laboratory Test 
from Baselinea) 
Grades 3-4 (% of Patients with 
Worsening Laboratory Test 
from Baselinea) 
Hyponatremia 
35 
6 
Increased AST 
28 
2.8 
Increased alkaline phosphatase 
27 
1.1 
Increased ALT 
23 
2.4 
Increased creatinine 
18 
0 
Increased TSHb 
17 
N/A 
a 
Each test incidence is based on the number of patients who had both baseline and at least on on-
study laboratory available, range 280 to 287 patients 
b 
Not graded per NCI CTCAE v4 
Table 5: Selected Immune-Related Adverse Reactions Occurring in Nivolumab-Treated Patients (28) 
Adverse Reaction 
All Grades 
N (% of Patients) 
Grades 3-4 
N (% of Patients) 
Time to Onset 
Median (Range) 
Pneumonitis (including 
interstitial lung disease) 
10 (3.4) 
5 (1.7) 
7.2 months 
(2.7 to 13.1 months) 
Diarrhea or colitis 
50 (17) 
3 (0.01) 
2.7 months 
(4 weeks to 19 
months) 
Hepatitis 
1 (0.003) 
1 (0.003) 
7.8 months 
Adrenal insufficiency 
1 (0.003) 
N/A 
Not reported 
Hypothyroidism 
(including thyroiditis) 
20 (7) 
N/A 
2.9 months 
(1.4 to 11.8 months) 
Hyperthyroidism 
4 (1.4) 
0 (0) 
2 months 
(4.1 weeks to 2.8 
months) 
Renal dysfunction 
1 (0.3) 
0 (0) 
1.5 months 
Rash 
17 (6) 
4 (1.4) 
Not reported 
Limbic encephalitis, fatal 
(Grade 5) 
1 (1) 
0 (0) 
7.2 months 
Toxicity was graded per NCI CTCAE v4. 
More recently, PD-1/PD-L1 immune checkpoint blockade has been studied to treat early-stage NSCLC in 
the adjuvant or preoperative setting. At the 2016 ESMO Congress, Forde and colleagues reported the 
data from 16 patients with Stage I-IIIA NSCLC who received two doses of nivolumab at four and two 
weeks prior to surgical resection (38). Treatment-related toxicities were consistent with those seen in 
other studies of nivolumab, and there were no treatment-related deaths. Of 19 patients evaluated for 
safety, adverse events of any grade were reported by six patients (32%); only one patient (5%) had 
grade 3/4 toxicity, and this led to treatment discontinuation. Although the sample size was small, these 
data suggest that nivolumab is safe in patients who have never received chemotherapy or any other 
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2.3.1.2 RISK OF BRONCHOSCOPY, ENDOBRONCHIAL BIOPSY, AND BRUSHINGS 
Bronchoscopy is a semi-invasive procedure that involves sedation, local anesthesia, and insertion of a 
bronchoscope into the airways. In large series, the incidence of serious complications was less than 
0.05% (5 in 10,000) in over 23,000 bronchoscopies. Adverse events include laryngospasm, 
bronchospasm, hypoxemia, allergy or adverse reaction to the sedation, fever following the procedure, 
or infection. The most common adverse event is fever which occurs in approximately 5% of patients and 
is self-limited. Infection requiring antibiotics occurs in about 0.5% of patients. Some patients report mild 
chest soreness, hoarseness, or sore throat the day after the procedure, which is self-limited. 
Endobronchial biopsy and brushings can lead to hemoptysis, which is self-limited. More serious 
complications such as major bleeding, lung collapse, vocal cord and bronchial spasm, and cardiac 
irregularity have been reported but are very rare. Since the patient will be sedated for this procedure, 
arrangements for transportation home after the procedure will be required.  
2.3.1.3 RISK OF PHLEBOTOMY 
Phlebotomy to monitor for adverse reactions to nivolumab may result in pain and discomfort, as well as 
anxiety related to additional testing and the implications of test results. In about 10% of cases, a small 
amount of bleeding under the skin will produce bruising or a hematoma. The risk of infected hematoma 
or significant blood loss is less than 0.1%.  
2.3.1.4 RISK OF IV INFUSIONS 
During bronchoscopy, an intravenous catheter will be placed in participants’ arms for infusion of fluids 
and sedation. In addition to possible pain and hematoma, which is similar to that for phlebotomy, the 
risk of temporary clotting of the vein is less than 1%. Participants can have allergy or adverse reactions 
to sedation administered during bronchoscopy. In CheckMate 057 (28), Grade 2 infusion reactions 
requiring corticosteroids occur in 1.0% (3/287) of patients receiving nivolumab.  
2.3.1.5 RISK OF SPUTUM COLLECTION 
The risks associated with a routine sputum collection are minimal. If the induced sputum technique 
using saline is performed, there is a minimal risk of chest tightness and bronchospasm. If this occurs, 
participants will be administered albuterol (either via inhaler or nebulizer) and monitored until 
symptoms have resolved. 
 
2.3.2 KNOWN POTENTIAL BENEFITS  
There has been no clinical trial so far assessing the clinical benefit of nivolumab in patients with 
premalignant lung lesions. The studies summarized below describe the clinical efficacy of nivolumab in 
patients with NSCLC. 
2.3.2.1 NIVOLUMAB MONOTHERAPY IN ADVANCED SQUAMOUS NSCLC 
CheckMate 017 was a randomized (1:1), open-label study enrolling 272 patients with metastatic 
squamous NSCLC who had experienced disease progression during or after one prior platinum doublet-
based chemotherapy regimen (29). Patients received nivolumab (n=135) administered intravenously at 3 
mg/kg every 2 weeks or docetaxel (n=137) administered intravenously at 75 mg/m2 every 3 weeks. This 

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study included patients regardless of their PD-L1 status. The first tumor assessments were conducted 9 
weeks after randomization and continued every 6 weeks thereafter. The major efficacy outcome 
measure was overall survival (OS). The median age was 63 years (range: 39 to 85) with 44% ≥65 years of 
age and 11% ≥75 years of age. The majority of patients were white (93%) and male (76%). Baseline 
ECOG performance status was 0 (24%) or 1 (76%). In this study, median OS was 9.2 months with 
nivolumab versus 6.0 months with docetaxel (P<0.001). At 1 year, the OS rate was 42% with nivolumab 
versus 24% with docetaxel. The response rate was 20% with nivolumab versus 9% with docetaxel 
(P=0.008). The median progression-free survival was 3.5 months with nivolumab versus 2.8 months with 
docetaxel (P<0.001). Thus, among patients with advanced, previously treated squamous-cell NSCLC, 
overall survival, response rate, and progression-free survival were significantly better with nivolumab 
than with docetaxel.  
2.3.2.2 NIVOLUMAB MONOTHERAPY IN ADVANCED NON-SQUAMOUS NSCLC 
CheckMate 057 was a randomized (1:1), open-label, study of 582 patients with metastatic non-
squamous NSCLC and progression on or after one prior platinum doublet-based chemotherapy regimen 
(28). Appropriate prior targeted therapy in patients with known sensitizing EGFR mutation or ALK 
translocation was allowed. Patients received nivolumab (n=292) administered intravenously at 3 mg/kg 
every 2 weeks or docetaxel (n=290) administered intravenously at 75 mg/m2 every 3 weeks. 
Randomization was stratified by prior maintenance therapy and number of prior therapies. The trial 
excluded patients with autoimmune disease, medical conditions requiring systemic immunosuppression, 
symptomatic interstitial lung disease, or untreated brain metastasis. Patients with treated brain 
metastases were eligible if neurologically stable. The first tumor assessments were conducted 9 weeks 
after randomization and continued every 6 weeks thereafter. The major efficacy outcome measure was 
OS. The median age of all randomized patients was 62 years (range: 21 to 85) with 42% of patients ≥65 
years of age and 7% of patients ≥75 years of age. The majority of patients were white (92%) and male 
(55%). Baseline ECOG performance status was 0 (31%) or 1 (69%), 79% were former/current smokers, 
3.6% had NSCLC with ALK rearrangement, 14% had NSCLC with EGFR mutation, and 12% had previously 
treated brain metastases. Prior therapy included platinum-doublet regimen (100%) and 40% received 
maintenance therapy as part of the first-line regimen. Histologic subtypes included adenocarcinoma 
(93%), large cell (2.4%), and bronchoalveolar (0.9%). In this study, the median OS was 12.2 months 
among patients in the nivolumab group and 9.4 months among patients in the docetaxel group 
(P=0.002). At 1 year, the OS rate was 51% with nivolumab versus 39% with docetaxel; at 18 months, the 
OS rate was 39% with nivolumab versus 23% with docetaxel. The response rate was 19% with nivolumab 
versus 12% with docetaxel (P=0.02). Although progression-free survival did not favor nivolumab over 
docetaxel (median, 2.3 months and 4.2 months, respectively), the rate of progression-free survival at 1 
year was higher with nivolumab than with docetaxel (19% and 8%, respectively). 
 
2.3.3 OVERALL RISK/BENEFIT ASSESSMENT 
Currently, the only way to prevent lung cancer is smoking cessation. However, roughly 80% of new lung 
cancers are diagnosed in former and never smokers, highlighting the need for effective prevention 
strategies. Most chemoprevention studies have been negative, with the only exception being a 
randomized phase II trial conducted by our group demonstrating that oral iloprost reverses bronchial 
dysplasia in former smokers (13). High risk subjects include resected lung cancer patients >1 year post 
resection, head and neck cancer patients >1 year post definitive therapy, and heavy (≥ 30 pack years) 
current or former smokers with bronchial dysplasia. Thus, it is possible to detect a large population of 

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patients at very high risk of developing invasive cancer for whom there is no standard therapy.  
Effective, early intervention in these situations has the potential to reduce the morbidity and mortality 
from lung cancer in this population.  At the same time, since the risk of cancer is not 100%, any 
proposed intervention must be safe without significant short or long-term toxicity. PD-1/PD-L1 immune 
checkpoint inhibitors represent a major breakthough in lung cancer therapy, and their clinical activity in 
NSCLC demonstrates that the immune system plays a critical role in the pathogenesis of lung cancer. 
There is increasing evidence that short courses of PD-1 immune checkpoint inhibitors are safe and highly 
effective in patients with early stage lung cancers. In this project we will test the clinical hypothesis that 
early intervention with nivolumab in patients at high risk of developing lung cancer is safe and can 
improve bronchial dysplasia, thereby reducing the risk of lung cancer.  
3 
OBJECTIVES AND ENDPOINTS 
3.1 
OBJECTIVES 
3.1.1 PRIMARY OBJECTIVE 
To determine whether immune checkpoint blockade using nivolumab can reverse premalignant 
histological changes in the bronchial epithelium of subjects at high risk for developing lung cancer as 
defined by mild or worse sputum cytologic atypia or known bronchial dysplasia; and either 30 pack-
years of tobacco exposure with sputum cytologic atypia, or history of early-stage lung or head and neck 
cancer at least 1 year after definitive treatment.  
3.1.2 SECONDARY OBJECTIVE 
To assess the safety and tolerability of nivolumab in patients with bronchial dysplastic lesions. 
3.1.3 EXPLORATORY OBJECTIVES 
An important aspect of this trial is to identify novel prognostic and predictive markers present at the 
time of diagnosis. As such, radiologic data and blood will also be collected throughout the study period. 
The markers to be assessed will be determined according to the best scientific knowledge and 
technology available. Correlative studies will be interpreted as hypothesis-generating data, to be 
validated in subsequent trials. 
3.2 
ENDPOINTS 
3.2.1 PRIMARY ENDPOINT: IMPROVEMENT IN ENDOBRONCHIAL HISTOLOGY 
It has long been established that abnormal bronchial histology (endobronchial dysplasia) is associated 
with cigarette smoking and increased risk for lung cancer (47-49). However, because of the 
inaccessibility of the airway mucosa, few studies have documented the extent of abnormalities in 
bronchial epithelium in at risk subjects prior to the development of lung cancer. Fluorescence 
bronchoscopy has repeatedly been shown to afford greater accessibility to premalignant lesions in the 
airways and has increased the need for an acceptable and generally applicable morphological 
classification of lower airway premalignant lesions. The WHO has recognized the importance of these 
lesions and added a classification for pre-invasive lesions to the WHO lung cancer classification. The 

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classification recognizes three distinct grades of dysplasia (mild, moderate, severe) as well as carcinoma 
in situ (11). Using the WHO classification as a template, we have extended the grading scheme, enabling 
us to evaluate histological responses to lung cancer preventive agents. The histologic classification 
consists of:  normal (grade 1.0), reserve cell hyperplasia (grade 2.0), squamous metaplasia (grade 3.0), 
mild dysplasia (grade 4.0), moderate dysplasia (grade 5.0), severe dysplasia (grade 6.0), carcinoma in 
situ (grade 7.0) and invasive cancer (grade 8.0). 
The primary endpoint is the dichotomous endpoint of whether or not a subject responds to nivolumab.  
Response to treatment will be based on the 6-month change (difference between 6-month score and 
baseline score) in worst (i.e. maximum) histologic classification score.  A subject will be considered a 
responder if his/her worst (i.e. maximum) histology classification score improves (i.e. the score lowers) 
at the 6 month bronchoscopy as compared with the baseline bronchoscopy. Non-responders will be 
subjects with similar or higher maximum histologic scores. 
3.2.2 SECONDARY ENDPOINTS 
3.2.2.1 SAFETY AND TOLERABILITY OF NIVOLUMAB IN HIGH RISK CURRENT AND FORMER 
SMOKERS 
This trial is also designed to evaluate the safety and tolerability of nivolumab in patients at high risk for 
lung cancer. Results from this trial will be used to support regulatory filing for nivolumab use in patients 
at high risk for lung cancer. The dosing of nivolumab (240 mg IV every 2 weeks) is based on the dose 
approved by the US FDA for the treatment of metastastic non-small cell lung cancer (NSCLC), including 
patients who have been treated for over 2 years. The duration of treatment (4 doses = 8 weeks) is based 
on published clinical trials that randomized patients with advanced NSCLC who progressed after 
platinum-based chemotherapy to either nivolumab or docetaxel (28,29). These trials showed a median 
time to response of 2 months. Similarly, the early stage lung cancer neoadjuvant trial reported by Forde 
and colleagues demonstrated a high response rate (80%) after two doses of nivolumab (38), and has 
now been expanded to three doses of nivolumab (NCT02259621). 
Patients will be evaluated by one of the study investigators every 2 weeks prior to study drug infusions 
to determine whether patients have any immune-related adverse events (irAEs) using the National 
Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE). In particular, patients will 
be monitored closely for evidence of dermatological (e.g., pruritis, rash, vitiligo), gastrointestinal (e.g., 
diarrhea, colitis, abdominal pain, hepatitis), endocrine (e.g., thyroid dysfunction, diabetes, adrenal 
insufficiency), renal (e.g., acute renal failure, interstitial nephritis), and pulmonary (e.g., pneumonitis) 
irAEs. Systemic corticosteroids or other immunosuppressive agents will be initiated at the discretion of 
the study investigators. Complete blood count, comprehensive metabolic profile, and thyroid function 
tests (TSH [thyroid-stimulating hormone], free T4, and total T3 levels) will be obtained at baseline and 
every 3 months for 1 year. A comprehensive metabolic profile will also be checked every 2 weeks before 
each infusion. Subjects will be followed for a total of 1 year to monitor for development of irAEs after 
discontinuation of the study drug. 
3.2.2.2 OTHER ENDOBRONCHIAL HISTOLOGY ENDPOINTS 
Although the primary endpoint will be the change in the worst histology after 6 months, additional 
histology summary measures (change in average histology and change in dysplasia index = the 

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percentage of biopsies with dysplasia score ≥ 4.0) will also be analyzed. The three summary measures 
will be analyzed on different subsets of the data (all matched biopsies vs matched biopsies restricted to 
the reference sites). Additionally, subjects will be classified as being a responder or non-responder 
based on the change in their average histology or dysplasia index. The same analyses will be also be 
conducted on biopsies after 2 months, to determine the rate of change in bronchial dysplasia in 
response to nivolumab, and to determine whether there may be effects of nivolumab that disappear 
after discontinuation of the drug. 
3.2.3 EXPLORATORY ENDPOINTS 
An important aspect of this trial 
is to identify novel prognostic 
and predictive markers present 
at the time of diagnosis. As 
such, radiologic data and blood 
will also be collected 
throughout the study period. 
The markers to be assessed will 
be determined according to the 
best scientific knowledge and 
technology available. 
Correlative studies will be 
interpreted as hypothesis-
generating data, to be validated 
in subsequent trials. 
3.2.3.1 PD-1 EXPRESSION ON 
T LYMPHOCYTES, PD-L1 
EXPRESSION ON EPITHELIAL 
CELLS AND MACROPHAGES, 
AND CHARACTERIZATION OF 
INFLAMMATORY INFILTRATES 
ASSOCIATED WITH 
BRONCHIAL DYSPLASTIC 
LESIONS AT BASELINE AND 
FOLLOWING TREATMENT 
WITH NIVOLUMAB 
Characterizing the polarization 
state and activation status of 
inflammatory infiltrates in 
bronchial dysplasia will 
represent key assessments in 
our exploratory endpoints. Our 
preliminary work has 
demonstrated that dual 
immunofluorescence (IF) is an 

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accurate and sensitive method by which inflammatory infiltrates can be characterized in biopsies of 
bronchial tissue. We predict that the character of the inflammatory infiltrate in BD will be a determinant 
of response to PD-1 inhibition. Our gene expression data indicate that decreased M1 versus M2 
macrophage ratios, decreased T-helper 1 (Th1) versus T-helper 2 (Th2) lymphocyte ratios, and increased 
T-regulatory lymphocytes (Treg) support persistence of BD, which leads to a high risk of developing 
invasive squamous cell carcinoma. An ongoing project employing dual IF has generated preliminary data 
showing a range of M1:M2 ratios as indicated by CD68/HLA-DRA and CD68/CD206 dual positivity, 
respectively, and a strong trend toward increased CD4/FoxP3 dual positive Treg infiltrates in persistent 
BD (Figure 1). 
 
For this current study, we will characterize the inflammatory infiltrate in baseline and post-treatment 
biopsy tissue, and correlate inflammatory infiltrate composition with response to nivolumab by 
multiplex immunohistochemistry using a Vectra 3 automated quantitative pathology imaging system  
(University of Colorado Human Immune Monitoring Shared Resource), which detects and distinguishes 
up to seven stains by immunofluorescence using formalin-fixed, paraffin-embedded tissue sections. 
Comparison of the infiltrates in the pre- and post-treatment biopsies will identify changes in both the 
inflammatory cells and the epithelium that correspond to response. These will be assessed using the M1 

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and M2 macrophage and Th1, Th2 and Treg IF stains described above. We have also optimized IF assays 
to assess PD-1 expression by T lymphocytes via dual CD3/PD-1 IF (Figure 2 A-C). 
 
Multiplex immunohistochemistry will also provide the ability to detect PD-L1 expression both by 
macrophages (CD68) as well as by epithelial cells (pan-cytokeratin)and will allow us to assess whether 
premalignant epithelial cell PD-L1 expression is predictive of response to nivolumab, as has been seen in 
invasive lung cancer. Currently, PD-L1 staining has been 
optimized in single primary antibody assays in lung tissue 
(Figure 2D).  
 
Although relatively modest in intensity, preliminary data have 
shown the presence of PD-L1 expression in the epithelial cells of 
a subset of bronchial dysplasias (Figure 3). These data will help 
establish the mechanism by which potential responses are 
achieved. Furthermore, it may identify biological markers of 
desired responses that could be used for clinical management 
in patients receiving PD-1 checkpoint inhibitor-based 
immunoprevention. Indeed, an important aspect of lung cancer 
prevention is accurately identifying patients that are likely to 
benefit from therapy so that associated side effects can be 
avoided in those that are unlikely to respond.  
3.2.3.2 MUTATIONAL BURDEN OF BRONCHIAL DYSPLASTIC LESIONS 
The use of mutational burden has been studied as a predictive biomarker in patients given checkpoint 
inhibitor immunotherapies. Rizvi and colleagues showed that higher mutational burden based on tumor 
whole-exome sequencing was associated with durable clinical benefit (partial or stable response lasting 
>6 months) in a study of patients with NSCLC given the PD-1 inhibitor pembrolizumab (46). High 
mutational burden (≥ 178 non-synonymous mutations) was associated with significantly longer 
progression-free survival. Similar results have been shown in a study by Johnson and colleagues of 
patients with advanced melanoma treated with anti-PD-1 and anti-PD-L1 immune checkpoint inhibitors 
(50). High mutational load (measured by targeted next-generation sequencing) was associated with 
improved response rate, progression-free survival, and overall survival. In addition, the phase 2 study of 
atezolizumab for locally advanced and metastatic urothelial carcinoma showed that patients who 
achieved a complete or partial response had a higher mutational load than patients with stable disease 
or progressive disease as their best response (51).  Thus, to determine whether mutational burden 
predicts response to nivolumab, we will perform whole-exome sequencing of bronchial dysplasia 
samples obtained in our study. 
3.2.3.3 PERIPHERAL BLOOD MARKERS 
Testing of peripheral blood markers is a non-invasive source of potential biomarkers in patients 
receiving anti-PD-1/PD-L1 immune checkpoint therapies. Although associations with clinical benefit and 
survival have been noted, none so far have been validated as predictive biomarkers in prospective 
studies. In this study, we will collect and store peripheral blood for future potential biomarker analysis. 
A variety of factors that could potentially predict clinical response to nivolumab will be investigated in 
peripheral blood from subjects prior to treatment. Data from these investigations will be evaluated for 

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associations with response and/or safety (adverse event) data. All samples collected may also be used 
for further exploratory analyses to assess biomarkers associated with bronchial dysplastic lesions or 
nivolumab treatment. Candidate markers to be evaluated may include (depending on specimen 
availability and resources): 
 
1. Exploratory serum biomarkers: Blood samples for exploratory serum biomarker analyses will be 
drawn at baseline, at 2 months, and at 6 months. Blood samples will be processed to collect 
serum and then put in frozen storage. Samples may be assessed by ELISA, seromics, and/or 
other relevant multiplex-based protein assay methods for immune or NSCLC-related factors that 
will predict for nivolumab benefit or correlate with nivolumab efficacy. Numerous potential 
serum-based biomarkers are currently under investigation for their potential to predict or 
correlate with efficacy to nivolumab or other immunotherapy, including but not limited to levels 
of soluble PD-L1, cytokines, chemokines, inflammatory factors, and microRNAs. 
2. Characterization and immunophenotyping of immune cell populations in peripheral blood by 
mass cytometry. Mass cytometry offers single-cell analysis of over 40 parameters without issues 
of spectral overlap. This technique utilizes rare earth metal isotopes in the form of soluble metal 
ions as tags bound to antibodies, instead of fluorophores to detect multiple analytes. The high-
dimensionality of mass cytometry enables simultaneous measurement of both phenotypic cell 
surface markers and intracellular cytokine networks. We propose to analyze the major immune 
cell subsets found in human peripheral blood, including neutrophils, eosinophils, basophils, 
monocytes, dendritic cells, T cells, B cells, and NK cells (and their subsets). Within these immune 
cell subsets, we will monitor changes in signaling activation of protein involved in JAK (Janus 
Kinase)/STAT (Signal Transducer and Activator of Transcription), MAPK (Mitogen Activated 
Protein Kinase), NF-κB (Nuclear Factor Kappa-light-chain enhancer of activated B cells), PI3K 
(PhosphoInositide 3-Kinase), TCR (T cell Receptor), and BCR (B cell Receptor) signaling pathways, 
and downstream cytokines (Th1, Th2, Th17, type I and type II interferons). This detailed analysis 
will potentially translate into new biomarkers that can be used to stratify patients into 
categories based on peripheral blood “immune profile.” Serum from enrolled participants will 
also be collected for proteomic analysis should the above mass cytometry analysis yield 
candidate proteins that may be identified as predictors of response to nivolumab. 
3. Peripheral T cell repertoire analysis. One theory in immune-oncology suggests a diverse and 
activated immune environment is more adept at eradicating premalignant lesions and tumors 
than a skewed repertoire of naïve and tolerized T cells. In a pilot study by Postow and 
colleagues, increased T-cell receptor gene richness (i.e., a repertoire containing many different 
V-J rearrangements) and evenness (i.e., evenly distributed frequencies) in pretreatment 
peripheral blood samples were associated with clinical benefit to the immune checkpoint 
inhibitor ipilimumab (response or stable disease lasting ≥9 months) (52). Thus, pretreatment T 
cell receptor repertoire may have a potential role as a predictive biomarker of response to 
nivolumab. In order to explore whether a diverse T cell repertoire is predictive of response to 
nivolumab, next generation, high-throughput, DNA sequencing will be performed on DNA 
isolated from peripheral blood to quantify the composition of the T cell repertoire prior to and 
after nivolumab therapy. 
3.2.3.4 SPUTUM INFLAMMATORY CELL ANALYSIS 
Because BD is a lesion of the central airways, evidence of the process can be detected in sputa from at 
risk individuals. Sputa contain atypical epithelial cells that are shed from dysplastic lesions, but also 

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contain abundant inflammatory cells. Sputa will be collected and used to identify at risk subjects that 
qualify for enrollment, and thus a baseline sputum sample will be available on many trial participants. In 
conjunction with the analyses planned above, trial associated sputa provide an excellent resource to 
assess the potential value of using these specimens for non-invasive predictive testing. Initial analyses 
will focus on comparing the features of the inflammatory cells with those seen in the biopsy tissue to 
determine how closely the inflammatory cells in sputa represent the findings seen in the bronchial 
dysplastic lesions. This will help inform the second objective, which will focus on identifying a signature 
in sputa that would predict response to nivolumab. Sputa are collected in the mild, methanol-based 
Carnoy’s fixative and thus would be expected to preserve antigen epitopes in a relatively unaltered 
state. 
3.2.3.5 EPITHELIAL CELL CULTURE 
Bronchial epithelial cells will be cultured from one or more endobronchial biopsies in serum free media. 
Epithelial progenitor cells will be isolated and assessed for the ability to self replicate and differentiate into 
basal, ciliated and secretory cells. Gene expression by RNAseq and mutational load by whole exome 
sequencing will be performed on a subset of these cells. 
4 
STUDY DESIGN  
 
4.1 
OVERALL DESIGN 
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. 
The estimated time to accrue 42 evaluable subjects (accounting for subject dropout) is two years and 
the total proposed study time is 3 years. The duration of participation for each subject will be one year. 
Assuming the study progresses to stage two, enrollment will be stopped once 42 subjects have 
completed the study. 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
This trial utilizes a Simon’s two-stage design. Patient enrollment will occur in two successive stages. 
During stage one of the study, 18 subjects will be enrolled. If there are less than or equal to six positive 
responses (defined as improvement in worst histology score by ≥1.0 histology unit after six months) in 
these 18 subjects, the study will be terminated for lack of efficacy. If at least seven responses are 

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observed (i.e., seven subjects who have improvement in their worst histology score), the study will 
progress to stage two, where an additional 24 subjects will be enrolled. This study design minimizes the 
number of people exposed to a potentially ineffective treatment. 
4.3 
JUSTIFICATION FOR DOSE 
Although nivolumab was originally approved for NSCLC at a single dose of 3 mg/kg IV every 2 weeks, the 
new recommended dosage regimen for nivolumab is 240 mg IV every 2 weeks. The safety and efficacy of 
240 mg q2w flat dose of nivolumab is expected to be similar to 3 mg/kg q2w dosing regimen. A flat dose 
of nivolumab 240 mg q2w was selected since it is identical to a dose of 3 mg/kg for subjects weighing 80 
kg, the observed median body weight in nivolumab treated cancer patients. Using a population 
pharmacokinetics model, the overall distributions of nivolumab exposures (Cavgss, Cminss, Cmaxss, and 
Cmin1) are comparable after treatment with either 3 mg/kg or 240 mg nivolumab. The predicted range 
of nivolumab exposures (median and 90% prediction intervals) resulting from a 240 mg flat dose across 
the 35 to 160 kg weight range is maintained well below the corresponding exposures observed with the 
well tolerated 10 mg/kg nivolumab q2w dosage. Across various tumor types, nivolumab has been shown 
to be safe and well tolerated up to a dose of 10 mg/kg, and the relationship between nivolumab 
exposure produced by 3 mg/kg and efficacy and safety has been found to be relatively flat. Given the 
similarity of nivolumab pharmacokinetics across tumor types and the similar exposures predicted 
following administration of 240 mg flat dose compared to 3 mg/kg q2w regimen, it is expected that the 
safety and efficacy profile of 240 mg q2w nivolumab will be similar to that of 3 mg/kg nivolumab. 
4.4 
END OF STUDY DEFINITION 
A participant is considered to have completed the study if he or she has completed all phases of the 
study including the last visit or the last scheduled procedure shown in the Schedule of Activities (SoA), 
Section 8.1. 
5 
STUDY POPULATION 
 
5.1 
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 or known bronchial dysplasia, 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. An ex-smoker is defined as no tobacco use in the prior 12 months 
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 

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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 
 
5.2 
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 

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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 
5.3 
REPRODUCTIVE STATUS 
Women of childbearing potential (WOCBP) are defined as females who have experienced menarche, 
who have not undergone surgical sterilization (hysterectomy or bilateral oophorectomy)and are not 
postmenopausal. Menopause is defined as 12 months of amenorrhea in a woman over the age of 45 
years in the absence of other biological or physiological causes. In addition, females under the age of 55 
years must have a serum follicle stimulating hormone (FSH) level >40 mIU/mL to confirm menopause. 
 
Women of childbearing potential (WOCBP) must agree to follow instructions for method(s) of 
contraception for the duration of treatment with nivolumab and for at least five months following the 
last dose of nivolumab. WOCBP who are continuously not heterosexually active are exempt from 
contraceptive requirements, but still must undergo pregnancy testing as described in this section. 
 
Men who are sexually active with WOCBP must agree to follow instructions for method(s) of 
contraception for the duration of treatment with nivolumab and for at least seven months following the 
last dose of nivolumab. Azoospermic males are exempt from contraceptive requirements. 
At a minimum, WOCBP and female partners of male subjects, who are WOCBP, must agree to the use of 
two methods of contraception, with one method being highly effective and the other method being 
highly or less effective as listed below: 
1. Highly effective methods of contraception (failure rate <1% when used consistently and 
correctly): 
a. Progestogen only hormonal contraception associated with inhibition of ovulation 
b. Hormonal methods of contraception including oral contraceptive pills containing 
combined estrogen + progesterone, vaginal rings, injectable, implants and intrauterine 
devices (IUDs) such as Mirena 
c. Nonhormonal IUDs, such as ParaGard 
d. Bilateral tubal occlusion 

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e. Vasectomied partner with documented azoospermia 90 days after procedure 
f. Intrauterine hormone-releasing system (IUS) 
g. Complete abstinence 
i. Complete abstinence is defined as the complete avoidance of heterosexual 
intercourse 
ii. Complete abstinence must be used throughout the duration of study and for 
the duration of time as specified above following the last dose of nivolumab 
iii. It is not necessary to use any other method of contraception when complete 
abstinence is elected 
iv. Subjects who choose complete abstinence must undergo pregnancy testing as 
described in this section 
v. Acceptable alternate methods of highly effective contraception must be 
discussed in the event that the subject chooses to forego complete abstinence 
vi. The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the subject 
2. Less effective methods of contraception: 
a. Diaphragm with spermicide 
b. Cervical cap with spermicide 
c. Vaginal sponge with spermicide 
d. Male or female condom with or without spermicide 
e. Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mode of action 
3. Unacceptable methods of contraception: 
a. Periodic abstinence (calendar, symptothermal, post-ovulation methods) 
b. Withdrawal (coitus interruptus) 
c. Spermicide only 
d. Lactation amenorrhea method (LAM) 
5.4 
RECRUITMENT PLAN 
Patients for this trial will be recruited from the Rocky Mountain Regional Veterans Affairs Medical 
Center (RMR VAMC), the University of Colorado Cancer Center, and affiliated clinics. Potential research 
subjects will be identified by a member of the patient’s treatment team, the protocol investigator, or 
research staff. Potential subjects contacted by their treating physician will be referred to the 
investigator/research staff of the study. 
The investigators and research staff may also screen the medical records of patients with whom they do 
not have a treatment relationship for the limited purpose of identifying patients who would be eligible 
to enroll in the study and to record appropriate contact information in order to approach these patients 
regarding the possibility of enrolling in the study. Specifically, medical records of patients being treated 
at the DVAMC Chest Clinic and the University of Colorado Pulmonary Nodule Clinic will be screened for 
cigarette smoking history. Medical records of patients with lung cancer or head and neck cancer being 
treated at the University of Colorado Cancer Center and DVAMC Oncology Clinic will be screened for 
patients who have undergone definitive therapy at least one year prior to study enrollment.  
During the initial conversation between the investigator/research staff and the patient, the patient may 
be asked to provide certain health information that is necessary to the recruitment and enrollment 
process. The investigator/research staff may also review portions of their medical records at DVAMC 

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and the University of Colorado in order to assess eligibility further. They will use the information 
provided by the patient and/or medical record to confirm that the patient is eligible and to contact the 
patient regarding study enrollment. If the patient is ineligible for the research study, the research staff 
will destroy all information collected on the patient during the initial conversation and medical records 
review, except for any information that must be maintained for screening log purposes. 
In most cases, the initial contact with the prospective subject will be conducted either by the treatment 
team, investigator or the research staff working in consultation with the treatment team. The 
recruitment process outlined presents no more than minimal risk to the privacy of the patients who are 
screened and minimal PHI will be maintained as part of a screening log. For these reasons, we seek a 
(partial) limited waiver of authorization for the purposes of (1) reviewing medical records to identify 
potential research subjects and obtain information relevant to the enrollment process; (2) conversing 
with patients regarding possible enrollment; (3) handling of PHI contained within those records and 
provided by the potential subjects; and (4) maintaining information in a screening log of patients 
approached (if applicable). 
Participants will be recruited for this study protocol by the investigator or research staff to reach a 
target sample size of 48 participants. A HIPAA authorization form will be provided to the subject at the 
time of consent. This authorization will designate the specific health information that will be required to 
be released and to whom. We have experience with a cohort study collecting sputum samples on 
patients with 30 pack years of smoking. This study will include individuals with biopsy proven 
endobronchial dysplasia and either > 30 pack years of smoking or previous history of non-small cell lung 
cancer (stage I, II, or IIIA) or head and neck cancer (stage I, II, III, or IVA). 
6 
STUDY INTERVENTION 
 
6.1 
STUDY INTERVENTION(S) ADMINISTRATION 
 
6.1.1 STUDY INTERVENTION DESCRIPTION 
All protocol-specified investigational products are considered study drug.  An investigational product, 
also known as investigational medicinal product in some regions, is defined as a pharmaceutical form of 
an active substance being tested in a clinical study, including products already with a marketing 
authorization but used or assembled (formulated or packaged) differently than the authorized form, or 
used for an unauthorized indication, or when used to gain further information about the authorized 
form. 
The investigational product should be stored in a secure area according to local regulations. It is the 
responsibility of the investigator to ensure that investigational product is only dispensed to study 
subjects. The investigational product must be dispensed only from official study sites by authorized 
personnel according to local regulations. 
In this protocol, the investigational product is: BMS-936558 (nivolumab). Nivolumab is a human 
monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2. 
Nivolumab is an IgG4 kappa immunoglobulin that has a calculated molecular mass of 146 kDa. 
6.1.2 DOSING AND ADMINISTRATION 

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Subjects will receive nivolumab 240 mg IV every two weeks until subject discontinuation or until they 
have completed four cycles. Subjects will receive treatment with nivolumab as a 30 minute IV infusion 
on Day 1 of a treatment cycle every two weeks (14 days). There will be no dose escalations or reductions 
allowed. Treatment may be delayed for up to a maximum of 2 weeks from the scheduled re-treatment 
date. Subjects may be dosed no less than 12 days from the previous dose. 
Subjects will receive nivolumab infusions at the site of enrollment (i.e., research subjects enrolled at 
UCHealth will receive nivolumab infusions at UCHealth and research subjects enrolled at the RMR VAMC 
will receive nivolumab infusions at the RMR VAMC).  
Subjects will be monitored continuously for AEs while on study. Treatment modifications (e.g., dose 
delay) will be based on specific laboratory and adverse event criteria. 
Nivolumab infusion must not be administered as intravenous push or bolus injection. The nivolumab 
infusion will be administered intravenously over a period of 30 minutes. Nivolumab infusion should not 
be infused at the same time in the same intravenous line with other agents. A separate infusion line 
must be used for the infusion. 
An infusion set and an in-line, sterile, non-pyrogenic, low protein binding filter (pore size of 0.2 m to 
1.2 m) will be used. 
Nivolumab infusion is compatible with PVC and polyolefin containers, glass bottles, PVC infusion sets 
and in-line filters with polyethersulfone membranes with pore sizes of 0.2 m to 1.2 m. 
After administration of the nivolumab dose, the line will be flushed with sodium chloride 9 mg/mL 
(0.9%) solution for injection or 50 mg/mL (5%) glucose solution for injection. 
Any unused portion of the infusion solution should not be stored for reuse. Any unused medicinal 
product or waste material will be disposed of in accordance with local requirements. 
 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
 
6.2.1 ACQUISITION AND ACCOUNTABILITY 
Nivolumab will be provided by the manufacturer, Bristol-Myers Squibb (BMS). 
 
6.2.2 FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
OPDIVO is a sterile, preservative-free, non-pyrogenic, clear to opalescent, colorless to pale-yellow liquid 
that may contain light (few) particles. OPDIVO injection for intravenous is supplied in single-dose vials. 
Each mL of OPDIVO solution contains nivolumab (10 mg), mannitol (30 mg), pentetic acid (0.008 mg), 
polysorbate 80 (0.2 mg), sodium chloride (2.92 mg), sodium citrate dehydrate (5.88 mg), and water. 
OPDIVO may also contain hydrochloric acid and/or sodium hydroxide to adjust pH to 6. 
 
OPDIVO will be packaged in an open-label fashion. Each mL of OPDIVO concentrate contains 10 mg of 
nivolumab. OPDIVO is available as 40 mg/4 mL single-dose vials and 100 mg/10 mL single-dose vials. The 
vials are not subject specific, although there will be specific vial assignments by subject in order to track 
drug usage and re-supply. 

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6.2.3 PRODUCT STORAGE AND STABILITY 
OPDIVO should be stored under refrigeration at 2°C to 8°C (36°F to 46°F). OPDIVO should be protected 
from light by storing in the original package until time of use. OPDIVO should not be frozen or shaken. 
Unopened, OPDIVO is stable for 2 years. From a microbiological point of view, once opened, the 
medicinal product should be infused or diluted and infused immediately. If not used immediately, 
chemical and physical in-use stability of OPDIVO has been demonstrated for 24 hours at 2°C to 8°C 
protected from light and a maximum of 4 hours at 20°C-25°C and room light (this 4-hour period of the 
total 24 hours should be inclusive of the product administration period). 
 
6.2.4 PREPARATION 
The prescribed dose for the patient is 240 mg. The volume of OPDIVO concentrate to prepare the dose is 
24 mL. Care will be taken to ensure aseptic handling when preparing the infusion. The infusion should be 
prepared in a laminar flow hood or safety cabinet using standard precautions for the safe handling of 
intravenous agents. 
OPDIVO can be used for intravenous administration either: 
• 
without dilution, after transfer to an infusion container using an appropriate sterile syringe; or 
• 
after diluting to concentrations as low as 1 mg/mL. The final infusion concentration should 
range between 1 and 10 mg/mL. OPDIVO concentrate may be diluted with either: 
o sodium chloride 9 mg/mL (0.9%) solution for injection; or 
o 50 mg/mL (5%) glucose solution for injection. 
STEP 1 
• 
OPDIVO concentrate will be inspected for particulate matter of discoloration. The vial should 
not be shaken. OPDIVO concentrate is a clear to opalescent, colorless to pale yellow liquid. The 
vial will be discarded if the solution is cloudy, is discolored, or contains particulate matter other 
than a few translucent-to-white particles. 
• 
The required volume (24 mL) of OPDIVO concentrate will be withdrawn using an appropriate 
sterile syringe. 
STEP 2 
• 
The concentrate will be transferred into a sterile, evacuated glass bottle or intravenous 
container (PVC or polyolefin). 
• 
If applicable, the concentrate will be diluted with the required volume of sodium chloride 9 
mg/mL (0.9%) solution for injection or 50 mg/mL (5%) glucose solution for injection. The 
infusion will be gently mixed by manual rotation. The infusion should not be shaken. 
After preparation, the OPDIVO infusion will be stored either: 
• 
at room temperature for no more than 4 hours from the time of preparation. This includes room 
temperature storage of the infusion in the IV container and time for administration of the 
infusion or 
• 
under refrigeration at 2°C to 8°C (36°F to 46°F) for no more than 24 hours from the time of 
infusion preparation. 
6.2.5 DESTRUCTION OF STUDY DRUG 

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For this study, study drugs (those supplied by BMS or sourced by the investigator) such as partially used 
study drug containers, vials, and syringes, may be destroyed on site. The unused study drugs can only be 
destroyed after being inspected and reconciled by the responsible BMS Study Monitor. On-site 
destruction is allowed provided the following minimal standards are met: 
• 
On-site disposal practices must not expose humans to risks from the drug 
• 
On-site disposal practices and procedures are in agreement with applicable laws and 
regulations, including any special requirements for controlled or hazardous substances. 
• 
Written procedures for on-site disposal are available and followed. The procedures must be filed 
with the site’s SOPs and a copy provided to BMS upon request. 
• 
Records are maintained that allow for traceability of each container, including the date disposed 
of, quantity disposed, and identification of the person disposing the containers. The method of 
disposal (i.e., incinerator, licensed sanitary landfill, or licensed waste disposal vendor) must be 
documented. 
• 
Accountability and disposal records are complete, up-to-date, and available for the Monitor to 
review throughout the clinical trial period.  
If conditions for destruction cannot be met, the responsible BMS Study Monitor will make arrangements 
for return of study drug. 
It is the investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, local, and 
institutional guidelines and procedures, and provided that appropriate records of disposal are kept. 
6.2.6 RETURN OF STUDY DRUG 
Study drug will not be returned. All unused and/or partially used study drug may be destroyed on site 
providing the site has an applicable standard operating procedure on file. 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
This is a single-institution, open-label, single-arm study. Thus, subjects, investigators, and research staff 
will be unblinded. However, blinding of endobronchial biopsies will be utilized to minimize bias by the 
pathologist. 
 
6.4 
STUDY INTERVENTION COMPLIANCE 
Treatment compliance will be monitored by drug accountability as well as the subject’s medical record 
and case report form (CRF). 
6.5 
CONCOMITANT THERAPY 
All concomitant prescription medications taken during study participation will be recorded. For this 
protocol, a prescription medication is defined as a medication that can be prescribed only by a properly 
authorized/licensed clinician. Medications reported on the CRF include concomitant prescription 
medications, over-the-counter medications, and non-prescription medications. 
History of prior cancer therapy will be recorded at screening on the CRF for each participant. Reasonable 
effort will be made to collect information on all prior cancer therapy received by the participant (e.g., 

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surgeries, chemotherapy, radiotherapy, immunotherapy, biologics). The information must be obtained 
from the participant’s medical chart and recorded on the appropriate CRF. 
Concomitant medications for all ongoing medical history conditions or AEs must be reported from the 
date the informed consent is signed until the last study visit, and for all concomitant medications related 
to serious or study drug-related toxicities until the medication is no longer taken or until participant 
contact discontinues. 
To account for any potential interaction with nivolumab, concomitant medications, treatments, or 
procedures should be reviewed with study participant and updated on the participant’s medical record 
at every study visit. 
6.5.1 PROHIBITED AND/OR RESTRICTED TREATMENTS 
The following medications are prohibited during the study (unless utilized to treat a drug-related 
adverse event): 
• 
Immunosuppressive agents (e.g., mycophenolate, azathioprine) 
• 
Immunosuppressive doses of systemic corticosteroids (except as stated in Section 6.5.3) 
• 
Any concurrent antineoplastic therapy (i.e., chemotherapy, hormonal therapy, immunotherapy, 
extensive radiation therapy, or stand or investigational agents for treatment of lung cancer or 
head and neck cancer) 
6.5.2 OTHER RESTRICTIONS AND PRECAUTIONS 
Subjects with any active autoimmune disease or a history of recent known or suspected autoimmune 
disease or history of syndrome that required systemic corticosteroids or immunosuppressive 
medications, except for subjects with vitiligo or resolved childhood asthma/atopy or other syndromes 
that would not be expected to recur in the absence of an external trigger (e.g., drug-related serum 
sickness or post-streptococcal glomerulonephritis) are excluded from the study. Subjects with type 1 
diabetes mellitus or hypothyroidism requiring thyroid hormone replacement are permitted to enroll. 
6.5.3 PERMITTED THERAPY 
Subjects are permitted the use of topical, ocular, intra-articular, intranasal, and inhalational 
corticosteroids (with minimal systemic absorption). Physiologic replacement doses of systemic 
corticosteroids (e.g., prednisone ≤ 10 mg/day) are permitted. A brief course of corticosteroids for 
prophylaxis (e.g., contrast dye allergy) or for treatment of non-autoimmune conditions (e.g., delayed-
type hypersensitivity reaction caused by a contact allergen) is permitted. 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
 
7.1 
DELAY OR DISCONTINUATION OF STUDY INTERVENTION 
7.1.1 DOSE DELAY CRITERIA 
Nivolumab administration should be delayed for the following AEs: 

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• 
Any Grade 2 non-skin, drug-related adverse event, except for fatigue and laboratory 
abnormalities 
• 
Any Grade 3 drug-related laboratory abnormality (except lymphopenia, AST, ALT, or total 
bilirubin) 
• 
Any 2-Grade drug-related shift from baseline in AST, ALT, or total bilirubin 
o If a subject has a baseline AST, ALT, or total bilirubin that is within normal limits, dosing 
will be delayed for drug-related Grade 2 toxicity 
o If a subject has a baseline AST, ALT, or total bilirubin within the Grade 1 toxicity range, 
dosing will be delayed for drug-related Grade 3 toxicity 
• 
Any Grade 3 skin drug-related AE 
• 
Any AE, laboratory abnormality or inter-current illness which, in the judgment of the 
investigator, warrants skipping the dose of study medication 
 
In some cases, the natural history of immunotherapy-related AEs can differ and be more severe than 
AEs caused by other therapeutic classes. Early recognition and management may mitigate severe 
toxicity. Evaluation and Management Guidelines were developed to assist investigators and can be 
found in the Investigator Brochure: 
• 
General Guideline 
• 
Diarrhea and Colitis 
• 
Endocrinopathies 
• 
Hepatotoxicity (including asymptomatic elevated liver function tests [LFTs]) 
7.1.2 DOSE REDUCTIONS 
Nivolumab dose reductions are not permitted in this study. 
7.1.3 CRITERIA TO RESUME TREATMENT WITH NIVOLUMAB 
Subjects may resume treatment with nivolumab when the drug-related AE(s) resolve(s) to Grade 1 or 
baseline value (except Grade 2 fatigue for which subjects are not required to delay treatment). Subjects 
with baseline AST/ALT or total bilirubin in the Grade 1 toxicity range who require dose delays for 
reasons other than a 2-grade shift in AST/ALT OR total bilirubin may resume treatment in the presence 
of Grade 2 AST/ALT OR total bilirubin. Subjects with combined Grade 2 AST/ALT AND total bilirubin 
values meeting discontinuation parameters (Section 7.1.4) should have treatment permanently 
discontinued. 
Drug-related pulmonary toxicity, diarrhea, or colitis must have resolved to baseline before treatment is 
resumed. 
In the case of endocrine-related AEs, hormone replacement therapy or glucose controlling agents may 
be utilized to restore physiologic function and to permit retreatment with nivolumab. 
If the criteria to resume treatment are met, the subject should restart treatment at the next scheduled 
timepoint per protocol. However, if the treatment is delayed past the scheduled timepoint per protocol, 
the scheduled study treatment administration will be delayed, but not skipped, until dosing resumes. 
This is to ensure that subjects will receive 4 administrations of nivolumab treatment if toxicity allows. 

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If treatment is delayed > 4 weeks from the last dose, the subject must be permanently discontinued 
from study therapy. 
7.1.4 DISCONTINUATION CRITERIA 
Nivolumab administration should be discontinued if at least one of the following drug-related adverse 
event(s) occurs: 
• 
Any ≥ Grade 2 eye pain or reduction of visual acuity that does not respond to topical therapy 
and does not improve to Grade 1 severity within the re-treatment period OR requires systemic 
treatment 
• 
Any ≥ Grade 2 drug-related pneumonitis that that does not respond to delay of nivolumab and 
systemic corticosteroid treatment after 2 weeks 
• 
Any ≥ Grade 3 non-skin, drug-related adverse event lasting > 7 days, with the exception of 
laboratory abnormalities, drug-related bronchospasm, and hypersensitivity reactions 
o Grade 3 drug-related laboratory abnormalities do not require treatment discontinuation 
except for Grade 3 febrile neutropenia > 1 day or Grade 3 thrombocytopenia ≥ 7 days or 
associated with bleeding 
o Grade 3 drug-related bronchospasm, hypersensitivity reaction, or infusion reaction of 
any duration 
• 
Any liver function tests (LFTs) that meet the following criteria: 
o AST or ALT > 5 x ULN for > 2 weeks 
o AST or ALT > 10 x ULN 
o Total bilirubin > 5 x ULN 
o Concurrent AST or ALT > 3 x ULN AND total bilirubin > 2 x ULN 
• 
Any drug-related Grade 4 laboratory abnormalities, except for the following which do not 
require discontinuation: 
o Grade 4 neutropenia ≤ 7 days 
o Grade 4 lymphopenia 
o Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with 
clinical sequelae and are corrected with supplementation/appropriate management 
within 72 hours of their onset 
o For Grade 4 endocrinopathy adverse events such as adrenal insufficiency, ACTH 
deficiency, hyper- or hypothyroidism, or glucose intolerance, which resolve or are 
adequately controlled with physiologic hormone replacement (e.g., steroids, thyroid 
hormones) or glucose controlling agents, respectively, retreatment can be considered 
after discussion with the BMS Medical Monitor 
• 
Any dosing interruption lasting > 4 weeks with the following exceptions: 
o Dosing interruptions to allow for prolonged steroid tapers to manage drug-related 
adverse events are allowed. Prior to re-initiating treatment in a subject with a dosing 
interruption lasting > 4 weeks, the BMS medical monitor must be consulted. 
o Dosing interruptions > 4 weeks that occur for non-drug-related reasons may be allowed 
if approved by the BMS medical monitor. Prior to re-initiating treatment in a subject 
with a dosing interruption lasting > 4 weeks, the BMS medical monitor must be 
consulted. 
• 
Any adverse event, laboratory abnormality, or concurrent illness which, in the judgment of the 
investigator, presents a substantial clinical risk to the subject with continued nivolumab dosing. 

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7.1.5 ADVERSE EVENT MANAGEMENT ALGORITHMS 
Because of the potential for clinically meaningful nivolumab related AEs requiring early recognition and 
prompt intervention, management algorithms have been developed for suspected pulmonary toxicity, 
GI toxicity, hepatotoxicity, endocrinopathy, skin toxicity, neurological toxicity, and nephrotoxicity. The 
algorithms recommended for utilization in this study are contained in Appendix 2. 
7.1.6 TREATMENT OF NIVOLUMAB RELATED INFUSION REACTIONS 
Since nivolumab contains only human immunoglobulin protein sequences, it is unlikely to be 
immunogenic and induce infusion or hypersensitivity reactions. However, if such a reaction were to 
occur, it might manifest with fever, chills, rigors, headache, rash, pruritis, arthralgias, hypo- or 
hypertension, bronchospasm, or other symptoms. All Grade 3 or 4 infusion reactions should be reported 
within 24 hours to the study medical monitor and reported as an SAE if it meets the criteria. Infusion 
reactions should be graded according to NCI CTCAE (Version 5.0) guidelines. 
Treatment recommendations are provided below and may be modified based on local treatment 
standards and guidelines, as appropriate: 
For Grade 1 symptoms (mild reaction; infusion interruption not indicated; intervention not indicated): 
Remain at bedside and monitor subject until recovery from symptoms. The following prophylactic 
premedications are recommended for future infusions: diphenhydramine 50 mg (or equivalent) and/or 
acetaminophen 325 to 1000 mg at least 30 minutes before nivolumab administrations. 
For Grade 2 symptoms (moderate reaction requires therapy or infusion interruption but responds 
promptly to symptomatic treatment [e.g., antihistamines, non-steroidal anti-inflammatory drugs, 
narcotics, corticosteroids, IV fluids]; prophylactic medications indicated for ≤ 24 hours): Stop the 
nivolumab infusion, begin an IV infusion of normal saline, and treat the subject with diphenhydramine 
50 mg IV (or equivalent) and/or acetaminophen 325 to 1000 mg; remain at bedside and monitor subject 
until resolution of symptoms. Corticosteroid therapy may also be administered as appropriate. If the 
infusion is interrupted, then restart the infusion at 50% of the original infusion rate when symptoms 
resolve; if no further complications ensue after 30 minutes, the rate may be increased to 100% of the 
original infusion rate. Monitor subject closely. If symptoms recur then no further nivolumab will be 
administered at that visit. Administer diphenhydramine 50 mg IV, and remain at bedside and monitor 
the subject until resolution of symptoms. The amount of study drug infused must be recorded on the 
CRF. The following prophylactic premedications are recommended for further infusions: 
diphenhydramine 50 mg (or equivalent) and/or acetaminophen 325 to 1000 mg should be administered 
at least 30 minutes before additional nivolumab administrations. If necessary, corticosteroids (up to 25 
mg of hydrocortisone or equivalent) may be used. 
For Grade 3 or Grade 4 symptoms (severe reaction, Grade 3: prolonged  [i.e., not rapidly responsive to 
symptomatic medication and/or brief interruption of infusion]; recurrence of symptoms following 
initial improvement; hospitalization indicated for other clinical sequelae [e.g., renal impairment, 
pulmonary infiltrates]. Grade 4: life-threatening; pressor or ventilator support indicated): Immediately 
discontinue infusion of nivolumab. Begin an IV infusion of normal saline, and treat the subject as 
follows: bronchodilators, epinephrine 0.2 to 1 mg of a 1:1,000 solution for subcutaneous administration 
or 0.1 to 0.25 mg of a 1:10,000 solution injected slowly for IV administration, and/or diphenhydramine 
50 mg IV with methylprednisolone 100 mg IV (or equivalent), as needed. Subject should be monitored 
until the investigator is comfortable that the symptoms will not recur. Nivolumab will be permanently 

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discontinued. Investigators should follow their institutional guidelines for the treatment of anaphylaxis. 
Remain at bedside and monitor subject until recovery from symptoms. 
In the case of late-occurring hypersensitivity symptoms (e.g., appearance of a localized or generalized 
pruritis within 1 week after treatment), symptomatic treatment may be given (e.g., oral antihistamine or 
corticosteroids). 
7.1.7 STOPPING RULES FOR TOXICITY 
A toxicity stopping rule will be implemented, and a 25% rate of serious adverse events will be 
considered unacceptable. If at least five of the first 18 subjects treated, or at least 11 of the 42 total 
patients enrolled, develop a non-skin-related Grade 3 or Grade 4 toxicity (attributable to nivolumab) 
that cannot be alleviated or controlled by appropriate care and/or steroid therapy within 14 days, 
accrual will be suspended until the investigators have reviewed the events and in consultation with 
BMS, determined whether to: 
• 
continue accrual as planned; 
• 
assess a lower dose of nivolumab; or 
• 
discontinue further enrollment. 
Subjects who received at least 1 dose of nivolumab will be evaluable for an analysis of toxicity. 
 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
Subjects MUST discontinue investigational product for any of the following reasons: 
• 
Withdrawal of informed consent (subject’s decision to withdraw for any reason) 
• 
Any clinical AE, laboratory abnormality or intercurrent illness which, in the opinion of the 
investigator, indicates that continued participation in the study is not in the best interest of the 
subject 
• 
Pregnancy 
• 
Termination of the study by Bristol-Myers Squibb (BMS) 
• 
Loss of ability to freely provide consent through imprisonment or involuntarily incarceration for 
treatment of either a psychiatric or physical (e.g., infectious disease) illness 
• 
Protocol defined reasons for discontinuation (Section 7.1.4) 
 
All subjects who discontinue study treatment will remain in the study and must continue to be followed 
for protocol specified follow-up procedures. The only exception to this requirement is when a subject 
withdraws consent for all study procedures including follow-up or loses the ability to consent freely (i.e., 
is imprisoned or involuntarily incarcerated for the treatment of either a psychiatric or physical illness). 
Subjects should notify the investigator of the decision to withdraw consent from future follow-up in 
writing, whenever possible. The withdrawal of consent should be explained in detail in the medical 
records by the investigator, as to whether the withdrawal is from further treatment with study drug only 
or also from study procedures and/or post treatment study follow-up and entered on the appropriate 
CRF page. If study treatment is discontinued prior to the subject’s completion of the study, the reason 
for discontinuation must be documented in the subject’s medical records and entered on the 
appropriate CRF page. 
7.3 
LOST TO FOLLOW-UP 

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All reasonable efforts must be made to locate subjects to determine and report their ongoing status. 
This includes follow-up with persons authorized by the subject. Lost to follow-up is defined by the 
inability to reach the subject after a minimum of three documented phone calls, faxes, or emails as well 
as lack of response by subject to one registered mail letter. All attempts should be documented in the 
subject’s medical records. If it is determined that the subject has died, the site will use permissible local 
methods to obtain the date and cause of death. 
 
 

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8 
STUDY ASSESSMENTS AND PROCEDURES 
8.1 
SCHEDULE OF ACTIVITIES (SOA) 
 
 
Pre Screening 
Pre-treatment 
Dose 1 (Week 0) 
Dose 2 (Week 2) 
Dose 3 (Week 4) 
Dose 4 (Week 6) 
Week 8 
Month 3 
Month 6 
Month 9 
Month 12 
FU*** 
PHYSICAL 
 
 
 
 
 
 
 
 
 
 
 
 
History and Physical 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height/Weight 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Smoking History 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Performance Status 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Toxicity Assessment 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
LABORATORY  
VALUES 
 
 
 
 
 
 
 
 
 
 
 
 
CBC 
 
X 
 
 
 
 
 
X 
X 
X 
X 
X 
Complete metabolic profile 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Thyroid function tests 
 
X 
 
 
 
 
 
X 
X 
X 
X 
X 
Research blood 
 
X 
 
 
 
 
X 
 
X 
 
 
 
Pregnancy Test 
 
  X* 
 
 
  
X* 
 
  
X* 
  
X* 
  
X* 
  
X* 
  
X* 
 
MISC. PROCEDURE 
 
 
 
 
 
 
 
 
 
 
 
 
Bronchoscopy/ 
Biopsies/BAL 
 
X 
 
 
 
 
X 
 
X 
 
 
 
Sputum 
X**** X 
 
 
 
 
X 
 
X 
 
 
 
CT chest 
 
X 
 
 
 
 
 
 
X* 
X* 
X* 
X* 
Urine** 
 
X 
 
 
 
 
X 
 
X 
 
 
 
TREATMENT 
 
 
 
 
 
 
 
 
 
 
 
 
Nivolumab 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
  *     If indicated 
**     Urine for banking   
***   Follow up: patients who have developed drug-related toxicities will have follow-up clinic visits 
monthly until the toxicity resolves, and then contacted yearly by telephone for 5 years. Patients who 
experience no toxicities will be followed yearly by telephone for 5 years. The telephone survey is 
attached (Appendix 3). 
**** Subjects who are current or ex-smokers with a > 30 pack year history of smoking will be offered 
a pre-consent consent form to collect sputum to determine if they are eligible for the trial. 
 
 
 

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8.2 
EFFICACY ASSESSMENTS 
All bronchoscopies will be performed at the RMR VAMC Screening/baseline bronchoscopy should be 
performed within 30 days prior to first dose of nivolumab. 
For this trial, each endobronchial biopsy will be scored using the histologic scale in Section 3.2.1, and a 
summary measure calculated which will be used as the histologic endpoint. The primary endpoint will be 
the change (follow-up – baseline) in the summary measure of worst (i.e. maximum) histology after 8 
weeks of nivolumab and at 6 months (to determine whether responses persist after discontinuation of 
nivolumab). The data from which these scores will be calculated are sets of all matched pairs of biopsies.  
Study procedures mandated to answer the primary endpoint include: 
1. Bronchoscopy (Baseline, Week 8, Month 6) 
• 
Study subjects will undergo a screening bronchoscopy with white-light bronchoscopy 
and either LIFE (laser-induced fluorescence endoscopy) or narrow-band imaging (NBI) 
after fasting for a minimum of six hours 
• 
The patient will be monitored with continuous electrocardiographic, respiratory, and 
oximetric monitoring, and with intermittent blood pressure monitoring 
• 
A complete endobronchial inspection will be performed and suspicious areas identified 
under fluorescence, narrow-band imaging, or white light will be biopsied 
• 
A Bronchoscopy Patient Communication Log Form is attached (Appendix 3) to follow-up 
with patients after the bronchoscopy is performed. Patients are called 24 hours and 72 
hours after the bronchoscopy and are instructed to call within 30 days if they develop 
fever, increased sputum production, increased shortness of breath, or any perceived 
deterioration of respiratory condition. 
2. Endobronchial biopsies (Baseline, Week 8, Month 6) 
• 
Biopsies will be taken from six predetermined sites (left and right upper lobe orifices, 
left and right superior segment orifices, carina between left upper lobe division and 
lingular orifices, and right middle lobe orifice). In addition, biopsies will be taken from 
any sites that appear suspicious under white light, fluorescence, or narrow-band 
imaging. 
• 
On follow-up bronchoscopies, all sites from the original bronchoscopy will be re-
biopsied, along with any new abnormal appearing areas under white light, fluorescence, 
or narrow-band imaging. 
• 
Biopsies will be formalin-fixed and paraffin-embedded for hematoxylin and eosin 
staining, as well as for immunohistochemical staining. 
• 
One or more biopsies may be cultured or snap frozen for protein, RNA or DNA analysis. 
• 
Depending on patient tolerance and operator discretion, endobronchial biopsies may be 
terminated at any time. However, an attempt will be made to biopsy between 6 and 12 
sites on each patient during each bronchoscopy. Additional sites may be biopsied if 
deemed clinically indicated but more than 12 endobronchial biopsies will not be 
routinely taken. 
All research samples will be stored at the SPORE Tissue Bank located within the Biorepository Core 
Facility on the University of Colorado Anschutz Medical Campus. 

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8.3 
SAFETY ASSESSMENTS 
At baseline, a medical history will be obtained to capture relevant underlying conditions. The baseline 
examinations should be performed within 14 days prior to first dose and should include signs and 
symptoms, weight, height, ECOG Performance Status, blood pressure, heart rate, temperature, and 
oxygen saturation by pulse oximetry at rest. Smoking history and concomitant medications will also be 
collected from within 14 days prior to first dose and through the study period (See Schedule of Activities 
Table in Section 8.1). 
Subjects will be evaluated for safety and toxicity assessments will be continuous during the treatment 
phase. During the follow-up phase, toxicity assessments should be done in person. 
Adverse events and laboratory values will be graded according to the NCI-CTCAE version 4.0. 
Vital signs, body weight, and ECOG performance status should be assessed at each on study visit prior to 
nivolumab dosing. Vital signs should also be taken as per institutional standard of care prior to, during 
and after nivolumab dosing. Oxygen saturation by pulse oximetry at rest should be assessed at each on 
study visit prior to nivolumab dosing. The start and stop time of the study drug infusion should be 
documented. Physical examinations are to be performed as clinically indicated. If there are any new or 
worsening clinically significant changes since the last exam, report changes on the appropriate non-
serious or serious adverse event page. 
Baseline laboratory assessments should be done within 14 days prior to the first dose and include: 
complete blood count (CBC) with differential, comprehensive metabolic panel (CMP: sodium, potassium, 
bicarbonate, BUN, creatinine, glucose, calcium, total protein, albumin, total bilirubin, AST, ALT, alkaline 
phosphatase), TSH (thyroid-stimulating hormone), free T4, and total T3 levels. Pregnancy testing for 
WOCBP must be performed within 72 hours prior to the initial administration of study drug at baseline, 
then every 4 weeks during the treatment phase (week 0 – week 8), and then at the follow-up visits 
(months 3, 6, 9, and 12). CMP should be drawn within 72 hours prior to each subsequent scheduled 
cycle and then at the follow-up visits. CBC with differential, TSH, free T4, and total T3 levels should be 
drawn every 3 months. Additional measures including non-study required laboratory tests should be 
performed as clinically indicated. 
Laboratory toxicities (e.g., suspected drug induced liver enzyme elevations) will be monitored during the 
follow-up phase until all study drug related toxicities resolve, return to baseline, or are deemed 
irreversible. 
Pulse oximetry should be obtained prior to each dose of nivolumab and at any time a subject has any 
new or worsening respiratory symptoms. A reading at rest and on exertion should be obtained at each 
time point. The extent of the exertion should be based on the judgment of the investigator, but should 
remain consistent for each individual subject throughout the study. If the patient’s status changes, the 
investigator can alter the extent of exertion based on their medical judgment. If a subject shows 
changes on pulse oximetry or other pulmonary-related signs (hypoxia, fever) or symptoms (e.g., 
dyspnea, cough, fever) consistent with possible pulmonary adverse events, the patient should be 
immediately evaluated to rule out pulmonary toxicity. An algorithm for the management of suspected 
pulmonary toxicity can be found in Appendix 2. 
Safety assessments will be performed at the site of enrollment/nivolumab infusion (i.e., research 
subjects enrolled at UCHealth will undergo physical examinations, medical histories, and laboratory 

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assessments at UCHealth; research subjects enrolled at the RMR VAMC will undergo physical 
examinations, medical histories, and laboratory assessments at the RMR VAMC). 
8.4 
EXPLORATORY ASSESSMENTS 
An important aspect of this trial is to identify novel prognostic and predictive markers present at the 
time of diagnosis. As such, sputum, CT chest, endobronchial biopsies, endobronchial brushings, 
bronchoalveolar lavages, and peripheral blood will also be collected throughout the study period. The 
markers to be assessed will be determined according to the best scientific knowledge and technology 
available. Correlative studies will be interpreted as hypothesis-generating data, to be validated in 
subsequent trials. 
All research samples from both institutions (including bronchoscopy specimens; research urine, blood, 
and sputum) will be stored at the SPORE Tissue Bank located within the Biorepository Core Facility on 
the University of Colorado Anschutz Medical Campus. 
8.4.1.1 SPUTUM INFLAMMATORY CELL ANALYSIS 
For subjects without prior history of lung cancer or prior history of head and neck cancer, sputum 
cytology will be obtained if a specimen has not been obtained within 3 months of study entry.  
Subjects who are current or ex-smokers with a > 30 pack year history of smoking will be offered a pre-
consent form to collect sputum to determine if they are eligible for the trial.  Subjects will be asked to 
perform an early morning sputum collection over a six day period (Appendix 4). The sputum will be 
collected in a container containing a mild, methanol-based Carnoy’s fixative that will preserve antigen 
epitopes in an unaltered state. Sputum samples will be collected by research subjects at home and 
mailed directly to the SPORE Tissue Bank. Incoming sputum specimens will be processed by a 
cytotechnologist using the Saccomanno two slide pull technique. Two slides will be stained by the 
Papanicolaou method and screened by both a cytotechnologist and by the study pathologist. 
In addition to determining whether subjects should undergo screening bronchoscopy to evaluate for 
bronchial dysplasia, sputa collected during this study provide an excellent resource to assess the 
potential value of using these specimens for non-invasive predictive testing. Initial analyses will focus on 
comparing the features of the inflammatory cells with those seen in the biopsy tissue to determine how 
closely the inflammatory cells in sputa represent the findings seen in the bronchial dysplastic lesions. 
Secondary analyses will focus on identifying a signature in sputa that predicts response to nivolumab.  
8.4.1.2 RADIOLOGIC MARKERS 
In subjects without prior history of lung cancer or prior history of head and neck cancer, but with ≥ 30 
pack-year smoking history and sputum atypia, CT scanning of the chest will be performed as standard of 
care to evaluate for evidence of lung cancer. In subjects who have undergone curative-intent surgical 
resection of lung cancer or of head and neck cancer, CT scanning of the chest will be performed as 
standard of care for follow-up and surveillance. CT scans will be obtained at the site of enrollment (i.e., 
research subjects enrolled at UCHealth will undero CT scans at UCHealth, and research subjects enrolled 
at the RMR VAMCwill undergo CT scans at the RMR VAMC). 
Participants found to have no nodules and definitely benign nodules (Lung-RADS category 1), nodules 
with benign appearance (Lung-RADS category 2), or nodules that are probably benign (Lung-RADS 

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category 3) are eligible for this trial. CT scans for subjects in this trial may be used in future efforts to 
utilize advanced segmentation and quantitative analysis beyond size criteria for better discrimination of 
pulmonary nodules. 
Participants with findings on CT chest suspicious for lung cancer (Lung-RADS category 4) will be referred 
for additional evaluation designed to confirm the presence of the finding and the likelihood of lung 
cancer by documenting growth characteristics and morphology. Participants with suspected malignancy 
will not be allowed to enroll in this trial and undergo treatment with nivolumab until they have 
undergone additional evaluation. The intention of all subsequent management will be to confirm the 
presence of malignancy, establish clinical stage, and to attempt curative resection or optimal treatment. 
These efforts will be under the direction of the participant’s treating physicianand may involve 
percutaneous lung (or other organ) needle aspiration biopsy, bronchoscopic sampling, thoracoscopic-
directed or open biopsy, or nodal sampling with endobronchial ultrasound, transcervical 
mediastinoscopy, or thoracotomy. 
Participants found to have abnormalities of clinical significance unrelated to lung cancer will be referred 
to their physician according to standard practices. Sites may or may not provide recommendations for 
further evaluation depending upon their local practice. The management of these participants is beyond 
the scope of this trial. 
8.4.1.3 SAMPLES OBTAINED DURING BRONCHOSCOPY 
8.4.1.3.1 ENDOBRONCHIAL BIOPSY-BASED BIOMARKER MEASURES 
Expression of PD-L1 and PD-1, characterization of inflammatory infiltrates, and total mutational burden 
analysis of bronchial dysplastic lesions will be performed on endobronchial biopsies as described in 
Section 3.2.3. 
8.4.1.3.2 ENDOBRONCHIAL BRUSHINGS 
A cytology brush will be placed in a microcentrifuge tube containing 0.5 mL Trizol reagent, labeled with a 
non-identifiable subject ID and time-point (baseline, Week 8, or Month 6), snap-frozen in liquid nitrogen 
and stored at < -70°C. 
A second cytology brush, if available, will be placed in a microcentrifuge tube containing 0.5 mL cell lysis 
reagent (RIPA buffer supplemented with protease inhibitors), labeled with a non-identifiable subject ID 
and time-point (enrollment, immediately post-treatment, or 6 months), frozen and stored at < -70°C. 
Samples should be maintained at < -70°C until a sufficient number has been collected for a batch 
shipment. 
Additional brush biopsies, one normal and one suspicious, will be obtained under direct visualization. 
Brushes will be placed in Saccomanno’s fixative. An aliquot will be removed for cytological examination 
and differential. 
8.4.1.3.3 BRONCHOALVEOLAR LAVAGE 

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Depending on patient tolerance and operator discretion, after biopsies are completed, the 
bronchoscope will be wedged in the right middle lobe or lingular orifice. Aliquots of 30 mL sterile saline 
will be sequentially instilled and retrieved by gentle suction, pooled, and placed on ice for later analysis 
and storage. Percent recovery will be recorded.  
8.4.1.3.4 BRONCHIAL SECRETIONS 
During the bronchoscopy procedure, bronchial secretions will be suctioned, collected, and saved for 
cytological and biomarker analyses. 
8.4.1.4 PERIPHERAL BLOOD MARKERS 
In this study, we will collect and store approximately 30 mL of peripheral blood for future potential 
biomarker analysis. A variety of factors that could potentially predict clinical response to nivolumab will 
be investigated in peripheral blood from subjects as described in Section 3.2.3. Candidate markers to be 
evaluated may include (depending on specimen availability and resources): 
 
1. Exploratory serum biomarkers 
2. Characterization and immunophenotyping of immune cell populations in peripheral blood by 
mass cytometry 
3. Peripheral T cell repertoire analysis 
8.4.1.5 URINE 
Urine will be collected and adjusted to a final concentration of 2N glacial acetic acid and stored at –70C 
for future biomarker testing. 
8.5 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
 
8.5.1 ADVERSE EVENTS (AE) 
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a preexisting 
medical condition in a clinical investigation participant administered study drug and that does not 
necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and 
unintended sign (such as an abnormal laboratory finding), symptom, or disease temporally associated 
with the use of investigational product, whether or not considered related to the investigational 
product.  
8.5.2 CLASSIFICATION OF AN ADVERSE EVENT 
8.5.2.1 SEVERITY OF EVENT 
Adverse events (AEs) will be assessed by the clinician using Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.0 (https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_5x7.pdf  [Accessed on: December 21, 2016]) 

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For AEs not included in the protocol-defined grading system, the following guidelines will be used to 
describe severity. 
• 
Mild – Events require minimal or no treatment and do not interfere with the participant’s 
daily activities. 
• 
Moderate – Events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning. 
• 
Severe – Events interrupt a participant’s usual daily activity and may require systemic drug 
therapy or other treatment. Severe events are usually potentially life-threatening or 
incapacitating. 
 
8.5.2.2 RELATIONSHIP TO STUDY INTERVENTION 
The causal relationship to study drug is determined by a physician and should be used to assess all 
adverse events (AE). The casual relationship can be one of the following: 
Related: There is a reasonable causal relationship between study drug administration and the 
AE. 
Not related: There is not a reasonable causal relationship between study drug administration 
and the AE.  
The term "reasonable causal relationship" means there is evidence to suggest a causal relationship.  
Adverse events can be spontaneously reported or elicited during open-ended questioning, examination, 
or evaluation of a subject. (In order to prevent reporting bias, subjects should not be questioned 
regarding the specific occurrence of one or more AEs.) 
8.5.3 SERIOUS ADVERSE EVENTS (SAE)  
8.5.3.1 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE) 
A Serious Adverse Event (SAE) is any untoward medical occurrence that:  
• 
results in death 
• 
is life-threatening (defined as an event in which the participant was at risk of death at the time of 
the event; it does not refer to an event which hypothetically might have caused death if it were 
more severe) 
• 
requires inpatient hospitalization or causes prolongation of existing hospitalization (see NOTE 
below) 
• 
results in persistent or significant disability/incapacity 
• 
is a congenital anomaly/birth defect  
• 
is an important medical event (defined as a medical event(s) that may not be immediately life-
threatening or result in death or hospitalization but, based upon appropriate medical and scientific 
judgment, may jeopardize the subject or may require intervention [eg, medical, surgical] to prevent 
one of the other serious outcomes listed in the definition above.) Examples of such events include, 

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but are not limited to, intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization.)  
Suspected transmission of an infectious agent (e.g., pathogenic or nonpathogenic) via the study drug is 
an SAE.  
Although pregnancy, overdose, potential drug-induced liver injury (DILI), and cancer are not always 
serious by regulatory definition, these events must be handled as SAEs. 
The following hospitalizations are not considered SAEs:  
− 
a visit to the emergency room or other hospital department < 24 hours, that does not result in 
admission (unless considered an important medical or life-threatening event) 
− 
elective surgery, planned prior to signing consent 
− 
admissions as per protocol for a planned medical/surgical procedure 
− 
routine health assessment requiring admission for baseline/trending of health status (e.g., routine 
colonoscopy) 
− 
medical/surgical admission other than to remedy ill health and planned prior to entry into the 
study. Appropriate documentation is required in these cases. 
− 
admission encountered for another life circumstance that carries no bearing on health status and 
requires no medical/surgical intervention (e.g., lack of housing, economic inadequacy, caregiver 
respite, family circumstances, administrative reason). 
8.5.3.2 SERIOUS ADVERSE EVENT COLLECTION AND REPORTING 
All Serious Adverse Events (SAEs) that occur following the subject’s written consent to participate in the 
study through 100 days of discontinuation of dosing must be reported to BMS Worldwide Safety, 
whether related or not related to study drug. If applicable, SAEs must be collected that relate to any 
later protocol-specified procedure (e.g., a follow-up skin biopsy). 
Following the subject’s written consent to participate in the study, all SAEs, whether related or not related 
to study drug, are collected, including those thought to be associated with protocol-specified procedures. 
The investigator should report any SAE occurring after these aforementioned time periods, which is 
believed to be related to study drug or protocol-specified procedure.  
An SAE report should be completed for any event where doubt exists regarding its seriousness;  
If the investigator believes that an SAE is not related to study drug, but is potentially related to the 
conditions of the study (such as withdrawal of previous therapy or a complication of a study procedure), 
the relationship should be specified in the narrative section of the SAE Report Form. 
SAEs, whether related or not related to study drug, and pregnancies must be reported to BMS within 24 
hours. SAEs must be recorded on the SAE Report Form; pregnancies must be reported on a Pregnancy 
Surveillance Form. 
SAE Email Address:  Worldwide.Safety@BMS.com 
SAE Facsimile Number:  +1 609-818-3804 

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If only limited information is initially available, follow-up reports are required. (Note: Follow-up SAE 
reports should include the same investigator term(s) initially reported.)  
If an ongoing SAE changes in its intensity or relationship to study drug or if new information becomes 
available, a follow-up SAE report should be sent within 24 hours to BMS (or designee) using the same 
procedure used for transmitting the initial SAE report.  
All SAEs should be followed to resolution or stabilization. 
8.5.4 NON-SERIOUS ADVERSE EVENTS 
8.5.4.1 DEFINITION OF NON-SERIOUS ADVERSE EVENTS 
A non-serious adverse event is an AE not classified as serious.  
8.5.4.2 NON-SERIOUS ADVERSE EVENT COLLECTION AND REPORTING 
The collection of non-serious AE information should begin at initiation of study drug. All non-serious 
adverse events (not only those deemed to be treatment-related) should be collected continuously 
during the treatment period and for a minimum of 30 days following the last dose of study treatment.  
Non-serious AEs should be followed to resolution or stabilization, or reported as SAEs if they become 
serious. Follow-up is also required for non-serious AEs that cause interruption or discontinuation of 
study drug and for those present at the end of study treatment as appropriate.  
 
8.5.5 LABORATORY TEST ABNORMALITIES 
All laboratory test results captured as part of the study should be recorded on the nonserious AE CRF 
page or SAE Report Form. Test results that constitute SAEs should be documented and reported as such. 
The following laboratory abnormalities should be documented and reported appropriately: 
• 
any laboratory test result that is clinically significant or meets the definition of an SAE 
• 
any laboratory abnormality that required the participant to have study drug discontinued or 
interrupted 
• 
any laboratory abnormality that required the subject to receive specific corrective therapy.  
It is expected that wherever possible, the clinical rather than laboratory term would be used by the 
reporting investigator (e.g., anemia versus low hemoglobin value). 
8.5.6 POTENTIAL DRUG INDUCED LIVER INJURY (DILI) 
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should occur 
prior to the reporting of a potential DILI event. All occurrences of potential DILIs, meeting the defined 
criteria, must be reported as SAEs. 

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Potential drug induced liver injury is defined as:  
1) ALT or AST elevation > 3 times upper limit of normal (ULN) 
AND 
2) Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase) 
AND 
3) No other immediately apparent possible causes of AT elevation and hyperbilirubinemia, including, 
but not limited to, viral hepatitis, pre-existing chronic or acute liver disease, or the administration of 
other drug(s) known to be hepatotoxic. 
8.5.7 PREGNANCY 
If, following initiation of the investigational product, it is subsequently discovered that a study 
participant is pregnant or may have been pregnant at the time of investigational product exposure, 
including during at least 5 half-lives after product administration, the investigational product will be 
permanently discontinued.  
The investigator must immediately notify Worldwide.Safety@bms.com of this event via the Pregnancy 
Surveillance Form in accordance with SAE reporting procedures.  
Protocol-required procedures for study discontinuation and follow-up must be performed on the 
participant. 
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal outcome 
and, where applicable, offspring information must be reported on the Pregnancy Surveillance Form 
[provided upon request from BMS]. 
Any pregnancy that occurs in a female partner of a male study participant should be reported to BMS. 
Information on this pregnancy will be collected on the Pregnancy Surveillance Form. In order for 
Sponsor or designee to collect any pregnancy surveillance information from the female partner, the 
female partner must sign an informed consent form for disclosure of this information.  
8.5.8 OVERDOSE 
An overdose is defined as the accidental or intentional administration of any dose of a product that is 
considered both excessive and medically important. All occurrences of overdose must be reported as an 
SAE. 
8.5.9 OTHER SAFETY CONSIDERATIONS 
Any significant worsening noted during interim or final physical examinations, electrocardiograms, X-
rays, and any other potential safety assessments, whether or not these procedures are required by the 
protocol, should also be recorded as a non-serious or serious AE, as appropriate, and reported 
accordingly.  

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9 
STATISTICAL CONSIDERATIONS  
The primary endpoint of this single-arm phase II trial is the dichotomous endpoint of whether or not a 
subject responds to treatment. Response to treatment will be based on the 6-month change (difference 
between 6-month score and baseline score) in worst (i.e. maximum) histologic classification score, using 
the 2004 WHO classification scale for endobronchial dysplasia. The data from which these scores will be 
calculated are sets of all matched pairs of biopsies. A positive treatment response will be defined as 
improvement in bronchial dysplasia by ≥1.0 histology unit. 
We have analyzed histology endpoints from two completed SPORE chemoprevention trials, in which 
patients with a 30 pack-year or more smoking history and sputum atypia were randomized to receive 
study drug or placebo for 6 months. Patients underwent a baseline bronchoscopy followed by a 
bronchoscopy at 6 months. Results from the two completed chemoprevention trials (oral iloprost and 
oral pioglitazone) were used to estimate the response rate in un-treated subjects (i.e., the null response 
rate, p0). Of 71 subjects treated with placebo who had baseline histology scores ≥ 4.0, 21 subjects had 
improvement in their bronchial dysplasia by ≥1.0 histology unit. Thus, we estimate that the null 
response rate (p0) is 0.30 (21/71). 
Simon’s two-stage design will be used. The null hypothesis that the true response rate is 0.30 will be tested 
against a 1-sided alternative.  In the first stage 18 subjects will be enrolled.  If there are 6 or fewer 
responses in these 18 subjects, the study will be stopped. Otherwise, if there are 7 or more responses 
among the first 18 subjects, 24 additional subjects will be enrolled for a total of 42 subjects. The trial will 
continue to the total of 42 subjects as soon as the 7th response is observed, so there will not be a delay 
when proceeding to the 2nd cohort of the trial if the 7th response occurs prior to the 18th subject.  If 17 or 
fewer subjects are responders at the end of the trial, no further investigation of the drug is warranted. The 
null hypothesis will be rejected if 18 or more responses are observed in the 42 total subjects. This design 
has 80.2% power to reject the null hypothesis when the true response rate is 0.50, controlling the type I 
error rate at 0.05 (actual =0.044). Based on our experience with other chemoprevention trials (13 cis-
retinoic acid, pioglitazone, and iloprost), there is typically a 10% drop out rate. To account for subjects who 
drop out, we expect to enroll six additional subjects (48 total) to obtain 42 evaluable subjects. This trial 
plans to enroll half of the subjects (24) with > 30 pack-year history of smoking and sputum cytologic atypia, 
and the other half of the subjects with history of early stage lung or early stage head and neck cancer. 
The expected accrual rate for this study is approximately 1-2 patients every month with an estimated 
study length of approximately 3 years. 
Subjects will be eligible for an analysis of nivolumab efficacy (change in bronchial dysplasia) if they meet 
the following criteria: (1) underwent baseline bronchoscopy and endobronchial biopsies, (2) received at 
least one dose of nivolumab, and (3) underwent one protocol-defined follow up bronchoscopic 
examination to evaluate response to therapy. Subjects who do not meet these criteria or who do not 
have a 6-month bronchoscopy will be replaced and will not count towards the Simon two-stage design, 
because change in histology score at 6 months is the primary endpoint. 
The analysis population for efficacy is the full analysis set. Subjects who complete 4 doses of nivolumab 
will also be analyzed separately. Subset analyses according to history of cancer and smoking status are 
also planned. 

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Safety analyses will be performed in all subjects who receive nivolumab. Descriptive statistics of safety 
will be presented using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0. All on-study AEs, Grade 3-4 AEs, treatment-related AEs, Grade 3-4 treatment-
related AEs, SAEs, treatment-related SAEs, and AEs leading to discontinuation will be tabulated using 
worst grade per NCI CTCAE v 4.0 criteria by system organ class and preferred term. On-study lab 
parameters including hematology, chemistry, liver function, and renal function, and Grade 3-4 Lab 
Abnormalities will be summarized using worst grade NCI CTCAE v 4.0 criteria.  
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
 
10.1 ETHICAL CONSIDERATIONS 
 
10.1.1 GOOD CLINICAL PRACTICE 
This study will be conducted in accordance with Good Clinical Practice (GCP), as defined by the 
International Conference on Harmonisation (ICH) and in accordance with the ethical principles 
underlying European Union Directive 2001/20/EC and the United States Code of Federal Regulations, 
Title 21, Part 50 (21CFR50). 
The study will be conducted in compliance with the protocol. The protocol and any amendments and 
the subject informed consent will receive IRB/IEC approval/favorable opinion prior to initiation of the 
study. 
All potential serious breaches must be reported to BMS immediately. A serious breach is a breach of the 
conditions and principles of GCP in connection with the study or the protocol, which is likely to affect, to 
a significant degree, the safety or physical or mental integrity of the subjects of the study or the 
scientific value of the study. 
Study personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective task(s). 
This study will not use the services of study personnel where sanctions have been invoked or where 
there has been scientific misconduct or fraud (e.g., loss of medical licensure, debarment). 
 
10.1.2 INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE 
 
Before study initiation, the investigator must have written and dated approval/favorable opinion from 
the IRB/IEC for the protocol, consent form, subject recruitment materials/process (e.g., advertisements), 
and any other written information to be provided to subjects. The investigator or sponsor should also 
provide the IRB/IEC with a copy of the Investigator Brochure or product labeling, information to be 
provided to subjects, and any updates. 
The investigator or sponsor should provide the IRB/IEC with reports, updates, and other information 
(e.g., expedited safety reports, amendments, and administrative letters) according to regulatory 
requirements or institutional procedures. 
 
10.1.3 INFORMED CONSENT 

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Investigators must ensure that subjects, or, in those situations where consent cannot be given by 
subjects, their legally acceptable representatives, are clearly and fully informed about the purpose, 
potential risks, and other critical issues regarding clinical studies in which they volunteer to participate. 
BMS will provide the investigator with an appropriate (i.e., Global or Local) sample informed consent 
form which will include all elements required by ICH, GCP, and applicable regulatory requirements. The 
sample informed consent form will adhere to the ethical principles that have their origin in the 
Declaration of Helskinki. 
Investigators must: 
1. Provide a copy of the consent form and written information about the study in the language in 
which the subject is most proficient prior to clinical study participation. The language must be non-
technical and easily understood. 
2. Allow time necessary for subject or subject’s legally acceptable representative to inquire about the 
details of the study. 
3. Obtain an informed consent signed and personally dated by the subject or the subject’s legally 
acceptable representative and by the person who conducted the informed consent discussion. 
4. Obtain the IRB/IEC’s written approval/favorable opinion of the written informed consent form and 
any other information to be provided to the subjects, prior to the beginning of the study, and after 
any revisions are completed for new information. 
5. If informed consent is initially given by a subject’s legally acceptable representative or legal 
guardian, and the subject subsequently becomes capable of making and communicating their 
informed consent during the study, then consent must additionally be obtained from the subject. 
6. Revise the informed consent whenever important new information becomes available that is 
relevant to the subject’s consent. The investigator, or a person designated by the investigator, 
should fully inform the subject or the subject’s legally acceptable representative or legal guardian, of 
all pertinent aspects of the study and of any new information relevant to the subject’s willingness to 
continue participation in the study. This communication should be documented. 
The confidentiality of records that could identify subjects must be protected, respecting the privacy and 
confidentiality rules applicable to regulatory requirements, the subjects’ signed ICF and, in the US, the 
subjects’ signed HIPAA Authorization. 
The consent form must also include a statement that BMS and regulatory authorities have direct access 
to subject records. 
Subjects unable to give their written consent (e.g., stroke patients, or subjects with severe dementia) 
may only be enrolled in the study with the consent of a legally acceptable representative. The subject 
must also be informed about the nature of the study to the extent compatible with the subjects’  
understanding, and should they become capable, personally sign and date the consent form as soon as 
possible. The explicit wish of a subject unable to give his or her written consent, who is capable of 
forming an opinion and assessing this information to refuse participation in, or to be withdrawn from, 
the clinical study at any time should be considered by the investigator. 
The rights, safety, and well-being of the study subjects are the most important considerations and 
should prevail over interests of science and society. 
 

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10.2 STUDY MANAGEMENT 
 
10.2.1 COMPLIANCE 
 
10.2.1.1 COMPLIANCE WITH THE PROTOCOL AND PROTOCOL REVISIONS 
The study shall be conducted as described in this approved protocol. All revisions to the protocol must 
be discussed with, and be prepared by, Bristol-Myers Squibb (BMS). The investigator should not 
implement any deviation or change to the protocol without prior review and documented 
approval/favorable opinion from the Institutional Review Board/Independent Ethics Committee 
(IRB/IEC) of an amendment, except where necessary to eliminate an immediate hazard(s) to study 
subjects. 
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior to 
obtaining IRB/IEC approval/favorable opinion, as soon as possible the deviation or change will be 
submitted to: 
• 
IRB/IEC for review and approval/favorable opinion 
• 
Bristol-Myers Squibb 
• 
Regulatory authority(ies), if required by local regulations 
Documentation of approval signed by the chairperson or designee of the IRB(s)/IEC(s) must be sent to 
BMS. 
If an amendment substantially alters the study design or increases the potential risk to the subject: (1) 
the consent form must be revised and submitted to the IRB(s)/IEC(s) for review and approval/favorable 
opinion; (2) the revised form must be used to obtain consent from subjects currently enrolled in the 
study if they are affected by the amendment; and (3) the new form must be used to obtain consent 
from new subjects prior to enrollment. 
If the revision is an administrative letter, investigators must inform their IRB(s)/IEC(s). 
 
10.2.1.2 MONITORING AND OVERSIGHT 
The sponsor investigator will be responsible for monitoring the trial per the trial monitoring plan, in 
addition to overseeing the safety and efficacy of the trial including any specimens collected, executing 
the data and safety monitoring (DSM) plan, and complying with all reporting requirements to local and 
federal authorities. This oversight will be accomplished through additional oversight from the Data and 
Safety Monitoring Committee (DSMC) at the University of Colorado Cancer Center (CU Cancer Center). 
The DSMC is responsible for ensuring data quality and study participant safety for all clinical studies at 
the CU Cancer Center, which is the coordinating institution of this trial. A summary of the DSMC’s 
activities is as follows:  
• Conduct of internal audits  

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• Ongoing review of all serious adverse events (SAEs) and unanticipated problems (UAPs)  
• May submit recommendations for corrective actions to the CU Cancer Center’s Executive Committee  
Per the CU Cancer Center Institutional DSM Plan, SAEs and UAPs are reported to the DSMC, IRB and the 
sponsor investigator per protocol. All SAEs and UAPs are to be reported to the DSMC within 7 (for fatal 
or life-threatening events) or 15 (non-life-threatening events) calendar days of the sponsor investigator 
receiving notification of the occurrence. 
Each subject’s treatment outcomes will be discussed by the site PI and appropriate staff at regularly 
scheduled meetings. Data regarding number of subjects, significant toxicities, dose modifications, and 
treatment responses will be discussed and documented in the meeting’s minutes.  
The sponsor investigator will provide a DSM progress report to the CU Cancer Center DSMC on a 
recurring basis (either every six or twelve months based on DSMC vote). The DSM report will include a 
protocol summary, current enrollment numbers, summary of toxicity data to include specific SAEs, UAPs 
and AEs, any dose modifications, all protocol deviations, and protocol amendments. The DSM progress 
report submitted to the DSMC will also include, if applicable, the results of any efficacy data analysis 
conducted. Results and recommendations from the review of this progress report by the DSMC will then 
be provided to the sponsor investigator in a DSMC review letter. The sponsor investigator is then 
responsible for ensuring this letter is submitted to the site’s IRB of record at the time of IRB continuing 
review.  
10.2.1.3 QUALITY CONTROL AND QUALITY ASSURANCE 
Site monitoring visits will be performed by the sponsor investigator’s authorized representative on a 
regular basis, pursuant to the Monitoring Plan. During these visits, information recorded on the CRFs will 
be verified against source documents.  Additional computer programs that identify selected protocol 
deviations, out-of-range data, and other data errors within the electronic data entry may also be used to 
help monitor the study.  As necessary, requests for data clarification or correction will be sent to the 
appropriate site PI. 
Independent auditors from the sponsor investigator’s authorized representative will be allowed by the 
site’s PI to audit.  In addition, audits may be conducted at any time by appropriate regulatory authorities 
and/or the IRB. 
Representatives of BMS must be allowed to visit all study site locations periodically to assess the data 
quality and study integrity. On site they will review study records and directly compare them with 
source documents, discuss the conduct of the study with the investigator, and very that the facilities 
remain acceptable 
In addition, the study may be evaluated by BMS internal auditors and government inspectors who must 
be allowed access to CRFs, source documents, other study files, and study facilities. BMS audit reports 
will be kept confidential. 
The investigator must notify BMS promptly of any inspections scheduled by regulatory authorities, and 
promptly forward copies of inspection reports to BMS. 

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10.2.2 RECORDS 
10.2.2.1 
RECORDS RETENTION 
The investigator must retain all study records and source documents for the maximum period required 
by applicable regulations and guidelines, or institution procedures, or for the period specified by the 
sponsor, whichever is longer. The investigator must contact BMS prior to destroying any records 
associated with the study. 
BMS will notify the investigator when the study records are no longer needed. 
If the investigator withdraws from the study (e.g., relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (e.g., another investigator, IRB). Notice of such transfer 
will be given in writing to BMS.  
10.2.2.2 
STUDY DRUG RECORDS 
It is the responsibility of the investigator to ensure that a current disposition record of investigational 
product (those supplied by BMS) is maintained at each study site where study drug is inventoried and 
dispensed. Records or logs must comply with applicable regulations and guidelines, and should include: 
• 
Amount received and placed in storage area 
• 
Amount currently in storage area 
• 
Label identification number or batch number 
• 
Amount dispensed to and returned by each subject, including unique subject identifiers 
• 
Amount transferred to another area/site for dispensing or storage 
• 
Nonstudy disposition (e.g., lost, wasted) 
• 
Amount destroyed at study site, if applicable 
• 
Amount returned to BMS 
• 
Retain samples for bioavailability/bioequivalence, if applicable 
• 
Dates and initials of person responsible for Investigational Product dispensing/accountability, as per 
the Delegation of Authority Form 
BMS will provide forms to facilitate inventory control if the investigational site does not have an 
established system that meets these requirements. 
10.2.2.3 
CASE REPORT FORMS 
An investigator is required to prepare and maintain adequate and accurate case histories designed to 
record all observations and other data pertinent to the investigation on each individual treated in the 
investigation. Data reported on the CRF that are derived from source documents must be consistent 
with the source documents or the discrepancies must be explained. Additional clinical information may 
be collected and analyzed in an effort to enhance understanding of product safety. CRFs may be 
requested for AEs and/or laboratory abnormalities that are reported or identified during the course of 
the study. 

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For sites using the BMS electronic data capture tool, electronic CRFs will be prepared for all data 
collection fields except for fields specific to SAEs and pregnancy, which will be reported on the SAE form 
and Pregnancy Surveillance form, respectively. Spaces may be left blank only in those circumstances 
permitted by study-specific CRF completion guidelines provided by the sponsor. 
The confidentiality of records that could identify subjects must be protected, respecting the privacy and 
confidentiality rules in accordance with the applicable regulatory requirement(s). 
The investigator will maintain a signature sheet to document signatures and initials of all persons 
authorized to make entries and/or corrections on CRFs. 
The completed CRF, including any paper SAE/pregnancy CRFs, must be promptly reviewed, signed, and 
dated by a qualified physician who is an investigator or subinvestigator and who is delegated this task on 
the Delegation of Authority Form. For electronic CRFs, review and approval/signature is completed 
electronically through the BMS electronic data capture tool. The investigator must retain a copy of the 
CRFs including records of the changes and corrections. 
Each individual electronically signing electronic CRFs must meet BMS training requirements and must 
only access the BMS electronic data capture tool using the unique user account provided by the 
sponsor. User accounts are not to be shared or reassigned to other individuals. 
10.2.3 PUBLICATIONS 
 
The data collected during this study are confidential and proprietary to the sponsor. Any publications or 
abstracts arising from this study require approval by the sponsor prior to publication or presentation 
and must adhere to the sponsor’s publication requirements as set forth in the approved clinical trial 
agreement (CTA). All draft publications, including abstracts or detailed summaries of any proposed 
presentations, must be submitted to the sponsor at the earliest practicable time for review, but at any 
event not less than 30 days before submission or presentation unless otherwise set forth in the CTA. 
Sponsor shall have the right to delete any confidential or proprietary information contained in any 
proposed presentation or abstract and delay publication for up to 60 days for purposes of filing a patent 
application.  
11 ABBREVIATIONS 
The list below includes abbreviations utilized in this template.  However, this list should be customized for 
each protocol (i.e., abbreviations not used should be removed and new abbreviations used should be 
added to this list). 
 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
BD 
Bronchial Dysplasia 
BMS 
Bristol-Myers Squibb 
CFR 
Code of Federal Regulations 
CLIA 
Clinical Laboratory Improvement Amendments 
CMP 
Clinical Monitoring Plan 
COC 
Certificate of Confidentiality 
CONSORT Consolidated Standards of Reporting Trials 
CRF 
Case Report Form 

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CTA 
Clinical Trial Agreement 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTLA4 
Cytotoxic T-Lymphocyte Associated Protein 4 
DCC 
Data Coordinating Center 
DHHS 
Department of Health and Human Services 
DILI 
Drug Induced Liver Injury 
DSMB 
Data Safety Monitoring Board 
DRE 
Disease-Related Event 
DSM 
Data and Safety Monitoring 
DSMC 
Data and Safety Monitoring Committee 
DVAMC 
Denver Veterans Affairs Medical Center 
EC 
Ethics Committee 
eCRF 
Electronic Case Report Forms 
FDA 
Food and Drug Administration 
FDAAA 
Food and Drug Administration Amendments Act of 2007 
FFR 
Federal Financial Report 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices 
GMP 
Good Manufacturing Practices 
GWAS 
Genome-Wide Association Studies 
HIPAA 
Health Insurance Portability and Accountability Act  
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation  
ICMJE 
International Committee of Medical Journal Editors 
IDE 
Investigational Device Exemption 
IEC 
Independent Ethics Committee 
IF 
Immunofluorescence 
IND 
Investigational New Drug Application 
irAEs 
Immune Related Adverse Events 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
ISO 
International Organization for Standardization 
ITT 
Intention-To-Treat 
IUD 
Intrauterine Device 
LFTs 
Liver Function Tests 
LIFE 
Laser Induced Fluorescence Endoscopy 
LSMEANS 
Least-squares Means 
MedDRA 
Medical Dictionary for Regulatory Activities 
MOP 
Manual of Procedures 
MSDS 
Material Safety Data Sheet 
NAC 
N-Acetylcysteine 
NBI 
Narrow-band imaging 
NCI 
National Cancer Institute 
NCT 
National Clinical Trial 
NIH  
National Institutes of Health 

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NIH IC 
NIH Institute or Center 
NSCLC 
Non-Small Cell Lung Cancer 
OHRP 
Office for Human Research Protections 
ORR 
Objective Response Rate 
OS 
Overall Survival 
PD-1 
Programmed Death Receptor 1 
PFS 
Progression Free Survival 
PI 
Principal Investigator 
QA 
Quality Assurance 
QC 
Quality Control 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SMC 
Safety Monitoring Committee 
SOA 
Schedule of Activities 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
Th1 
T-Helper 1 
Th2 
T-Helper 2 
TIL 
Tumor-Infiltrating Lymphocyte 
TME 
Tumor Microenvironment 
TSH 
Thyroid-Stimulating Hormone 
ULN 
Upper Limit of Normal 
UP 
Unanticipated Problem 
US 
United States 
WHO 
World Health Organization 
WOBCP 
Women of Childbearing Potential 
 
 

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27. Iwai Y, Okazaki T, Nishimura H, Kawasaki A, Yagita H, Honjo T. Microanatomical localization of PD-1 in human 
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Nonsquamous Non-Small-Cell Lung Cancer. The New England journal of medicine 2015. 
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Advanced Squamous-Cell Non-Small-Cell Lung Cancer. The New England journal of medicine 2015;373(2):123-35. 
30. Topalian SL, Sznol M, McDermott DF, Kluger HM, Carvajal RD, Sharfman WH, et al. Survival, durable tumor 
remission, and long-term safety in patients with advanced melanoma receiving nivolumab. Journal of clinical 
oncology : official journal of the American Society of Clinical Oncology 2014;32(10):1020-30. 
31. Gettinger SN, Horn L, Gandhi L, Spigel DR, Antonia SJ, Rizvi NA, et al. Overall Survival and Long-Term Safety of 
Nivolumab (Anti-Programmed Death 1 Antibody, BMS-936558, ONO-4538) in Patients With Previously Treated 
Advanced Non-Small-Cell Lung Cancer. Journal of clinical oncology : official journal of the American Society of Clinical 
Oncology 2015;33(18):2004-12. 
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Nonsquamous Non-Small-Cell Lung Cancer. The New England journal of medicine 2015;373(17):1627-39. 

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33. Reck M, Rodriguez-Abreu D, Robinson AG, Hui R, Csoszi T, Fulop A, et al. Pembrolizumab versus Chemotherapy 
for PD-L1-Positive Non-Small-Cell Lung Cancer. The New England journal of medicine 2016;375(19):1823-33. 
34. Herbst RS, Baas P, Kim DW, Felip E, Perez-Gracia JL, Han JY, et al. Pembrolizumab versus docetaxel for previously 
treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet 
2016;387(10027):1540-50. 
35. Rittmeyer A, Barlesi F, Waterkamp D, Park K, Ciardiello F, von Pawel J, et al. Atezolizumab versus docetaxel in 
patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised 
controlled trial. Lancet 2017;389(10066):255-65. 
36. Fehrenbacher L, Spira A, Ballinger M, Kowanetz M, Vansteenkiste J, Mazieres J, et al. Atezolizumab versus 
docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 
2 randomised controlled trial. Lancet 2016;387(10030):1837-46. 
37. Gooden MJ, de Bock GH, Leffers N, Daemen T, Nijman HW. The prognostic influence of tumour-infiltrating 
lymphocytes in cancer: a systematic review with meta-analysis. British journal of cancer 2011;105(1):93-103. 
38. Forde PM, Smith KN, Chaft JE, Hellmann M, Merghoub T, Wolchok JD, et al. Neoadjuvant anti-PD1, nivolumab, 
in early stage resectable non-small-cell lung cancer. 2016 ESMO Congress. Abstract LBA41_PR. Presented October 7, 
2016. Ann Oncol 2016;27(Supplement 6). 
39. Neville BW, Day TA. Oral cancer and precancerous lesions. CA: a cancer journal for clinicians 2002;52(4):195-215. 
40. Kamata T, Jin H, Giblett S, Patel B, Patel F, Foster C, et al. The cholesterol-binding protein NPC2 restrains 
recruitment of stromal macrophage-lineage cells to early-stage lung tumours. EMBO molecular medicine 
2015;7(9):1119-37. 
41. Hatam LJ, Devoti JA, Rosenthal DW, Lam F, Abramson AL, Steinberg BM, et al. Immune suppression in 
premalignant respiratory papillomas: enriched functional CD4+Foxp3+ regulatory T cells and PD-1/PD-L1/L2 
expression. Clinical cancer research : an official journal of the American Association for Cancer Research 
2012;18(7):1925-35. 
42. Schietinger A, Philip M, Krisnawan VE, Chiu EY, Delrow JJ, Basom RS, et al. Tumor-Specific T Cell Dysfunction Is a 
Dynamic Antigen-Driven Differentiation Program Initiated Early during Tumorigenesis. Immunity 2016;45(2):389-
401. 
43. Spitz MR, Etzel CJ, Dong Q, Amos CI, Wei Q, Wu X, et al. An expanded risk prediction model for lung cancer. 
Cancer prevention research 2008;1(4):250-4. 
44. Bach PB, Kattan MW, Thornquist MD, Kris MG, Tate RC, Barnett MJ, et al. Variations in lung cancer risk among 
smokers. J Natl Cancer Inst 2003;95(6):470-8. 
45. Johnson BE. Second lung cancers in patients after treatment for an initial lung cancer. J Natl Cancer Inst 
1998;90(18):1335-45. 
46. Rizvi NA, Hellmann MD, Snyder A, Kvistborg P, Makarov V, Havel JJ, et al. Cancer immunology. Mutational 
landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 2015;348(6230):124-8. 
47. Franklin WA. Diagnosis of lung cancer: pathology of invasive and preinvasive neoplasia. Chest 2000;117(4 Suppl 
1):80S-89S. 
48. Auerbach O, Stout AP, Hammond EC, Garfinkel L. Changes in bronchial epithelium in relation to sex, age, 
residence, smoking and pneumonia. The New England journal of medicine 1962;267:111-9. 

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49. Auerbach O, Forman JB, Gere JB, Kassouny DY, Muehsam GE, Petrick TG, et al. Changes in the bronchial 
epithelium in relation to smoking and cancer of the lung; a report of progress. The New England journal of medicine 
1957;256(3):97-104. 
50. Johnson DB, Frampton GM, Rioth MJ, Yusko E, Xu Y, Guo X, et al. Targeted Next Generation Sequencing Identifies 
Markers of Response to PD-1 Blockade. Cancer Immunol Res 2016;4(11):959-67. 
51. Rosenberg JE, Hoffman-Censits J, Powles T, van der Heijden MS, Balar AV, Necchi A, et al. Atezolizumab in patients 
with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-
based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet 2016;387(10031):1909-20. 
52. Postow MA, Manuel M, Wong P, Yuan J, Dong Z, Liu C, et al. Peripheral T cell receptor diversity is associated with 
clinical outcomes following ipilimumab treatment in metastatic melanoma. J Immunother Cancer 2015;3:23. 
 
 

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13  APPENDICES  
13.1 APPENDIX 1 – ECOG PERFORMANCE STATUS 
 
 
 
 
 
 

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13.2 APPENDIX 2 – ADVERSE EVENT MANAGEMENT ALGORITHMS 

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13.3 APPENDIX 3 – BRONCHOSCOPY PATIENT COMMUNICATION LOG 
Protocol: Nivolumab 
Source Document :  
 
Patient Name:___________________________ Phone:________________________ 
SPORE #____________________ 
 
Pre-Case Communication: 
Date of Consent: _________________ (The patient verbalized understanding of the consent, and a copy 
of the signed consent was provided to the patient.) 
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
_______ 
_____________________________________________________________________________________
___________________________________________________________ 
SIGNATURE:___________________________   DATE:__________________________ 
Procedure Date: 
 
Date:__________________________ 
Time:_________________ 
Physician:______________________ 
Notified:_______________ 
24-Hour Follow-up: 
Date:__________________ 
Comments: 
_____________________________________________________________________________________
_____________________________________________________________________________________
________________________________________ 
SIGNATURE:__________________________ 
72-Hour Follow-up: 
Date:__________________ 
Comments: 
_____________________________________________________________________________________
_____________________________________________________________________________________
______________________________________________ 
The patient was instructed to call within 30 days if febrile or with increased sputum production, increasing 
shortness of breath, or any perceived deterioration of respiratory condition:   
Yes:________ No:________ 
Signature:_______________________ 

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13.4 APPENDIX 4 – SPUTUM COLLECTION PATIENT INSTRUCTION SHEET 
INSTRUCTIONS FOR OPENING AND CLOSING CONTAINERS 
❑ How to open containers:  To open container, unscrew the top of the first canister and slide out 
second metal canister.  Unscrew the lid on the second canister.  Inside this canister are two small 
containers.  When you open these small containers, do so slowly so that the liquid inside does not 
spill. 
BLUE DOT CONTAINER:  You must use the small clear container with the blue dot for the first 
three-day collection of sputum. 
RED DOT CONTAINER:  You must use the small clear container with the red dot for the second 
three-day collection of sputum. 
PROCEDURES FOR PERFORMING THE EARLY MORNING SPONTANEOUS COUGH TECHNIQUE 
❑ When you wake up in the morning, clear your throat and mouth of any food and debris which 
may have accumulated overnight and spit it out. 
❑ Next, rinse your mouth out with water and spit the water into the sink, not into the sputum 
container. 
❑ Begin coughing deep from your diaphragm.  We need sputum from the lungs.  Spit sputum into 
the small clear container and close container. 
❑ Do this procedure within the first hour you are awake for six mornings in a row.  (Note:  If you do 
not produce sputum in the first hour you are awake, you are permitted to use the first sputum 
you cough up that day, regardless of the time of day.) 
❑ Collect the first three days of coughed up sputum in the blue dotted container. 
❑ Collect the second three days of sputum in the red dotted container. 
After you have collected sputum for six days, individually place the two small clear containers inside each 
biohazard bag (in case there is leakage during shipping).  Put them inside the steel canister and then place 
the steel canister inside the larger postage paid container that has our address on the outside.  Please 
make sure all lids are on tightly.  Drop the mailing container in the any U.S. mailbox or at the U.S. post 
office.  If you have any questions, please contact either: 
Mary Jackson: 303-724-1650 
Brandi Bagwell: 303-724-1657 
 
YOUR PARTICIPATION IS GREATLY APPRECIATED. YOUR PHYSICIAN WILL RECEIVE THE RESULTS OF 
YOUR SPUTUM EXAMINATION.  
 
 

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13.5 APPENDIX 5 – NIVOLUMAB FOLLOW-UP SCRIPT 
1. 
Hello.  This is _{your_name}__ calling on behalf of the Rocky Mountain Regional VA Medical 
Center and the University of Colorado Cancer Center. May I please speak with __{participant}____?_ 
 
⁪  Unavailable  
 
 
→ 7a [Reschedule, page 2 ] 
 
⁪  Not home  
 
→ 7a [Reschedule, page 2] 
 
⁪  Not a good time 
 
→ 7a [Reschedule, page 2] 
 
⁪  Deceased  
 
→ 9a [Cause of death, page 3] 
 
⁪  Respondent refuses 
→ 8   [Refusal exit, page 2] 
 
⁪  Household refuses  
→ 7a [Reschedule, page 2] 
 
⁪  Yes  
 
 
→ 2 
2. 
Hello _{participant}_. I am calling in regards to your participation in the Nivolumab study at the 
Rocky Mountain Regional VA Medical Centerand University of Colorado Cancer Center. We would like to 
follow up on your health status.  Do you have a few moments to help me with that?  
 
⁪  Yes  
 
 
→ 3 
 
⁪  No  
 
 
→ 7a [Reschedule, page 2] 
3.   
First, I need to verify your current mailing address.  Are you still residing at (give most recent 
address)?  (If no, obtain current address.) → 4 
4. 
Is this the best telephone number for us to reach you? (If not, obtain current phone number) → 
5a 
5a.  
Have you been diagnosed with cancer since you completed the Nivolumab study? 
 
⁪  Yes  
 
 
→ 5b 
 
⁪  No   
 
 
 
5b.  
What was your diagnosis? 
 
 
 
 
 
 
 
 
 
 
 
 
 
5c. 
What was the date of the diagnosis? 
 
(_ _/_ _/_ _)  
 
MM/DD/YY 
CLOSING 
Thank you very much for talking with me today.  Do you have any questions you would like to ask?   
Thank you very much for your time.  Take care! 
 

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---END CALL--- 
SCHEDULING A BETTER TIME TO REACH PARTICIPANT 
7a. 
What would be a good day and time to call back within the next couple of weeks to reach 
you/him/her? 
 
 
Date:_______________________    Time:____________________ 
7b. 
At what phone number should I try to reach you/him/her? 
 
 
⁪  Home:___________________ 
 
 
⁪  Work:___________________ 
 
 
⁪  Other:___________________ 
 
REFUSAL EXIT AND CLOSING 
8. 
That’s no problem.  You certainly don’t need to feel any obligation to complete this follow-up.  
May we contact you again next year? 
 
⁪  Yes  
 
 
→ Thank you for your time and have a nice day. 
 
⁪  No  
 
 
 
 
Note: If the respondent says, “I don’t know” or is reluctant check “YES.” 
CAUSE OF DEATH 
9a. 
If patient is deceased:  (Apologize and give condolences, ask for the name of the person with 
whom you are speaking so that you may keep the conversation more personal by referring to them by 
name).  I’m sorry to hear about your loss.  Would you be willing to share the causes of death with me? 
 
 
⁪  Yes 
 
→ 9a1 
 
 
⁪  No 
 
→ Thank you for taking the time to talk with me today.   
 
 
 
 
Good bye. 
 
9a1.   
What were the causes? 
9b. 
What was the date of his/her death? 
 
 
(_ _/_ _/_ _)  or unknown 
 
    
MM/DD/YY 
9c. 
Was __{participant}_ ever diagnosed with lung cancer? 
 
 
⁪ Yes  
 
→ 9d 
 
 
⁪  No 
 
→ Thank you for taking the time to talk with me today.  

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    Good bye. {END CALL} 
 
9d. 
What was the date of his/ her diagnosis? 
 
 
(_ _/_ _/_ _) or approximate  
→ Thank you for taking the time to talk with  
MM/DD/YY       
 
 
 me today.  Good bye. {END CALL}