Single-Arm, Phase II of Immunotherapy With Pembrolizumab for the Prevention of Lung Cancer (IMPRINT-Lung)
Phase: PHASE2
Conditions: Lung Non-Small Cell Carcinoma, Stage I Lung Cancer AJCC v8, Stage IA1 Lung Cancer AJCC v8, Stage IA2 Lung Cancer AJCC v8, Stage IA3 Lung Cancer AJCC v8, Stage IB Lung Cancer AJCC v8, Stage II Lung Cancer AJCC v8, Stage IIA Lung Cancer AJCC v8, Stage IIB Lung Cancer AJCC v8
Sponsor: M.D. Anderson Cancer Center

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MD Anderson IND Sponsor Cover Sheet 
 
Protocol ID 
2018-0366 
Protocol Title 
Single-arm, phase II of Immunotherapy with Pembrolizumab for the 
Prevention of Lung Cancer (IMPRINT-Lung) 
Protocol Phase 
II 
Protocol Version 
21 
Version Date 
10/20/2023 
 
Protocol PI 
Jianjun Zhang, MD, PhD 
Department 
Thoracic/Head and Neck Medical Oncology 
 
IND Sponsor 
MD Anderson Cancer Center 
IND # 
140410 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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SPONSOR: The University of Texas MD Anderson Cancer Center (IND Office) 
 
TITLE: Single-arm, phase II trial of Immunotherapy with Pembrolizumab for the Prevention of 
Lung Cancer (IMPRINT-Lung) 
 
IND NUMBER: 140410 
 
Protocol History 
Version 0 submitted to IND - 4/27/2018 
Version 1 resubmitted to IND - 11MAY2018 
Version 2 resubmitted to CRC-25MAY2018 
Version 3 resubmitted to IRB -29JUNE2018 
Version 4 resubmitted to FDA- 03AUG2018 
Version 5 resubmitted to FDA- 07AUG2018 
Version 6 resubmitted to IRB-18OCT2018 
Version 7 resubmitted to IRB-23JAN2019 
Version 8 resubmitted to IRB-19MAR2019 
Version 8 resubmitted to IND-01MAY2019 
Version 9 resubmitted to IND- 18 SEPT 2020 
Version 10 resubmitted to IND- 25 FEB 2021  
Version 11 resubmitted to IND – 07APR2021 
Version 12 resubmitted to IND – 30APR2021 
Version 13 resubmitted to IND – 27AUG2021 
Version 14 resubmitted to IND – 23NOV2021 
Version 15 resubmitted to IND – 10DEC2021 
Version 16 resubmitted to IND – 01FEB2022 
Version 17 resubmitted to IND – 05APR2022 
Version 18 resubmitted to IND – 10AUG2022 
Version 19 resubmitted to IND – 24DEC2022 
Version 20 resubmitted to IND – 14JUN2023 
Version 21 resubmitted to IND – 20OCT2023 
 
 
 
Principal Investigator and study center: 
Jianjun Zhang, MD, PhD 
Department of Thoracic/Head and Neck Medical Oncology 
1515 Holcombe Blvd. Unit 432 
Houston, TX 77030 
Phone: 713.792.6363 
Fax: 713.792.1220 
Email: JZhang20@mdanderson.org 
 
Additional study centers: 
Daniel H Sterman, MD 
Director, Division of Pulmonary, Critical Care, and Sleep Medicine 
Director, Multidisciplinary, Pulmonary Oncology Program 
New York University School of Medicine 

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NYU Langone Medical Center 
555 First Avenue 
New York, New York 10016 
Phone: 212.731.6162 
Fax: 212.731.5545 
Email: Daniel.Sterman@nyulangone.org 
 
 
Robert L. Keith, MD 
Daniel W. Bowles, MD 
York E. Miller, MD 
Melissa New, MD 
Jessica McDermott, MD 
Rocky Mountain Regional VA Medical Center 
1700 N. Wheeling St., A3-350  
Aurora, CO 80045 
Phone #: 720-857-5120 
Fax: 720-723-6014 
Email: Robert.keith@cuanschutz.edu 
 
Co-PI: John Heymach, MD, PhD 
 
Co-Investigators: J. Jack Lee, PhD; Mara Antonoff, MD; Myrna Godoy, MD; Stephen Swisher, 
MD; Ara Vaporciyan, MD; Edwin Ostrin, MD; Samir Hanash, PhD; Ignacio Wistuba, MD; P. 
Andrew Futreal, PhD; Alda Tam, MD, Boris Sepesi, MD; Brett Carter, MD; Hai Tran, MD; 
Junya Fujimoto, MD; Ryan Williams, MD; Celyne Bueno Hume, MD; Janet Tu, MD; Jenny 
Pozazides, MD; Bignan Zhang, MD; Mehment Altan, MD; George Blumenschein, MD; Lauren 
Byers, MD; Tina Cascone, MD; Yasir Elamin, MD; Frank Fossella, MD; Carl Gay, MD; Don 
Gibbons, MD; Myrna Godoy, MD; Xiuning Le, MD; Charles Lu, MD; Ferdinandos Skoulidis, 
MD; Anne Tsao, MD; Marcelo Vailati Negrao, MD; Natalie Vokes, MD 
 

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TABLE OF CONTENTS 
1.0 
TRIAL SUMMARY.................................................................................................... 8 
2.0 
TRIAL DESIGN.......................................................................................................... 8 
2.1 
Trial Design ............................................................................................................. 8 
2.2 
Trial Diagram .......................................................................................................... 8 
3.0 
OBJECTIVE(S) & HYPOTHESIS(ES) .................................................................... 9 
3.1 
Primary Objective(s) & Hypothesis(es) ................................................................ 9 
3.2 
Secondary Objective(s) & Hypothesis(es)............................................................. 9 
3.3 
Exploratory Objective ............................................................................................ 9 
4.0 
BACKGROUND & RATIONALE .......................................................................... 10 
4.1 
Background ........................................................................................................... 10 
4.1.1 Pharmaceutical and Therapeutic Background .................................................... 10 
4.1.2 Preclinical and Clinical Trial Data ...................................................................... 11 
4.2 
Rationale ................................................................................................................ 12 
4.2.1 Rationale for the Trial and Selected Population ................................................. 12 
4.2.2 Justification for Dose, Schedule, and Treatment Duration ................................. 18 
4.2.3 Rationale for Endpoints ...................................................................................... 19 
4.2.4 Risk/Benefit Ratio ................................................ Error! Bookmark not defined. 
5.0 
METHODOLOGY ................................................................................................... 25 
5.1 
Study Population ................................................................................................... 25 
5.1.1 Participant Inclusion Criteria .............................................................................. 25 
5.1.2 Participant Exclusion Criteria ............................................................................. 27 
5.1.3 Lifestyle Restrictions .......................................................................................... 29 
5.1.4 Pregnancy ............................................................................................................ 29 
5.1.5 Use in Nursing Women ....................................................................................... 29 
5.2 
Trial Treatments ................................................................................................... 29 

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5.2.1 Timing of Dose Administration ............................................................................. 30 
5.2.2 Dose Modification and toxicity management for immune-related AEs associated 
with pembrolizumab ........................................................................................... 30 
5.2.3 General description on the assessment of health-related quality of life (QoL) .. 30 
5.3 
Randomization or Treatment Allocation ............................................................ 37 
5.4 
Stratification ............................................................... Error! Bookmark not defined. 
5.5 
Concomitant Medications/Vaccinations (allowed & prohibited) ..................... 37 
5.5.1 Acceptable Concomitant Medications ................................................................ 37 
5.5.2 Prohibited Concomitant Medications.................................................................. 38 
5.5.3 Rescue Medications & Supportive Care ............................................................. 38 
• 
Pneumonitis: .............................................................................................................. 39 
• 
Diarrhea/Colitis: ........................................................................................................ 39 
• 
Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) or
..................................................................................................................................... 40 
• 
Hypophysitis: ............................................................................................................. 40 
• 
Hyperthyroidism or Hypothyroidism: .................................................................... 40 
• 
Hepatic: ...................................................................................................................... 41 
• 
Renal Failure or Nephritis: ...................................................................................... 41 
5.6 
Participant Withdrawal/Discontinuation Criteria ............................................ 42 
5.7 
Participant Replacement Strategy ...................................................................... 43 
5.8 
Clinical Criteria for Early Trial Termination ................................................... 43 
6.0 
TRIAL FLOW CHART ........................................................................................... 45 
6.1 
Study Flow Chart .................................................................................................. 45 
7.0 
TRIAL PROCEDURES ........................................................................................... 48 
7.1 
Trial Procedures ................................................................................................... 48 
7.1.1 Administrative Procedures .................................................................................. 48 
7.1.2 Clinical Procedures/Assessments ........................................................................ 50 

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7.1.3 Laboratory Procedures/Assessments .................................................................. 52 
7.1.4 Other Procedures ................................................................................................. 54 
7.1.5 Visit Requirements .............................................................................................. 54 
7.2 
Assessing and Recording Adverse Events .......................................................... 55 
7.2.1 Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor and to Merck ......................................................................................... 61 
7.2.2 Reporting of Pregnancy and Lactation to the Sponsor and to Merck ................. 62 
7.2.3 Immediate Reporting of Adverse Events to the Sponsor and to Merck.............. 62 
8.0 
STATISTICAL Considerations ............................................................................... 61 
8.1 
Sample Size Calculation ....................................................................................... 61 
8.2 
Statistical Analysis Plan ............................................ Error! Bookmark not defined. 
8.3 Statistical consideration on the assessment of health-related quality of life (QoL)63 
9.0 
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ................................................................................................................. 64 
9.1 
Investigational Product ........................................................................................ 64 
9.2 
Packaging and Labeling Information ................................................................. 64 
9.3 
Clinical Supplies Disclosure ................................................................................. 64 
9.4 
Storage and Handling Requirements .................................................................. 64 
9.5 
Returns and Reconciliation .................................................................................. 65 
10.0 
ADMINISTRATIVE AND REGULATORY DETAILS ....................................... 65 
11.0 
References .................................................................................................................. 66 
12.0 
APPENDICES ........................................................................................................... 70 
Appendix 1: ECOG Performance Status ........................................................................ 70 
Appendix 2: Common Terminology Criteria for Adverse Events V4.0 (CTCAE) ..... 71 
Appendix 3: Contraceptive Guidance and Pregnancy Testing .................................... 72 
Contraception Requirements ........................................................................................... 72 
Pregnancy Testing ........................................................................................................... 74 
 

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1.0 TRIAL SUMMARY 
Abbreviated Title 
Pembrolizumab for high risk IPN 
Trial Phase 
II 
Clinical Indication 
High-risk indeterminate pulmonary nodules 
Trial Type 
Single arm  
Type of control 
Standard of care: histological control 
Route of administration 
Intravenous 
Trial Blinding 
Open label 
Treatment Groups  
Pembrolizumab 
Number of trial participants 
60  
Estimated enrollment period 
42 months 
 
Estimated duration of trial 
48 months 
Duration of Participation 
8 months  
Estimated average length of 
treatment per patient 
12 weeks 
 
 
 
 
2.0 TRIAL DESIGN 
2.1 
Trial Design 
This is a single arm, multi-center, phase 2 study of pembrolizumab in immunotherapy-
naïve patients with high-risk indeterminate pulmonary nodules. 
 
2.2 
Trial Diagram 
 
 
 

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3.0 OBJECTIVE(S) & HYPOTHESIS(ES) 
3.1 
Primary Objective(s) & Hypothesis(es) 
(1) Objective: To determine whether immune checkpoint blockade using pembrolizumab 
eliminates persistent (on two CT scans at least 3 months apart with no evidence of shrinkage 
or regression) high-risk indeterminate pulmonary nodules (IPNs) at 6 months after initiation 
of treatment.  
Hypothesis:  Immune evasion contributes to malignant transformation of pre-neoplastic lung 
lesions into invasive lung cancers and modulation of immune checkpoint pathways augments 
immunosurveillance and prevents or delays the development of invasive lung cancers. 
3.2 
Secondary Objective(s) & Hypothesis(es) 
(1) Objective: To determine whether immune checkpoint blockade using pembrolizumab 
decreases the incidence of lung cancers confirmed by histology (biopsy or resection). 
(2) To determine whether immune checkpoint blockade using pembrolizumab prolongs cancer 
free survival (DFS) in patients with high-risk IPNs.  
(3) To determine whether immune checkpoint blockade using pembrolizumab prolongs lung 
cancer-specific survival in patients with high-risk IPNs. 
(4)  To determine whether immune checkpoint blockade using pembrolizumab prolongs overall 
survival (OS) in patients with high-risk IPNs. 
(5) To assess the safety and tolerability of pembrolizumab in patients with high-risk IPNs. 
(6) To assess quality of life patient reported outcomes in patients treated with pembrolizumab. 
(7) To determine whether immune checkpoint blockade using pembrolizumab decreases the solid 
component of high-risk IPNs. 
(8) To assess the health-related quality of life (QoL) on subjects enrolled in the study. 
3.3 
Exploratory Objective 
(1) 
Objective: An important aspect of this trial is to identify novel prognostic and predictive 
markers present at diagnosis, and to determine modulation of markers by immunotherapy in 
order to inform future translational studies. As such, radiographic data as well as blood and 
tissues (from either biopsy or surgical resection) will be collected throughout the study period 
(at MD Anderson and New York University). 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 may include (depending on tissue availability): 
1. To explore the radiographic (including radiomic features) evolution of high-risk IPNs with 
and without treatment of pembrolizumab and to assess their association with risks of risk of 
lung cancer as well as their association with clinical benefit/toxicities in patients treated with 
pembrolizumab. 
2. To explore the germline DNA profile and genomic evolution of circulating tumor DNA 
(ctDNA) of patients with high-risk IPNs and assess their association with risks of risk of lung 
cancer as well as their association with clinical benefit/toxicities in patients treated with 
pembrolizumab. 

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3. To explore the TCR repertoire evolution of patients with high-risk IPNs and assess their 
association with risks of risks of lung cancer as well as their association with clinical 
benefit/toxicities in patients treated with pembrolizumab. 
4. To explore the evolution of serum soluble factors, such as IFN-gamma and interferon 
inducible factors (such as CXCL9 and CXCL10), IL-12, TNFα, IL-10, TGF-β, VEGF, IL-6, 
IL-8, IL-17, IL-18, C-reactive protein etc. and assess their association with risks of risks of 
lung cancer as well as their association with clinical benefit/toxicities in patients treated with 
pembrolizumab. 
5. To explore the evolution of immunophenotyping or characterization of the immune cell 
subsets in the periphery, including, but not limited to, T cells, B cells, NK cells, or 
subpopulations of the aforementioned immune cell types and assess their association with risks 
of lung cancer as well as their association with clinical benefit/toxicities in patients treated 
with pembrolizumab. 
6. To explore the evolution of microbiome and assess their association with risks of lung cancer 
as well as their association with clinical benefit/toxicities in patients treated with 
pembrolizumab. 
 
4.0 BACKGROUND & RATIONALE 
4.1 
Background 
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody (mAb) 
with high specificity of binding to the programmed cell death 1 (PD-1) receptor, thus inhibiting its 
interaction with programmed cell death ligand 1 (PD-L1) and programmed cell death ligand 2 (PD-
L2).  Based on preclinical in vitro data, pembrolizumab has high affinity and potent receptor 
blocking activity for PD-1.  Pembrolizumab has an acceptable preclinical safety profile and is in 
clinical development as an intravenous (IV) immunotherapy for advanced malignancies.  
Keytruda® (pembrolizumab) is indicated for the treatment of patients across a number of 
indications because of its mechanism of action to bind the PD-1 receptor on the T cell.  For more 
details on specific indications refer to the Investigator brochure. 
 
4.1.1 Pharmaceutical and Therapeutic Background 
The importance of intact immune surveillance function in controlling outgrowth of neoplastic 
transformations has been known for decades [Disis, 2010].  Accumulating evidence shows a 
correlation between tumor-infiltrating lymphocytes in cancer tissue and favorable prognosis in 
various malignancies.  In particular, the presence of CD8+ T-cells and the ratio of CD8+ effector 
T-cells/FoxP3+ regulatory T-cells (T-regs) correlates with improved prognosis and long-term 
survival in solid malignancies, such as ovarian, colorectal, and pancreatic cancer; hepatocellular 
carcinoma; malignant melanoma; and renal cell carcinoma.  Tumor-infiltrating lymphocytes can 
be expanded ex vivo and reinfused, inducing durable objective tumor responses in cancers such as 
melanoma [Dudley et al., 2005; Hunder et al., 2008]. 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress immune 
control.  The normal function of PD-1, expressed on the cell surface of activated T-cells under 
healthy conditions, is to down-modulate unwanted or excessive immune responses, including 

11 
 
autoimmune reactions. PD-1 (encoded by the gene Pdcd1) is an immunoglobulin (Ig) superfamily 
member related to cluster of differentiation 28 (CD28) and cytotoxic T-lymphocyte-associated 
protein 4 (CTLA-4) that has been shown to negatively regulate antigen receptor signaling upon 
engagement of its ligands (PD-L1 and/or PD-L2) [Greenwald et al., 2005; Okazaki et al., 2001]. 
The structure of murine PD-1 has been resolved [Zhang et al., 2004].  PD-1 and its family members 
are type I transmembrane glycoproteins containing an Ig-variable–type (IgV-type) domain 
responsible for ligand binding and a cytoplasmic tail responsible for the binding of signaling 
molecules.  The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an 
immunoreceptor tyrosine-based inhibition motif, and an immunoreceptor tyrosine-based switch 
motif.  Following T-cell stimulation, PD-1 recruits the tyrosine phosphatases, SHP-1 and SHP-2, 
to the immunoreceptor tyrosine-based switch motif within its cytoplasmic tail, leading to the 
dephosphorylation of effector molecules such as CD3 zeta (CD3ζ), protein kinase C-theta (PKCθ), 
and zeta-chain-associated protein kinase (ZAP70), which are involved in the CD3 T-cell signaling 
cascade [Okazaki et al., 2001; Chemnitz et al., 2004; Sheppard et al., 2004; and Riley, 
2009].  The mechanism by which PD-1 down-modulates T-cell responses is similar to, but distinct 
from, that of CTLA-4, because both molecules regulate an overlapping set of signaling proteins 
[Parry et al., 2005; Francisco, 2010].  As a consequence, the PD-1/PD-L1 pathway is an attractive 
target for therapeutic intervention in lung cancer.  
The role of Pembrolizumab in treatment of lung cancers: Immune surveillance is an important 
host protection process inhibiting carcinogenesis and controlling the outgrowth of cancer 1. The 
interactions between the host immune system and cancer cells are governed by a complex network 
of biological pathways. Despite the expectations that the host immune system should automatically 
attack and eliminate cancer cells as 'foreign,' the molecular evolution of cancer cells can often lead 
to tolerance, representing a natural balance between the immune system and cancer, which is 
maintained by regulatory immune cells, immunosuppressive cytokines and chemokines, and 
immune checkpoint pathways. The programmed cell death protein 1 (PD1) – PD1 ligand 1 (PDL1) 
receptor–ligand pair is a dominant immune checkpoint pathway that can be induced in cancer cells 
to suppress host anti-tumor immune functions and evade immune attack 2,3. Monoclonal antibodies 
(mAbs) that block this pathway have shown great clinical benefit to patients with various cancer 
types including NSCLC 4-10.  
Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of the 
IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-
L1 and PD-L2. KeytrudaTM
 
(pembrolizumab) has demonstrated significant improvement in overall 
survival in patients with metastatic NSCLC with progression on or after platinum-based 
chemotherapy as compared with standard of care second-line chemotherapy agent docetaxel and 
was approved in the United States for the treatment of patients with metastatic NSCLC in the 
second-line setting 11. Most recently, the results from KEYNOTE-024 have shown Keytruda was 
associated with longer progression-free and overall survival than platinum-based combination 
chemotherapy in patients with previously untreated advanced NSCLC and a PD-L1 tumor 
proportion score of 50% or greater, and has become the only PD-1 inhibitor approved for the 
treatment of advanced NSCLC in the first line setting. Pembrolizumab is very well tolerated and 
has shown favorable toxicity profiles in multiple studies 11-14. 
4.1.2 Preclinical and Clinical Trial Data 
Refer to the Investigator’s Brochure for Preclinical and Clinical data. 

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4.2 
Rationale 
4.2.1 Rationale for the Trial and Selected Population 
Indeterminate pulmonary nodules and preinvasive neoplastic lung lesions: Despite advances 
in its management, lung cancer remains the leading cause of cancer-related deaths worldwide. One 
major problem is that most lung cancer patients are diagnosed at an advanced stage of disease, 
when cure is less feasible. Low-dose helical CT screening (LDCT) was demonstrated to result in 
a reduction in lung-cancer mortality of 20% 
in former and current heavy smokers 
compared to chest x-rays, advocating the 
importance of early detection and early 
intervention 15. 
Furthermore, growing implementation of 
LDCT-guided screening and the advent of 
high resolution CT for diagnostic imaging 
have resulted in a dramatic increase in the 
number of indeterminate pulmonary nodules 
(IPN) identified, most of which present as 
ground glass opacities (GGOs) 
15. As 
reported in the initial LDCT screening study, 
nearly 30% of subjects were found to have 
pulmonary nodules, the majority of which 
were IPNs 15. Clinicians have encountered a 
tremendous increase in number of patients 
with IPNs. While many of these lesions may 
be resected with minimal morbidity, the cost 
and relevance of surgical resection have been called into question 16. In addition, multifocality is 
a relatively common occurrence, with up to 25% of the patients harboring multiple IPNs 17,18, 
which makes surgical resection more challenging. Chemoprevention is a theoretically appealing 
approach to reduce lung cancer incidence and mortality. However, randomized trials have 
produced only disappointing results to date 19-27. This may be due to the constellation of many 
factors including the lack of reliable molecular biomarkers to identify high-risk patients, the lack 
of appropriate molecular targets, and the lack of appropriate drugs based on our rudimentary 
knowledge on early carcinogenesis of lung cancers.  
Over the past decade, progress has been made in our understanding of early non-small cell lung 
cancer (NSCLC) 28. Historically, GGOs have been the most common type of IPNs that were 
thought to correlate with the fairly imprecise category of bronchioloaveolar carcinomas (BAC) if 
they persisted or grew. In early 2011, the IASLC/ATS/ERS jointly proposed a reclassification of 
BAC to highlight the spectrum of invasiveness that may be delineated within this group of lesions. 
It has been postulated that atypical adenomatous hyperplasia (AAH) represents a preneoplastic 
lung lesion that can progress to adenocarcinoma in situ (AIS), to minimally invasive 
adenocarcinoma (MIA), and further to frankly invasive adenocarcinoma 29. However, the 
biological nature of these lesions is poorly understood and the definition and management of these 
lesions remain controversial 30.  
Fig. 1. Carcinogenesis of lung is analogous to a growing 
tree. Adapted from Gazdar, et al CCR, 2008. 

13 
 
Investigations into the early carcinogenesis of lung cancer are difficult due to the unpredictable 
clinical course of these preinvasive lesions, lack of specimens to study due to the small size of 
these lesions, and the challenge in obtaining longitudinal samples at different time points of disease 
progression.  
A 
B 
Fig. 3. Genomic heterogeneity evolution during early carcinogenesis of lung adenocarcinoma. A.  Progressive 
increase of somatic mutation heterogeneity with disease evolution.  Median tumor variant frequency derived entropy 
(Shannon index) in the AAH, AIS, MIA and ADC stages was labeled by solid brown dots. B. Progressive increase of 
copy number aberration heterogeneity with disease evolution. The median log2 ratio of segments derived entropy in 
the AAH, AIS, MIA and ADC stages was labeled by solid brown dots, each small dot represent entropy in one lesion Hu, 
et al, WCLC, 2017. 

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It has been proposed that carcinogenesis 
results from accumulation of molecular 
events in a branched evolutionary model like 
a growing tree (Fig. 1) 31-34. The trunk 
harbors early founder mutations, while the 
branches represent subsequent mutations 
acquired later during carcinogenesis. Multi-
region sequencing can depict genomic 
events to their relative molecular time with 
early trunk mutations ubiquitously present in 
every tumor region and late branch 
mutations confined to spatially separated 
tumor regions (Fig. 2). Using this approach, 
our recent work has delineated the genomic 
evolution 
of 
11 
early 
stage 
lung 
adenocarcinomas (8 stage I, 2 stage II and 1 
stage III) and demonstrated that 20/21 
known cancer gene mutations were early 
genetic events (Fig. 2). In addition, our 
results suggested that complex genomic 
heterogeneity is associated with inferior 
survival in patients with early stage lung 
cancers35. With the intent to delineate the 
pivotal molecular events driving early 
carcinogenesis of lung cancer, we have collected 154 resected GGOs and matched normal lung 
tissues. The pathology of these GGOs ranges from preneoplastic lesions (AAH) to preinvasive 
cancers (AIS) to early invasive cancers (MIA) and invasive lung cancers. Using the same multi-
region exome sequencing approach, our prelim data have demonstrated that with disease evolution 
from AAH, to AIS, MIA and ADC, genomic landscape has become progressively more complex 
including mutation burden, APOBEC signature and genomic heterogeneity (Fig. 3)36.  
The rationale of using pembrolizumab for immunoprevention of NSCLC: Although immune 
checkpoint blockade therapy has demonstrated unprecedented rates of durable clinical benefits in 
patients with various cancer types, the response rate is only modest for patients with advanced 
NSCLC4-10. While tremendous efforts are being made to increase the response rate in patients with 
advanced disease, there has been increasing enthusiasm for the use of immune checkpoint 
blockade to treat early-stage NSCLC in the adjuvant or preoperative setting 37 because early-stage 
cancers theoretically have less “immunoediting” capacity than cancers of advanced stages, thus 
may potentially respond better to immunotherapy than advanced diseases 38. Immunoediting is a 
dynamic interaction between the host immune system and evolving tumor cells. It is made up of 
three phases: elimination, equilibrium, and escape. The elimination phase refers to the phase when 
host innate and adaptive immune responses are able to eradicate tumor cells of early carcinogenesis 
when the cancer cell molecular architectures are relatively simple. With selection and evolution, 
cancer cells become molecularly more complex and cancer immunoediting enters the next phase, 
equilibrium, during which tumor cells that have escaped elimination and have a non-immunogenic 
phenotype are selected for growth. During this phase, new tumor cell variants emerge with various 
mutations that further increase overall resistance to immune attack. The last phase of 
immunoediting is the escape phase when tumor cell variants selected in the equilibrium phase have 
breached the host immune defenses, with various genetic and epigenetic changes conferring further 
resistance to immune detection39. Our recent work has demonstrated that heterogeneous T cell 
Fig. 2. Phylogenetic trees of 11 localized lung 
adenocarcinomas. The lengths of trunks and branches are 
proportional to the numbers of mutations acquired on the 
corresponding trunks or branches. Known cancer gene 
mutations are mapped to the trunks/branches: point mutation, 
amplification (+) and deletion (-). *Patients who have had 
relapse. Adapted from Zhang, et al, Science 2014. 

15 
 
repertoire is associated with heterogeneous genomic landscape and increased risks of postsurgical 
recurrence in patients with early stage lung adenocarcinomas (Fig. 4) suggesting the complex 
interaction between evolving tumors and host immune surveillance40.   
 
Figure 4. Correlation of T cell repertoire ITH with clinical and genomic features of localized lung adenocarcinomas. 
A) Spearman correlation between patient age and MOI. Red dots = patients who relapsed; Blue dots = patients who 
have not relapsed. B) Spearman correlation between MOI and percent predicted branch MHC I neoantigens in each 
patient. Red dots = patients who relapsed; Blue dots = patients who have not relapsed. C) Recurrence status based on 
MOI. Red = patients who relapsed; Blue = patients who have not relapsed. D) Disease-free survival in patients with a 
high (median or above, green) or low (below median, purple) MOI. * = p<0.05. Abated from Reuben et al, 2017. 

16 
 
Evidence has started to emerge suggesting that late stage cancer may have more prominent 
“immunosuppressive” microenvironment than early stage cancers. A large meta-analysis study on 
the prognostic influence of tumor infiltrating lymphocytes (TIL) has demonstrated TIL density 
was associated with survival across different cancer types, supporting the protective role of host 
anti-tumor immune response. However, the protective impact of TILs faded away in later stage 
cancers, suggesting a more immunosuppressive tumor microenvironment may have developed in 
advanced cancers 41. Our analyses on gene expression profiles of TCGA lung adenocarcinoma 
cohorts revealed significantly higher immune scores in early stage cancers than later stage cancers 
(Fig. 5A.). Given the important role of T cells in anti-tumor immune response, we have recently 
investigated the T cell receptor repertoire of resected NSCLC. Our data has demonstrated that T 
cell infiltration is significantly prominent in smaller tumors than larger tumors (Fig. 5B.). Taken 
together, these findings suggest that early-stage lung cancers may have less immunosuppressive 
microenvironment, thus may respond better to immune checkpoint blockade. At the 2016 ESMO 
Congress in Copenhagen, Forde et al. reported data from 16 patients with Stage I-IIIA NSCLC 
who received two doses of nivolumab, an PD1 mAB, at four and two weeks prior to surgical 
resection. The investigators found that 11 of 15 patients (73%) had regression of their tumors, 
including 6 of 15 patients 
(40%) 
demonstrating 
major 
pathological 
regression, defined as 
either 
a 
complete 
pathologic response or 
isolated 
remaining 
tumor cells (less than 
10% viable tumor cells) 
following treatment with 
nivolumab. Although the 
sample size was small, 
the response rate is very 
encouraging compared 
to the 20% response rate 
to nivolumab in patients 
with advanced NSCLC 4-
10.  
According to the concept 
of 
immunoediting, 
preneoplastic 
lesions 
(such as AAH) and preinvasive lung cancers (such as AIS) may have even less suppressive 
immune microenvironment and thus may respond even more favorable than localized lung cancers. 
However, because of the challenge of obtaining study materials, the immune landscape of 
preneoplastic lesions (AAH), preinvasive (AIS) and minimally invasive lung cancer (MIA) has 
not been systemically studied. Our preliminary data leveraging the large cohort of resected GGOs 
has suggested more active immune microenvironment in preneoplastic and preinvasive stages. 
With disease evolution from AAH to AIS, MIA and ADC, there progressive decrease in infiltrating 
T cell density, progressive  decrease in TCR clonality, an indicator for T cell expansion and 
activation as well as progressive increase in TCR inverse Simpson evenness suggesting 
progressive immunosuppressive microenvironment with disease evolution (Fig. 6)36. 
 
P=0.0028 
                                                                       < median (N=120)         > median (N=121)   
Fig. 5. Advanced cancers may have more immune suppressive microenvironment. 
A. Different tumor infiltrating immune scores in TCGA lung adenocarcinomas by 
staging. Immune scores are derived from gene expression profiles using ESTIMATE 
algorithm. B. Different T cell density in resected NSCLC by tumor size. T cell density 
is measured by T cell receptor sequencing and presented as percent nucleated cells in each 
resected NSCLC tumor.  
A 
B 

17 
 
The efficacy of immune checkpoint blockade in the treatment of human preneoplastic disease is 
unknown. Our most recent data in 4-Nitroquinoline-1- oxide (4-NQO) mouse model and Kras-
mutant genetically engineered murine lung cancer model has demonstrated that PD1 blockade 
increases CD4+ and CD8+ T cell infiltration preneoplastic diseases and prevents progression of 
preneoplasia into invasive cancers (Fig. 7)42.   
Figure 6. Progressive TCR repertoire evolution from preneopalstic stage to invasive lung adenocarcinoma. A) Infiltrating 
T cell density is higher in invasive lung adenocarcinomas (ADC) compared to normal lung, but numerically lower than 
neoplastic lesions of earlier stages. B) TCR clonality is lower in invasive lung adenocarcinomas (ADC) compared to neoplastic 
lesions of earlier stages. C) Progressive decrease in T cell density from AAH, to AIS, to MIA and ADC. D). Progressive increase 
in T cell inverse Simpson evenness from AAH, to AIS, to MIA and ADC. Abated from Hu et al, WCLC, 2017. 
         NL         AAH+AIS+MIA      ADC   
    NL         AAH+AIS+MIA       ADC 
      NL        AAH        AIS        MIA       ADC 
      NL         AAH        AIS          MIA       ADC 
A 
D 
C 
B 

18 
 
Taken together, the above findings 
provide the basis for our primary 
hypothesis that immune evasion 
contributes 
to 
malignant 
transformation of pre-neoplastic 
lung lesions into invasive lung 
cancers and that modulation of 
immune checkpoint pathways 
augments 
immunosurveillance 
and prevents or delays the 
development of invasive lung 
cancers. We therefore propose the 
single-arm, phase II trial of 
immunotherapy for the prevention 
of non-small cell lung cancers 
using pembrolizumab. 
4.2.2 Justification for Dose, Schedule, and Treatment Duration  
The planned dose of pembrolizumab for this study is 200 mg every 3 weeks (Q3W).  Based on the 
totality of data generated in the Keytruda development program, 200 mg Q3W is the appropriate 
dose of pembrolizumab for adults across all indications and regardless of tumor type.  As outlined 
below, this dose is justified by: 
• Clinical data from 8 randomized studies demonstrating flat dose- and exposure-efficacy 
relationships from 2 mg/kg Q3W to 10 mg/kg every 2 weeks (Q2W),  
• Clinical data showing meaningful improvement in benefit-risk including overall survival 
at 200 mg Q3W across multiple indications, and 
• Pharmacology data showing full target saturation in both systemic circulation (inferred 
from pharmacokinetic [PK] data) and tumor (inferred from physiologically-based PK 
[PBPK] analysis) at 200 mg Q3W 
Among the 8 randomized dose-comparison studies, a total of 2262 participants were enrolled with 
melanoma and non-small cell lung cancer (NSCLC), covering different disease settings (treatment 
naïve, previously treated, PD-L1 enriched, and all-comers) and different treatment settings 
(monotherapy and in combination with chemotherapy).  Five studies compared 2 mg/kg Q3W 
versus 10 mg/kg Q2W (KN001 Cohort B2, KN001 Cohort D, KN002, KN010, and KN021), and 
3 studies compared 10 mg/kg Q3W versus 10 mg/kg Q2W (KN001 Cohort B3, KN001 Cohort F2 
and KN006). KN10 dosing was q 3 weeks for both 2 and 10 mg /kg. All of these studies 
demonstrated flat dose- and exposure-response relationships across the doses studied representing 
an approximate 5- to 7.5-fold difference in exposure.  The 2 mg/kg (or 200 mg fixed-dose) Q3W 
provided similar responses to the highest doses studied.  Subsequently, flat dose-exposure-
response relationships were also observed in other tumor types including head and neck cancer, 
bladder cancer, gastric cancer and classical Hodgkin Lymphoma, confirming 200 mg Q3W as the 
appropriate dose independent of the tumor type.  These findings are consistent with the mechanism 
of action of pembrolizumab, which acts by interaction with immune cells, and not via direct 
binding to cancer cells. 
Fig. 7. PD1 blockade decreases incidence of oral and lung cancers. A. 
Treatment with PD1 blockade significantly decreases incidence of severe 
dysplasia and oral cancer compared to IgG control in 4-Nitroquinoline-1-
oxide mouse model. Adapted from Wang et al, 2017. B. Treatment with 
PD1 blockade decreases incidence of lung adenocarcinoma in KRAS 
mutant genetically engineered murine model. NT: no treatment. Heymach 
Lab, unpublished data.  
A 
B 

19 
 
Additionally, pharmacology data clearly show target saturation at 200 mg Q3W.  First, PK data in 
KN001 evaluating target-mediated drug disposition (TMDD) conclusively demonstrated 
saturation of PD-1 in systemic circulation at doses much lower than 200 mg Q3W.  Second, a 
PBPK analysis was conducted to predict tumor PD-1 saturation over a wide range of tumor 
penetration and PD-1 expression.  This evaluation concluded that pembrolizumab at 200 mg Q3W 
achieves full PD-1 saturation in both blood and tumor. 
Finally, population PK analysis of pembrolizumab, which characterized the influence of body 
weight and other participant covariates on exposure, has shown that the fixed-dosing provides 
similar control of PK variability as weight based dosing, with considerable overlap in the 
distribution of exposures from the 200 mg Q3W fixed dose and 2 mg/kg Q3W dose.  Supported 
by these PK characteristics,  and given that fixed-dose has advantages of reduced dosing 
complexity and reduced potential of dosing errors, the 200 mg Q3W fixed-dose was selected for 
evaluation across all pembrolizumab protocols. 
The treatment duration of 4 doses was chosen to balance the therapeutic efficacy and risks of 
adverse effects. Currently, metastatic NSCLC patients receive pembrolizumab treatment for up to 
2 years11,12. In neoadjuvant clinical trials, early stage NSCLC patients typically receive 2 to 3 doses 
of immune checkpoint blockade agents to avoid delay of surgical resection (the definitive 
treatment), and have shown promising anti-tumor activity and safety profiles43-45. The current 
study is the first clinical trial using an immune checkpoint blockade agent for lung cancer 
prevention, thus, there is no concern for delay of definitive treatment. On the other hand, since the 
study subjects will be patients without definitive cancer diagnosis, we want to limit the treatment 
doses to avoid accumulative toxicities. Therefore, we have designed this study using 4 doses of 
pembrolizumab. In patients with metastatic non-small cell lung cancer treated with pembrolizumab 
in the second-line setting for up to 2 years, the rate of toxicity leading to discontinuation of 
treatment is only 8%. Although these patients do not have a diagnosis of cancer, they are at a high 
risk (at least 15%) of developing cancer. An ongoing cancer prevention trial for high-risk oral 
intra-epithelial neoplasias titled  “Personalized, randomized, phase 2 study of pembrolizumab for 
high risk oral intra-epithelial neoplasias”46 also uses 4 doses of pembrolizumab. 
4.2.3 Rationale for Endpoints 
4.2.3.1 Efficacy Endpoints 
Surrogate markers to assess efficacy of treatment in individuals with high-risk IPNs are yet to 
be developed. As a “signal-finding” study, we selected “regression of high-risk IPNs” based 
on modified RECIST criteria detailed below in Table 1 at 6 months after initiation of treatment 
as the primary efficacy endpoint to have an early readout. Although there is the concern that 
response rates would inaccurately ascertain the efficacy of the agent, we believe that regression 
of high-risk IPNs will be translated into preventing invasive cancers in a good number of 
patients because a high-risk population is targeted for this study.  In the meanwhile, in order to 
truly evaluate the possible effects of pembrolizumab in reducing development of invasive 
cancer, decreasing the solid component of high-risk IPNs, reduction of incidence of 
histologically proven cancer, prolongation of cancer free survival and overall survival have been 
selected as secondary endpoints. 
 
Table 1 Evaluation of Target and Non-target Lesions by Response Evaluation Criteria in 
Indeterminate Pulmonary Nodules  

20 
 
Response Assessment 
Modified RECIST Guideline*** 
  
  
Evaluation of target lesions* 
CR 
Disappearance of all target lesions 
PR 
≥ 30% decrease in the sum of the longest diameters of target 
lesions compared with baseline  
PD 
≥ 20% increase in the sum of the longest diameter of target 
lesions compared with baseline or the appearance of one or more 
new lesions with predicted cancer risk > 15% by Brock criteria 
SD 
Neither PR or PD  
  
Evaluation of non-target 
lesions**  
  
CR 
Disappearance of all non-target lesions  
Incomplete response, SD  
Persistence of one or more non-target lesions 
PD  
 
Appearance of one or more new lesions with predicted cancer 
risk > 15% by Brock criteria regardless of shrinkage or 
disappearance of existing IPNs 
Note—CR = complete response, PR = partial response, PD = progressive disease, SD = stable disease.  
* Target lesions: Each pulmonary nodule will be identified and assessed using Brock University criteria described above. 
Pulmonary nodules with predicted cancer risk > 5% for patients with no history of lung cancer or >10% for patients with history 
of stage I-III NSCLC who complete surgery and standard adjuvant chemotherapy if indicated will be identified as the targeted 
lesions. Patients with IPNs that are difficult to uniquely identify or follow will be excluded.  
** Nontarget lesions: Other pulmonary nodules that can be uniquely identified and followed, but do not meet the criteria for 
target lesions will be identified as nontarget lesions.  
*** Ground-glass nodules/opacities will be evaluated and measured on CT lung window setting (WL -600, WW 1500). 
 
4.2.3.2 Biomarker Research 
There is substantial interest in identifying biomarkers predictive of response to immune 
checkpoint inhibitors in invasive solid tumors and the same principles apply to the setting of 
preinvasive lung neoplastic lesions. Furthermore, the interactions of non-invasive lesions with 
the immune system, microbiome, and genetic and epigenetic changes in the epithelium, and how 
they are influenced by PD-1 blockade are largely unknown. As such, the biomarkers to be 
evaluated on this study aim at: 
 
(1) understanding the risk of malignant transformation in individuals exposed or not to 
pembrolizumab, thus providing novel prognostic markers for risk assessment 
(2) identifying the population more likely to benefit from pembrolizumab 
(3) characterizing the immune response in the setting of non-invasive lesions, before and 
after treatment 
(4) evaluating the interplay between the immune system, the microbiome, the non-invasive 
epithelial lesions, and their genetic, epigenetic, transcriptomic and phenotypic changes before 
and after treatment with pembrolizumab. 
 

21 
 
Because the biomarker research embedded in this protocol is exploratory, a broad panel of 
markers will be studied, utilizing the most updated knowledge from other clinical and pre- 
clinical studies related to the biology of high-risk IPNs and immune checkpoint blockade at the 
time of the analysis. 
4.2.4 Rationale to make updated the current IMPRINT-Lung protocol 
IMPRINT-Lung was initiated in November 2018. As a novel trial in this space, it has raised a lot 
of interest in the medical community and patients. It has been showing very good safety profile, 
but there are a couple of issues. 1) The enrollment has been slow. One major reason was that many 
motivated patients declined the trial because it is a randomized trial. Therefore we propose to 
change it to a single arm study based on histologic data and patients in our database. In our database, 
if IPNs are persistent (2 CT scans, 3 months apart), the predicted risk score is >3%, the spontaneous 
regression rate is 0. 2) The current inclusion criteria miss some real high-risk IPNs. The current 
risk score based on Brock algorithm gives one snapshot of the disease course while it is well known 
the change of property of nodules (emergence of solid component in pure GGO IPNs or 
enlargement of solid component in partial solid IPNs even the size of the IPNs does not increase) 
is associated with risk of lung cancer development. Therefore, we add additional inclusion criteria 
listed below to increase the predicted risk and lower the spontaneous regression rate. 3) In this 
high risk yet non-cancer population, more safety measures, particularly pulmonary functions, 
should be incorporated when enrolling patients. Therefore, we propose the following changes. 
1. Change IMPRINT-lung to a single arm study without observation arm. 
2. Add exclusion criteria:  
a. Patient has lung diseases requiring oxygen supplement. 
b. Patient with lung diseases requiring steroids treatment. Patients has a history of 
(non-infectious) pneumonitis/interstitial lung disease that required steroids or has 
current pneumonitis/interstitial lung disease. 
c. Patient has other lung diseases requiring steroids treatment (10mg of prednisone or 
equivalent) within 4 weeks at the time of screening. 
3. Add the following inclusion criteria. 
a. With or without personal history of lung cancer AND 
b. Predicted risk > 5% at the time of screening AND 
c. Emergence of solid components within 12 months before the time of screening for 
patients with pure GGO nodules OR 
d. Enlargement of solid components within 12 months before the time of screening 
for patients with partial solid nodules OR 
e. Enlargement of the overall size of lung nodule leading to increase in predicted 
risk by 5% within 12 months before the time of screening 
 
Patients who are currently on the observation arm will continue tumor imaging, survival status, 
SAEs and QLQ-C30 and EORTC QLQ-LC29 at 3 and 6 months as previously planned. These 
patients who completed 6 months on observation arm can have the option to receive 
pembrolizumab.  
 

22 
 
4.2.5 Risk/Benefit Ratio 
This protocol has been carefully designed to optimize the risk / benefit ratio, as outlined 
below: 
 
(a) Selection of a high-risk patient population. The patients enrolled in this study are at high 
risk for developing invasive lung cancers. For patients with no personal history of lung cancer, 
we choose patients detected with IPNs of cancer probability 10% at least using validated 
predicting algorithms.  We will also enroll patients with IPNs and a history of lung cancer and 
patients with progressing IPNs (emergence of solid component, enlargement of solid 
component or enlargement of overall size of IPNs). For these patients, there is no reliable 
predicting algorithms, but are known to be at high risk of developing into cancer.  Therefore, a 
big portion of the study population will develop into invasive cancer if untreated and the current 
standard of care is observation.  
 
(b) Selection of regression of high-risk IPNs as the primary endpoint. The widespread use 
of CT for lung cancer screening and other reasons has resulted in a dramatic increase in 
the number of IPNs. While many of IPNs can be resected with minimal morbidity, the 
cost has been called into question. Furthermore, multifocality is a relatively common, 
which makes decisions on extent of surgical resection and potential benefit less clear. 
Treatment of diagnosed lung cancers on the other hand entails surgery, radiation and 
systemic, that may result in treatment-related complications (e.g., infections, 
pneumonias, radiation-induced pulmonary fibrosis, cisplatin-induced neuropathies, renal 
failure and ototoxicity). As such, a reduction in high-risk of IPNs and potentially the 
incidence of lung cancer may lead to lesser need for morbid therapeutic interventions, 
possibly improving functional outcomes. 
 
(c) Selection of an immunotherap y drug with a favorable adverse event profile. In contrast 
to anti-CTLA4 drug ipilimumab, the anti-PD-1 antibody pembrolizumab has been 
shown to have a more favorable adverse event profile.15 In randomized studies 
comparing pembrolizumab to docetaxel, pembrolizumab was also found to have a 
lower incidence of toxic effects16. The tables below outline the incidence of adverse 
events associated with pembrolizumab single agent in a clinical trial including 550 
NSCLC patients (an FDA-approved indication for the drug). The overall incidence of 
grade 3-5 adverse events was 9.5%. While severe immune mediated adverse events may 
occur, the incidence was low (3.8% grade 3-5), fatalities were extremely rare (0.2%), 
and the vast majority of patients (69.3%) exhibited complete resolution of toxicities to 
grade 0.  
 
Table 2 Immune-Mediated AE Summary in patients with metastatic non-small cell lung 
cancer treated with pembrolizumab in the KEYNOTE-001 study 
Category 
Total N-550 
Any, n (%) 
80 (14.5) 
Grade ≥3, n (%) 
21 (3.8) 

23 
 
Led to deatha, n (%) 
1 (0.2) 
Let to discontinuation, n (%) 
15 (2.7) 
Events resolved b,c, % 
69.3 
aPneumonitis. bIncludes all events of any grade, excluding hypothyroidism. cResolution is defined as a return to grade 0 
or baseline. Data cutoff date: January 23, 2015 
 
 
 
 
 
 
 
 
 
 

24 
 
Table 3 Adverse Events in patients with NSCLC treated with pembrolizumab in 
KEYNOTE-001* 
 
(d) Selection of a short treatment course. The three-month treatment period utilized within 
this protocol is likely to reduce the incidence of adverse events and/or limit their 
duration. 
 

25 
 
5.0 METHODOLOGY 
5.1 
Study Population 
5.1.1 Participant Inclusion Criteria 
Patients with no history of lung cancer who are identified with IPNs detected by lung cancer 
screening or imaging studies for any reason (incidentolomas) with cancer probability at least 10% 
will be screened for the study. For patients who have a history of lung cancer status post 
treatments with curative intent who presented with persistent IPNs will also be screened for this 
study. 
 
1. Participants are eligible to be included in the study only if one of the following criteria 
applies: 
a. Patients with no history of lung cancer, who have IPNs detected by LDCT-guided 
lung cancer screening or imaging studies for other reasons (incidentalomas) with 
10 - 30% cancer probability by Brock University cancer prediction equation as 
following47. This is one of the most frequently utilized cancer risk prediction 
equations and has been confirmed to be highly effective in catching the disease in 
its very early stages by large national studies48.  
b. Patients with no history of lung cancer, who have IPNs detected by LDCT-guided 
lung cancer screening or imaging studies for other reasons (incidentalomas) with > 
30% cancer probability by Brock University cancer prediction equation as 
following, but biopsy reveals no clear evidence of malignancy. 
c. Patients with history of Stage I-III NSCLC, who have completed curative treatment 
(surgery and/or radiation) with or without chemotherapy, who have persistent IPNs 
(on two CT scans at least 3 months apart with no evidence of shrinkage or 
regression) with 5-30% cancer probability by Brock University cancer prediction 
equation as following.  
d. Patients with history of Stage I-III NSCLC, who have completed curative treatment 
(surgery and/or radiation) with or without  chemotherapy, who have persistent IPNs 
(on two CT scans at least 3 months apart with no evidence of shrinkage or 
regression) with > 30% cancer probability by Brock University cancer prediction 
equation as following, but biopsy reveals no clear evidence of malignancy.  
e. Persistent IPNs with estimated cancer probability ≥ 5% AND at least one of the 
following criteria 
i. Emergence of solid components within 12 months before the time of 
screening for patients with pure GGO nodules OR 
ii. Enlargement of solid components within 12 months before the time of 
screening for patients with partial solid nodules OR 
iii. Enlargement of the overall size of lung nodule leading to increase in 
predicted risk by 5% within 12 months before the time of screening 
 
 
Log odds = (0.0287 * (Age - 62)) + Sex (female= +0.6011; male = 0) + Family History Lung Cancer 
(yes= + 0.2961; no=0) + Emphysema - (5.3854* ((Nodule size/10)-0.5 - 1.58113883)) + Nodule type + 
Nodule Upper Lung - (0.0824 * (Nodule count - 4)) + Spiculation - 6.7892.  

26 
 
Cancer probability = 100 * (e(Log odds) / (1 + e(Log odds))) 
 
Brock University cancer prediction equation. This calculator estimates the probability that a lung nodule 
described above will be diagnosed as cancer within a two to four year follow-up period. Equation 
parameters, such as Sex, have two or more discrete values that may be used in the calculation. The 
numbers in the parentheses, eg, (0.6011), represent the values that will be used47. 
 
2. Male/female participants who are at least 18 years of age on the day of signing informed 
consent with diagnosis of high-risk IPNs as defined below will be enrolled in this study. 
3. A male participant must agree to use a contraception as detailed in Appendix 3 of this 
protocol during the treatment period and for at least 12 weeks while receiving 
pembrolizumab plus an additional 120 days (a spermatogenesis cycle) for study treatments 
with evidence of genotoxicity at any dose after the last dose of study treatment and refrain 
from donating sperm during this period. 
4. A female participant is eligible to participate if she is not pregnant (see Appendix 3), not 
breastfeeding, 
and 
at 
least 
one 
of 
the 
following 
conditions 
applies:  
a) Not a woman of childbearing potential (WOCBP) as defined in Appendix 3  
OR  
b) A WOCBP who agrees to follow the contraceptive guidance in Appendix 3 during the 
treatment period and for at least 120 days for study treatments with risk of genotoxicity 
after the last dose of study treatment. 
5. The participant (or legally acceptable representative if applicable) provides written 
informed consent for the trial.   
 
6. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. 
Evaluation of ECOG is to be performed within 7 days prior to the date of study enrollment.   
7. Have adequate organ function as defined in the following table (Table 4).  Specimens must 
be collected within 10 days prior to the start of study treatment. 
Table 4 Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
Hematological 
 
Absolute neutrophil count (ANC) 
≥1500/µL 
Platelets 
≥100 000/µL 
Hemoglobin 
≥9.0 g/dL or ≥5.6 mmol/La 
Renal 
 
Creatinine OR 
Measured or calculatedb creatinine clearance 
(GFR can also be used in place of creatinine or 
CrCl) 
≤1.5 × ULN OR 
≥30 mL/min for participant with creatinine 
levels >1.5 × institutional ULN 
Hepatic 
 

27 
 
 
5.1.2 Participant Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
1. Patient has lung diseases currently requiring oxygen supplement. 
2. Patients has a history of (non-infectious) pneumonitis/interstitial lung disease that required 
steroids or has current pneumonitis/interstitial lung disease. 
3. Patient has other lung diseases requiring steroids treatment (10mg of prednisone or 
equivalent) within 4 weeks at the time of screening. 
4. A WOCBP who has a positive urine pregnancy test within 72 hours prior to treatment  (see 
Appendix 3).  If the urine test is positive or cannot be confirmed as negative, a serum 
pregnancy test will be required. Note: in the event that 72 hours have elapsed between the 
screening pregnancy test and the first dose of study treatment, another pregnancy test (urine 
or serum) must be performed and must be negative in order for subject to start receiving 
study medication. 
5. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an 
agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX-40, 
CD137). 
6. Has received prior systemic anti-cancer therapy including investigational agents within 
4 weeks [could consider shorter interval for kinase inhibitors or other short half-life drugs] 
prior to treatment. 
Note: Participants must have recovered from all AEs due to previous therapies to ≤Grade 1 
or baseline. Participants with ≤Grade 2 neuropathy may be eligible. 
Total bilirubin 
≤1.5 ×ULN OR direct bilirubin ≤ULN for 
participants 
with 
total 
bilirubin 
levels 
>1.5 × ULN 
AST (SGOT) and ALT (SGPT) 
≤2.5 × ULN  
Coagulationc 
 
International normalized ratio (INR) OR 
prothrombin time (PT) 
Activated partial thromboplastin time (aPTT) 
≤1.5 × ULN unless participant is receiving 
anticoagulant therapy as long as PT or aPTT is 
within therapeutic range of intended use of 
anticoagulants 
ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase); AST (SGOT)=aspartate 
aminotransferase (serum glutamic oxaloacetic transaminase); GFR=glomerular filtration rate; ULN=upper 
limit of normal. 
a Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) 
transfusion within last 2 weeks.  
b Creatinine clearance (CrCl) should be calculated per institutional standard. 
c PT(INR),aPTT  only required for patients having a biopsy and/or if clinically indicated 
Note: This table includes eligibility-defining laboratory value requirements for treatment; laboratory value 
requirements should be adapted according to local regulations and guidelines for the administration of 
specific chemotherapies. 

28 
 
Note: If participant received major surgery, they must have recovered adequately from the 
toxicity and/or complications from the intervention prior to starting study treatment. 
7. Has received prior chest radiotherapy and the radiation field overlaps with IPNs. 
Has received a live vaccine within 30 days prior to the first dose of study drug.  Examples 
of live vaccines include, but are not limited to, the following:  measles, mumps, rubella, 
varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette–Guérin (BCG), and 
typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus 
vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live 
attenuated vaccines and are not allowed. 
 
8. Is currently participating in or has participated in a study of an investigational agent or has 
used an investigational device within 4 weeks prior to the first dose of study treatment. 
Note:  Participants who have entered the follow-up phase of an investigational study may 
participate as long as it has been 4 weeks after the last dose of the previous investigational 
agent. 
9. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in 
dosing exceeding 10 mg daily of prednisone equivalent) or any other form of 
immunosuppressive therapy within 7 days prior to the first dose of study drug. 
 
10. Has a known additional metastatic malignancy that is progressing or requiring active 
treatment.  Note:  Participants with basal cell carcinoma of the skin, squamous cell 
carcinoma of the skin, carcinoma in situ (e.g. breast carcinoma, cervical cancer in situ), or 
potentially curable early-stage malignancies including localized NSCLC, head and neck 
squamous carcinoma, breast cancer, bladder cancer etc., that have undergone potentially 
curative therapy (surgery and/or radiation with or without chemotherapy) are not excluded. 
11. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients. 
 
12. Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. 
with use of disease modifying agents, corticosteroids or immunosuppressive drugs). 
Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement 
therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic 
treatment.  
13. Has an active infection requiring systemic therapy. 
14. Has a known history of Human Immunodeficiency Virus (HIV).   
15. Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] 
reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is detected) 
infection. Note: no testing for Hepatitis B and Hepatitis C is required unless mandated by 
local health authority.  
16. Has a known history of active TB   (Bacillus Tuberculosis).  
 
17. Has a history or current evidence of any condition, therapy, or laboratory abnormality that 
might confound the results of the study, interfere with the subject’s participation for the 

29 
 
full duration of the study, or is not in the best interest of the subject to participate, in the 
opinion of the treating investigator.   
18. Has known psychiatric or substance abuse disorders that would interfere with cooperation 
with the requirements of the trial. 
19. Is pregnant or breastfeeding or expecting to conceive or father children within the projected 
duration of the study, starting with the screening visit through 120 days after the last dose 
of trial treatment. 
 
5.1.3 Lifestyle Restrictions 
5.1.3.1 Meals and Dietary Restrictions 
Participants should maintain a normal diet unless modifications are required to manage an AE such 
as diarrhea, nausea or vomiting. 
5.1.3.2 Contraception 
Pembrolizumab may have adverse effects on a fetus in utero.  Refer to Appendix 3 for approved 
methods of contraception. 
For this study, male participants will be considered to be of non-reproductive potential if they have 
azoospermia (whether due to having had a vasectomy or due to an underlying medical condition).   
5.1.4 Pregnancy 
If a participant inadvertently becomes pregnant while on treatment with pembrolizumab, the 
participant will be immediately discontinued from study treatment.  The site will contact the 
participant at least monthly and document the participant’s status until the pregnancy has been 
completed or terminated.  The outcome of the pregnancy will be reported to Merck within 2 
working days if the outcome is a serious adverse experience (eg, death, abortion, congenital 
anomaly, or other disabling or life-threatening complication to the mother or newborn).  The study 
Investigator will make every effort to obtain permission to follow the outcome of the pregnancy 
and report the condition of the fetus or newborn to Merck.  If a male participant impregnates his 
female partner, the study personnel at the site must be informed immediately and the pregnancy 
must be reported to Merck and followed as described in Section 7.2.2. 
5.1.5 Use in Nursing Women 
It is unknown whether pembrolizumab is excreted in human milk.  Since many drugs are excreted 
in human milk, and because of the potential for serious adverse reactions in the nursing infant, 
participants who are breast-feeding are not eligible for enrollment. 
5.2 
Trial Treatments 
The treatment to be used in this trial is outlined below in Table 5. 

30 
 
Table 5   Trial Treatment 
 
Drug 
Dose/Potency 
Dose 
Frequency 
Route of 
Administration 
Regimen/Treatment 
Period 
Use 
Pembrolizumab 
200 mg 
Q3W 
IV infusion 
Day 1 of each 3 weeks 
cycle for 4 cycles 
Experimental 
 
5.2.1 Timing of Dose Administration 
Trial treatment should be administered on Day 1 of each cycle after all procedures/assessments 
have been completed as detailed on the Trial Flow Chart (Section 6.0).  Trial treatment may be 
administered up to 7 days before or after the scheduled Day 1 of each cycle due to administrative 
reasons. 
All trial treatments will be administered on an outpatient basis. 
Pembrolizumab 200 mg will be administered as a 30 minute IV infusion every 3 weeks.  Sites 
should make every effort to target infusion timing to be as close to 30 minutes as possible.  
However, given the variability of infusion pumps from site to site, a window of -5 minutes and 
+10 minutes is permitted (i.e., infusion time is 30 minutes: -5 min/+10 min). 
The Pharmacy Manual contains specific instructions for the preparation of the pembrolizumab 
infusion fluid and administration of infusion solution. 
5.2.2 Dose Modification and toxicity management for immune-related AEs associated 
with pembrolizumab 
AEs associated with pembrolizumab exposure may represent an immunologic etiology. These 
immune-related AEs (irAEs) may occur shortly after the first dose or several months after the last 
dose of pembrolizumab treatment and may affect more than on body system simultaneously. 
Therefore, early recognition and initiation of treatment is critical to reduce complications.  Based 
on existing clinical study data, most irAEs were reversible and could be managed with 
interruptions of pembrolizumab, administration of corticosteroids and/or other supportive care. 
For suspected irAEs, ensure adequate evaluation to confirm etiology or exclude other causes. 
Additional procedures or tests such as bronchoscopy, endoscopy, skin biopsy may be included as 
part of the evaluation. Based on the severity of irAEs, withhold or permanently discontinue 
pembrolizumab and administer corticosteroids. Dose modification and toxicity management 
guidelines for irAEs associated with pembrolizumab are provided in Table 6.  
 
5.2.3 General description on the assessment of health-related quality of life (QoL) 
To assess the health-related quality of life (QoL) of subjects enrolled in the study, we will apply 
two validated instruments, The European Organization for Research and Treatment of Cancer 
Quality of Life Questionnaire – Core Questionnaire (EORTC QLQ-C30) as well as the Quality of 
Life Lung Cancer 29 Module (EORTC QLQ-LC29) (it will be used in conjunction with EORTC 
QLQ-C30), to all enrolled subjects.  These two questionnaire will be given at three time points: 
(1) at baseline (screening visit 2) after signing the informed consent form but prior to the first dose 
treatment , (2) at completion of treatments, i.e., end of cycle 4 (approximately 3 months after the 

31 
 
first dose of treatment) or at time of treatment termination, and (3) at 6 months follow-up after 
treatment initiation.  The goal is to assess the QoL of patients treated with pembrolizumab.       
The QLQ-C30 consists of 30 items covering five function subscales (physical, role, emotional, 
cognitive and social), nine symptom subscales/items (fatigue, nausea/vomiting, pain, dyspnea, 
insomnia, appetite loss, constipation, diarrhea and financial difficulties) and a global health/QoL 
subscale.  
EORTC QLQ-LC29 provides 29 items, retained 12 of the 13 original EORTC QLQ-LC13 items 
to access cough, short of breath, sore mouth/tongue, swallowing, tingling in hands or feet, hair 
loss, pain, etc; supplemented with 17 items to  primarily assess side effects of targeted therapy, 
radio-chemotherapy, and thoracic surgery etc.  Several studies have validated and applied these 
two QoL instruments in both healthy populations and lung cancer patients.49-53

 
32 
 
 

 
33 
 
Table 6 Dose modification and toxicity management guidelines for immune-related AEs associated with pembrolizumab  
General instructions: 
1. Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks. 
2. For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to Grade 1 or 0 and 
corticosteroid has been tapered. Pembrolizumab should be permanently discontinued if AE does not resolve within 12 weeks of last dose or 
corticosteroids cannot be reduced to ≤10 mg prednisone or equivalent per day within 12 weeks.  
3. For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other immunosuppressive treatment 
should be initiated if irAEs cannot be controlled by corticosteroids. 
 
Immune-related 
AEs 
Toxicity grade or 
conditions 
(CTCAEv4.0) 
Action taken to 
pembrolizumab 
irAE management with 
corticosteroid and/or other 
therapies  
Monitor and follow-up  
Pneumonitis  
Grade 2 
Withhold  
• Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper 
 
• 
Monitor participants for signs and 
symptoms of pneumonitis 
• 
Evaluate participants with suspected 
pneumonitis with radiographic imaging and 
initiate corticosteroid treatment 
• 
Add prophylactic antibiotics for 
opportunistic infections 
Grade 3 or 4, or 
recurrent Grade 2 
Permanently 
discontinue 
Diarrhea / Colitis  Grade 2 or 3 
Withhold 
• Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper 
 
• 
Monitor participants for signs and symptoms 
of enterocolitis (ie, diarrhea, abdominal 
pain, blood or mucus in stool with or 
without fever) and of bowel perforation 
(ie, peritoneal signs and ileus). 
• 
Participants with ≥ Grade 2 diarrhea 
suspecting colitis should consider GI 
consultation and performing endoscopy to 
rule out colitis.  
• 
Participants with diarrhea/colitis should be 
advised to drink liberal quantities of clear 
fluids.  If sufficient oral fluid intake is not 
feasible, fluid and electrolytes should be 
substituted via IV infusion. 
Grade 4 
Permanently 
discontinue 
AST / ALT 
elevation or 
Grade 2 
Withhold 
• Administer corticosteroids (initial 
dose of 0.5- 1 mg/kg prednisone or 
equivalent) followed by taper 
• 
Monitor with liver function tests (consider 
weekly or more frequently until liver 

 
34 
 
Increased 
bilirubin 
Grade 3 or 4  
Permanently 
discontinue 
• Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper 
enzyme value returned to baseline or is 
stable 
Type 1 diabetes 
mellitus (T1DM) 
or 
Hyperglycemia 
 
Newly onset 
T1DM or  
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of β-cell 
failure 
Withhold 
• Initiate insulin replacement 
therapy for participants with 
T1DM  
• Administer anti-hyperglycemic in 
participants with hyperglycemia  
 
• 
Monitor participants for hyperglycemia or 
other signs and symptoms of diabetes. 
Hypophysitis 
Grade 2 
Withhold 
• Administer corticosteroids and 
initiate hormonal replacements as 
clinically indicated.   
 
• 
Monitor for signs and symptoms of 
hypophysitis (including hypopituitarism and 
adrenal insufficiency)  
Grade 3 or 4  
Withhold or 
permanently 
discontinue1  
Hyperthyroidism  
Grade 2 
Continue  
• Treat with non-selective beta-
blockers (eg, propranolol) or 
thionamides as appropriate  
• 
Monitor for signs and symptoms of thyroid 
disorders.  
 
Grade 3 or 4  
Withhold or  
permanently 
discontinue1 
Hypothyroidism 
Grade 2-4 
Continue  
• Initiate thyroid replacement 
hormones (eg, levothyroxine or 
liothyroinine) per standard of care 
• 
Monitor for signs and symptoms of thyroid 
disorders.  
 
Nephritis and 
Renal 
dysfunction 
Grade 2 
Withhold  
• Administer corticosteroids 
(prednisone 1-2 mg/kg or 
equivalent) followed by taper. 
• 
Monitor changes of renal function 
 
Grade 3 or 4  
Permanently 
discontinue 
Myocarditis 
Grade 1 or 2 
Withhold 
• Based on severity of AE 
administer corticosteroids 
• 
Ensure adequate evaluation to confirm 
etiology and/or exclude other causes 
 
Grade 3 or 4 
Permanently 
discontinue 
All other 
immune-related 
AEs 
Intolerable/ 
persistent Grade 2 
Withhold 
• Based on type and severity of AE 
administer corticosteroids  
• 
Ensure adequate evaluation to confirm 
etiology and/or exclude other causes 
 
Grade 3 
Withhold or 
discontinue based 
on the type of 

 
35 
 
event.  Events that 
require 
discontinuation 
include and not 
limited to:  
Gullain-Barre 
Syndrome, 
encephalitis 
Grade 4 or 
recurrent Grade 3  
Permanently 
discontinue 
1. Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician.   
NOTE:  
For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, pembrolizumab may be resumed 
when AE resolves to ≤ Grade 2 and is controlled with hormonal replacement therapy or achieved metabolic control (in case of T1DM).   
 
 
 
 
Dose modification and toxicity management of infusion-reactions related to pembrolizumab 
Pembrolizumab may cause severe or life threatening infusion-reactions including severe hypersensitivity or anaphylaxis. Signs and symptoms usually 
develop during or shortly after drug infusion and generally resolve completely within 24 hours of completion of infusion. Dose modification and toxicity 
management guidelines on pembrolizumab associated infusion reaction are provided in Table 7. 

 
36 
 
 
 
Table 7  Pembrolizumab Infusion Reaction Dose modification and Treatment Guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at Subsequent 
Dosing 
Grade 1 
Mild reaction; infusion 
interruption not 
indicated; intervention 
not indicated 
Increase monitoring of vital signs as medically 
indicated until the participant is deemed medically 
stable in the opinion of the investigator. 
None 
Grade 2 
Requires therapy or 
infusion interruption but 
responds promptly to 
symptomatic treatment 
(e.g., antihistamines, 
NSAIDs, narcotics, IV 
fluids); prophylactic 
medications indicated 
for ≤24 hrs 
Stop Infusion. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDs 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as medically 
indicated until the participant is deemed medically 
stable in the opinion of the investigator. 
If symptoms resolve within 1 hour of stopping drug 
infusion, the infusion may be restarted at 50% of 
the original infusion rate (e.g. from 100 mL/hr to 
50 mL/hr).  Otherwise dosing will be held until 
symptoms resolve and the participant should be 
premedicated for the next scheduled dose. 
Participants who develop Grade 2 toxicity 
despite adequate premedication should be 
permanently discontinued from further study 
drug treatment 
Participant may be 
premedicated 1.5h (± 30 
minutes) prior to infusion of 
pembrolizumab with: 
Diphenhydramine 50 mg po 
(or equivalent dose of 
antihistamine). 
Acetaminophen 500-1000 mg 
po (or equivalent dose of 
analgesic). 
Grades 3 or 4 
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 ventilatory support 
indicated 
Stop Infusion. 
Additional appropriate medical therapy may 
include but is not limited to: 
Epinephrine** 
IV fluids 
Antihistamines 
NSAIDs 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Increase monitoring of vital signs as medically 
indicated until the participant is deemed medically 
stable in the opinion of the investigator. 
Hospitalization may be indicated. 
**In cases of anaphylaxis, epinephrine should be 
used immediately. 
Participant is permanently discontinued from 
further study drug treatment. 
No subsequent dosing 
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the period of 
drug administration. 
For further information, please refer to the Common Terminology Criteria for Adverse Events v4.0 (CTCAE) at 
http://ctep.cancer.gov 
 
 
 
 

 
37 
 
Other allowed dose interruption for pembrolizumab  
Pembrolizumab may be interrupted for situations other than treatment-related AEs such as 
medical / surgical events or logistical reasons not related to study therapy. Participants should be 
placed back on study therapy within 3 weeks of the scheduled interruption, unless otherwise 
discussed with the Sponsor. The reason for interruption should be documented in the patient's 
study record. 
 
5.3 
 Treatment Allocation 
Patients seeking treatment at one of treatment sites will be screened for this trial. Subjects 
may also be identified at the multidisciplinary planning conferences, or through databases 
maintained by the Thoracic Program or other departments. Patients in these databases who 
have a diagnosis of IPN may be contacted by phone or mail or during their clinic visits at 
one of the treatment sites to offer participation in the study. 
 
Study-related procedures must not commence before obtaining consent. However, results from 
assessments performed before obtaining informed consent that are considered “routine 
standard of care” (e.g., laboratory results, CT scans, etc.) may be used to determine eligibility. 
 
This will be a single arm study of 40 eligible patients. No randomization will be performed. To 
account for 8 patients enrolled in the early phase of the study who did not receive treatment, the 
total enrollment was set at 48 patients. The sample size will be increased to 60 patients to yield 
the 40 eligible patients.  The sample size of 60 randomized patients will not change the 
preplanned analysis of 40 eligible patients as it is recommended for screen failures and early 
drop outs/therapy discontinuation during or at response. 
 
 
 
5.4 
Concomitant Medications/Vaccinations (allowed & prohibited) 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed during 
the ongoing trial.  If there is a clinical indication for one of these or other medications or 
vaccinations specifically prohibited during the trial, discontinuation from trial therapy or 
vaccination may be required.  The final decision on any supportive therapy or vaccination rests 
with the investigator and/or the participants' primary physician.  
5.4.1 Acceptable Concomitant Medications 
All treatments that the investigator considers necessary for a participant’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care.  
Clinical data capture called DMI (Data Management Initiative) will be the electronic database used 
for this study’s electronic case report forms. All concomitant medication will be recorded on the 
case report form (CRF) including all prescription, over-the-counter (OTC), herbal supplements, 
and IV medications and fluids.  If changes occur during the trial period, documentation of drug 
dosage, frequency, route, and date may also be included on the CRF.  

 
38 
 
All concomitant medications received within 28 days before the first dose of trial treatment and 
30 days after the last dose of trial treatment should be recorded.  Concomitant medications 
administered after 30 days after the last dose of trial treatment should be recorded for SAEs and 
ECIs as defined in Section 7.2. 
5.4.2 Prohibited Concomitant Medications 
Participants are prohibited from receiving the following therapies during the Screening and 
Treatment Phase (including retreatment for post-complete response relapse) of this trial: 
• Antineoplastic systemic chemotherapy or biological therapy  
• Immunotherapy not specified in this protocol 
• Chemotherapy not specified in this protocol 
• Investigational agents other than pembrolizumab 
• Radiation therapy  
o Note:  Radiation therapy to a symptomatic solitary lesion or to the brain may be 
allowed at the investigator’s discretion.   
• Live vaccines within 30 days prior to the first dose of study treatment and while 
participating in the study.  Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and 
typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus 
vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live 
attenuated vaccines and are not allowed.  
• Systemic glucocorticoids for any purpose other than to modulate symptoms from an event 
of clinical interest of suspected immunologic etiology.  The use of physiologic doses of 
corticosteroids may be approved after consultation with the Sponsor. 
Participants who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the study.  All 
treatments that the Investigator considers necessary for a participant’s welfare may be 
administered at the discretion of the Investigator in keeping with the community standards of 
medical care.   
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed during 
the ongoing study.  If there is a clinical indication for any medication or vaccination specifically 
prohibited during the study, discontinuation from study therapy or vaccination may be required.  
The final decision on any supportive therapy or vaccination rests with the investigator and/or the 
participant's primary physician.  However, the decision to continue the participant on study 
treatment requires the mutual agreement of the investigator, the Sponsor and the participant. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
5.4.3 Rescue Medications & Supportive Care 
Participants should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Suggested supportive care measures for the management of AEs with 
potential immunologic etiology are outlined along with the dose modification guidelines in 
Section 5.2.2, [Table 4].  Where appropriate, these guidelines include the use of oral or IV 
treatment with corticosteroids, as well as additional anti-inflammatory agents if symptoms do not 

 
39 
 
improve with administration of corticosteroids.  Note that several courses of steroid tapering may 
be necessary as symptoms may worsen when the steroid dose is decreased.  For each disorder, 
attempts should be made to rule out other causes such as metastatic disease or bacterial or viral 
infection, which might require additional supportive care.  The treatment guidelines are intended 
to be applied when the Investigator determines the events to be related to pembrolizumab.  
Note: If after the evaluation of the event, it is determined not to be related to pembrolizumab, the 
Investigator does not need to follow the treatment guidance.  Refer to Table 6 in Section 5.2.2 for 
guidelines regarding dose modification and supportive care.  
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or skin 
photography as part of evaluation of the event.  
• PNEUMONITIS: 
 
o For Grade 2 events, treat with systemic corticosteroids. When symptoms 
improve to Grade 1 or less, steroid taper should be started and continued over 
no less than 4 weeks. 
o For Grade 3-4 events, immediately treat with intravenous steroids. 
Administer additional anti-inflammatory measures, as needed. 
o Add prophylactic antibiotics for opportunistic infections in the case of 
prolonged steroid administration. 
 
• DIARRHEA/COLITIS: 
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such 
as diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of 
bowel perforation (such as peritoneal signs and ileus). 

 
40 
 
 
 
 
o All subjects who experience diarrhea/colitis should be advised to drink liberal 
quantities of clear fluids. If sufficient oral fluid intake is not feasible, fluid 
and electrolytes should be substituted via IV infusion. For Grade 2 or higher 
diarrhea, consider GI consultation and endoscopy to confirm or rule out colitis. 
o For Grade 2 diarrhea/colitis that persists greater than 3 days, administer oral 
corticosteroids. 
o For Grade 3 or 4 diarrhea/colitis that persists > 1 week, treat with intravenous 
steroids followed by high dose oral steroids. 
o When symptoms improve to Grade 1 or less, steroid taper should be started 
and continued over no less than 4 weeks. 
 
• TYPE 1 DIABETES MELLITUS (IF NEW ONSET, INCLUDING DIABETIC 
KETOACIDOSIS [DKA]) OR 
≥ Grade 3 Hyperglycemia, if associated with ketosis (ketonuria) or metabolic 
acidosis (DKA) 
o For T1DM or Grade 3-4 Hyperglycemia 
• Insulin replacement therapy is recommended for Type I diabetes mellitus 
and for Grade 3-4 hyperglycemia associated with metabolic 
acidosis or ketonuria. 
• Evaluate patients with serum glucose and a metabolic panel, urine 
ketones, glycosylated hemoglobin, and C-peptide. 
 
• HYPOPHYSITIS: 
o For Grade 2 events, treat with corticosteroids. When symptoms improve to 
Grade 1 or less, steroid taper should be started and continued over no less than 4 
weeks. Replacement of appropriate hormones may be required as the steroid dose 
is tapered. 
o For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed 
by oral corticosteroids. When symptoms improve to Grade 1 or less, steroid 
taper should be started and continued over no less than 4 weeks. Replacement of 
appropriate hormones may be required as the steroid dose is tapered. 
 
• HYPERTHYROIDISM OR HYPOTHYROIDISM: 
Thyroid disorders can occur at any time during treatment. Monitor patients for 
changes in thyroid function (at the start of treatment, periodically during treatment, 
and as indicated based on clinical evaluation) and for clinical signs and symptoms of 
thyroid disorders. 
 
o Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism): 
• In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are 
suggested as initial therapy.  
• In hypothyroidism, thyroid hormone replacement therapy, with 

 
41 
 
levothyroxine or liothyroinine, is indicated per standard of care.  
o Grade 3-4 hyperthyroidism 
• Treat with an initial dose of IV corticosteroid followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid 
taper should be started and continued over no less than 4 weeks. 
Replacement of appropriate hormones may be required as the steroid 
dose is tapered. 
 
• HEPATIC: 
o For Grade 2 events, monitor liver function tests more frequently until returned 
to baseline values (consider weekly). 
• Treat with IV or oral corticosteroids 
o For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 
hours. 
o When symptoms improve to Grade 1 or less, a steroid taper should be started 
and continued over no less than 4 weeks. 
 
• RENAL FAILURE OR NEPHRITIS: 
 
o For Grade 2 events, treat with corticosteroids. 
o For Grade 3-4 events, treat with systemic corticosteroids. 
o When symptoms improve to Grade 1 or less, steroid taper should be started 
and continued over no less than 4 weeks. 
 
 
• Management of Infusion Reactions: Signs and symptoms usually develop during or 
shortly after drug infusion and generally resolve completely within 24 hours of 
completion of infusion. 
 
Table 8 below shows treatment guidelines for subjects who experience an infusion 
reaction associated with administration of pembrolizumab (MK-3475). 
 
Table 8 Infusion Reaction Treatment Guidelines 
 
NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
Grade 1 
Mild reaction; infusion interruption 
not indicated; intervention not 
indicated 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
None 
 
 
 
 

 
42 
 
 
NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
Grade 2 
Requires infusion interruption but 
responds promptly to symptomatic 
treatment (e.g., antihistamines, 
NSAIDS, narcotics, IV fluids); 
prophylactic medications indicated for 
< =24 hrs 
Stop Infusion and monitor symptoms. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
If symptoms resolve within one hour of stopping 
drug infusion, the infusion may be restarted at 
50% of the original infusion rate (e.g., from 100 
mL/hr to 50 mL/hr).  Otherwise dosing will be 
held until symptoms resolve and the subject 
should be premedicated for the next scheduled 
dose. 
Subjects who develop Grade 2 toxicity despite 
adequate premedication should be 
permanently discontinued from further trial 
treatment administration. 
Subject may be premedicated 1.5h 
(± 30 minutes) prior to infusion of 
pembrolizumab (MK-3475) with: 
Diphenhydramine 50 mg po (or 
equivalent dose of antihistamine). 
Acetaminophen 500-1000 mg po 
(or equivalent dose of antipyretic). 
Grades 3 or 4 
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 ventilatory 
support indicated 
Stop Infusion. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
Hospitalization may be indicated. 
Subject is permanently discontinued from 
further trial treatment administration. 
No subsequent dosing 
Appropriate resuscitation equipment should be available in the room and a physician readily available during the period of drug 
administration. 
 
5.5 
Participant Withdrawal/Discontinuation Criteria 
Participants may discontinue study treatment at any time for any reason or be dropped from 
the study treatment at the discretion of the investigator should any untoward effect occur.  In 
addition, a participant may be discontinued from study treatment by the investigator or the 
Sponsor if study treatment is inappropriate, the trial plan is violated, or for administrative 
and/or other safety reasons.  Specific details regarding procedures to be performed at study 
treatment discontinuation are provided in Section 7.1.4 – Other Procedures. 
A participant must be discontinued from study treatment but continue to be monitored in the 
study for any of the following reasons: 

 
43 
 
• The participant or participant’s legally acceptable representative requests to 
discontinue study treatment 
• Confirmed radiographic disease progression outlined in Section 7.1.2.6 
• Any progression or recurrence of any malignancy, or any occurrence of another 
malignancy that requires active treatment 
• Unacceptable adverse experiences as described in Section 5.2.2. 
• The participant has a medical condition or personal circumstance which, in the opinion 
of the investigator and/or sponsor, placed the participant at unnecessary risk from 
continued administration of study treatment. 
• The participant has a confirmed positive serum pregnancy test 
• Noncompliance with study treatment or procedure requirements 
• Recurrent Grade 2 pneumonitis 
• The participant is lost to follow-up 
• Completion of 35 treatments (approximately 2 years) with pembrolizumab 
Note: The number of treatments is calculated starting with the first dose.   
• Administrative reasons 
5.6 
Participant Replacement Strategy 
MD Anderson is well suited to identify patients with high-risk IPNs. The MDA Lung Cancer 
Screening Trial (MST; PI Hanash, a collaborator of this trial), a multi-site trial will be the 
major source for high-risk IPN patients without personal history of lung cancer. More than 
1,000 individuals have enrolled thus far. In addition, chest CTs are routinely applied for 
imaging surveillance of cancer patients at MD Anderson that will provide a big cohort of 
patients with high-risk IPNs with or without personal history of lung cancer. Dr. Antonoff, a 
collaborator of this trial has identified 35,386 MD Anderson patients with GGOs on chest CT 
scans and 1,491 patients have had at least two chest CT scans54. In addition, IPNs have 
become a very common clinical entity that is frequently encountered in the clinic. We are 
therefore very confident that we will be able to successfully accrue patients as planned. 
5.7 
Clinical Criteria for Early Trial Termination 
Early trial termination will be the result of the criteria specified below: 
1. Quality or quantity of data recording is inaccurate or incomplete 
2. Poor adherence to protocol and regulatory requirements 

 
44 
 
3. Incidence or severity of adverse drug reaction in this or other studies indicates a potential 
health hazard to participants 
4. Plans to modify or discontinue the development of the study drug 
In the event of Merck decision to no longer supply study drug, ample notification will be 
provided so that appropriate adjustments to participant treatment can be made. 
 

 
 
45 
 
6.0 TRIAL FLOW CHART 
6.1 
Study Flow Chart 
Trial Period: 
Screening Phase 
Treatment Cycles 
After the first dose of treatment 
Treatment Cycle/Title: 
 
Main Study 
Screening  
1 
2  
3 
4 
 
(± 1 Month)  
Scheduling Window (Days): 
 
-28 to -1 
± 7d 
± 7d 
± 7d 
± 7d 
 
 
3m 
6m 
 
 
Treatment/Pembrolizumab  
 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
Administrative Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
 
X 
 
 
 
 
 
 
 
 
 
 
Demographics and Medical History 
 
X 
 
 
 
 
 
 
 
 
 
 
Prior and Concomitant Medication Review 
 
X 
X 
X 
X 
X 
 
 
X 
X 
 
 
Trial Treatment Administration 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
Survival Status q 
 
 
X 
X 
X 
X 
 
 
X 
X 
 
 
 
Clinical Procedures/Assessments 
Review Adverse Events a 
 
 
 
X 
X 
X 
 
 
X 
X 
 
 
Physical Examination b 
 
X 
 
 
 
 
 
 
X 
X 
 
 
Directed Physical Examination c 
 
 
X 
X 
X 
X 
 
 
X 
X 
 
 
Vital Signs and Weight d 
 
X 
X 
X 
X 
X 
 
 
X 
X 
 
 
ECOG Performance Status e 
 
X 
X 
X 
X 
X 
 
 
X 
X 
 
 
 
Laboratory Procedures/Assessments: analysis performed by LOCAL laboratory 
Pregnancy Test – Urine or Serum β-HCG f 
 
X 
 
 
 
 
 
 
 
 
 
 
CBC with Differential g,PT(INR)g,n,aPTT g,n 
 
X 
X 
X 
X 
X 
 
 
X 
X 
 
 
Comprehensive Serum Chemistry Panel h 
 
X 
X 
X 
X 
X 
 
 
X 
X 
 
 
Urinalysis i 
 
X 
 
 
 
 
 
 
 
 
 
 

 
 
46 
 
Trial Period: 
Screening Phase 
Treatment Cycles 
After the first dose of treatment 
Treatment Cycle/Title: 
 
Main Study 
Screening  
1 
2  
3 
4 
 
(± 1 Month)  
Scheduling Window (Days): 
 
-28 to -1 
± 7d 
± 7d 
± 7d 
± 7d 
 
 
3m 
6m 
 
 
Treatment/Pembrolizumab  
 
 
X 
X 
X 
X 
 
 
 
 
 
 
T3, FT4 and TSH j 
 
X 
 
 
X 
 
 
 
X 
X 
 
 
 
Efficacy Measurements 
Tumor Imaging k 
 
X 
 
 
X 
 
 
 
X 
X 
 
 
 
Tumor Biopsies/Archival Tissue Collection/Correlative Studies Blood 
Archival or Newly Obtained Tissue 
Collection l 
 
X 
 
 
 
 
 
 
 
 
 
 
Correlative Studies Blood Collection m,p 
 
 
X 
X 
X 
X 
X 
 
 
X 
X 
 
 
Correlative Studies for Stool Collection m 
 
X 
 
X 
 
 
 
 
 
X 
 
 
Health-related quality of life (QoL) EORTC 
QLQ-C30 and EORTC QLQ-LC29 .   
 
X 
 
 
 
 
 
 
X 
X 
 
 
 
a, b, c, d, e, g, h, k, m After 6 months on trial, these will be performed as the standard of care. Imaging, cancer 
diagnosis and survival data will be collected beyond the trial duration as standard of care. Please refer to 
Table 9 Laboratory Tests for the required lab assessments. 
f, i, j Pregnancy test must be performed <72 hours prior to the first dose of study medication. 
l Pre-treatment tissue will be obtained as indicated (estimated cancer probability ≥ 30%) post-enrollment tissue will be 
obtained as indicated if cancer probability increase ≥15% over baseline or when patients develop lung cancer as the 
standard of care. All archival tissue will be collected by site and sent to MDA as per the lab manual excluding UC/Rocky 
Mountain Regional VA Medical Center.  
mMicrobiome Stool samples will be collected at screening, before Cycle 2 and 6 months after the first dose of 
treatment. Samples will be sent directly to sites ambient and shipped to MDACC ITB lab as per lab manual 
excluding UC/ Mountain Regional VA Medical Center.  
 n PT(INR), aPTT only to be performed prior to biopsy and/or if clinically indicated. 

 
 
47 
 
Trial Period: 
Screening Phase 
Treatment Cycles 
After the first dose of treatment 
Treatment Cycle/Title: 
 
Main Study 
Screening  
1 
2  
3 
4 
 
(± 1 Month)  
Scheduling Window (Days): 
 
-28 to -1 
± 7d 
± 7d 
± 7d 
± 7d 
 
 
3m 
6m 
 
 
Treatment/Pembrolizumab  
 
 
X 
X 
X 
X 
 
 
 
 
 
 
p Correlative study blood samples will be collected at Screening; Day 1 of Cycles 1,2, 3, 4; 3 and 6 after the 
first dose of treatment at all sites and be shipped/stored in batches at MDACC ITB lab as per attached manual 
excluding UC/Rocky Mountain Regional VA Medical Center.   
q Participants who experience confirmed disease progression or start a new anticancer therapy will be contacted by telephone 
every 12 weeks to assess for survival status until death, withdrawal of consent, or the end of the trial, whichever occurs first. 
 
 

 
48 
 
7.0 TRIAL PROCEDURES  
7.1 
Trial Procedures 
The Trial Flow Chart - Section 7.1 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to perform 
these procedures at unscheduled time points if deemed clinically necessary by the investigator. 
Furthermore, additional evaluations/testing may be deemed necessary by the Sponsor and/or 
Merck for reasons related to participant safety. In some cases, such evaluation/testing may be 
potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations may 
require that additional informed consent be obtained from the participant.  In these cases, such 
evaluations/testing will be performed in accordance with those regulations. 
7.1.1 Administrative Procedures  
7.1.1.1 Informed Consent 
The Investigator must obtain documented consent from each potential participant prior to 
participating in a clinical trial. 
7.1.1.1.1 General Informed Consent 
Consent must be documented by the participant’s dated signature or by the participant’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature 
of the person conducting the consent discussion.  
A copy of the signed and dated consent form should be given to the participant before 
participation in the trial. 
The initial informed consent form, any subsequent revised written informed consent form and 
any written information provided to the participant must receive the IRB/ERC’s 
approval/favorable opinion in advance of use.  The participant or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available 
that may be relevant to the participant’s willingness to continue participation in the trial.  The 
communication of this information will be provided and documented via a revised consent 
form or addendum to the original consent form that captures the participant’s dated signature 
or by the participant’s legally acceptable representative’s dated signature. 
Specifics about a trial and the trial population will be added to the consent form template at 
the protocol level.   
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations 
and Sponsor requirements. 
 

 
49 
 
7.1.1.2 Inclusion/Exclusion Criteria 
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the participant qualifies for the trial.  
7.1.1.3 Medical History 
A medical history will be obtained by the investigator or qualified designee.  Medical history 
will include all active conditions, and any condition diagnosed within the prior 10 years that 
are considered to be clinically significant by the Investigator.  Details regarding the disease for 
which the participant has enrolled in this study will be recorded separately and not listed as 
medical history.   
7.1.1.4 Prior and Concomitant Medications Review 
7.1.1.4.1 Prior Medications 
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the participant 
within 28 days before starting the trial.  Treatment for the disease for which the participant has 
enrolled in this study will be recorded separately and not listed as a prior medication.  
7.1.1.4.2 Concomitant Medications 
The investigator or qualified designee will record medication, if any, taken by the participant 
during the trial.  All medications related to reportable SAEs and ECIs should be recorded as 
defined in Section 7.2. 
7.1.1.5 Disease Details and Treatments 
7.1.1.5.1 Disease Details 
The investigator or qualified designee will obtain prior and current details regarding disease 
status.  
7.1.1.5.2 Prior Treatment Details 
The investigator or qualified designee will review all prior cancer treatments including 
systemic treatments, radiation and surgeries. 
7.1.1.5.3 Subsequent Anti-Cancer Therapy Status 
The investigator or qualified designee will review all new anti-neoplastic therapy initiated after 
the last dose of trial treatment.  If a participant initiates a new anti-cancer therapy within 30 
days after the last dose of trial treatment, the 30-day Safety Follow-up visit must occur before 
the first dose of the new therapy.  Once new anti-cancer therapy has been initiated the 
participant will move into survival follow-up.  

 
50 
 
7.1.1.6 Assignment of Screening Number 
All subjects must be registered through an electronic data capture (EDC) system (CORe). A 
subject is considered registered when an “On Study” date is entered into the EDC system. 
Subjects must be registered prior to starting protocol therapy.  
Data collection for this trial will be via means of electronic data capture through the Data 
Management Initiative (DMI) database.    The DMI is a secured password protected 
system.  Access to the system is restricted to the PI, study coordinators, data coordinators, 
database analyst, and other members of the team who require needed access.  
Electronic Case Report Forms (eCRFs) will be completed in the DMI.  Data collected in the 
eCRFs will be abstracted from the electronic health record and other available source 
documentation. 
 
7.1.1.7 Trial Compliance (Medication/Diet/Activity/Other) 
Subjects should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea or vomiting. 
7.1.2 Clinical Procedures/Assessments 
7.1.2.1 Adverse Event (AE) Monitoring 
The investigator or qualified designee will assess each participant to evaluate for potential new 
or worsening AEs as specified in the Trial Flow Chart and more frequently if clinically 
indicated.  Adverse experiences will be graded and recorded throughout the study and during 
the follow-up period according to NCI CTCAE Version 4.0 (see Appendix 2).  Toxicities will 
be characterized in terms regarding seriousness, causality, toxicity grading, and action taken 
with regard to trial treatment.  
Please refer to section 7.2 for detailed information regarding the assessment and recording of 
AEs.   
7.1.2.2 Physical Exam 
The investigator or qualified designee will perform a physical exam during the screening 
period.  Clinically significant abnormal findings should be recorded as medical history. 
Physical exam during screening will include vitals, weight, ECOG status, and an examination 
of skin, HEENT (head, eyes, ears, nose, and throat), lymph nodes, heart, chest, lungs, abdomen, 
extremities, and neurological system. 
7.1.2.3 Directed Physical Exam 
For cycles that do not require a physical exam per the Trial Flow Chart, the investigator or 
qualified designee will perform a directed physical exam as clinically indicated prior to trial 
treatment administration.  

 
51 
 
7.1.2.4 Vital Signs 
The investigator or qualified designee will take vital signs and weight at: 1) screening, 2) prior 
to the administration of each dose of trial treatment and 3) at treatment discontinuation as 
specified in the Trial Flow Chart (Section 6.0).  Vital signs should include temperature, pulse, 
respiratory rate and blood pressure.  Height will be measured at screening only. 
7.1.2.5 Eastern Cooperative Oncology Group (ECOG) Performance Scale 
The investigator or qualified designee will assess ECOG status (see Appendix 1) at screening, 
prior to the administration of each dose of trial treatment and discontinuation of trial treatment 
as specified in the Trial Flow Chart.   
7.1.2.6 Lung Lesion Measurements 
Chest CT scans will be used to monitor the IPNs and recorded in the patient’s electronic 
medical record for assessment of clinical response to treatment. If IPNs disappear, this will 
also be recorded in the patient’s record. 
 
7.1.2.7 Tumor Biopsies/Archival Tissue Collection/Correlative Studies Blood/Stool 
Biospecimens collected (including archival and newly obtained biopsied and resected 
tissues) will be used for evaluation of histological response to treatment as well as 
correlative studies. As part of the study, a biospecimen repository will be created. 
The objective of this repository will be to provide material for future evaluations 
of other relevant biomarkers that may be associated with clinical outcomes. All 
samples will be stored at the Institutional Tissue Bank and de-identified and logged 
using Tissue Station. A written informed consent will be obtained from patients 
enrolled in this study so that these samples may be analyzed in the future for 
biomarkers not described in this protocol.  Biopsies when clinically indicated will be 
performed as standard of care. Archival tissue will be collected by site and be shipped 
in batches to MDACC lab as per the attached manual.  
 
Microbiome stool samples will be shipped ambient to MDACC ITB lab excluding 
UC/Rocky Mountain VA Regional Medical Center).   
  
Correlative blood specimens will be collected at sites and stored/shipped in batches as 
per the attached lab manual excluding UC/Rocky Mountain VA Regional Medical 
Center.  
 
The correlative studies to be evaluated in the biospecimens include (but are not limited 
to): 
• expression of PD-L1, PD-L2, B7-H3, B7-x/H4, PD-1, LAG-3, 2B4, BTLA, Tim3 in 
neoplastic cells, immune cells and epithelium 
• expression of CD3, CD4, FoxP3, CD8, CD68, CD57, CD45RO in immune cells 
• T cell receptor profiling by massive parallel sequencing, and/or T cell receptor 

 
52 
 
expression assay (DTEA) 
• whole exome sequencing to determine presence of neo-antigens 
• genomic analysis (including genome sequencing and SNP analysis) 
• proteomic analysis 
• phosphorylation status of multiple kinases (using antibody arrays when appropriate) 
• non-coding-RNA and messenger-RNA levels, including the expression signatures 
interferon gamma, TCR signaling, expanded-immune, de novo. 
• identification of sub-populations of T-cells (e.g. CD4+ helper T-cells, CD8+ cytotoxic 
T-cells, CD4+ CD25+ regulatory T-cells, FOXP3) and myeloid derived suppressor 
cells (CD19-, CD3-, CD14-, HLADR-, CD11b+, CD33+, CD45+) as well as immune 
phenotypic markers including ICOS/ICOSL; OX40/OX40-L; 41BB/41BB-L; PD- 
1/PD-L1 and PD-L2; CD69, and HLA-DR (activation markers that affect T cell 
function) 
• Cytokine profiling 
 
 
7.1.2.8 Stool-based biomarkers 
Patients will provide their stool samples as detailed in the tables above. Stool collection will 
be performed with commercially available collection kits from DNA Genotek company. These 
kits will be provided to patients at no cost and shipped to their respective sites for data analysis.  
 
Other biomarkers that may emerge to be important related to the biology of lung cancer and/or 
pembrolizumab therapy 
7.1.3 Laboratory Procedures/Assessments 
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below.  
Laboratory tests for hematology, chemistry, urinalysis, and others are specified in Table 9.  
 
 

 
53 
 
Table 9 Laboratory Tests 
Hematology 
Chemistry 
Urinalysis 
Other 
Hematocrit 
Albumin 
Blood 
Serum β-human chorionic gonadotropin† 
Hemoglobin 
Alkaline phosphatase 
Glucose 
  (β-hCG)† 
Platelet count 
Alanine aminotransferase (ALT) 
Protein 
PT (INR)* 
WBC (total and differential) 
Aspartate aminotransferase (AST) 
Specific gravity  
aPTT* 
Red Blood Cell Count 
Lactate dehydrogenase (LDH) 
Microscopic exam (If abnormal)  
Total triiodothyronine (T3) 
Absolute Neutrophil Count 
Carbon Dioxide ‡ 
results are noted 
Free tyroxine (T4) 
Absolute Lymphocyte Count 
  (CO2 or bicarbonate) 
Urine pregnancy test † 
Thyroid stimulating hormone (TSH) 
 
Uric Acid 
 
 
 
Calcium 
 
 
 
Chloride 
 
Blood for correlative studies 
 
Glucose 
 
 Stool Sample for microbiome analysis for 
correlative Studies  
 
Phosphorus 
 
  
 
Potassium   
 
  
 
Sodium 
 
  
 
Magnesium 
 
  
 
Total Bilirubin 
 
  
 
Direct Bilirubin (If total bilirubin is 
elevated above the upper limit of 
normal) 
 
 
 
Total protein 
 
 
 
Blood Urea Nitrogen 
 
 
† Perform on women of childbearing potential only. If urine pregnancy results cannot be confirmed as negative, a serum pregnancy test will be required.   
‡ If considered standard of care in your region. 
* Only to be performed prior to biopsy and/or if clinically indicated. 
 
 
 

 
54 
 
 
7.1.4 Other Procedures 
7.1.4.1 Withdrawal/Discontinuation 
When a participant discontinues/withdraws prior to trial completion, all applicable activities 
scheduled for the final trial visit should be performed at the time of discontinuation.  Any 
adverse events which are present at the time of discontinuation/withdrawal should be followed 
in accordance with the safety requirements outlined in Section 7.2 - Assessing and Recording 
Adverse Events.  Participants who complete 12 weeks of treatment with pembrolizumab may 
discontinue treatment. After discontinuing treatment, these participants should return to the 
site for a Safety Follow-up Visit (described in Section 7.1.5.3.1) and then proceed to the 
Follow-Up Period of the study (described in Section 7.1.5.3.2). 
7.1.4.2 Blinding/Unblinding 
This is an open-label trial; therefore, IND Office, investigator and subject will know 
the treatment administered. 
 
7.1.5 Visit Requirements 
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.   Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures. 
7.1.5.1 Screening 
7.1.5.1.1 Screening Period 
We anticipate to complete enrollment within 4 years. 
7.1.5.2 Treatment Period 
The treatment will be complete in 12 weeks - 4 cycles of pembrolizumab every 3 weeks. Visit 
requirements are outlined in Section 6.0 - Trial Flow Chart. Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures. 
7.1.5.3 Post-Treatment Visits 
7.1.5.3.1 Safety Follow-Up Visit 
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the 
last dose of study treatment or before the initiation of a new anti-cancer treatment, whichever 
comes first. All AEs that occur prior to the Safety Follow-Up Visit should be recorded.  
Participants with an AE of Grade > 1 will be followed until the resolution of the AE to Grade 
0-1 or until the beginning of a new anti-cancer therapy, whichever occurs first.  SAEs that 

 
55 
 
occur within 90 days of the end of treatment or before initiation of a new anti-cancer treatment 
should also be followed and recorded.  
7.1.5.3.2 Follow-up Visits 
Participants who discontinue study treatment for a reason other than disease progression will 
move into the Follow-Up Phase and should be assessed accordingly as outlined in Section 6.0 
- Trial Flow Chart by radiologic imaging to monitor disease status. Every effort should be 
made to collect information regarding disease status until the start of new anti-cancer therapy, 
disease progression, death, end of the study. Information regarding post-study anti-cancer 
treatment will be collected if new treatment is initiated. 
7.1.5.3.3 Survival Follow-up 
Participants who experience confirmed disease progression or start a new anticancer therapy, 
will move into the Survival Follow-Up Phase and will be contacted by telephone every 
12 weeks to assess for survival status until death, withdrawal of consent, or the end of the trial, 
whichever occurs first.  
 
7.2 
Assessing and Recording Adverse Events 
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation participant administered a pharmaceutical product and which does not 
necessarily have to have a causal relationship with this treatment. An adverse event can 
therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, 
for example), symptom, or disease temporally associated with the use of a medicinal product 
or protocol-specified procedure, whether or not considered related to the medicinal product or 
protocol-specified procedure.  Any worsening (i.e., any clinically significant adverse change 
in frequency and/or intensity) of a preexisting condition that is temporally associated with the 
use of the Merck’s product, is also an adverse event. Clinical data capture called DMI (Data 
Management Initiative) will be the electronic database used for this study’s electronic case 
report forms. 
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  Examples 
of this may include, but are not limited to, onset of menses or menopause occurring at a 
physiologically appropriate time. 
Merck product includes any pharmaceutical product, biological product, device, diagnostic 
agent or protocol-specified procedure, whether investigational (including active comparator 
medication) or marketed, manufactured by, licensed by, provided by or distributed by Merck 
for human use. 
Adverse events may occur during the course of the use of Merck product in clinical trials, or 
as prescribed in clinical practice, from overdose (whether accidental or intentional), from abuse 
and from withdrawal. 

 
56 
 
● All AEs from the time of treatment through 90 days following cessation of study treatment 
or 30 days following cessation of study treatment if the participant initiates new anticancer 
therapy, whichever is earlier, must be reported by the investigator.  
● All AEs meeting serious criteria, from the time of treatment through 90 days following 
cessation of study treatment, or 30 days following cessation of study treatment if the participant 
initiates new anticancer therapy, whichever is earlier must be reported by the investigator.  
● All pregnancies and exposure during breastfeeding, from the time of treatment through 120 
days following cessation of study treatment, or 30 days following cessation of study treatment 
if the participant initiates new anticancer therapy must be reported by the investigator.  
● Additionally, any SAE brought to the attention of an investigator at any time outside of the 
time period specified above must be reported immediately by the investigator if the event is 
considered to be drug-related. 
Investigators are not obligated to actively seek AE or SAE or other reportable safety events in 
former study participants. However, if the investigator learns of any SAE, including a death, 
at any time after a participant has been discharged from the study, and he/she considers the 
event to be reasonably related to the study treatment or study participation, the investigator 
must promptly notify Merck. 
 
Evaluating Adverse Events 
An investigator who is a qualified physician will evaluate all adverse events according to the 
NCI Common Terminology for Adverse Events (CTCAE), version 4.0. Any adverse event 
which changes CTCAE grade over the course of a given episode will have each change of 
grade recorded on the adverse event case report forms/worksheets. 
All adverse events regardless of CTCAE grade must also be evaluated for seriousness. 
Table 10 Evaluating Adverse Events 
An investigator who is a qualified physician, will evaluate all adverse events as to: 
V4.0 CTCAE 
Grading 
Grade 1 
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention not indicated. 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL. 
 
Grade 3 
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation or 
hospitalization indicated; disabling; limiting self-care ADL. 
 
Grade 4 
Life threatening consequences; urgent intervention indicated. 
 
Grade 5 
Death related to AE 
Seriousness 
A serious adverse event is any adverse event occurring at any dose or during any use of Merck product that: 

 
57 
 
 
†Results in death; or 
 
†Is life threatening; or places the participant, in the view of the investigator, at immediate risk of death from the event as it occurred 
(Note: This does not include an adverse event that, had it occurred in a more severe form, might have caused death.); or 
 
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); 
or 
 
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of 
length of stay, even if the hospitalization is a precautionary measure for continued observation. (Note: Hospitalization for an elective 
procedure to treat a pre-existing condition that has not worsened is not a serious adverse event.  A pre-existing condition is a clinical 
condition that is diagnosed prior to the use of a Merck product and is documented in the patient’s medical history.); or 
 
†Is a congenital anomaly/birth defect (in offspring of participant taking the product regardless of time to diagnosis);or 
 
Is a new cancer (that is not a condition of the study) (although not serious per ICH definition, is reportable to the Sponsor within 24 
hours and to Merck within 2 working days to meet certain local requirements); or 
 
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse 
event for collection purposes. An overdose that is not associated with an adverse event is considered a non-serious event of clinical 
interest and must be reported within 24 hours to the Sponsor and to Merck within 2 working days.. 
 
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered 
a serious adverse event when, based upon appropriate medical judgment, the event may jeopardize the participant and may require 
medical or surgical intervention to prevent one of the outcomes listed previously (designated above by a †). 
Duration 
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units 
Action taken  
Did the adverse event cause Merck product to be discontinued? 
Relationship to 
Merck Product  
Did Merck product cause the adverse event? The determination of the likelihood that Merck  product caused the adverse event will be 
provided by an investigator who is a qualified physician. The investigator’s signed/dated initials on the source document or worksheet 
that supports the causality noted on the AE form, ensures that a medically qualified assessment of causality was done. This initialed 
document must be retained for the required regulatory time frame. The criteria below are intended as reference guidelines to assist the 
investigator in assessing the likelihood of a relationship between the test drug and the adverse event based upon the available 
information. 
The following components are to be used to assess the relationship between Merck product and the AE; the greater the correlation 
with the components and their respective elements (in number and/or intensity), the more likely Merck product caused the adverse 
event (AE): 
 
Exposure 
Is there evidence that the participant was actually exposed to Merck product such as: reliable history, acceptable 
compliance assessment (pill count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite 
in bodily specimen? 
 
Time Course 
Did the AE follow in a reasonable temporal sequence from administration of Merck product?  
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal 
product)? 
 
Likely Cause 
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other 
host or environmental factors 
 

 
58 
 
Relationship 
The following components are to be used to assess the relationship between the test drug and the AE: (continued) 
to Merck 
Product 
(continued)  
Dechallenge 
Was Merck product discontinued or dose/exposure/frequency reduced? 
If yes, did the AE resolve or improve? 
If yes, this is a positive dechallenge. If no, this is a negative dechallenge. 
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the AE 
resolved/improved despite continuation of the Sponsor’s product; or (3) the trial is a single-dose drug 
trial); or (4) Sponsor’s product(s) is/are only used one time.) 
 
Rechallenge 
Was the participant re-exposed to Merck product in this study? 
If yes, did the AE recur or worsen? 
If yes, this is a positive rechallenge. If no, this is a negative rechallenge. 
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, or (2) 
the trial is a single-dose drug trial); or (3) Sponsor’s product(s) is/are used only one time). 
NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS 
AND WHICH MAY HAVE BEEN CAUSED BY MERCK PRODUCT, OR IF REEXPOSURE TO 
MERCK PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT RISK TO THE 
PARTICIPANT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE 
SPONSOR AS PER DOSE MODIFICATION GUIDELINES IN THE PROTOCOL. 
 
Consistency 
with Trial 
Treatment 
Profile 
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding Merck 
product or drug class pharmacology or toxicology? 
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according 
to his/her best clinical judgment, including consideration of the above elements. 
Record one of the following 
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of 
Merck product relationship). 
Yes, there is a reasonable 
possibility of Merck product 
relationship. 
There is evidence of exposure to Merck product.  The temporal sequence of the AE onset relative to the 
administration of Merck product is reasonable.  The AE is more likely explained by Merck product than 
by another cause. 
No, there is not a reasonable 
possibility of Merck product 
relationship 
Participant did not receive the Merck  product OR temporal sequence of the AE onset relative to 
administration of Merck product is not reasonable OR the AE is more likely explained by another cause 
than the Merck product.  (Also entered for a participant with overdose without an associated AE.) 
 
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations.  
The investigator (or physician designee) is responsible for verifying and providing source 
documentation for all adverse events and assigning the attribution for all adverse events for 
subjects enrolled. 
 
 

 
59 
 
 
 
Table 11 Recommended adverse event recording guidelines 
 
 
Serious Adverse Event (SAE) Reporting 
 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of either 
the investigator or the sponsor, it results in any of the following outcomes: 
• Death 
• A life-threatening adverse drug experience – any adverse experience that places the patient, in 
the view of the initial reporter, at immediate risk of death from the adverse experience as it 
occurred. It does not include an adverse experience that, had it occurred in a more severe form, 
might have caused death. 
• Inpatient hospitalization or prolongation of existing hospitalization 
• A persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions. 
• A congenital anomaly/birth defect. 
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require medical 
or surgical intervention to prevent one of the outcomes listed in this definition. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an emergency 
room or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, 
or the development of drug dependency or drug abuse (21 CFR 312.32). 

 
60 
 
• Important medical events as defined above, may also be considered serious adverse events. 
Any important medical event can and should be reported as an SAE if deemed appropriate by 
the Principal Investigator or the IND Sponsor, IND Office. 
• All events occurring during the conduct of a protocol and meeting the definition of a SAE must 
be reported to the IRB in accordance with the timeframes and procedures outlined in “The 
University of Texas M. D. Anderson Cancer Center Institutional Review Board Policy for 
Investigators on Reporting Serious Unanticipated Adverse Events for Drugs and Devices”.   
 
The MD Anderson Lead-site will utilize the electronic SAE application (eSAE) for 
reporting SAEs to the IND office & IRB 
 
Reporting for all sites:  
 
• A written report should be submitted to the Institutional Review Board (IRB) according to the 
requirements of the assigned IRB for patients enrolled at each site. 
• Unless stated otherwise in the protocol, all SAEs, expected or unexpected, must be reported to 
the IND Office, within 5 working days of knowledge of the event regardless of attribution. 
• Death or life-threatening events, that are unexpected, possibly, probably or definitely related 
to drug, must be reported within 24 hours of knowledge of the event. 
• Serious adverse events will be captured from the time of the first protocol-specific intervention, 
until 90 days after the last dose of drug, unless the participant withdraws consent. Serious 
adverse events must be followed until clinical recovery is complete and laboratory tests have 
returned to baseline, progression of the event has stabilized, or there has been acceptable 
resolution of the event. 
• Additionally, any serious adverse events that occur after the 90-day time period that are related 
to the study treatment must be reported to the IND Office. This may include the development 
of a secondary malignancy. 
 
• All events reported to the supporting company must also be reported to IND Office. 
Reporting for Non-Lead site: 
• SAEs will be reported to the IND Office (sponsor) on a template form that will be provided to each non-
lead site. If available, a copy of all relevant examinations that have been carried out and the dates on 
which these examinations were performed should be attached. For laboratory results, normal ranges 
should be included. Patient name should be marked out and initials and study number included on all 
attachments.  
 
• In case of a serious adverse event, the following actions must be undertaken by the non-lead 
site principal investigator: (Please note that these are in addition to the reporting that is required 
by the local IRB and supporting company). Complete the SAE form and upload it to the MD 
Anderson Box system or through secure electronic submission of SAE report(s) via e-mail to 
the MD Anderson IND Office safety inbox: MDACCSafetyReports@mdanderson.org 
 
• The non-lead site will receive an electronic confirmation of receipt, and approval of the SAE 
report and it should be filed in the study regulatory binder at the non-lead site. 

 
61 
 
 
• The University of Texas M.D. Anderson Cancer Center IND Office Medical Affairs & Safety 
Contact Information: 
 
Carla Tuttle, Medical Monitor 
7007 Bertner, 1MC12.2225 
Houston, Texas 77030 
Tel no.: 713-563-5466 
Fax no.: 713-792-8987 
e-mail: mdaccsafetyreports@mdanderson.org 
Reporting to FDA: 
• Serious adverse events will be forwarded to FDA by the IND Sponsor (Safety Project Manager 
IND Office) according to 21 CFR 312.32. 
 
It is the responsibility of the PI and the research team to ensure serious adverse events are 
reported according to the Code of Federal Regulations, Good Clinical Practices, the 
protocol guidelines, the sponsor’s guidelines, and Institutional Review Board policy. 
 
7.2.1 Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor and to Merck 
For purposes of this study, an overdose of pembrolizumab will be defined as any dose of 1,000 
mg or greater (≥5 times the indicated dose).  No specific information is available on the 
treatment of overdose of pembrolizumab. In the event of overdose, the participant should be 
observed closely for signs of toxicity.  Appropriate supportive treatment should be provided if 
clinically indicated. 
 
If an adverse event(s) is associated with (“results from”) the overdose of a Merck product, the 
adverse event(s) is reported as a serious adverse event, even if no other seriousness criteria are 
met. 
If a dose of Merck’s product meeting the protocol definition of overdose is taken without any 
associated clinical symptoms or abnormal laboratory results, the overdose is reported as a non-
serious Event of Clinical Interest (ECI), using the terminology “accidental or intentional 
overdose without adverse effect.” 
All reports of overdose with and without an adverse event must be reported within 24 hours to 
the Sponsor and within 2 working days hours to Merck Global Safety. (Attn: Worldwide 
Product Safety; FAX 215-661-6229) 

 
62 
 
 
7.2.2 Reporting of Pregnancy and Lactation to the Sponsor and to Merck 
Although pregnancy and infant exposure during breast feeding are not considered adverse 
events, it is the responsibility of investigators or their designees to report any pregnancy or 
lactation in a participant (spontaneously reported to them) that occurs during the study. 
Pregnancies and infant exposures during breastfeeding that occur after the consent form is 
signed but before treatment  must be reported by the investigator if they cause the participant 
to be excluded from the trial, or are the result of a protocol-specified intervention, including 
but not limited to washout or discontinuation of usual therapy, diet, or a pre-treatment 
procedure.   
Pregnancies and infant exposures during breastfeeding that occur from the time of treatment 
initiation through 120 days following cessation of Sponsor’s product, or 30 days following 
cessation of treatment if the participant initiates new anticancer therapy, whichever is earlier, 
must be reported by the investigator.  All reported pregnancies must be followed to the 
completion/termination of the pregnancy. Pregnancy outcomes of spontaneous abortion, 
missed abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, 
miscarriage and stillbirth must be reported as serious events (Important Medical Events). If 
the pregnancy continues to term, the outcome (health of infant) must also be reported. 
Such events must be reported within 24 hours to the Sponsor and within 2 working days to 
Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215-661-6229) 
7.2.3 Immediate Reporting of Adverse Events to the Sponsor and to Merck 
7.2.3.1 Serious Adverse Events 
A serious adverse event is any adverse event occurring at any dose or during any use of 
Merck’s product that: 
• Results in death; 
• Is life threatening; 
• Results in persistent or significant disability/incapacity; 
• Results in or prolongs an existing inpatient hospitalization; 
• Is a congenital anomaly/birth defect; 
• Is another important medical event;    
• Note: In addition to the above criteria, adverse events meeting either of the below 
criteria, although not serious per ICH definition, are reportable to the Merck in the same 
timeframe as SAEs to meet certain local requirements. Therefore, these events are 
considered serious by Merck for collection purposes. 
• Is a new cancer (that is not a condition of the study); 
• Is associated with an overdose. 
 
Refer to Table 10 for additional details regarding each of the above criteria. 

 
63 
 
For the time period beginning when the consent form is signed until initiation of treatment, 
any serious adverse event, or follow up to a serious adverse event, including death due to any 
cause that occurs to any participant must be reported within 2 working days to Merck Global 
Safety if it causes the participant to be excluded from the trial, or is the result of a protocol-
specified intervention, including but not limited to washout or discontinuation of usual therapy, 
diet, or a pre-treatment procedure. 
For the time period beginning at treatment initiation through 90 days following cessation of 
treatment, or 30 days following cessation of treatment if the participant initiates new anticancer 
therapy, whichever is earlier, any serious adverse event, or follow up to a serious adverse event, 
including death due to any cause whether or not related to the Merck product, must be reported 
within 2 working days to Merck Global Safety. 
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to Merck product that is brought to the attention of the investigator at 
any time following consent through the end of the specified safety follow-up period specified 
in the paragraph above, or at any time outside of the time period specified in the previous 
paragraph also must be reported immediately to Merck Global Safety. 
All participants with serious adverse events must be followed up for outcome. 
SAE reports and any other relevant safety information are to be forwarded to the Merck 
Global Safety facsimile number:  +1-215-661-6229 
A copy of all 15 Day Reports and Annual Progress Reports is submitted as required by FDA, 
European Union (EU), Pharmaceutical and Medical Devices agency (PMDA) or other local 
regulators. Investigators will cross reference this submission according to local regulations to 
the Merck Investigational Compound Number (IND, CSA, etc.) at the time of submission.  
Additionally, investigators will submit a copy of these reports to Merck & Co., Inc. (Attn: 
Worldwide Product Safety; FAX 215-661-6229) at the time of submission to FDA. 
7.2.3.2 Events of Clinical Interest 
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported within 2 working days to Merck Global Safety. (Attn: Worldwide 
Product Safety; FAX 215-661-6229). 
For the time period beginning when the consent form is signed until treatment initiation, any 
ECI, or follow up to an ECI, that occurs to any participant must be reported within 2 working 
days to Merck Global Safety if it causes the participant to be excluded from the trial, or is the 
result of a protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, or a pre-treatment procedure. 
For the time period beginning at treatment  through 90 days following cessation of treatment, 
or 30 days following cessation of treatment if the participant initiates new anticancer therapy, 
whichever is earlier, any ECI, or follow up to an ECI, whether or not related to Merck product, 
must be reported within 2 working days to Merck Global Safety. 
Events of clinical interest for this trial include: 

 
64 
 
1.  an overdose of Merck product, as defined in Section 7.2.1 - Definition of an Overdose for 
This Protocol and Reporting of Overdose to the Sponsor, that is not associated with clinical 
symptoms or abnormal laboratory results.  
2.  an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the upper 
limit of normal and, at the same time, an alkaline phosphatase lab value that is less than 2X the 
upper limit of normal, as determined by way of protocol-specified laboratory testing or 
unscheduled laboratory testing.* 
*Note:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology.  
 

 
61 
 
8.0 STATISTICAL CONSIDERATIONS 
8.1 
Sample Size Calculation  
In this single-arm phase II study, eligible patients will receive pembrolizumab for 4 doses every 
3 weeks with a total treatment duration of 12 weeks.  The primary efficacy endpoint of the study 
is regression (CR or PR by modified RECIST criteria, Table 1) of high-risk IPNs by 6 months 
after the initiation of treatment. Assuming the spontaneous regression of high-risk IPNs occurs in 
5% of patients based on histological control (estimated based on the analysis of NELSON study55 
and our own cohort), the regression (CR or PR by modified RECIST criteria, Table 1) rate 
increases to 20% in the pembrolizumab group and 10% patients may not be evaluable for the 
primary endpoint, we will need to enroll 40 patients to detect the difference with 87% power and 
one-sided 5% type I error rate with the one-sample exact binomial test. 
Details of the assumptions used for the sample size calculation are listed below. 
 
1. The study has a 39 months period to accrue 40 patients with high-risk IPNs, with an 
additional 9 months of follow-up after last patient is enrolled. The total study duration was  
48 months (4 years).  The sample size will be increased to 60 patients to yield the 40 eligible 
patients.  The sample size of 60 randomized patients will not change the preplanned analysis of 
40 eligible patients as it is recommended for screen failures and early drop-outs/therapy 
discontinuation during or at response. 
2. Based on the NELSON study, the spontaneous regression rate of any IPNs was 8% by 3 
months55. Based on own study, for persistent IPNs (at least 2 CT scans, 3 months apart, no 
evidence of regression) with estimated risk score ≥5%, the regression rate was 0% without 
treatment. We chose 5% spontaneous regression rate to be conservative.   
3. The majority of high-risk IPNs are preneoplastic lesions or pre-invasive lung neoplasms. 
The response rate of these lesions to checkpoint blockade agent including is unknown. In 
metastatic NSCLC, the response rate to checkpoint blockade agent including pembrolizumab, 
is ~20%. We therefore chose 20% as the regression (CR or PR by modified RECIST criteria, 
Table 1) rate in the pembrolizumab treated arm. 
4. One-sample exact binomial test is used to compare the regression rate between the 
pembrolizumab group and the spontaneous regression rate obtained from the historical data. 
 
Based on the above assumptions, a total of 40 eligible and treated patients will be 
enrolled to yield 36 evaluable patients in order to reach 87% power with a one-sided 5% type 
I error rate by applying the one-sample exact binomial test. To account for 8 patients enrolled in 
the early phase of the study who did not receive treatment, the total enrollment was  set at 48 
patients.  The sample size will be increased to 60 patients to yield the 40 eligible patients.  The 
sample size of 60 randomized patients will not change the preplanned analysis of 40 eligible 
patients as it is recommended for screen failures and early drop-outs/therapy discontinuation 
during or at response.  
 
8.2 
Statistical Analysis Plan 
Our understanding of biology and clinical course of high-risk IPNs is rudimentary. Although 
decrease the incidence of histologically-confirmed cancer, prolongation of cancer-free survival 
and overall survival may be the ultimate goal of immune prevention. Very large sample size 

 
62 
 
and long follow up are needed to provide the definitive answers to these questions. Therefore, 
as a “signal finding” study, this single-arm phase 2 trial focuses on the rate of regression (CR 
or PR by modified RECIST criteria, Table 1) of high-risk IPNs.  
 
The study population is a high-risk population with at least ≥15% risk of being diagnosed with 
lung cancer within 2-4 years of follow up period. A big proportion of this study population are 
patients who have had personal history of lung cancer and/or progressing IPNs, a very high-risk 
group for second primary lung cancer but there are no reliable prediction tools available. 
Therefore, regression (CR or PR by modified RECIST criteria, Table 1) of these very-high risk 
IPNs will lead to decrease of incidence of invasive cancers. The advantages of selecting a high 
risk group as the eligible population include: (1) avoidance of exposure of low-risk individuals 
to the drug, who are unlikely to develop lung cancer and therefore, unlikely to benefit from 
prevention interventions; (2) improvement of benefit/risk rations and benefit/cost ratios, 
justifying further use of the drug if positive effects are identified. 
 
The proposed study will be an open-label single-arm study to evaluate the effect of 
pembrolizumab in a high-risk group of IPN patients.  
 
Study Duration: We expect to accrue 1-2 patients per month. The trial period is 48 
months (4 years) with 39 months of accrual and 9 additional months of follow-up after last 
patient’s enrollment. Patient will be followed and data will be collected as standard of care. 
 
Study Endpoints: The primary endpoint is regression of IPNs (CR or PR by modified RECIST 
criteria, Table 1) at 6 month after treatment in patients receiving pembrolizumab. Multiple 
secondary and/or exploratory endpoints will be assessed as outlined in Section 3.2 and 3.3. 
 
Treatment Group: This is a single-arm open-label Phase II multi-center trial of pembrolizumab 
in patients with high-risk IPNs. The trial will enroll 40 eligible patients to receive 
pembrolizumab. 
The 95% exact confidence interval for the regression rate of high-risk IPNs by 6 months after 
treatment will be computed. Patients’ demographic and clinical characteristics at baseline will be 
summarized using descriptive statistics such as frequency distribution, mean (± s.d.) and median 
(range) accompanied by graphical analysis. Student t-test/Wilcoxon test and ANOVA/Kruskal- 
Wallis test will be used to compare continuous variables between different groups. The chi- square 
test or the Fisher’s exact test will be applied to assess the association between two categorical 
variables. 
Time-to-event endpoints will be computed using the Kaplan-Meier method. 
 CONSORT diagram will be used to summarize the conduct of the trial.17 
 
The primary endpoint of the study Is regression (CR or PR by modified RECIST criteria, Table 1) rate of 
high-risk IPNs at 6 months after treatment. The primary endpoint will be analyzed by the 
one-sample exact binomial test as described in the above Section 8.1. For events 
that have not occurred by the time of data analysis, times will be censored at the last contact at which 

 
63 
 
the patient was known to be lung cancer- free. The distribution of time to lung cancer development will 
be estimated by the Kaplan-Meier method. One-sample log-rank test18 will be used to compare cancer-
free survival of the treatment group with the prespecified target. The Cox (proportional hazards) regression 
model will be used to incorporate potential prognostic factors as covariates.  
 
The Investigator is responsible for completing efficacy/safety summary reports and submitting 
them to the IND Office Medical Affairs and Safety Group for review and approval. These should 
be submitted after the first 9 evaluable patients who initiated pembrolizumab treatment, complete 
6 months of study treatment, and every 9 evaluable patients thereafter. Toxicity assessment must 
include the first cycle of study therapy, and response assessment the first six months. 
 
A copy of the cohort summary should be placed in the Investigator’s Regulatory Binder 
under “sponsor correspondence”.  
 
8.3 Statistical consideration on the assessment of health-related quality of life (QoL) 
In this study, the eligible subjects have persistent IPNs with or without prior lung cancer but 
without active disease.  We expect that the general QoL for study subjects at baseline is good.  We 
expect that QoL may decline slightly due to the drug’s side effect during treatment period but will 
recover at 6-month follow-up.  The overall QoL scores and subscales for both instruments will be 
estimated at the three specified time points (baseline, 3-month, and 6-months after first dose of 
treatment.  Descriptive statistics such as mean, standard deviation, minimum, lower quartile, 
median, upper quartile, and maximum will be calculated. Histogram, boxplot, and change-over-
timeline plot will be generated to characterize the distribution.  The changes from baseline to 3-
month after first dose of treatment and from baseline to 6-month after first dose of treatment will 
be computed. The primary QoL endpoint is the global health/QoL of EORTC QLQ-C30. The 
primary objective is to assess the change of the global health/QoL of EORTC QLQ-C30 from 
baseline to 6-months after initiation of treatment. Exploratory analysis will be applied to compare 
the difference of change in QoL from baseline to 3 months and from baseline to 6 months after 
the first dose of treatment in the subscales of EORTC QLQ-C30 and all the measures of EORTC 
QLQ-LC29.  No multiple comparison adjustments will be applied in these exploratory analyses.    

 
64 
 
9.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES AND SAMPLES 
9.1 
Investigational Product  
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and 
regulations. 
Pembrolizumab will be provided by Merck as summarized in Table 12. 
Table 12 Product Descriptions 
Product Name & Potency 
Dosage Form 
Pembrolizumab 100 mg/ 4mL 
Solution for Injection 
 
9.2 
Packaging and Labeling Information 
Supplies will be labeled in accordance with regulatory requirements. 
9.3 
Clinical Supplies Disclosure 
This trial is open-label; therefore, the participant, the trial site personnel, the Sponsor and/or 
designee are not blinded to treatment. Drug identity (name, strength) is included in the label 
text; random code/disclosure envelopes or lists are not provided. 
9.4 
Storage and Handling Requirements 
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.   
Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site. 
Clinical supplies may not be used for any purpose other than that stated in the protocol. 
9.5 
Shipping and Handling of Biospecimen Samples 
Sites (excluding UC/Rocky Mountain Regional VA Medical Center) will be responsible for 
sending biospecimen (blood correlative and tissue) samples to MDACC.  Microbiome (stool) 
samples will be sent to sites and then shipped ambient to MDACC ITB lab as per lab manual. 
Data will include the following: protocol ID + the patient study ID + date of collection + study 
visit/time point. All patient health information will be de-identified. Subjects will be provided 
shipping packages, stool kits and labels to return directly to MDACC ITB Lab.  

 
65 
 
9.6 
Returns and Reconciliation 
The investigator is responsible for keeping accurate records of the clinical supplies received 
from Merck or designee, the amount dispensed to and returned by the participants and the 
amount remaining at the conclusion of the trial.  
Upon completion or termination of the study, all unused and/or partially used investigational 
product will be destroyed at the site per institutional policy. 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. 
 
10.0 ADMINISTRATIVE AND REGULATORY DETAILS 
The University of Texas MD Anderson Cancer Center IND Office will monitor the study 
investigators to assure satisfactory enrollment rate, data recording, and protocol adherence. 
The site principal investigator and staff are expected to cooperate and provide all relevant 
study documentation in detail at each site visit on request for review. MD Anderson Cancer 
Center will monitor and/or audit the other participating sites to assure satisfactory protocol 
adherence and enrollment.  
The site will be visited on a regular basis by the Clinical Study Monitor, who will check 
completed source documentation, discuss the progress of the study and monitor drug 
according to good clinical practice (GCP). The monitoring will also include source data 
verification (SDV). 
 
 

 
66 
 
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70 
 
12.0 APPENDICES 
Appendix 1: ECOG Performance Status 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, but 
unable to carry out any work activities. Up and about more than 50% 
of waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. 
Totally confined to bed or chair. 
5 
Dead. 
* As published in Am. J. Clin. Oncol.:  Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., 
McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology 
Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative Oncology Group, Robert Comis 
M.D., Group Chair. 
 
 
 

 
71 
 
Appendix 2: Common Terminology Criteria for Adverse Events V4.0 (CTCAE) 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.0 will be utilized for adverse event reporting. 
(http://ctep.cancer.gov/reporting/ctc.html) 
 
 
 

 
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Appendix 3: Contraceptive Guidance and Pregnancy Testing 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below)  
Women in the following categories are not considered WOCBP: 
● 
Premenarchal 
● 
Premenopausal female with 1 of the following: 
○ Documented hysterectomy 
○ Documented bilateral salpingectomy 
○ Documented bilateral oophorectomy 
Note:  Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview. 
● 
Postmenopausal female 
○ A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.  
▪ 
A high follicle stimulating hormone (FSH) level in the postmenopausal range may 
be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence of 
12 months of amenorrhea, confirmation with two FSH measurements in the 
postmenopausal range is required.  
○ Females on HRT and whose menopausal status is in doubt will be required to use one 
of the non-hormonal highly effective contraception methods if they wish to continue 
their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment. 
Contraception Requirements 
Male Participants: 
Male participants with female partners of childbearing potential are eligible to participate if 
they agree to one of the following during the protocol defined time frame in section 5.1.1:  
● 
Be abstinent from penile-vaginal intercourse as their usual and preferred lifestyle 
(abstinent on a long term and persistent basis) and agree to remain abstinent 
● 
Use a male condom plus partner use of a contraceptive method with a failure rate of 
<1% per year as described in Table 10 when having penile-vaginal intercourse with a woman 
of childbearing potential who is not currently pregnant. 
○ 
Note: Men with a pregnant or breastfeeding partner must agree to remain 
abstinent from penile-vaginal intercourse or use a male condom during each episode of 
penile penetration. 
 
 
 

 
73 
 
 
Female Participants: 
Female participants of childbearing potential are eligible to participate if they agree to use a 
highly effective method of contraception consistently and correctly as described in Table 13 
during the protocol-defined time frame in Section 5.1.1.  
 
Table 13 Highly Effective Contraception Methods 
 
Highly Effective Contraceptive Methods That Are User Dependent a  
Failure rate of < 1% per year when used consistently and correctly. 
● Combined (estrogen- and progestogen- containing) hormonal contraception b, c 
○ Oral  
○ Intravaginal  
○ Transdermal  
○ Injectable 
● Progestogen-only hormonal contraception b, c 
○ Oral  
○ Injectable  
Highly Effective Methods That Have Low User Dependency  
Failure rate of <1% per year when used consistently and correctly. 
● Progestogen- only contraceptive implant b, c  
● Intrauterine hormone-releasing system (IUS) b  
● Intrauterine device (IUD) 
● Bilateral tubal occlusion 
● Vasectomized partner  
A vasectomized partner is a highly effective contraception method provided that the partner is the sole 
male sexual partner of the WOCBP, and the absence of sperm has been confirmed.  If not, an additional 
highly effective method of contraception should be used.  
● Sexual abstinence  
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study treatment.  The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the 
preferred and usual lifestyle of the participant.)  
Notes:  
Use should be consistent with local regulations regarding the use of contraceptive methods for 
participants of clinical studies.  
 
a) Typical use failure rates are lower than perfect-use failure rates (i.e. when used consistently and 
correctly).  

 
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b) If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, 
acceptable hormonal contraceptives are limited to those which inhibit ovulation.  
 
 
Pregnancy Testing 
WOCBP should only be included after a negative highly sensitive urine or serum pregnancy 
test.  
Following initiation of treatment, pregnancy testing will be performed whenever an expected 
menstrual cycle is missed or when pregnancy is otherwise suspected, after the last dose of 
study treatment, and as required locally. 
Pregnancy testing will be performed whenever an expected menstrual cycle is missed or when 
pregnancy is otherwise suspected.