Clinical trial NCT02343952
Conditions: Carcinoma, Non-Small-Cell Lung
Keywords: Pembrolizumab MK-3475
Sponsor: Nasser Hanna, M.D.
Start date: 2015-03-09; Completion date: 2021-01-01
Enrollment: 93 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is an open label, multi-institutional, single arm phase II trial of consolidation therapy with pembrolizumab, following initial treatment with concurrent chemoradiation in patients with inoperable or unresectable stage IIIA or IIIB NSCLC. No randomization or blinding is involved.

Detailed description:
OUTLINE: This is a multi-center study.

Eligible patients must have completed concurrent chemoradiation with a standard chemotherapy regimen (either cisplatin/etoposide or carboplatin/paclitaxel) and a dose of radiation ranging from 59.4-66.6Gy, with restaging completed 28 days to 56 days post-chemoradiation. Patients with progressive disease will not be eligible for investigational treatment. Patients with stable disease/response will be eligible to register for investigational treatment of consolidation therapy to begin a minimum of 28 days and a maximum of 56 days from completion of chemoradiotherapy.

INVESTIGATIONAL TREATMENT:

Pembrolizumab, 200 mg IV every 3 weeks (until progressive disease (PD), unacceptable toxicity, or after 12 months (52 weeks) of therapy with pembrolizumab.

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

Hematopoietic:

* Absolute neutrophil count (ANC) ≥1,500/mcL
* Platelets ≥100,000/mcL
* Hemoglobin ≥9 g/dL or ≥5.6 mmol/L

Renal:

* Serum creatinine OR measured or calculated creatinine clearance ≤1.5 X institutional upper limit of normal (ULN) OR ≥60 mL/min for subject with creatinine levels \> 1.5 X institutional ULN (glomerular filtration rate (GFR) can also be used in place of creatinine or CrCl)

Hepatic:

* Serum total bilirubin ≤ 1.5 X institutional ULN OR direct bilirubin ≤ ULN for subjects with total bilirubin levels \> 1.5 institutional ULN
* Aspartate transaminase (AST), serum glutamic oxaloacetic transaminase (SGOT), alanine transaminase (ALT), serum glutamic pyruvic transaminase (SGPT) ≤ 2.5 X institutional ULN

Coagulation:

* International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5 X institutional ULN unless subject is receiving anticoagulant therapy as long as PT/INR/PTT is within therapeutic range of intended use of anticoagulants.

Arms: arm 1: Pembrolizumab -200 mg IV 3 weeks
Interventions: intervention 1: Pembrolizumab
Intervention descriptions: intervention 1: Pembrolizumab, 200 mg IV every 3 weeks (until PD, unacceptable toxicity, or after 12 months of therapy with pembrolizumab.

Protocol documents:
Prot_SAP_000.pdf: 
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Protocol Title 
A phase II trial of concurrent chemoradiation with consolidation Pembrolizumab for the 
treatment of inoperable or unresectable stage III non-small cell lung cancer (NSCLC): 
LUN14-179 
 
 
Sponsor-Investigator 
Nasser H. Hanna, MD 
Associate Professor, Department of Medicine, IU School of Medicine 
Indiana University Health Simon Cancer Center 
 
 
Co-Investigators  
Lawrence H. Einhorn, MD 
Shadia Jalal, MD 
Greg Durm, MD 
 
 
Statistician 
Ziyue Liu, PhD 
Indiana University, Schools of Public Health and Medicine  
 
 
Trial Management Provided by  
Hoosier Cancer Research Network, Inc. (HCRN) 
 
Funding Support and Pembrolizumab Provided By  
Merck Sharp & Dohme Corp. (“Merck”) 
 
Investigational New Drug (IND) Application ID#: 125073 
 
 
Initial Protocol Date: 08JAN2015 
Amended Protocol Version Date: 
08JAN2015 
09JUL2015  
26SEP2015  
14JAN2016 (current) 
 
 
 


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PROTOCOL SIGNATURE PAGE  
 
A phase II trial of concurrent chemoradiation with consolidation pembrolizumab for the 
treatment of inoperable or unresectable stage III non-small cell lung cancer (NSCLC): 
LUN14-179 
 
VERSION DATE: 14JAN2016 
I confirm I have read this protocol, I understand it, and I will work according to this protocol 
and to the ethical principles stated in the latest version of the Declaration of Helsinki, the 
applicable guidelines for good clinical practices, or the applicable laws and regulations of the 
country of the study site for which I am responsible, whichever provides the greater protection 
of the individual. I will accept the monitor’s overseeing of the study. I will promptly submit 
the protocol to applicable ethical review board(s). 
 
 
 
 
 
 
 
 
 
____________________________________ 
________________________ 
 Signature of Investigator 
Date 
 
 
____________________________________ 
 Investigator Name (printed) 
 
 
____________________________________ 
 Investigator Title 
 
 
____________________________________ 
 Name of Facility 
 
 
____________________________________ 
 Location of Facility (City and State) 
 
____________________________________ 
 Not Submitting to IRB 
 Expected IRB Approval Date 
 
COMPLETE AND EMAIL COPY TO HOOSIER CANCER RESEARCH NETWORK 
 
Instructions to the investigator: Please SIGN and DATE this signature page. 
PRINT your name and title, the name and location of the facility in which the 
study will be conducted, and the expected IRB approval date. Scan and email 
the completed form to Hoosier Cancer Research Network and keep a record 
for your files. 


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SYNOPSIS 
TITLE 
A phase II trial of concurrent chemoradiation with consolidation 
pembrolizumab for the treatment of inoperable or unresectable stage III non-
small cell lung cancer (NSCLC) 
SHORT TITLE 
Consolidation pembrolizumab following chemoradiation in subjects with 
inoperable/unresectable stage III NSCLC 
PHASE  
Phase II 
OBJECTIVES 
Primary Objective: 
To determine if consolidation therapy with pembrolizumab following 
concurrent chemoradiation improves time to death or distant metastatic 
disease, depending on which occurs first, in subjects with inoperable or 
unresectable stage IIIA or IIIB NSCLC.  Distant metastasis is defined as 
anything that is outside of the radiation field. 
 
Secondary Objectives: 
 To determine if consolidation therapy with pembrolizumab 
following concurrent chemoradiation improves progression free 
survival (PFS) and overall survival (OS) in subjects with inoperable 
or unresectable stage IIIA or IIIB NSCLC.  
 To assess toxicity and tolerability of consolidation therapy with 
pembrolizumab following concurrent chemoradiation in subjects 
with inoperable or unresectable stage IIIA or IIIB NSCLC. 
 Time To Death in evaluable set 
 
Exploratory Objectives: 
To assess PD-L1 expression levels in the tumor samples of subjects with 
inoperable or unresectable stage IIIA or IIIB NSCLC and correlate with 
time to distant metastatic disease, tumor histology, PFS, OS, and treatment 
toxicity. 
 
STUDY DESIGN 
This is an open label, multi-institutional, single arm phase II trial of 
consolidation therapy with pembrolizumab following initial treatment with 
concurrent chemoradiation in subjects with inoperable or unresectable stage 
IIIA or IIIB NSCLC. No randomization or blinding is involved. 
ESTIMATED 
NUMBER OF 
SUBJECTS  
N = 93 
 
 
 


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ELIGIBILITY 
CRITERIA  
Inclusion Criteria: 
1. Written informed consent and HIPAA authorization for release of 
personal health information.  
2. Age ≥ 18 years at the time of consent. 
3. Histological or cytological evidence of NSCLC.  
4. Must have unresectable or inoperable stage IIIA or IIIB disease. Subjects 
are considered unresectable or inoperable based on the judgment of the 
treating physician.  
5. Subjects may have completed concurrent chemoradiation with a standard 
chemotherapy regimen (Cisplatin/Etoposide, Carboplatin/Paclitaxel or 
Cisplatin/Pemetrexed) and a dose of radiation ranging from 59.4-66.6 
Gy.  Subjects must have stable disease or disease response as evidenced 
on CT or PET scan evaluation. For those eligible, pembrolizumab should 
begin a minimum of 28 days and a maximum 56 days following the 
completion of chemoradiation. OR 
6. Subjects may have completed up to 2 cycles of consolidation therapy 
started within 4 weeks of completion of radiation.  After completion of 
consolidation therapy, subjects must have stable disease or disease 
response as evidenced by CT or PET scan evaluation.  For those eligible, 
pembrolizumab should begin 3-4 weeks after the last cycle of 
chemotherapy. 
7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 
or 1 within 14 days prior to registration for protocol therapy. 
8. Adequate laboratory values obtained within 14 days prior to registration 
for protocol therapy (see protocol for details) 
9. Women of childbearing potential must be willing to use two methods of 
contraception or abstain from heterosexual activity from the point of 
registration through 120 days after the last dose of study drug.  
10. Male subjects of childbearing potential must agree to use an adequate 
method of contraception starting with the first dose of the study drug and 
through 120 days after the last dose of the study drug. 
 
Exclusion Criteria: 
11. Pregnant or breastfeeding, or expecting to conceive or father children 
within the projected duration of the trial, starting with the pre-screening 
or screening visit through 120 days after the last dose of trial treatment. 
12. Active central nervous system (CNS) metastases. Subjects must undergo 
a head computed tomography (CT) scan or brain MRI within 28 days 
prior to registration for protocol therapy to exclude brain metastases if 
symptomatic or without prior brain imaging.  
13. Treatment with any investigational agent within 28 days prior to 
registration for protocol therapy 
14. Prior chemotherapy, adjuvant therapy, or radiotherapy for lung cancer 
other than standard concurrent chemoradiation or up to 2 cycles of 
consolidation as described above 


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15. Prior therapy with a PD-1, PD-L1, PD-L2 or CTLA-4 inhibitor or a lung 
cancer-specific vaccine therapy 
16. Presence of metastatic disease (stage IV NSCLC) is not allowed. 
Subjects must be evaluated with a PET scan prior to registration for 
protocol therapy to exclude metastatic disease. 
17. Active second cancers. 
18. Active autoimmune disease requiring systemic treatment within the past 
90 days or a documented history of clinically severe autoimmune 
disease, or a syndrome that requires systemic steroids or 
immunosuppressive agents. Subjects with vitiligo or resolved childhood 
asthma/atopy would be an exception to this rule. Subjects that require 
intermittent use of bronchodilators or local steroid injections would not 
be excluded from the study. Subjects with hypothyroidism stable on 
hormone replacement or Sjogren’s syndrome will not be excluded from 
the study 
19. Presence of interstitial lung disease or history of pneumonitis requiring 
treatment with corticosteroids 
20. Diagnosis of immunodeficiency or receiving chronic systemic 
corticosteroid therapy or other immunosuppressive therapy (excludes 
inhaled corticosteroids) within 7 days of first dose of study drug 
21. History of psychiatric illness or social situations that would limit 
compliance with study requirements. 
22. Clinically active infection as judged by the site investigator (≥ Grade 2 
by CTCAE v4).  
23. History of human immunodeficiency virus (HIV) infection or chronic 
hepatitis B or C. 
24. History or current evidence of any condition, therapy, or laboratory 
abnormality that might confound the results of the trial, interfere with the 
subject’s participation for the full duration of the trial, or is not in the 
best interest of the subject to participate, in the opinion of the site 
investigator. 
25. Has a known history of active TB (Bacillus Tuberculosis). 
26. Hypersensitivity to pembrolizumab or any of its excipients. 
27. Has received a live vaccine within 30 days prior to planned start of study 
therapy. 
NOTE:  Seasonal influenza vaccines for injection are generally 
inactivated flu vaccines and are allowed; however intranasal influenza 
vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not 
allowed. 
 
 
 


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STATISTICAL 
CONSIDERATIONS 
 
Criteria for stopping the study 
After the 10th subject is treated with at least one dose of study drug and 
observed for a minimum of 90 days after first dose of study therapy, further 
accrual will be halted to evaluate “unacceptable toxicities warranting early 
closure of the trial” defined as a) any definitive pembrolizumab-related 
death; or b) any unexpected and previously unreported grade 4 toxicities 
definitely related to pembrolizumab. If such events are observed in one 
subject, the DSMB will discuss and provide recommendations to the 
sponsor-investigator whether to terminate the trial. If such events are 
observed in two or more subjects, the trial will be terminated. 
 
Evidence for pembrolizumab-related death will be continuously monitored 
through the trial.  
 
Pneumonitis of grade 3 and 4 will be continuously monitored. An overall 
rate of 20% or above would be considered unacceptable. If the probability of 
the grade 3/4 pneumonitis rate being less than 20% drops below 0.1, the trial 
will be terminated. 
 
Sample size, Accrual, Study Duration and Replacement Rules 
Efficacy of pembrolizumab will be quantified and evaluated by the time to 
death or distant metastasis, depending on which occurs first. Under the 
conventional chemotherapy, the median time is around 12-months. We 
expect pembrolizumab to improve the median time by 50%. Brookmeyer and 
Crowley method will be used to test the following one-sided hypotheses: H0: 
m ≤12-month versus Ha: m >12-month. The accrual period is expected to be 
24-months, following by an additional 12-months follow-up. Thus, the 
overall study duration will be 36 months. With type I error level as 0.05, 
N=83 subjects are required to obtain a power level of 0.80. The sample size 
is further adjusted to N = 93 to account for 10% lost-to-follow-up. If an 
ineligible subject is accidentally enrolled, that subject will be removed and 
replaced with an eligible subject. 
 
Primary Objective Analysis 
The primary objective is to evaluate the time to death or distant metastasis 
(TTD), depending on which occurs first. The enrolled set will be used for the 
primary analysis. 
 
Kaplan-Meier method will be used for estimation. Brookmeyer and Crowley 
method will be used to calculate the 95% confidence interval of the median 
time and to test the following one-sided hypotheses: H0: m ≤12-month 
versus Ha: m >12-month. P-value < 0.05 will be considered as significant. 
 
 
 
 


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Secondary Objectives Analysis 
Key secondary objectives are progression free survival (PFS), overall 
survival (OS) and toxicities of pembrolizumab TTD in evaluable set is also a 
secondary objective. 
 
PFS and OS will be estimated by Kaplan-Meier method. They will be 
analyzed for both the enrolled set and the evaluable set. TTD will be 
estimated by Kaplan-Meier method for the evaluable set. 
Toxicities will be presented as rates and 95% Agresti-Coull confidence 
intervals. The treated set will be used for toxicity analysis. 
 
Safety Analysis 
The Common Terminology Criteria for Adverse Events (CTCAE) v4 and the 
Merck criteria for immunological side effects will be used jointly to report 
toxicities. 
 
Safety analyses will be performed for the treated set. Toxicities will be 
summarized by grade level, with and without considering relevance to 
treatment. 
 
Exploratory Objective Analysis 
Exploratory analysis is planned to characterize the rate of expression PD-L1 
in stage III NSCLC, and correlate with histology, PFS, OS and toxicity. 
Rates and 95% confidence intervals will be generated for PD-L1 
expressions. Their associations with TTD, PFS and OS will be evaluated by 
Cox proportional hazard models. 
 
Subgroup Analysis  
Both efficacy and toxicity outcomes will be evaluated in subgroup analysis 
based on PD-L1 expressions, as well for subjects that have had up to 2 cycles 
of consolidation therapy. Additional subgroup analyses will be performed for 
toxicities based on primary treatment as chemotherapy or radiation therapy, 
and the dosage of radiations. 
ESTIMATED 
ENROLLMENT 
PERIOD 
Estimated months = 24 
ESTIMATED STUDY 
DURATION  
Estimated months = 36 
 
 
 


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TABLE OF CONTENTS 
SCHEMA ............................................................................................................................................. 9 
1. 
BACKGROUND AND RATIONALE ................................................................................ 10 
2. 
STUDY OBJECTIVES ........................................................................................................... 14 
3. 
ELIGIBLITY CRITERIA ..................................................................................................... 14 
4. 
SUBJECT REGISTRATION ............................................................................................... 17 
5. 
TREATMENT PLAN ............................................................................................................. 17 
6. 
TREATMENT DISCONTINUATION ............................................................................... 28 
7. 
STUDY SCHEDULE OF EVENTS ..................................................................................... 30 
8. 
CRITERIA FOR DISEASE EVALUATION .................................................................... 33 
9. 
BIOLIGICAL SPECIMEN PARAMETERS FOR CORRELATIVES ..................... 40 
10.  STUDY DRUG INFORMATION ........................................................................................ 40 
11.  ADVERSE EVENTS ............................................................................................................... 41 
12.  STATISTICAL CONSIDERATIONS ................................................................................ 46 
13.  TRIAL MANAGEMENT ...................................................................................................... 49 
14.  DATA HANDLING AND RECORD KEEPING ............................................................. 49 
15.  ETHICS ..................................................................................................................................... 51 
16.  REFERENCES ......................................................................................................................... 53 
 
 
 


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SCHEMA 
A phase II trial of concurrent chemoradiation with consolidation pembrolizumab for the 
treatment of inoperable or unresectable stage III non-small cell lung cancer (NSCLC) 
 
 
 
 
Concurrent Chemoradiation 
Cisplatin + Etoposide 
OR 
Carboplatin + Paclitaxel 
OR 
Cisplatin/Pemetrexed 
PLUS 
Radiation (Dose- 59.4-66.6 Gy) 
Subjects that have completed chemotherapy/radiation will 
have radiology scans 28-56 days after treatment is 
complete OR  
Subjects that have completed up to 2 cycles of 
consolidation therapy will have radiology scans after 
completion of treatment 
Completion of eligibility 
requirements and study registration
Stable Disease or Response 
Progressive Disease 
NOT ELIGIBLE 
Pembrolizumab 200 mg IV every 3 weeks (until PD, unacceptable 
toxicity, or after 12 months of therapy with pembrolizumab)  
 
Subjects that have completed chemotherapy and radiation will begin 
pembrolizumab 28-56 days after completion of treatment OR  
Subjects that have completed up to 2 cycles of consolidation therapy will 
begin pembrolizumab 21-28 days after completion of treatment 


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1. 
BACKGROUND AND RATIONALE 
 
1.1 
Background 
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background 
information on Pembrolizumab. 
 
1.1.1   General Background 
Lung cancer is currently the leading cause of cancer-related mortality in the United States 
and in the world. It is estimated that 159,260 patients will die of lung cancer in 2014, 
accounting for 27% of all cancer deaths. It accounts for more deaths than breast, prostate, and 
colorectal cancer combined [1, 2]. Non-small cell lung cancer (NSCLC) accounts for 
approximately 85% of all primary lung malignancies [3]. Outcomes for this disease are poor, 
with the five-year OS rate for NSCLC being only 16.8%. This is due largely to the fact that 
only a small minority of patients (15%) have localized disease at the time of diagnosis [2]. 
Furthermore, with the exception of molecularly targeted agents in metastatic disease, current 
therapies for advanced NSCLC provide only modest benefits, and new approaches are 
needed to improve future outcomes in this disease. 
 
Stage IIIA/IIIB NSCLC is one area with a specific need for new therapeutic modalities, 
particularly in those patients with unresectable or inoperable tumors. The five-year survival 
rate for patients with stage IIIA and IIIB NSCLC are 14% and 5%, respectively [4]. The 
landscape of treatment for these patients has not changed considerably in the last three 
decades, and the improvements that have been made are relatively limited.  Until the 1980s, 
radiotherapy alone was the standard of care for patients with locally or regionally advanced 
NSCLC, despite five-year survival rates of only 3-10% [5]. Therefore, two separate trials 
were done, from Cancer and Leukemia Group B (CALGB) and the Intergroup cooperative 
trial, which demonstrated that chemotherapy followed by sequential radiotherapy improved 
five-year OS [5, 6]. Future studies focused on the comparison between sequential and 
concurrent chemoradiation, and these trials showed a modest improvement in OS for 
concurrent treatment [7, 8]. This finding was confirmed in a meta-analysis showing an 
absolute benefit of 4.5% at five years, favoring concurrent chemoradiation over sequential 
chemoradiation [9]. Since that time, a number of therapeutic strategies have been tried 
including induction [10, 11], consolidation [11-15], and maintenance chemotherapy [16], but 
none of these approaches has demonstrated a significant improvement in OS. 
 
Recent trials involving immunotherapeutic targeting of T-cell regulation and activation have 
demonstrated encouraging results. Ipilimumab, an antibody against cytotoxic T-lymphocyte 
antigen-4 (CTLA-4), was one of the first therapies developed to target regulatory T-cell 
function and has demonstrated improved progression free survival (PFS) in a phase II trial of 
advanced NSCLC [17].  More recently, therapies targeting an alternate T-cell regulatory 
protein, programmed death-1 (PD-1), have shown very favorable results in early-phase trials. 
Like CTLA-4, PD-1 is a negative regulator of T-cell function, and new therapies are aimed at 
blocking this pathway to allow increased T-cell anti-tumor activity.  Previous studies have 
shown that tumor samples demonstrating higher numbers of tumor-infiltrating lymphocytes 
(TIL) are associated with longer OS [18]. Thus, it would seem logical that therapies directed 
toward activating the T-cell mediated antitumor immune response might also prolong 


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survival. One of the first PD-1 inhibitors, Nivolumab, has shown both single-agent activity 
[19] and activity in combination with a platinum doublet [20] in early-phase trials of patients 
with NSCLC. Pembrolizumab is also demonstrating encouraging results in phase I trials, 
including an expanded cohort of patients with advanced NSCLC. Patients treated with single-
agent pembrolizumab exhibited an objective response rate (ORR) of 24% based on immune-
related response criteria (irRC) and 21% using the response evaluation criteria in solid 
tumors (RECIST) 1.1. Furthermore, as of the time of the first analysis, seven of the nine 
responding patients by irRC remain on therapy [21]. Based on these promising results, future 
trials with therapies that target T-cell regulation and activation are certainly warranted.  
 
A recent abstract presented at the American Society of Clinical Oncology’s (ASCO) annual 
meeting in 2013 suggests that patients with stage III NSCLC may benefit from immune-
based therapies. This study randomized 1513 patients to receive either L-BLP25 
(Tecemotide), a mucin-1 (MUC1) antigen specific cancer vaccine, or placebo following 
initial treatment with chemoradiation for unresectable or inoperable stage III NSCLC. 
Approximately 65% of patients received concurrent chemoradiation, and 35% received 
sequential chemoradiation. Only 1239 patients were analyzed because of an FDA hold on 
further treatment with this medication during the initial treatment course in 274 patients. The 
study failed to meet its primary endpoint of improved OS, but a pre-planned subgroup 
analysis showed an improvement in median OS from 20.6 months to 30.8 months (p=0.016) 
in those patients treated with concurrent chemoradiation [22]. These findings in combination 
with the encouraging results from CTLA-4 and PD-1 inhibitors suggest that NSCLC may be 
more sensitive to immunoregulatory therapies than previous thought. Based on this, we 
propose a multi-institutional, single-arm phase II trial of consolidation therapy with PD-1 
inhibitor pembrolizumab following initial treatment with concurrent chemoradiation in 
patients with unresectable or inoperable stage IIIA or IIIB NSCLC. 
 
1.1.2 Pharmaceutical and Therapeutic Background 
 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades [23]. Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in 
various malignancies [24-28]. In particular, the presence of CD8+ T-cells and the ratio of 
CD8+ effector T-cells / FoxP3+ regulatory T-cells seems to correlate with improved 
prognosis and long-term survival in many solid tumors. 
 
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 autoimmune reactions. PD-1 (encoded by the gene Pdcd1) is an Ig 
superfamily member related to CD28 and CTLA-4 which has been shown to negatively 
regulate antigen receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2) 
[29, 30]. The structure of murine PD-1 has been resolved [31]. PD-1 and family members are 
type I transmembrane glycoproteins containing an Ig Variable-type (V-type) domain 
responsible for ligand binding and a cytoplasmic tail which is responsible for the binding of 
signaling molecules. The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, 


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an immunoreceptor tyrosine-based inhibition motif (ITIM) and an immunoreceptor tyrosine-
based switch motif (ITSM). Following T-cell stimulation, PD-1 recruits the tyrosine 
phosphatases SHP-1 and SHP-2 to the ITSM motif within its cytoplasmic tail, leading to the 
dephosphorylation of effector molecules such as CD3ζ, PKCθ and ZAP70 which are 
involved in the CD3 T-cell signaling cascade [29, 32-34]. The mechanism by which PD-1 
down modulates T-cell responses is similar to, but distinct from that of CTLA-4 as both 
molecules regulate an overlapping set of signaling proteins [35, 36]. PD-1 was shown to be 
expressed on activated lymphocytes including peripheral CD4+ and CD8+ T-cells, B-cells, T 
regs and Natural Killer cells [37, 38]. Expression has also been shown during thymic 
development on CD4-CD8- (double negative) T-cells as well as subsets of macrophages and 
dendritic cells [39]. The ligands for PD-1 (PD-L1 and PD-L2) are constitutively expressed or 
can be induced in a variety of cell types, including non-hematopoietic tissues as well as in 
various tumors [35, 40-42]. Both ligands are type I transmembrane receptors containing both 
IgV- and IgC-like domains in the extracellular region and contain short cytoplasmic regions 
with no known signaling motifs. Binding of either PD-1 ligand to PD-1 inhibits T-cell 
activation triggered through the T-cell receptor. PD-L1 is expressed at low levels on various 
non-hematopoietic tissues, most notably on vascular endothelium, whereas PD-L2 protein is 
only detectably expressed on antigen-presenting cells found in lymphoid tissue or chronic 
inflammatory environments. PD-L2 is thought to control immune T-cell activation in 
lymphoid organs, whereas PD-L1 serves to dampen unwarranted T-cell function in peripheral 
tissues [35]. Although healthy organs express little (if any) PD-L1, a variety of cancers were 
demonstrated to express abundant levels of this T-cell inhibitor. PD-1 has been suggested to 
regulate tumor-specific T-cell expansion in subjects with melanoma (MEL) [43]. This 
suggests that the PD-1/PD-L1 pathway plays a critical role in tumor immune evasion and 
should be considered as an attractive target for therapeutic intervention. 
 
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 recently been approved in 
the United Stated for the treatment of patients with unresectable or metastatic melanoma and 
disease progression following ipilumumab and, if BRAF V600 mutation positive, a BRAF 
inhibitor. 
 
1.2 
Rationale 
 
1.2.1 Dose Selection Rationale 
The dose regimen of 200 mg Q3W of pembrolizumab is planned for all urothelial cancer 
trials. Available PK results in subjects with melanoma, NSCLC, and other solid tumor types 
support a lack of meaningful difference in PK exposures obtained at a given dose among 
tumor types. An open-label Phase 1 trial (PN001) in melanoma subjects is being conducted 
to evaluate the safety and clinical activity of single agent pembrolizumab.  The dose 
escalation portion of this trial evaluated three dose levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, 
administered every 2 weeks (Q2W) in subjects with advanced solid tumors.  All three dose 
levels were well tolerated and no dose-limiting toxicities were observed.  This first in human 
study of pembrolizumab showed evidence of target engagement and objective evidence of 


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tumor size reduction at all dose levels (1 mg/kg, 3 mg/kg and 10 mg/kg Q2W).  No 
maximum tolerated dose (MTD) has been identified. 
 
In KEYNOTE-001, two randomized cohort evaluations of melanoma subjects receiving 
pembrolizumab at a dose of 2 mg/kg versus 10 mg/kg Q3W have been completed.  The 
clinical efficacy and safety data demonstrate a lack of clinically important differences in 
efficacy response or safety profile at these doses.  For example, in Cohort B2, advanced 
melanoma subjects who had received prior ipilimumab therapy were randomized to receive 
pembrolizumab at 2 mg/kg versus 10 mg/kg Q3W.  The overall response rate (ORR) was 
26% (21/81) in the 2mg/kg group and 26% (25/79) in the 10 mg/kg group (full analysis set 
(FAS)).  The proportion of subjects with drug-related adverse events (AEs), grade 3-5 drug-
related AEs, serious drug-related AEs, death or discontinuation due to an AE was 
comparable between groups or lower in the 10 mg/kg group.   
 
Available pharmacokinetic results in subjects with melanoma, NSCLC, and other solid tumor 
types support a lack of meaningful difference in pharmacokinetic exposures obtained at a 
given dose among tumor types.  Population PK analysis has been performed and has 
confirmed the expectation that intrinsic factors do not affect exposure to pembrolizumab to a 
clinically meaningful extent.  Taken together, these data support the use of lower doses (with 
similar exposure to 2 mg/kg Q3W) in all solid tumor indications.  2 mg/kg Q3W is being 
evaluated in NSCLC in PN001, Cohort F30 and PN010, and 200 mg Q3W is being evaluated 
in head and neck cancer in PN012, which are expected to provide additional data supporting 
the dose selection. 
 
Selection of 200 mg as the appropriate dose for a switch to fixed dosing is based on 
simulation results indicating that 200 mg will provide exposures that are reasonably 
consistent with those obtained with 2 mg/kg dose and importantly will maintain individual 
patient exposures within the exposure range established in melanoma as associated with 
maximal clinical response.  A population PK model, which characterized the influence of 
body weight and other patient covariates on exposure, has been developed using available 
data from 476 subjects from PN001.   The distribution of exposures from the 200 mg fixed 
dose are predicted to considerably overlap those obtained with the 2 mg/kg dose, with some 
tendency for individual values to range slightly higher with the 200 mg fixed dose.   The 
slight increase in PK variability predicted for the fixed dose relative to weight-based dosing 
is not expected to be clinically important given that the range of individual exposures is well 
contained within the range of exposures shown in the melanoma studies of 2 and 10 mg/kg to 
provide similar efficacy and safety.  The population PK evaluation revealed that there was no 
significant impact of tumor burden on exposure. In addition, exposure was similar between 
the NSCLC and melanoma indications. Therefore, there are no anticipated changes in 
exposure between different tumor types and indication settings. 
 
1.2.2 Rationale for Endpoints 
The vast majority of patients with stage III NSCLC treated with chemoradiation will die from 
distant metastatic disease. The primary objective will be to assess whether pembrolizumab 
improves the time to metastatic disease. Immunotherapy is known to cause pseudo-
progression (the appearance of local progression), and in patients treated with radiotherapy 


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followed by immunotherapy, it will be difficult to determine the significance of small 
changes in tumor size. This will make the measurement of PFS challenging and potentially 
unreliable. Therefore, in order to provide the most objective measure of drug efficacy, the 
time to distant metastatic disease has been chosen as the primary endpoint. 
 
2. 
STUDY OBJECTIVES 
 
2.1. 
Primary Objective 
To determine if consolidation therapy with pembrolizumab following concurrent 
chemoradiation improves time to death or distant metastatic disease, depending on 
which occurs first, in subjects with inoperable or unresectable stage IIIA or IIIB 
NSCLC.  Distant metastasis is defined as anything that is outside of the radiation 
field. 
 
2.2. 
Secondary Objectives 
 To determine if consolidation therapy with pembrolizumab following concurrent 
chemoradiation improves PFS and OS in subjects with inoperable or unresectable 
stage IIIA or IIIB NSCLC. 
 
 To assess toxicity and tolerability of pembrolizumab consolidation therapy 
following concurrent chemoradiation in subjects with stage IIIA or IIIB NSCLC. 
 
 TTD in evaluable set 
 
2.3. 
Exploratory Objectives 
 To assess PD-L1 expression levels in the tumors of subjects with stage IIIA or 
IIIB NSCLC and then correlate expression with PFS, OS, treatment toxicity, and 
tumor histology. 
 
3. 
ELIGIBLITY CRITERIA 
 
3.1. 
Inclusion Criteria 
 
1. Written informed consent and HIPAA authorization for release of protected health 
information 
NOTE: HIPAA authorization may be included in the informed consent or 
obtained separately. 
 
2. Age ≥ 18 years at the time of consent 
 
3. Histological or cytological evidence of NSCLC  
 
4. Must have unresectable or inoperable stage IIIA or IIIB disease. Subjects are 
considered unresectable or inoperable based on the judgment of the treating 
physician.  
 
 


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5. Subjects may have completed concurrent chemoradiation with a standard 
chemotherapy regimen (Cisplatin/Etoposide, Carboplatin/Paclitaxel or 
Cisplatin/Pemetrexed) and a dose of radiation ranging from 59.4-66.6 Gy.  
Subjects must have stable disease or disease response as evidenced on CT or PET 
scan evaluation.  For those eligible, pembrolizumab should begin a minimum of 
28 days and a maximum 56 days following the completion of chemoradiation OR 
 
6. Subjects may have completed up to 2 cycles of consolidation therapy started 
within 4 weeks of completion of radiation.  After completion of consolidation 
therapy, subjects must have stable disease or disease response as evidenced by CT 
or PET scan evaluation.  For those eligible, pembrolizumab should begin 3-4 
weeks after the last cycle of chemotherapy. 
 
7. ECOG Performance Status of 0 or 1 within 14 days prior to registration for 
protocol therapy. 
 
8. Adequate laboratory values obtained within 14 days prior to registration for 
protocol therapy (as defined in table 1 below).  
 
9. Table 1 Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
Hematological 
 
Absolute neutrophil count (ANC) 
≥1,500 /mcL 
Platelets 
≥100,000 / mcL 
Hemoglobin 
≥9 g/dL or ≥5.6 mmol/L  
Renal 
 
Serum creatinine OR 
Measured or calculateda creatinine 
clearance 
(GFR can also be used in place of 
creatinine or CrCl) 
≤1.5 X upper limit of normal (ULN) OR 
 
≥60 mL/min for subject with creatinine levels > 1.5 
X institutional ULN 
Hepatic 
 
Serum total bilirubin 
≤ 1.5 X ULN OR 
 
Direct bilirubin ≤ ULN for subjects with total 
bilirubin levels > 1.5 ULN 
AST (SGOT) and ALT (SGPT) 
≤ 2.5 X ULN  
Coagulation 
International Normalized Ratio 
(INR) or Prothrombin Time (PT) 
≤1.5 X ULN unless subject is receiving 
anticoagulant therapy as long as PT/INR/PTT is 
within therapeutic range of intended use of 
anticoagulants 
 
 
aCreatinine clearance should be calculated per institutional standard. 
 
 
 


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10. Women of childbearing potential must be willing to use two methods of 
contraception or abstain from heterosexual activity from the point of registration 
through 120 days after the last dose of study drug.  
 
11. Male subjects of childbearing potential must agree to use an adequate method of 
contraception starting with the first dose of the study drug through 120 days after 
the last dose of the study drug. 
 
3.2 
Exclusion Criteria 
 
1. Pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the trial, starting with the pre-screening or screening visit 
through 120 days after the last dose of trial treatment. 
 
2. Active central nervous system (CNS) metastases. Subjects must undergo a head 
computed tomography (CT) scan or brain MRI within 28 days prior to registration 
for protocol therapy to exclude brain metastases if symptomatic or without prior 
brain imaging.  
 
3. Treatment with any investigational agent within 28 days prior to registration for 
protocol therapy.  
 
4. Prior chemotherapy, adjuvant therapy, or radiotherapy for lung cancer other than 
standard concurrent chemoradiation or up to 2 cycles of consolidation as 
described above. 
 
5. Prior therapy with a PD-1, PD-L1, PD-L2 or CTLA-4 inhibitor or a lung cancer-
specific vaccine therapy 
 
6. Presence of metastatic disease (stage IV NSCLC) is not allowed. Subjects must be 
evaluated with a CT or PET scan prior to registration for protocol therapy to 
exclude metastatic disease. 
 
7. No active second cancers. 
 
8. Evidence of active autoimmune disease requiring systemic treatment within the 
past 90 days or a documented history of clinically severe autoimmune disease, or 
a syndrome that requires systemic steroids or immunosuppressive agents. Subjects 
with vitiligo or resolved childhood asthma/atopy would be an exception to this 
rule. Subjects that require intermittent use of bronchodilators or local steroid 
injections would not be excluded from the study. Subjects with hypothyroidism 
stable on hormone replacement or Sjogren’s syndrome will not be excluded from 
the study 
 
9. Interstitial lung disease or history of pneumonitis requiring treatment with 
corticosteroids 
 
10. Diagnosis of immunodeficiency or is receiving chronic systemic corticosteroid 
therapy or other immunosuppressive therapy (excludes inhaled corticosteroids) 
within 7 days of first dose of study drug 
 


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11. History of psychiatric illness or social situations that would limit compliance with 
study requirements 
 
12. Clinically active infection as judged by the site investigator (≥ Grade 2 by 
CTCAE v4).  
 
13. History of human immunodeficiency virus (HIV) infection or chronic hepatitis B 
or C. 
 
14. Has a history or current evidence of any condition, therapy, or laboratory 
abnormality that might confound the results of the trial, interfere with the 
subject’s participation for the full duration of the trial, or is not in the best interest 
of the subject to participate, in the opinion of the site investigator. 
 
15. Has a known history of active TB (Bacillus Tuberculosis). 
 
16. Hypersensitivity to pembrolizumab or any of its excipients. 
 
17. Has received a live vaccine within 30 days prior to planned start of study therapy. 
Note:  Seasonal influenza vaccines for injection are generally inactivated flu 
vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) 
are live attenuated vaccines, and are not allowed. 
 
4. 
SUBJECT REGISTRATION 
All subjects must be registered through Hoosier Cancer Research Network (HCRN) 
electronic data capture (EDC) system prior to starting protocol therapy. A subject is 
considered to be registered to the protocol when an “On Study” date has been entered into the 
EDC System.   
 
Subjects must begin therapy within five business days of the “on study” date. 
 
5. 
TREATMENT PLAN 
 
5.1. 
Study Drug Administration and Treatment Schedule 
 
Table 2: Study Drug Administration 
Drug 
Dose 
Frequency of 
administration 
Route of 
administration 
Number of 
weeks 
Pembrolizumab  
200 mg 
Every 3 weeks 
IV 
Up to 52 
 
Pembrolizumab 200 mg will be administered as a 30 minute IV infusion on Day 1 of each 21 
day Cycle. 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 -five minutes and +10 minutes is permitted (i.e., infusion time is 30 minutes: -5 
min/+10 min).  Treatment will continue for up to 12 months, in the absence of prohibitive 
toxicities or disease progression. 
 


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The Pharmacy Manual contains specific instructions for the preparation of the 
pembrolizumab infusion fluid and administration of infusion solution. 
 
5.1.1 Dose Calculations 
The dose amount required to prepare the pembrolizumab infusion solution is a fixed dose 
(i.e., not based on the subject’s weight) as per Table 2.  
 
5.1.2 Pre-medications 
No premedications are required prior to protocol therapy administration. 
 
5.1.3 Concomitant Medications  
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 site investigator should discuss any questions regarding 
this with HCRN who will then communicate with the sponsor-investigator and Merck 
Clinical team regarding the situation.  The final decision on any supportive therapy or 
vaccination rests with the site investigator and/or the subject's primary physician. There are 
no prohibited therapies during the Post-Treatment Follow-up Phase. 
 
All treatments that the site investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the site investigator in keeping with the community 
standards of medical care. 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. 
 
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 more than 30 days after the last dose of trial treatment should be 
recorded for serious adverse events (SAE) and events of clinical interest (ECI) as defined in 
Section 11.1.6. 
 
5.1.4 Prohibited Concomitant Medications 
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase 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  
 Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial. Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, varicella/zoster, chicken pox, yellow fever, 
rabies, BCG, and typhoid (oral) vaccine. Seasonal influenza vaccines for injection are 


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generally killed virus vaccines and are allowed; however intranasal influenza 
vaccines (e.g. Flu-Mist®) 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 HCRN and the 
sponsor-investigator.  
 
Subjects who, in the assessment by the site investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial.  
The Exclusion Criteria describes other medications which are prohibited in this trial. 
 
5.2 
Evaluation of Adverse Events and Dose Modification  
The NCI Common Terminology Criteria for Adverse Events (CTCAE) v4 will be used to 
grade adverse events. Subjects enrolled in this study will be evaluated clinically and with 
standard laboratory tests before and at regular intervals during their participation in this study 
as specified in Section 7.  
 
Subjects will be evaluated for adverse events (all grades) and adverse events requiring study 
drug interruption or discontinuation at each study visit for the duration of their participation 
in the study. Subjects discontinued from the treatment phase of the study for any reason will 
be evaluated at least 30 days (± 7) after the last dose of study drug. 
 


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Table 3 Evaluating Adverse Event: A site investigator who is a qualified physician, will evaluate all adverse events as to determine: 
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: 
 
†Results in death; or 
 
†Is life threatening; or places the subject, in the view of the site 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 [including hospitalization for an elective procedure] for 
a preexisting condition which has not worsened does not constitute a serious adverse event.); or 
 
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis);or 
 
Is a new cancer; (that is not a condition of the study) or 
 
Is an overdose (whether accidental or intentional). Any adverse event associated with an overdose is considered a serious adverse event. 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. 
 
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 subject 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 the Merck product to be discontinued? 
Relationship to 
test drug  
Did the Merck product cause the adverse event? The determination of the likelihood that the Merck product caused the adverse event will be provided 
by a site investigator who is a qualified physician. The site 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 site 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 the Merck product and the AE; the greater the correlation with the 
components and their respective elements (in number and/or intensity), the more likely the Merck product caused the adverse event (AE): 
 
Exposure 
Is there evidence that the subject was actually exposed to the 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 the 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 


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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 the 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 Merck product; or (3) the trial is a single‐dose drug trial); or (4) Merck product(s) is/are only used one time.) 
 
Rechallenge 
Was the subject re‐exposed to the 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) Merck 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 THE 
MERCK PRODUCT, OR IF REEXPOSURE TO THE MERCK PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT RISK TO THE SUBJECT, 
THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE U.S. CLINICAL MONITOR 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 the Merck product or drug class 
pharmacology or toxicology? 
The assessment of relationship will be reported on the case report forms /worksheets by a site 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 a Merck product relationship). 
Yes, there is a reasonable 
possibility of Merck product 
relationship. 
There is evidence of exposure to the Merck product. The temporal sequence of the AE onset relative to the administration of the 
Merck product is reasonable. The AE is more likely explained by the Merck product than by another cause. 
No, there is not a reasonable 
possibility Merck product 
relationship 
Subject did not receive the Merck product OR temporal sequence of the AE onset relative to administration of the Merck product is 
not reasonable OR there is another obvious cause of the AE. (Also entered for a subject with overdose without an associated AE.) 


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5.2.1 Definition of treatment-limiting adverse events 
A treatment-limiting adverse event is any adverse event related to study drug experienced during 
the study resulting in treatment termination. 
 
5.2.2 Dose Modifications and Toxicity Management 
Pembrolizumab will be withheld for drug-related Grade 4 hematologic toxicities, non-
hematological toxicity ≥ Grade 3 including laboratory abnormalities, and severe or life-
threatening AEs as per Table 4 below. 
 
Table 4: Dose modification guidelines for drug-related adverse events. 
Toxicity 
Grade 
Hold 
Treatment 
(Y/N) 
Timing for 
restarting 
treatment 
Dose/Schedule 
for restarting 
treatment 
Discontinue 
Subject (after 
consultation 
with HCRN 
and sponsor-
investigator) 
Hematological Toxicity 
 
1, 2 
No 
N/A 
N/A 
N/A 
3* 
*Excluding 
Grade 3 
neutropenia, 
anemia, and 
thrombocytopenia 
Yes 
Toxicity 
resolves to 
Grade 0-1 or 
baseline 
May increase the 
dosing interval 
by 1 week 
(permanent 
change) 
Toxicity does 
not resolve 
within 12 
weeks of last 
infusion 
Permanent 
discontinuation 
should be 
considered for 
any severe or 
life-threatening 
event 
4 
Yes 
Toxicity 
resolves to 
Grade 0-1 or 
baseline 
May increase the 
dosing interval 
by 1 week  
(permanent 
change) 
Non-hematological toxicity 
 
Note: Exception to be treated 
similar to grade 1 toxicity  
 Grade 2 alopecia 
 Grade 2 fatigue 
 
For additional information 
regarding Adverse Events 
with a potential Immune-
Etiology see Section 5.3. 
1 
No 
N/A 
N/A 
N/A 
2 
Consider 
withholding 
for 
persistent 
symptoms 
Toxicity 
resolves to 
Grade 0-1 or 
baseline 
Clinical AE 
resolves within 4 
weeks: Same 
dose and 
schedule (see 
Section 5.3 for 
recommendations 
regarding 
pneumonitis) 
Clinical AE does 
not resolve 
within 4 weeks: 
May increase the 
dosing interval 
by 1 week for 
each occurrence 
Toxicity does 
not resolve 
within 12 
weeks of last 
infusion 


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Toxicity 
Grade 
Hold 
Treatment 
(Y/N) 
Timing for 
restarting 
treatment 
Dose/Schedule 
for restarting 
treatment 
Discontinue 
Subject (after 
consultation 
with HCRN 
and sponsor-
investigator) 
3, 4 
 
Yes 
 
Toxicity 
resolves to 
Grade 0-1 or 
baseline 
 
May increase the 
dosing interval 
by 1 week for 
each occurrence 
 
Toxicity does 
not resolve 
within 12 
weeks of last 
infusion 
Permanent 
discontinuation 
should be 
considered for 
any severe or 
life-threatening 
event 
 
 
In case toxicity does not resolve to Grade 0-1 within 12 weeks after last infusion, trial treatment 
should be discontinued after consultation with HCRN and the sponsor-investigator. With site 
investigator and sponsor-investigator agreement, subjects with a laboratory adverse event still at 
Grade 2 after 12 weeks may continue treatment in the trial only if asymptomatic and controlled. 
For information on the management of adverse events, see Section 5.3.1. If a subject has more 
than 3 delays in study drug dosing due to other toxicities they will be discontinued from the trial 
treatment. 
 
Subjects who experience a recurrence of the same severe or life-threatening event at the same 
grade or greater with re-challenge of pembrolizumab should be discontinued from trial treatment.   
 
5.3 
Rescue Medications & Supportive Care 
 
5.3.1 Supportive Care Guidelines 
Subjects should receive appropriate supportive care measures as deemed necessary by the site 
investigator. Suggested supportive care measures for the management of adverse events with 
potential immunologic etiology are outlined below. Where appropriate, these guidelines include 
the use of oral or intravenous treatment with corticosteroids as well as additional anti-
inflammatory agents if symptoms do not 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 the event is determined not to be related, the investigator is instructed 
to follow the ECI reporting guidelines. It may be necessary to perform conditional procedures such 
as bronchoscopy, endoscopy, or skin photography as part of evaluation of the event.  


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 Nausea/vomiting: Nausea and vomiting should be treated aggressively, and 
consideration should be given in subsequent cycles to the administration of prophylactic 
antiemetic therapy according to standard institutional practice. Subjects should be 
strongly encouraged to maintain liberal oral fluid intake. 
 
 Anti-infectives: Subjects with a documented infectious complication should receive oral 
or IV antibiotics or other anti-infective agents as considered appropriate by the site 
investigator for a given infectious condition, according to standard institutional practice. 
 
 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).   
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 subjects 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. 
 


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 Hyperthyroidism or Hypothyroidism:  
Thyroid disorders can occur at any time during treatment. Monitor subjects 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 
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:  Acute infusion reactions (which can include 
cytokine release syndrome, angioedema, or anaphylaxis) are different from 
allergic/hypersensitive reactions, although some of the manifestations are common to 
both AEs.  
 
Table 5 below shows treatment guidelines for subjects who experience an infusion reaction 
associated with administration of pembrolizumab. 
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 
Grade 2 
Requires infusion interruption but 
responds promptly to symptomatic 
treatment (e.g., antihistamines, 
NSAIDS, narcotics, IV fluids); 
Stop Infusion and monitor symptoms. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Subject may be premedicated 1.5h 
(± 30 minutes) prior to infusion of 
pembrolizumab with: 
 
Diphenhydramine 50 mg po (or 
equivalent dose of antihistamine). 
 


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NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
prophylactic medications indicated for 
< =24 hrs 
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.
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. 
 
5.3.2 Supportive Care Guidelines for Pneumonitis 
Subjects with symptomatic pneumonitis should immediately stop receiving Pembrolizumab and 
have an evaluation. The evaluation may include bronchoscopy and pulmonary function tests to 
rule out other causes such as infection. If the subject is determined to have study drug associated 
pneumonitis, the suggested treatment plan is detailed in Table 7. 
 
Table 7: Recommended Approach to Handling Pneumonitis 
Study drug associated 
pneumonitis 
Withhold/Discontinue 
Pembrolizumab 
Supportive Care 
Grade 1 (asymptomatic) 
No action 
Intervention not indicated 
Grade 2* 
Withhold pembrolizumab; 
may return to treatment if 
improves to Grade 1 or 
resolves within 12 weeks 
Systemic corticosteroids are indicated. When 
symptoms improve to Grade 1 or less, steroid taper 
should be started and continued over no less than 4 
weeks. 
Grade 3 and Grade 4 
Discontinue pembrolizumab 
Systemic corticosteroids are indicated. The use of 
infliximab may be indicated as appropriate.  Add 
prophylactic antibiotics for opportunistic infections 
in the case of prolonged steroid administration. 
 


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*For Grade 2 pneumonitis that improves to ≤ Grade 1 within 12 weeks, the following rules 
should apply: 
 First episode of pneumonitis 
o May increase dosing interval by one week in subsequent cycles (permanent change) 
 Second episode of pneumonitis – permanently discontinue pembrolizumab if upon 
rechallenge subject develops pneumonitis  Grade 2 
 
5.4 
Diet/Activity/Other Considerations 
 
5.4.1 Diet 
Subjects should maintain a normal diet unless modifications are required to manage an AE such 
as diarrhea, nausea or vomiting. 
 
5.4.2 Contraception 
Pembrolizumab may have adverse effects on a fetus in utero. Furthermore, it is not known if 
pembrolizumab has transient adverse effects on the composition of sperm. Non-pregnant, non-
breast-feeding women may be enrolled if they are willing to use 2 methods of birth control or are 
considered highly unlikely to conceive. Highly unlikely to conceive is defined as 1) surgically 
sterilized, or 2) postmenopausal (a woman who is ≥45 years of age and has not had menses for 
greater than 1 year will be considered postmenopausal), or 3) not heterosexually active for the 
duration of the study. The two birth control methods can be either two barrier methods or a 
barrier method plus a hormonal method to prevent pregnancy. Subjects should start using birth 
control from study Visit 1 throughout the study period up to 120 days after the last dose of study 
therapy.  
 
The following are considered adequate barrier methods of contraception: diaphragm, condom (by 
the partner), copper intrauterine device, sponge, or spermicide. Appropriate hormonal 
contraceptives will include any registered and marketed contraceptive agent that contains an 
estrogen and/or a progestational agent (including oral, subcutaneous, intrauterine, or 
intramuscular agents). 
 
Subjects should be informed that taking the study medication may involve unknown risks to the 
fetus (unborn baby) if pregnancy were to occur during the study. In order to participate in the 
study they must adhere to the contraception requirement (described above) for the duration of the 
study and during the follow-up period defined in section 11.4. If there is any question that a 
subject will not reliably comply with the requirements for contraception, that subject should not 
be entered into the study. 
 
5.4.3 Use in Pregnancy 
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab, the subject 
will immediately be removed from the study. The site will contact the subject at least monthly 
and document the subject’s status until the pregnancy has been completed or terminated. The 
outcome of the pregnancy will be reported to HCRN within 24 hours of discovery of event and 
HCRN will notify the sponsor-investigator within 1 business day and Merck within 2 business 
days if the outcome is a serious adverse experience (e.g., death, abortion, congenital anomaly, or 


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other disabling or life-threatening complication to the mother or newborn).  . The site 
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 HCRN who will report to Merck.  If a male 
subject impregnates his female partner the study personnel at the site must be informed 
immediately and the pregnancy reported to the HCRN who will report the event to Merck and 
followed as described above and in Section 11.4. 
 
5.4.4 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, 
subjects who are breast-feeding are not eligible for enrollment. 
 
6. 
TREATMENT DISCONTINUATION 
 
6.1. 
Subject Withdrawal/Discontinuation Criteria 
Subjects may withdraw consent at any time for any reason or be withdrawn from the trial at the 
discretion of the site investigator should any untoward effect occur. In addition, a subject may be 
withdrawn by the sponsor-investigator or HCRN if enrollment into the trial is inappropriate, the 
trial plan is violated, or for administrative and/or other safety reasons. Specific details regarding 
discontinuation or withdrawal are provided below.  
 
A subject must be discontinued from the trial treatment for any of the following reasons: 
 Confirmed radiographic disease progression by RECIST 1.1 criteria 
 Unacceptable adverse experiences as described in Section 5.2.3 
 Intercurrent illness that prevents further administration of treatment 
 Site investigator’s decision to withdraw the subject 
 The subject has a confirmed positive serum/urine pregnancy test 
 Noncompliance with trial treatment or procedure requirements 
 Completed 12 months of treatment with pembrolizumab  
 Subject refuses further treatment 
 
A subject must be discontinued from the trial for any of the following reasons: 
 Administrative reasons  
 The subject or legal representative (such as a parent or legal guardian) withdraws consent. 
 The subject is lost to follow-up 
 
The End of Treatment and Follow-up visit procedures are listed in Section 7 (Study Schedule of 
Events and Visit Requirements). After the end of treatment, each subject will be followed for 30 
days for adverse event monitoring (serious adverse events will be collected for 90 days after the 
end of treatment as described in Section 11.2.2). Subjects who discontinue for reasons other than 
progressive disease will have post-treatment follow-up for disease status until disease 
progression, initiating a non-study cancer treatment, withdrawing consent or becoming lost to 
follow-up. After documented disease progression each subject will be followed for overall 
survival until death, withdrawal of consent, or the end of the study, whichever occurs first. 


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When a subject 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 11.2.1 – AE Reporting). Subjects 
who a) attain a CR or b) complete 12 months of treatment with pembrolizumab will discontinue 
treatment.  After discontinuing treatment, following assessment of CR, these subjects should 
return to the site for a Safety Follow-up Visit and then proceed to the Follow-Up Period of the 
study. 
 


 
 
 
 
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7. 
STUDY SCHEDULE OF EVENTS 
Examination 
Screening 
On Treatment Cycle 1+ (± 3) 
Cycle = 21 days 
EOT 
Follow up8 
-28 days 
-14 days 
Day 1 
Day 8  
Day 15  
30 days (±7) 
after last dose 
(±14 days) 
REQUIRED ASSESSMENTS 
Informed Consent 
X 
 
 
 
 
 
 
Medical history and Height 
 
X 
 
 
 
 
 
Physical examination including vital 
signs (blood pressure, weight) 
 
X 
X 
 
 
X 
 
ECOG performance status 
 
X 
X 
 
 
X 
 
AEs & concomitant medications1 
 
X 
X 
 
 
X 
X 
LABORATORY TESTING 
CBC with differential and platelet ct 
 
X 
X5
 
 
X 
 
Complete Metabolic Profile 
 
X 
X5
 
 
X 
 
Direct bilirubin, Mg, Phos 
 
X 
X5 
 
 
X 
 
Measured or calculated creatinine 
clearance (GFR can also be used in 
place of serum creatinine or CrCl) 
 
X 
 
 
 
 
 
PT/INR and aPTT 
 
X 
 
 
 
 
 
Thyroid function (TSH, T3 and T4) 
 
X 
X5
 
 
 
 
Serum or Urine pregnancy test4 
 
X4 
 
 
 
 
 
DISEASE ASSESSMENT 
Pathology Report of diagnosis 
X2 
 
 
 
 
 
 
CT of chest/abdomen or PET CT 
X3 
 
CT chest/abd or PET/CT every 9 weeks 
during treatment  
 
X8 
CT or MRI Brain9 
X 
 
 
 
 
 
 
TREATMENT EXPOSURE 
Pembrolizumab 
 
X6 
 
 
 
 
CORRELATIVE STUDIES 
Optional Unstained Slide Submission 
for PD-L1 Analysis 
 
 
X7 
 
 
 
 
FOLLOW-UP 
Progression and survival8 
 
 
 
 
 
 
X 


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1. 
Treatment-related adverse events will be followed until resolution, return to baseline, or deemed clinically insignificant. Adverse events 
(from time of consent) and concomitant medications (28 days prior to start of protocol treatment) should be assessed and recorded until 30 
days after last dose of pembrolizumab. .  SAE’s and the conmeds used to treat them will be collected up to 90 days post treatment.   
2. 
A pathology report confirming the diagnosis of NSCLC must be obtained and reviewed by the treating physician prior to registration to 
study.  
3. 
Screening scan including at least CT portion of the chest and abdomen must be a minimum of 28 days and a maximum of 56 days following 
the completion of chemoradiation. PET CT may be done in place of regular CT scans at the discretion of the site investigator.  Scans should 
be done within 28 days prior to treatment initiation. A head CT or MRI will be performed within 28 days of treatment initiation if subject is 
symptomatic or no prior brain imaging done. 
4. 
For women of childbearing potential only. This must be completed and negative within 7 days of registration for protocol therapy. 
5. 
C1D1 testing does not need to be repeated if performed within 7 days of starting protocol therapy. 
6. 
For subjects who meet all eligibility criteria and have recovered sufficiently from treatment with chemoradiation, initial consolidation 
therapy with pembrolizumab will be started a minimum of 28 days and a maximum of 56 days after chemoradiation is complete. For 
subjects who meet all eligibility criteria after completion of up to two consolidation treatments, therapy with pembrolizumab will be started 
3-4 weeks after last cycle of chemotherapy. Treatment with a fixed dose of 200mg IV of pembrolizumab will occur on day 1 of each 3 week 
cycle until progressive disease or unacceptable toxicity develop or until the subject has completed 52 weeks of therapy with pembrolizumab. 
7. 
Optional submission of unstained slides from an archived tumor block for PD-L1 analysis.  See SPM for collection, labeling and shipping 
instructions.   
8. 
After completion of pembrolizumab subjects who discontinue for reasons other than progressive disease will have post-treatment follow-up 
for disease status until disease progression, initiating a non-study cancer treatment, withdrawing consent or becoming lost to follow-up. 
After documented disease progression each subject will be followed for overall survival until death, withdrawal of consent, or the end of the 
study (whichever occurs first). Radiographic disease assessment will be done every 9 weeks during study treatment.  Once treatment is 
complete, radiographic disease assessment should be performed every 3 months during year 1 and 2 then every 6 months during year 3-5 
then annually thereafter. PET CT may be done in place of regular CT scans at the discretion of the site investigator. This imaging may be 
done locally. 
9. 
A head MRI or CT should be done prior to study treatment for subjects that are symptomatic or have not had prior brain imaging.


 
 
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7.1 
Screening 
 
7.1.1 Within 28 days of study registration 
 Informed consent 
 Pathology Report Confirmation. A pathology report confirming the diagnosis of NSCLC 
must be obtained and reviewed by the treating physician prior to registration to the study.   
 Radiology Imaging: A CT of the chest and abdomen will be done a minimum of 28 days 
and a maximum of 56 days after chemoradiation. This imaging will be done within 28 
days of treatment initiation on study.  A PET CT may be done instead of regular CT 
scans.  A head MRI or CT should be done for subjects that are symptomatic or have not 
had prior brain imaging of study treatment. 
 Optional archived tumor block to obtain slides from for PD-L1 analysis.  See SPM for 
collection, labeling and shipping instructions.  
 
7.1.2 Within 14 days of study registration 
 Medical History 
 Height 
 Physical examination including vital signs (blood pressure, weight) 
 ECOG performance status  
 Complete Metabolic Profile to include Na, K, Cl, CO2, total bilirubin, direct bilirubin, 
total protein, albumin, alk phos, AST, ALT, serum creatinine, BUN, calcium, Mg, Phos, 
and glucose.  Please see Table 1 for additional information regarding serum creatinine, 
calculated creatinine clearance and GFR values. 
 Complete Blood Count with differential to include absolute neutrophil count (ANC), 
platelets and hemoglobin 
 PT/INR and aPTT 
 Thyroid function (TSH, T3 and T4) 
 Within 7 days: Serum or urine pregnancy test for women of childbearing potential. 
 Adverse events and concomitant medications.  This also includes events of clinical 
interest. 
 
7.1. 
On Treatment 
 
7.2.1 Day 1 of each Cycle unless otherwise specified 
 Physical examination including vital signs (blood pressure, weight) 
 ECOG performance status 
 Complete Metabolic Profile to include Na, K, Cl, CO2, total bilirubin, direct bilirubin, 
total protein, albumin, alk phos, AST, ALT, creatinine, BUN, calcium, Mg, Phos, and 
glucose (For C1D1 do not repeat if screening CMP within 7 days of starting protocol 
therapy) 
 Complete Blood Count with differential to include absolute neutrophil count (ANC), 
platelet and hemoglobin (For C1D1 do not repeat if screening CMP within 7 days of 
starting protocol therapy). 
 Thyroid function (TSH, T3 and T4) (For C1D1 do not repeat if screening CMP within 7 
days of starting protocol therapy). 


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 Adverse events and concomitant medications.  This also includes events of clinical 
interest. 
 Pembrolizumab 200 mg IV for up to 52 weeks 
 
7.2. 
End of Treatment (EOT) (30 days after last dose of study drug ±7 days) 
 Physical examination including vital signs (blood pressure, weight) 
 ECOG performance status 
 Complete Metabolic Profile to include Na, K, Cl, CO2, total bilirubin, direct bilirubin, 
total protein, albumin, alk phos, AST, ALT, creatinine, BUN, calcium, Mg, Phos, and 
glucose 
 Complete Blood Count with differential to include absolute neutrophil count (ANC), 
platelet and hemoglobin 
 Adverse events and concomitant medications must be assessed.  Events of clinical 
interest (ECIs) and serious adverse events must be assessed at least 90 days after dose of 
study drug (+7 days). 
 
7.3. 
Follow-up (±14 days) 
After completion of pembrolizumab, subjects who discontinue for reasons other than progressive 
disease will have post-treatment follow-up for disease status until disease progression, initiating 
a non-study cancer treatment, withdrawing consent or becoming lost to follow-up. After 
documented disease progression each subject will be followed for overall survival until death, 
withdrawal of consent, or the end of the study (whichever occurs first). 
 Adverse events. Follow treatment-related adverse events until resolution, return to 
baseline, or deemed clinically insignificant. This also includes events of clinical interest. 
 Radiographic disease assessment should be performed every 3 months during year 1 and 
2 then every 6 months during year 3-5 then annually thereafter. PET CT may be done in 
place of regular CT scans at the discretion of the site investigator.  This imaging may be 
done locally. 
 
8. 
CRITERIA FOR DISEASE EVALUATION 
Response assessments will be made both using the Immune Related Response Criteria, and using 
RECIST v1.1, allowing additional comparisons among these criteria for disease response 
assessment. The same measurable and non-measurable lesions will be followed by both RECIST 
v1.1 & irRC.  RECIST 1.1 will be used to determine the primary objective of the trial and 
RECIST 1.1 and Immune Related Response Criteria will be used in secondary objective of PFS. 
 
8.1. 
Immune Related Response Criteria: 
This study will utilize the Immune Related Response Criteria (irRC). These response criteria 
were developed to overcome the variable and unusual patterns of response to immunotherapeutic 
agents, in particular, ipilimumab [44]. The development of the guidelines were prompted by 
observations, mostly in subjects with metastatic melanoma, of initial disease progression 
followed by later response, late responses, and mixed responses with an overall decrease in 
tumor burden.  
 


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8.1.1. Antitumor response based on total measurable tumor burden 
For the irRC, only index and measurable new lesions are taken into account (in contrast to 
conventional WHO criteria, which do not require the measurement of new lesions, nor do they 
include new lesion measurements in the characterization of evolving tumor burden). At the 
baseline tumor assessment, the sum of the products of the two largest perpendicular diameters 
(SPD) of all index lesions (five lesions per organ, up to 10 visceral lesions) is calculated. At each 
subsequent tumor assessment, the SPD of the index lesions and of new, measurable lesions (up 
to 5 new lesions per organ; 10 visceral lesions) are added together to provide the total tumor 
burden: Tumor Burden = SPDindex lesions + SPDnew, measurable lesions  
 
Table 8: Comparison of WHO and irRC criteria 
 
WHO 
irRC 
New, measurable 
lesions  
Always represent PD 
Incorporated into tumor burden 
New, 
nonmeasurable 
lesions  
Always represent PD 
Do not define progression (but preclude 
irCR) 
Non-index lesions Changes contribute to defining BOR of CR, PR, SD, and 
PD 
Contribute to defining irCR (complete 
disappearance required) 
CR 
Disappearance of all lesions in two consecutive 
observations not less than 4 wk apart 
Disappearance of all lesions in two 
consecutive observations not less than 4 wk 
apart 
PR 
≥50% decrease in SPD of all index lesions compared 
with baseline in two observations at least 4 wk apart, in 
absence of new lesions or unequivocal progression of 
non-index lesions  
≥50% decrease in tumor burden compared 
with baseline in two observations at least 4 
wk apart 
SD 
50% decrease in SPD compared with baseline cannot be 
established nor 25% increase compared with nadir, in 
absence of new lesions or unequivocal progression of 
non-index lesions  
50% decrease in tumor burden compared with 
baseline cannot be established nor 25% 
increase compared with nadir 
PD 
At least 25% increase in SPD compared with nadir and/or 
unequivocal progression of non-index lesions and/or 
appearance of new lesions (at any single time point)  
At least 25% increase in tumor burden 
compared with nadir (at any single time 
point) in two consecutive observations at 
least 4 wk apart  
 
8.1.2. Time-point response assessment using irRC 
Percentage changes in tumor burden per assessment time point describe the size and growth 
kinetics of both conventional and new, measurable lesions as they appear. At each tumor 
assessment, the response in index and new, measurable lesions is defined based on the change in 
tumor burden (after ruling out irPD). Decreases in tumor burden must be assessed relative to 
baseline measurements (i.e., the SPD of all index lesions at screening). The irRC were derived 
from WHO criteria and, therefore, the thresholds of response remain the same. However, the 
irRC response categories have been modified from those of WHO criteria as detailed in Tables 8 
and 9.  
 
8.1.3. Overall response using the irRC 
The sum of the products of diameters at tumor assessment using the immune-related response 
criteria (irRC) for progressive disease incorporates the contribution of new measurable lesions. 
Each net Percentage Change in Tumor Burden per assessment using irRC criteria accounts for 
the size and growth kinetics of both old and new lesions as they appear. 
 


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Definition of Index Lesions Response Using irRC 
 irComplete Response (irCR): Complete disappearance of all index lesions. This category 
encompasses exactly the same subjects as “CR” by the mWHO criteria. 
 irPartial Response (irPR): Decrease, relative to baseline, of 50% or greater in the sum of 
the products of the two largest perpendicular diameters of all index and all new measurable 
lesions (ie., Percentage Change in Tumor Burden). Note: the appearance of new measurable 
lesions is factored into the overall tumor burden, but does not automatically qualify as 
progressive disease until the SPD increases by ≥25% when compared to SPD at nadir. 
 irStable Disease (irSD): Does not meet criteria for irCR or irPR, in the absence of 
progressive disease. 
 irProgressive Disease (irPD): At least 25% increase Percentage Change in Tumor Burden 
(i.e., taking sum of the products of all index lesions and any new lesions) when compared to 
SPD at nadir. 
 
Definition of Non-Index Lesions Response Using irRC 
 irComplete Response (irCR): Complete disappearance of all non-index lesions. This 
category encompasses exactly the same subjects as “CR” by the mWHO criteria. 
 irPartial Response (irPR) or irStable Disease (irSD): non-index lesion(s) are not 
considered in the definition of PR, these terms do not apply. 
 
irProgressive Disease (irPD): Increases in number or size of non-index lesion(s) does not 
constitute progressive disease unless/until the Percentage Change in Tumor Burden increases 
by 25% (i.e., the SPD at nadir of the index lesions increases by the required amount). 
 
Impact of New Lesions on irRC 
New lesions in and by themselves do not qualify as progressive disease. However their 
contribution to total tumor burden is included in the SPD which in turn feeds into the irRC 
criteria for tumor response. Therefore, new non-measurable lesions will not discontinue any 
subject from the study. 
 
Definition of Overall Response Using irRC 
Overall response using irRC will be based on these criteria (see Table 9): 
 Immune-Related Complete Response (irCR): Complete disappearance of all tumor lesions 
(index and nonindex together with no new measurable/unmeasurable lesions) for at least 4 
weeks from the date of documentation of complete response.  
 Immune-Related Partial Response (irPR): The sum of the products of the two largest 
perpendicular diameters of all index lesions is measured and captured as the SPD baseline. 
At each subsequent tumor assessment, the sum of the products of the two largest 
perpendicular diameters of all index lesions and of new measurable lesions are added 
together to provide the Immune Response Sum of Product Diameters (irSPD). A decrease, 
relative to baseline of the irSPD compared to the previous SPD baseline, of 50% or greater is 
considered an immune Partial Response (irPR).  
 Immune-Related Stable Disease (irSD): irSD is defined as the failure to meet criteria for 
immune complete response or immune partial response, in the absence of progressive 
disease.  
 Immune-Related Progressive Disease (irPD): It is recommended in difficult cases to 
confirm PD by serial imaging. Any of the following will constitute progressive disease: 


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 At least 25% increase in the sum of the products of all index lesions over nadir SPD 
calculated for the index lesions. 
 At least a 25% increase in the sum of the products of all index lesions and new 
measurable lesions (irSPD) over the baseline SPD calculated for the index lesions. 
 
Immune-Related Best Overall Response Using irRC (irBOR)  
irBOR is the best confirmed irRC overall response over the study as a whole, recorded between 
the date of first dose until the last tumor assessment before subsequent therapy (except for local 
palliative radiotherapy for painful bone lesions) for the individual subject in the study. For the 
assessment of irBOR, all available assessments per subject are considered. 
 
irCR or irPR determinations included in the irBOR assessment must be confirmed by a second 
(confirmatory) evaluation meeting the criteria for response and performed no less than 4 weeks 
after the criteria for response are first met  
 
Table 9: Derivation of irRC overall responses 
Measurable response 
Nonmeasurable response 
Overall 
response 
Index and new, measurable lesions (tumor 
burden),*% 
Non-index lesions 
New, nonmeasurable 
lesions 
Using irRC 
↓100 
Absent 
Absent 
irCR† 
↓100 
Stable 
Any 
irPR† 
↓100 
Unequivocal progression 
Any 
irPR† 
↓≥50 
Absent/Stable 
Any 
irPR† 
↓≥50 
Unequivocal progression 
Any 
irPR† 
↓<50 to <25↑ 
Absent/Stable 
Any 
irSD 
↓<50 to <25↑ 
Unequivocal progression 
Any 
irSD 
≥25 
Any 
Any 
irPD† 
*Decreases assessed relative to baseline (scan prior to start of any protocol therapy), including measurable lesions 
only  
†Assuming response (irCR) and progression (irPD) are confirmed by a second, consecutive assessment at least 4 wk 
apart.  
 
8.2. 
Definitions Associated with Response Evaluation Criteria in Solid Tumors 
(RECIST) version 1.1 
 
8.2.1. Measurable disease  
The presence of at least one measurable lesion. If the measurable disease is restricted to a 
solitary lesion, its neoplastic nature should be confirmed by cytology/histology.  
 
8.2.2. Measurable lesions  
Measurable lesions are defined as those that can be accurately measured in at least one 
dimension (longest diameter to be recorded) as >20 mm by chest x-ray, as >10 mm with CT 
scan, or >10 mm with calipers by clinical exam. All tumor measurements must be recorded in 
millimeters (or decimal fractions of centimeters). 
 


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8.2.3. Non-measurable lesions  
All other lesions (or sites of disease), including small lesions (longest diameter <10 mm or 
pathological lymph nodes with ≥ 10 to <15 mm short axis), are considered non-measurable 
disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed by CT or 
MRI), are considered as non-measurable. 
 
NOTE: Cystic lesions that meet the criteria for radiographically defined simple cysts should not 
be considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, 
if they meet the definition of measurability described above. However, if non-cystic lesions are 
present in the same subject, these are preferred for selection as target lesions. 
 
8.2.4. Malignant lymph nodes 
To be considered pathologically enlarged and measurable, a lymph node must be >15 mm in 
short axis when assessed by CT scan (CT scan slice thickness recommended to be no greater 
than 5 mm). At baseline and in follow-up, only the short axis will be measured and followed. 
 
8.2.5. Baseline documentation of “Target” and “Non-Target” lesions Target lesions.  
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, 
representative of all involved organs, should be identified as target lesions and recorded and 
measured at baseline. Target lesions should be selected on the basis of their size (lesions with the 
longest diameter), be representative of all involved organs, but in addition should be those that 
lend themselves to reproducible repeated measurements. It may be the case that, on occasion, the 
largest lesion does not lend itself to reproducible measurement in which circumstance the next 
largest lesion which can be measured reproducibly should be selected. A sum of the diameters 
(longest for non-nodal lesions, short axis for nodal lesions) for all target lesions will be 
calculated and reported as the baseline sum diameters. If lymph nodes are to be included in the 
sum, then only the short axis is added into the sum. The baseline sum diameters will be used as 
reference to further characterize any objective tumor regression in the measurable dimension of 
the disease. 
 
Non-target lesions.  
All other lesions (or sites of disease) including any measurable lesions over and above the 5 
target lesions should be identified as non-target lesions and should also be recorded at baseline. 
Measurements of these lesions are not required, but the presence, absence, or in rare cases 
unequivocal progression of each should be noted throughout follow-up. 
 
8.2.6. Response Criteria 
Evaluation of target lesions 
Complete Response (CR) 
Disappearance of all target lesions. Any 
pathological lymph nodes (whether target or non-


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target) must have reduction in short axis to <10 
mm. 
Partial Response (PR) 
At least a 30% decrease in the sum of the 
diameters of target lesions, taking as reference the 
baseline sum diameters 
Progressive Disease (PD) 
At least a 20% increase in the sum of the diameters 
of target lesions, taking as reference the smallest 
sum on study (this includes the baseline sum if that 
is the smallest on study). In addition to the relative 
increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm. (Note: the 
appearance of one or more new lesions is also 
considered progressions). 
Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as 
reference the smallest sum diameters while on 
study 
Evaluation of non-target lesions 
Complete Response (CR) 
Disappearance of all non-target lesions and 
normalization of tumor marker level. All lymph 
nodes must be non-pathological in size (<10 mm 
short axis) 
 
Note: If tumor markers are initially above the 
upper normal limit, they must normalize for a 
subject to be considered in complete clinical 
response. 
Non-CR/ Non-PD 
Persistence of one or more non-target lesion(s) 
and/or maintenance of tumor marker level above 
the normal limits 
Progressive Disease (PD) 
Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target 
lesions. Unequivocal progression should not 
normally trump target lesion status. It must be 
representative of overall disease status change, not 
a single lesion increase. 
* Although a clear progression of “non-target” lesions only is exceptional, the opinion of the 
treating physician should prevail. 
 
Evaluation of best overall response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for PD the smallest measurements recorded 
since the treatment started). In general, the subject's best response assignment will depend on the 
achievement of both measurement and confirmation criteria. 
 


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Table 3: Response Assignment 
Target Lesions 
Non-Target lesion 
New Lesion 
Overall response 
CR 
CR 
No 
CR 
CR 
Non-CR/ Non-PD 
No 
PR 
 
Not evaluated 
No 
PR 
PR 
Non-CR/ Non-PD/ not 
evaluated 
No 
PR 
SD 
Non-CR/ Non-PD/ not 
evaluated 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD* 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
*In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as 
disease progression. 
Subjects with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be classified as having 
“symptomatic deterioration.” Every effort should be made to document the objective progression 
even after discontinuation of treatment. 
 
In some circumstances, it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends on this determination, it is recommended that 
the residual lesion be investigated (fine needle aspirate/biopsy) to confirm the complete response 
status. 
 
8.2.7. Definitions for Response Evaluation –RECIST version 1.1 
 
8.2.7.1. 
First Documentation of Response 
The time between initiation of therapy and first documentation of PR or CR. 
 
8.2.7.2. 
Duration of Response 
Duration of overall response—the period measured from the time that measurement criteria are 
met for complete or partial response (whichever status is recorded first) until the date that 
recurrent or progressive disease is objectively documented, taking as reference for progressive 
disease the smallest measurements recorded since treatment started. 
 
8.2.7.3. 
Duration of Overall Complete Response 
The period measured from the time that measurement criteria are met for complete response until 
the first date that progressive disease is objectively documented. 
 
8.2.7.4. 
Objective response rate  
The objective response rate is the proportion of all subjects with confirmed PR or CR according 
to RECIST v1.1, from the start of treatment until disease progression/recurrence (taking as 
reference for progressive disease the smallest measurements recorded since the start of 
treatment). 
 


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8.2.7.5. 
Progression Free Survival 
A measurement from the start of the treatment until the criteria for disease progression is met as 
defined by RECIST 1.1 or death occurs, taking as reference the smallest measurements recorded 
since the treatment started.  
 
Progression free survival will be measured from the date of initial treatment to the earliest date of 
disease progression, resection of measurable tumor or death for subjects who fail; and to the date 
of last contact for subjects who remain at risk for failure. 
 
9. 
BIOLOGICAL SPECIMEN PARAMETERS FOR CORRELATIVES 
Optional submission of unstained slides from an archived tumor block for PD-L1 analysis.  
Unstained slides submitted for PD-L1 staining must be cut and sent within 7 days of analysis.  A 
fresh biopsy is NOT mandatory to participate in this trial.  Any slides that remain after the initial 
testing is complete will be stored for possible future studies with consent of subject. 
 
Fine needle aspiration or needle core biopsies that are formalin-fixed and paraffin-embedded are 
acceptable.  A frozen sample, plastic embedded sample, cell block, clot, bone, bone marrow or 
cytologic specimen are not be acceptable for PD-L1 analysis. 
 
Please refer to the Study Procedures Manual for processing, labeling and shipping instructions.  
 
10. 
STUDY DRUG INFORMATION 
 
10.1. Pembrolizumab  
Please see Investigator’s Brochure for detailed information regarding Pembrolizumab 
 
10.1.1 Chemical name and properties 
Humanized X PD-1_mAb (H409A11) IgG4 
 
10.1.2 Availability 
Pembrolizumab is an investigational drug and not available outside of a clinical trial. 
 
The site 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. 
 
10.1.3 Product Descriptions 
 Clinical Supplies will be provided by Merck as summarized below: 
Product Name & Potency 
Dosage Form 
Pembrolizumab 100 mg/4mL 
Solution for Injection 
 
10.1.4 Packaging and Labeling Information 
Clinical supplies will be affixed with a clinical label in accordance with regulatory requirements. 
 


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10.1.5 Clinical Supplies Disclosures 
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. 
 
10.1.6 Adverse Events 
Please see Investigator’s Brochure for complete details regarding adverse events related to 
Pembrolizumab 
 
Pembrolizumab is generally well tolerated immunomodulatory agent and demonstrates a 
favorable safety profile in comparison to chemotherapy. Important identified risks for 
pembrolizumab are of an immune mediate nature, including: pneumonitis, colitis, thyroid 
disorders (hypothryoidism/hyperthyroidism), hepatitis, hypophysitis, Type I diabetes mellitis, 
uveitis, and nephritis. After a recent review of data, events newly characterized as identified risks 
also include pancreatitis, myositis, and severe skin reaction; these are included in the reference 
safety information in the current IB. The majority of events were mild to moderate in severity, 
were manageable with appropriate care, and rarely required discontinuation of therapy. In 
addition to the previously noted identified risks, infusion-related reactions are a risk but are not 
considered immune mediated; these are also further described in the current IB. 
 
11. 
ADVERSE EVENTS 
 
11.1 
Definitions of AEs  
 
11.1.1 Adverse Event  
Adverse event (AE) means any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related. An adverse event (also referred to as an adverse 
experience) can be any unfavorable and unintended sign (e.g., an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a drug, and does not imply any 
judgment about causality. An adverse event can arise with any use of the drug (e.g., off-label 
use, use in combination with another drug) and with any route of administration, formulation, or 
dose, including 
A site investigator who is a qualified physician will evaluate all adverse events according to the 
NCI Common Terminology for Adverse Events (CTCAE), v4. 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. 
 
11.1.2 Suspected Adverse Reaction 
Suspected adverse reaction means any adverse event for which there is a reasonable possibility 
that the drug caused the adverse event. For the purposes of IND safety reporting, ‘reasonable 
possibility’ means there is evidence to suggest a causal relationship between the drug and the 


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adverse event. A suspected adverse reaction implies a lesser degree of certainty about causality 
than adverse reaction, which means any adverse event caused by a drug. 
 
11.1.3 Adverse Reaction 
An adverse reaction means any adverse event caused by a drug. Adverse reactions are a subset of 
all suspected adverse reactions where there is reason to conclude that the drug caused the event. 
 
11.1.4 Unexpected Adverse Event 
For this study, an AE is considered unexpected when it varies in nature, intensity or frequency 
from information provided in the current AE list, the IB, the package insert or when it is not 
included in the informed consent document as a potential risk. 
 
11.1.5 Serious Adverse Event 
A serious adverse event is any adverse event that: 
 Results in death; NOTE: Death due to progressive disease is not considered a SAE 
unless the event was related to the study drug. 
 Is life-threatening (defined as an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event which hypothetically might have caused 
death if it were more severe) 
 Requires inpatient hospitalization or prolongation of existing hospitalization 
 Results in persistent or significant disability/incapacity 
 Is a congenital anomaly or birth defect 
 Is an important medical event (defined as a medical event(s) that may not be immediately 
life-threatening or result in death or hospitalization but, based upon appropriate medical 
and scientific judgment, may jeopardize the subject or may require intervention (e.g., 
medical, surgical) to prevent one of the other serious outcomes listed in the definition 
above). Examples of such events include, but are not limited to:  
o Intensive treatment in an emergency room or at home for allergic bronchospasm 
o Blood dyscrasias or convulsions not resulting in hospitalization 
o An overdose (whether accidental or intentional).  Any adverse event associated with 
an overdose is considered a serious adverse event. An overdose that is not associated 
with an adverse event is considered a non-serious event of clinical interest. Both cases 
must be immediately reported. See section 11.3. 
 
11.1.6  Events of Clinical Interest 
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI).  ECIs must be reported from the date of first dose through 90 days following cessation of 
treatment, or 30 days after the initiation of a new anticancer therapy, whichever is earlier.  ECIs 
will be reported by sites within one business day to HCRN.  HCRN will report all ECIs to 
Merck Global Safety (Attn: Worldwide Product Safety; FAX 215-993-1220 within one business 
day of becoming aware of event). 
 
Events of clinical interest for this trial include: 
1. An overdose of Merck product, as defined in Section 11.3 that is not associated with clinical 
symptoms or abnormal laboratory results.  
 


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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.  
 
3. In the event a subject develops any of the following AEs, a detailed narrative of the event 
should be reported as an ECI to the HCRN within one business day and HCRN will report it to 
Merck Global Safety within one business day of the event: (Attn: Worldwide Product Safety; 
FAX 215 993-1220)).  
 
Subjects should be assessed for possible ECIs prior to each dose. Lab results should be evaluated 
and subjects should be asked for signs and symptoms. Subjects who develop an ECI thought to 
be immune-related should have additional testing to rule out other etiologic causes. If lab results 
or symptoms indicate a possible immune-related ECI, then additional testing should be 
performed to rule out other etiologic causes. If no other cause is found, then it is assumed to be 
immune-related.  
 
11.2 
Adverse Event Reporting 
 
11.2.1 Site Requirements for Recording Adverse Events  
Adverse events (AEs) will be recorded from the time of consent and for at least 30 days after 
treatment discontinuation, regardless of whether or not the event(s) are considered related to trial 
medications. All AEs considered related to trial medication will be followed until resolution, 
return to baseline, or deemed clinically insignificant, even if this occurs post-trial. 
 
Adverse events will not be collected for subjects during the pre-screening period (for 
determination of archival tissue status) as long as that subject has not undergone any protocol-
specified procedure or intervention. If the subject requires a blood draw, fresh tumor biopsy etc., 
the subject is first required to provide consent to the main study and AEs will be captured 
according to guidelines for standard AE reporting. 
 
11.2.2 SAE Reporting from Site to HCRN 
Site investigators will report to HCRN any SAE, or follow up to a SAE, including death due to 
any cause other than progression of the cancer under study, that occurs to any subject from the 
time the consent is signed through 90 days following the last dose of study drug, or the initiation 
of new anti-cancer therapy, whichever is earlier, whether or not related to Merck product. 
Progression of the cancer under study is not considered an adverse event unless it is considered 
to be drug related by the investigator. 
 


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All AEs and SAEs will be recorded in the subject’s medical record and on the appropriate study 
specific eCRF form within the EDC system.  In addition, all SAEs will be reported on the SAE 
Submission Form and submitted to HCRN per guidelines outlined in this section. 
 
Site investigators and other site personnel must report any SAEs occurring during the course of 
the study to HCRN within one business day of discovery of the event. This includes events both 
related and unrelated to the investigational product.  
 
The definition of "related" being that there is a reasonable possibility the drug caused the adverse 
experience. 
 
Unrelated 
The Adverse Event is clearly not related to the investigational agent(s) 
Unlikely 
The Adverse Event is doubtfully related to the investigational agent(s) 
Possible 
The Adverse Event may be related to the investigational agent(s) 
Probable 
The Adverse Event is likely related to the investigational agent(s) 
Definite 
The Adverse Event is clearly related to the investigational agent(s) 
 
The completed SAE Submission Form (see SPM) must be sent either electronically to 
SAFETY@hoosiercancer.org or by fax to (317-921-2053) to Hoosier Cancer Research Network.  
The site investigator is responsible for informing the IRB and/or the Regulatory Authority of the 
SAE as per local requirements.   
 
The original copy of the SAE Submission Form and the e-mail correspondence or the fax 
confirmation sheet must be kept within the study file at the study site. 
 
Follow-up information will be sent electronically or by fax to the Hoosier Cancer Research 
Network, using a new SAE Submission Form. Each re-occurrence, complication, or progression 
of the original event should be reported as a follow-up to that event regardless of when it occurs.  
 
11.2.3 HCRN Requirements for Reporting SAEs to Merck  
HCRN will report any SAE from the time the consent is signed through 90 days following the 
last dose of study drug, or the initiation of new anti-cancer therapy, whichever is earlier, whether 
or not related to Merck product.  The report will be sent to Merck within one business day of 
receipt of the SAE Submission Form.  Hoosier Cancer Research Network will fax follow up 
information as reasonably requested to Merck. 
 
SAE reports and any other relevant safety information are to be forwarded to the Merck Global 
Safety facsimile number:  +1-215-993-1220. 
 
11.2.4 Sponsor-Investigator Responsibilities  


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HCRN will send a SAE summary to the sponsor-investigator within 1 business day of receipt of 
SAE Submission Form from a site.  The sponsor-investigator will promptly review the SAE 
summary and assess for expectedness and relatedness.   
 
11.2.5 HCRN Requirements for Reporting to FDA 
HCRN will manage the Investigational New Drug Application (IND) associated with this 
protocol on behalf of the sponsor-investigator. HCRN will cross-reference this submission to the 
Merck’s parent IND at the time of submission. Additionally, HCRN will submit a copy of these 
documents to Merck at the time of submission to FDA. 
 
For protocols conducted under an IND, HCRN will be responsible for all communication with 
the FDA in accordance with 21CFR312 including but not limited to the 7 and 15 Day Reports, as 
well as an Annual Progress Report. Additionally HCRN will submit a copy of these reports to 
Merck at the time of submission to FDA. 
 
11.2.6 IND Safety Reports Unrelated to this Trial 
Merck will provide to HCRN IND safety reports from external studies that involve the study 
drug(s) per their guidelines.  HCRN will forward safety reports to the sponsor-investigator who 
will review these reports and determine if revisions are needed to the protocol or consent. HCRN 
will forward these reports to participating sites within 1 business day of receiving the sponsor-
investigator’s review.  Based on the sponsor-investigator’s review, applicable changes will be 
made to the protocol and informed consent document (if required).  All IND safety reports will 
also be made available to sites via OnCore®.    
 
Upon receipt from HCRN, site investigators (or designees) are responsible for submitting these 
safety reports to their respective IRBs, as per their IRB policies. 
 
11.2.7 Definition of an Overdose for This Protocol and Reporting of Overdose to HCRN 
and Merck 
For purposes of this trial, an overdose 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, pembrolizumab should be discontinued and the subject 
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 to HCRN within one 
business day (HCRN will report to Merck Global Safety within one business day of the event). 
(Attn: Worldwide Product Safety; FAX 215 993-1220). 


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11.4 
Reporting of Pregnancy and Lactation to HCRN and to Merck 
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
site investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them), including the pregnancy of a male subject's female partner that 
occurs during the trial or within 120 days of completing the trial completing the trial, or 30 days 
following cessation of treatment if the subject initiates new anticancer therapy, whichever is 
earlier. All subjects and female partners of male subjects who become pregnant 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 to HCRN within one business day on the SAE Submission Form 
(see SPM). (HCRN will report to Merck Global Safety within one business day of the event).  
(Attn: Worldwide Product Safety; FAX 215 993-1220). 
 
12. 
STATISTICAL CONSIDERATIONS 
 
12.1. General Considerations 
Statistical analysis will be the responsibility of the Department of Biostatistics at Indiana 
University School of Medicine (IUSM) & School of Public Health (SPH). Summary statistics 
will be generated for both continuous and categorical variables. Missing data will not be 
imputed. Changes from the analysis plan will not require an amendment to the protocol unless it 
changes a significant feature in the protocol. 
 
12.2. Study Design 
This is an open label, multi-institutional, single arm phase II trial. No randomization or blinding 
will be involved. 
 
12.3.  Criteria for Stopping Study  
After the first 10 subjects are treated with at least one dose of study drug and observed for a 
minimum of 3 months after first dose of study therapy, further accrual will be halted to evaluate 
“unacceptable toxicities warranting early closure of the trial” defined as a) any definitive 
pembrolizumab-related death; or b) any unexpected and previously unreported grade 4 toxicities 
definitely related to pembrolizumab. If such events are observed in one subject, the DMSB will 
discuss and decide whether to recommend termination of the trial. If such events are observed in 
two or more subjects, the trial will be terminated. 
Pembrolizumab-related death will be continuously monitored through the trial. Whenever the 
first case happens, the DMSB will meet and discuss whether to recommend stoppage of the trial. 
Whenever there are two cases in cumulative, the trial will be terminated.  
 
Pneumonitis of grade 3 and 4 will be continuously monitored starting from N=10. An overall 
rate of 20% or above is considered as unacceptable. If the probability of the grade 3/4 
pneumonitis rate being less than 20% drops below 0.1, the trial will be terminated. A priori, the 
rate is assumed to follow ߠ~ܾ݁ݐܽሺ1,1ሻ. Conditional on observing ݕ events out of ݊ subjects, the 


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rate follows ߠ|ݕ, ݊~ܾ݁ݐܽሺ1 ൅ݕ, 1 ൅݊െݕሻ. The probability of ߠ൏20% is ׬
݂ሺߠ|݊, ݕሻ݀ߠ
଴.ଶ
଴
. 
The threshold is defined as the smallest ݕ corresponding to the integral being smaller than 0.1, 
which will lead to termination of the trial.  
Table 10: Thresholds “k” for N=10 to N=93  
N 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
k 
4 
4 
4 
5 
5 
5 
6 
6 
6 
6 
7 
7 
7 
7 
8 
N 
25 
26 
27 
28 
29 
30 
31 
32 
33 
34 
35 
36 
37 
38 
39 
k 
8 
8 
8 
9 
9 
9 
9 
10 
10 
10 
10 
11 
11 
11 
11 
N 
40 
41 
42 
43 
44 
45 
46 
47 
48 
49 
50 
51 
52 
53 
54 
k 
12 
12 
12 
12 
12 
13 
13 
13 
13 
14 
14 
14 
14 
15 
15 
N 
55 
56 
57 
58 
59 
60 
61 
62 
63 
64 
65 
66 
67 
68 
69 
k 
15 
15 
16 
16 
16 
16 
16 
17 
17 
17 
17 
18 
18 
18 
18 
N 
70 
71 
72 
73 
74 
75 
76 
77 
78 
79 
80 
81 
82 
83 
84 
k 
19 
19 
19 
19 
19 
20 
20 
20 
20 
21 
21 
21 
21 
22 
22 
N 
85 
86 
87 
88 
89 
90 
91 
92 
93 
 
 
 
 
 
 
k 
22 
22 
22 
23 
23 
23 
23 
24 
24 
 
 
 
 
 
 
12.4. Analysis Datasets 
The definitions of the study populations are listed below.  
Population 
Definition 
Enrolled 
This will comprise all subjects who meet the eligibility 
criteria and are registered onto the study.  
Evaluable for Primary 
Objective 
This will comprise all subjects who receive at least one 
dose of trial drug and either undergo at least one post-
baseline assessment 
Evaluable for Secondary 
objectives 
This will comprise all subjects who receive at least one 
dose of trial drug and either undergo at least one post-
baseline assessment or die before any evaluation.  
Evaluable for Safety 
This will comprise all subjects who receive at least one 
dose of trial drug 
Intention-to-treat (ITT) 
This will comprise all subjects who meet the eligibility 
criteria and are registered onto the study irrespective of 
their compliance to the planned course of treatment.  
Treated 
This will comprise all subjects who have been exposed to 
the planned course of treatment to any extent. 
12.5.  Sample Size, Accrual, Study Duration and Replacement Rules  
Efficacy of pembrolizumab will be quantified and evaluated by the time to death or distant 
metastasis, depending on which occurs first. Under the conventional chemoradiation, the median 
time is around 12-months. This estimate is generated based upon the previous trial by the 
Hoosier Oncology Group (LUN 01-24) [35, 36]. In this trial, subjects were randomized to 
observation vs. docetaxel if they had completed chemoradiation, had non-progressive disease, 
good performance status and end organ function. The median time to progression (mostly with 
distant mets) was 12 months in the observation arm. This group of subjects will most closely 
resemble the subject population enrolled onto this trial.  We expect pembrolizumab to improve 
the median time by 50%. Brookmeyer and Crowley’s method will be used to test the following 


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one-sided hypotheses: H0: m ≤12-month versus Ha: m >12-month. The accrual period is 
expected to be 24-months, following by an additional 12-months follow-up. Thus, the overall 
study duration will be 36 months. With type I error level as 0.05, N=83 subjects are required to 
obtain a power level of 0.80. The sample size is further adjusted to N = 93 to account for 10% 
lost-to-follow-up. If an ineligible subject is accidentally enrolled, that subject will be removed 
and replaced with an eligible subject. 
 
12.6.  Subject Demographics/Other Baseline Characteristics 
Demographic and other baseline data will be summarized descriptively for all subjects in the ITT 
set. 
 
12.7.  Concomitant Medications 
Concomitant medications and significant non-drug therapies prior and after the start of the study 
drug will be summarized for the treated set. 
 
12.8. Primary Objective 
The primary objective is to evaluate the time to death or distant metastasis (TTD), depending on 
which occurs first. The enrolled set will be used for the primary analysis. 
 
Kaplan-Meier method will be used for estimation. Brookmeyer and Crowley’s method will be 
used to calculate the 95% confidence interval of the median time and to test the following one-
sided hypotheses: H0: m ≤12-month versus Ha: m >12-month. P-value < 0.05 will be considered 
as significant. 
 
12.9. Secondary Objectives 
Key secondary objectives are progression free survival (PFS), overall survival (OS) and 
toxicities of pembrolizumab TTD in evaluable set is also a secondary objective. 
PFS and OS will be estimated by Kaplan-Meier method. They will be analyzed for both the 
enrolled set and the evaluable set. TTD will be estimated by Kaplan-Meier method for the 
evaluable set. 
 
Toxicities will be presented as rates and 95% Agresti-Coull confidence intervals. The treated set 
will be used for toxicity analysis. 
 
12.10. Safety Analysis 
The Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 and the Merck 
criteria for immunological side effects will be used jointly to report toxicities. 
 
Safety analyses will be performed for the treated set. Toxicities will be summarized by grade 
level, with and without considering relevance to treatment. 
 
12.11. Exploratory Objectives  
Exploratory analysis is planned to characterize the rate of expression PD-L1 in stage III NSCLC, 
and correlate with histology, PFS, OS and toxicity. 
 


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Rates and 95% confidence intervals will be generated for PD-L1 expressions. Their associations 
with TTD, PFS and OS will be evaluated by Cox proportional hazard models. 
 
12.12. Subgroup Analysis 
Both efficacy and toxicity outcomes will be evaluated in subgroup analysis based on PD-L1 
expressions, as well for subjects that have had up to 2 cycles of consolidation therapy. Additional 
subgroup analyses will be performed for toxicities based on primary treatment as chemotherapy 
or radiation therapy, and the dosage of radiations. 
 
13. 
TRIAL MANAGEMENT 
 
13.1 
Data and Safety Monitoring Plan 
This study will be conducted in accordance with the IU Simon Cancer Center’s (IUSCC) Data 
and Safety Monitoring Plan.  Study monitoring will include a risk-based monitoring strategy as 
defined in the Data Management Plan associated with this protocol. This study will have a Data 
Safety Monitoring Board as described below and a DSMB Charter. 
 
In addition HCRN data and safety monitoring activities include: 
 Conduct review of clinical trial for progress and safety 
 Review of all adverse events requiring expedited reporting as defined in the protocol 
 Provide sponsor-investigator with trial progress and safety information as required.  
 Notification of participating sites of adverse events requiring expedited reporting and 
subsequent committee recommendations for study modifications 
 
13.2 
Data and Safety Monitoring Board 
This study will have a Data and Safety Monitoring Board (DSMB) that will review and monitor 
study progress, toxicity, safety and other data from this trial. The DSMB is separate from the IU 
Simon Cancer Center (IUSCC) Data and Safety Monitoring Committee (DSMC). The board is 
chaired by an independent medical oncologist external to this trial. Questions about subject 
safety or protocol performance will be addressed with the sponsor-investigator, statistician and 
study team members. Should any major concerns arise; the DSMB will offer recommendations 
regarding whether or not to suspend the trial.  
 
The DSMB will meet after the first 10 subjects are treated with at least one dose of study drug 
and observed for a minimum of 3 months after first dose of study therapy, then twice a year 
thereafter to review accrual, toxicity, response and reporting information. Information to be 
provided to the DSMB may include: subject accrual, treatment regimen information, adverse 
events and serious adverse events reported by category, summary of any deaths on study, audit 
and/or monitoring results.  
The DSMB will provide a recommendation to the team after all information is reviewed. This 
information will also be provided to the site investigator sites for submission to the respective 
IRB according to the local IRB’s policies and procedures. 
 
14. 
DATA HANDLING AND RECORD KEEPING 
 
14.1 
Case Report Forms and Submission 


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This study will utilize electronic case report form (eCRF) in the Hoosier Cancer Research 
Network (HCRN) electronic data capture (EDC) system. The EDC system is a comprehensive 
database used by HCRN and properly used is compliant with Title 21 CFR Part 11. Access to the 
data through EDC system is restricted by user accounts and assigned roles. Once logged into the 
EDC system with a user ID and password, the EDC system defines roles for each user, which 
limits access to appropriate data. User information and passwords can be obtained by contacting 
HCRN at (317) 921-2050.  
 
Generally, clinical data will be electronically captured in the EDC system and correlative results 
will be captured in the EDC system or other secure database. If procedures on the study calendar 
are performed for standard of care, at minimum, that data will be captured in the source 
document. Select standard of care data will also be captured in the EDC system, according to 
study-specific objectives. Please see the SPM guidelines for further details.  
 
The completed dataset is the sole property of the sponsor-investigator’s institution. It should not 
be made available in any form to third parties, except for authorized representatives of 
appropriate Health/Regulatory Authorities, without written permission from the sponsor-
investigator and HCRN. 
 
14.2 
Record Retention 
To enable evaluations and/or audits from Health Authorities/HCRN, the site investigator agrees 
to keep records, including the identity of all participating subjects (sufficient information to link 
records; e.g., hospital records), all original signed informed consent forms, copies of all source 
documents, and detailed records of drug disposition. To comply with international regulations, 
the records should be retained by the site investigator in compliance with regulations. 
 
During data entry, range and missing data checks will be performed on-line. The checks to be 
performed will be documented in the Data Monitoring Plan for the study. A summary report (QC 
Report) of these checks together with any queries resulting from manual review of the eCRF’s 
will be generated for each site and transmitted to the site and the site monitor. Corrections will be 
made by the study site personnel. This will be done on an ongoing basis. 
 
14.3 
Confidentiality 
There is a slight risk of loss of confidentiality of subject information. All records identifying the 
subject will be kept confidential and, to the extent permitted by the applicable laws and/or 
regulations, will not be made publicly available.  
 
Information collected will be maintained on secure, password protected electronic systems. 
Paper files that contain personal information will be kept in locked and secure locations only 
accessible to the study team. Samples that are collected will be identified by a subject study 
number assigned at the time of registration to the trial. Any material issued to collaborating 
researchers will be anonymized and only identified by the subject study number. 
Subjects will be informed in writing that some organizations including the sponsor-investigator 
and his/her research associates, HCRN, Merck, IRB, or government agencies, like the FDA, may 
inspect their medical records to verify the information collected, and that all personal 


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information made available for inspection will be handled in strictest confidence and in 
accordance with local data protection laws. 
 
If the results of the study are published, the subject’s identity will remain confidential. 
 
14.4 
Changes to the Protocol 
Study procedures will not be changed without the mutual agreement of the sponsor-investigator, 
Hoosier Cancer Research Network, and Merck. 
 
If it is necessary for the study protocol to be amended, the amendment or a new version of the 
study protocol (amended protocol) will be generated by the Hoosier Cancer Research Network 
and must be approved by each IRB, Merck, and if applicable, also the local regulatory authority. 
Local requirements must be followed. 
 
If a protocol amendment requires a change to the Written Informed Consent Form, then the IRB 
must be notified. Approval of the revised Written Informed Consent Form by the IRB is required 
before the revised form is used.  
 
The site investigator is responsible for the distribution of these documents to his or her IRB, and 
to the staff at his or her center. The distribution of these documents to the regulatory authority 
will be handled according to local practice. 
 
Merck’s willingness to supply study drug is predicated upon the review of the protocol. The 
Hoosier Cancer Research Network agrees to provide written notice to Merck of any 
modifications to the protocol or informed consent. 
 
15. 
ETHICS 
 
15.1 
Ethics Review 
The final study protocol, including the final version of the Written Informed Consent Form, must 
be approved in writing by an IRB. The site investigator must submit written approval to the 
HCRN office before he or she can enroll any subject into the study.  
 
The site investigator is responsible for informing the IRB of any amendment to the protocol in 
accordance with local requirements. In addition, the IRB must approve all advertising used to 
recruit subjects for the study. The protocol must be re-approved by the IRB annually, as local 
regulations require.  
 
Progress reports and notifications of serious unexpected adverse drug reactions will be provided 
to the IRB according to local regulations and guidelines. 
The site investigator is also responsible for providing the IRB with reports of any serious adverse 
drug reactions from any other study conducted with the investigational product. Merck will 
provide this information to HCRN. These reports will be reviewed by the sponsor-investigator 
and those considered unexpected and possibly related to protocol therapy plus all deaths within 
90 days of discontinuing treatment will be forwarded to participating sites for submission to their 


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Institutional Review Boards per their guidelines. All other events will be held and submitted to 
the sites for continuing review. 
 
15.2 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles originating from the 
Declaration of Helsinki, which are consistent with ICH/Good Clinical Practice, and applicable 
regulatory requirements. 
 
15.3 
Informed Consent Process 
The site investigator will ensure the subject is given full and adequate oral and written 
information about the nature, purpose, possible risks and benefits of the study. Subjects must 
also be notified they are free to discontinue from the study at any time. The subject should be 
given the opportunity to ask questions and allowed time to consider the information provided. 
The subject’s signed and dated informed consent must be obtained before conducting any 
procedure specifically for the study. The site investigator must store the original, signed Written 
Informed Consent Form. A copy of the signed Written Informed Consent Form must be given to 
the subject. 
 
 


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