Clinical trial NCT03190213
Conditions: Neuroendocrine Tumors
Keywords: high grade
Sponsor: University of Utah
Start date: 2017-12-04; Completion date: 2019-03-11
Enrollment: 6 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is an open label, non-randomized phase 2 study to assess overall response rate (ORR), clinical benefit rate (CBR), overall survival (OS) and progression free survival (PFS) in patients with high grade neuroendocrine tumors treated with pembrolizumab 200mg Q 3 Weeks.

Detailed description:

Arms: arm 1: None
Interventions: intervention 1: Pembrolizumab Injection
Intervention descriptions: intervention 1: Pembrolizumab at a dose of 200 mg will be administered as an IV infusion over 30 minutes every 3 weeks until disease recurrence or discontinuation due to unacceptable toxicity for a maximum of 2 years. We anticipate on average patients will remain on treatment for approximately 24 weeks.

Protocol documents:
Prot_SAP_000.pdf: 
Full Study Protocol and Statistical Analysis Plan 
 
 
 
Study Title:  Pembrolizumab for the Treatment of Recurrent High 
Grade Neuroendocrine Carcinoma (PembroNEC) 
 
Protocol Version 3: 10DEC2018 
 
 
 
NCT #: NCT03190213 
Unique Protocol ID: HCI102310 
U of U IRB#: IRB_00102310 
 
 
 
Principal Investigator:  G. Weldon Gilcrease, MD 
Huntsman Cancer Institute 
 


Short Title: Pembrolizumab for the treatment of recurrent high grade neuroendocrine (PembroNEC) 
Version Date: 10DEC2018 
Principal Investigator: G. Weldon Gilcrease, MD  
 
Pembrolizumab for the Treatment of Recurrent High Grade 
Neuroendocrine Carcinoma (PembroNEC) 
Merck Protocol Number: MK-3475: PN713 
Lead Org. ID HCI102310 / IRB# 102310 
Coordinating Center 
 
Principal Investigator 
Huntsman Cancer Institute – University of Utah 
 
G. Weldon Gilcrease, MD 
Huntsman Cancer Institute, University of Utah 
2000 Circle of Hope Drive 
Salt Lake City, UT 84112 
Glynn.Gilcrease@hci.utah.edu  
Sub-investigator(s) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ignacio Garrido-Laguna, MD  
Huntsman Cancer Institute - University of Utah 
Salt Lake City, Utah 84112  
ignacio.garrido-laguna@hci.utah.edu 
 
John Weis, MD  
Huntsman Cancer Institute - University of Utah 
Salt Lake City, Utah 84112  
john.weis@hci.utah.edu 
 
 
Nicole Orgain, APRN  
Huntsman Cancer Institute - University of Utah 
Salt Lake City, Utah 84112  
nicole.orgain@hci.utah.edu 
 
Ken Boucher, PhD (Statistician) 
Huntsman Cancer Institute - University of Utah 
Salt Lake City, Utah 84112  
ken.boucher@hci.utah.edu 
 


Protocol name: Pembrolizumab for the treatment of recurrent high grade neuroendocrine 
Version Date: 10DEC2018 
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Intermountain Precision 
Genomics Research Clinic  
Dixie Regional Medical Center 
Subsite Principal Investigator 
 
 
 
 
Satellite Site Information 
 
 
 
 
 
 
 
 
 
 
 
Intermountain Precision 
Genomics Research Clinic 
Subsite Principal Investigator 
 
 
 
 
 
 
Intermountain Medical 
Oncology McKay-Dee Hospital 
Subsite Principal Investigators 
 
 
 
Satellite Site Information 
 
 
 
 
 
 
 
 
Drug Manufacturer  
 
Terence Rhodes, MD 
Intermountain Precision Genomics Research Clinic 
Dixie Regional Medical Center 
544 South 400 East 
St. George, Utah 84770 
Terence.rhodes@imail.org 
 
 
Intermountain Healthcare 
Dixie Regional Medical Center 
River Road Campus 
1380 East Medical Center Drive 
St. George, Utah 84790 
 
Cedar City Hospital  
Southwest Cancer Clinic-Cedar City 
1303 North Main Street 
Cedar City, Utah 84720 
 
 
Mark Lewis, MD 
Intermountain Precision Genomics 
Cancer Research Clinic 
5169 South Cottonwood Street 
Eccles Outpatient Building, Suite 610 
Murray, Utah 84107 
Mark.lewis2@imail.org 
 
 
Vincent Hansen, MD 
Intermountain Medical Oncology McKay-Dee 
Hospital 
4403 Harrison Blvd, Suite 1685 
Ogden, Utah 84403 
Vincent.hansen@imail.org 
Intermountain Medical Oncology Layton 
2132 North 1700 West, Suite 301 
Layton, Utah 84041 
 
Intermountain Medical Oncology South Ogden 
5290 South 400 East 
Ogden, Utah 84405 
 
 
Merck 


Protocol name: Pembrolizumab for the treatment of recurrent high grade neuroendocrine 
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Investigational Agent 
 
 
Pembrolizumab  
 
IND Number 
Exempt  
 
 
Historical Protocol Versions 
Version 1: 02MAY2017 
Version 2: 11APR2018 
Version 3: 10DEC2018 
 


Protocol name: Pembrolizumab for the treatment of recurrent high grade neuroendocrine 
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TABLE OF CONTENTS 
Page 
LIST OF ABBREVIATIONS ......................................................................................................... 6 
PROTOCOL SIGNATURE ............................................................................................................ 9 
STUDY SUMMARY.................................................................................................................... 10 
SCHEMA ...................................................................................................................................... 11 
1 
OBJECTIVES ....................................................................................................................... 12 
1.1 
Primary Objectives and Endpoint .................................................................................. 12 
1.2 
Secondary Objectives and Endpoint .............................................................................. 12 
1.3 
Exploratory Objectives and Endpoint ............................................................................ 12 
2 
BACKGROUND .................................................................................................................. 12 
2.1 
Hypothesis ...................................................................................................................... 12 
2.2 
Neuroendocrine carcinoma (NECs) / Neuroendocrine Tumors (NETs) ........................ 12 
2.3 
NET / NEC Classification and Grading ......................................................................... 13 
2.4 
Prognosis and Treatment ................................................................................................ 13 
3 
DRUG INFORMATION ...................................................................................................... 14 
3.1 
Pembrolizumab............................................................................................................... 14 
3.2 
Rationale for the Trial and Selected Subject Population................................................ 15 
4 
STUDY DESIGN.................................................................................................................. 17 
4.1 
Description ..................................................................................................................... 17 
4.2 
Number of Patients ......................................................................................................... 17 
4.3 
Number of Study Centers ............................................................................................... 18 
4.4 
Study Duration ............................................................................................................... 18 
5 
ELIGIBILITY CRITERIA.................................................................................................... 19 
5.1 
Inclusion Criteria ............................................................................................................ 19 
5.2 
Exclusion Criteria ........................................................................................................... 21 
6 
STRATIFICATION FACTORS ........................................................................................... 23 
7 
TREATMENT PLAN ........................................................................................................... 23 
7.1 
Administration Schedule ................................................................................................ 23 
7.2 
Pembrolizumab (MK-3475) Treatment .......................................................................... 23 
7.3 
Dose Calculation ............................................................................................................ 25 
7.4 
Preparation of Infusion Solution .................................................................................... 25 
7.5 
Administration ................................................................................................................ 26 
7.6 
Accountability and Compliance ..................................................................................... 27 
7.7 
Concomitant Medications .............................................................................................. 27 
7.8 
Duration of Therapy ....................................................................................................... 28 
8 
TOXICITIES AND DOSAGE MODIFICATION ............................................................... 29 
8.1 
Dose modification and toxicity management guidelines for pembrolizumab................ 29 
8.2 
Dose modification and toxicity management of infusion-reactions related to 
pembrolizumab ......................................................................................................................... 32 
8.3 
Other allowed dose interruption for pembrolizumab ..................................................... 33 
8.4 
Diet/Activity/Other Considerations: .............................................................................. 33 
9 
STUDY CALENDAR .......................................................................................................... 36 
10 STUDY PROCEDURES ...................................................................................................... 38 
10.1 
Screening Evaluations ................................................................................................ 38 
10.2 
On-Treatment Evaluations (every three weeks unless otherwise noted) .................... 38 


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10.3 
End of Treatment Assessments: ................................................................................. 39 
10.4 
Follow-up Assessments .............................................................................................. 39 
11 CRITERIA FOR EVALUATION AND ENDPOINT .......................................................... 39 
11.1 
Efficacy ....................................................................................................................... 39 
11.2 
Safety .......................................................................................................................... 41 
11.3 
Stopping Rules ............................................................................................................ 42 
12 STATISTICAL CONSIDERATIONS.................................................................................. 42 
13 REGISTRATION GUIDELINES ......................................................................................... 42 
14 DATA SUBMISSION SCHEDULE .................................................................................... 43 
15 Special Instructions ............................................................................................................... 44 
15.1 
Pathology review for PD-L1 analysis at central laboratory ....................................... 44 
15.2 
Pathology review for tumor mutational burden analysis ............................................ 44 
Screening tissue analyzed for correlation of tumor mutational burden will be performed locally 
per treatment center’s standard protocol. If not performed previously and not clinically 
indicated at the time of screening, TMB will not be required. ................................................. 44 
15.3 
Pathology review for Ki-67 antibody staining ........................................................... 44 
15.4 
Correlative Studies ..................................................................................................... 44 
16 ETHICAL AND REGULATORY CONSIDERATIONS .................................................... 44 
16.1 
Recruitment Strategies ................................................................................................ 44 
16.2 
Informed consent ........................................................................................................ 45 
16.3 
Human Subjects Protections ....................................................................................... 45 
16.4 
Institutional Review .................................................................................................... 45 
16.5 
Data and Safety Monitoring Plan ............................................................................... 45 
16.6 
Adverse Events / Serious Adverse Events .................................................................. 45 
16.7 
SAE Reporting Requirements .................................................................................... 47 
16.8 
Events of Clinical Interest (ECI) ................................................................................ 48 
16.9 
Definition of an Overdose for this Protocol and Reporting of Overdose to HCI and to 
Merck 49 
16.10 
Reporting of Pregnancy and Lactation to HCI Sponsor, IRB, DSMC and Merck ..... 49 
16.11 
Protocol Amendments ................................................................................................ 50 
16.12 
Protocol Deviations .................................................................................................... 50 
16.13 
FDA Annual Reporting .............................................................................................. 50 
16.14 
Clinical Trials Data Bank ........................................................................................... 51 
16.15 
Record Keeping .......................................................................................................... 51 
17 BIBLIOGRAPHY ................................................................................................................. 52 
 
 


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LIST OF ABBREVIATIONS 
Abbreviation or Term1 
Definition/Explanation 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
ANOVA 
Analysis of variance 
APTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
AV 
Atrioventricular 
β-HCG 
Beta-human chorionic gonadotropin 
BID 
Twice daily 
BLQ 
Below limit of quantification 
BMI 
Body mass index 
BP 
Blood pressure 
BUN 
Blood urea nitrogen 
Ca++ 
Calcium 
CBC 
Complete blood count 
CFR 
Code of Federal Regulations 
CHF 
Congestive heart failure 
CI 
Confidence interval 
Cl- 
Chloride 
CLcr 
Creatinine clearance 
Cmax 
Maximum observed concentration 
Cmin 
Trough observed concentration 
CNS 
Central nervous system 
CR 
Complete response 
CRF 
Case report form 
CT 
Computed tomography 
CTCAE 
Common Toxicity Criteria for Adverse Events 
CV 
Coefficient of variation 
CYP 
Cytochrome P450 
D/C 
Discontinue 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 


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Abbreviation or Term1 
Definition/Explanation 
DLT 
Dose Limiting Toxicity 
ECG 
Electrocardiogram 
Eg 
Exempli gratia (for example) 
FACS 
Fluorescence Activated Cell Sorting  
FDA 
Food and Drug Administration 
FDG-PET 
Fluorodeoxyglucose (FDG)-positron emission tomography (PET) 
GCP 
Good Clinical Practice 
GFR 
Glomerular filtration rate 
GGT 
Gamma glutamyl transferase 
GLP 
Good laboratory practice  
HBsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B virus 
HCO3- 
Bicarbonate 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
HR 
Heart rate 
hr 
Hour or hours 
IC50 
Half maximal inhibitory concentration 
i.e. 
Id est (that is) 
IEC 
Independent ethics committee 
INR 
International normalized ratio 
IRB 
Institutional review board 
IU 
International unit 
IV 
Intravenous, intravenously 
LDH 
Lactate dehydrogenase 
LLQ 
Lower limit of quantitation 
MedRA 
Medical Dictionary for Drug Regulatory Activities 
MRI 
Magnetic resonance imaging 
MRSD 
Maximum recommended starting dose 
MTD 
Maximum tolerated dose  
NOAEL 
No-observed-adverse-effect level 
NOEL 
No-observed-effect-level 
PD 
Pharmacodynamic(s) 
PFS 
Progression Free Survival 


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Abbreviation or Term1 
Definition/Explanation 
PK 
Pharmacokinetic(s) 
PO 
Per os (administered by mouth) 
PR 
Partial response 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
QC 
Quality control 
RBC 
Red blood cell 
QD 
Once daily 
QTc 
QT interval corrected  
QTcF 
QT interval corrected using Frederichia equation 
SAE 
Serious adverse event 
SD 
Standard deviation or stable disease 
T1/2 
Terminal elimination half-life 
T3 
Triiodothyronine 
T4 
Thyroxine 
Tmax 
Time of maximum observed concentration 
TID 
Three times daily 
TSH 
Thyroid-stimulating hormone 
ULN 
Upper limit of normal 
ULQ 
Upper limit of quantitation 
UV 
Ultraviolet 
WBC 
White blood cell 
WOCBP 
Women of childbearing potential 
WONCBP 
Women of non-childbearing potential 
All of these abbreviations may or may not be used in protocol.  
 
 


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PROTOCOL SIGNATURE 
I confirm that I have read this protocol, and I will conduct the study as outlined herein and 
according to the ethical principles stated in the latest version of the Declaration of Helsinki, the 
applicable ICH guidelines for good clinical practice, and the applicable laws and regulations of 
the federal government. I will promptly submit the protocol to the IRB for review and approval. 
Once the protocol has been approved by the IRB, I understand that any modifications made 
during the course of the study must first be approved by the IRB prior to implementation except 
when such modification is made to remove an immediate hazard to the subject. 
 
I will provide copies of the protocol and all pertinent information to all individuals responsible to 
me who assist in the conduct of this study. I will discuss this material with them to ensure that 
they are fully informed regarding the study treatment, the conduct of the study, and the 
obligations of confidentiality. 
 
Note: This document is signed electronically through submission and approval by the Principal 
Investigator in the University of Utah IRB Electronic Research Integrity and Compliance 
Administration (ERICA) system. 
 
 
 
Instructions to multi-site Principal Investigators at locations other than Huntsman Cancer 
Institute: SIGN and DATE this signature page and PRINT your name. Return the original, 
completed and signed, to the HCI Research Compliance Office (compliance@hci.utah.edu). 
Retain a copy in the regulatory binder.  
 
 
 
 
 
____________________________________ 
_______________ 
Signature of Principal Investigator  
 
Date 
 
 
____________________________________ 
Principal Investigator Name (Print) 
 
 
____________________________________ 
Name of Institution 
 


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STUDY SUMMARY 
Title 
Pembrolizumab for the treatment of recurrent high grade 
neuroendocrine carcinoma 
Short Title 
Pembro NEC 
Protocol Number 
IRB#102310 
IND 
IND Exempt 
Phase 
Phase 2 
Design 
Open label, non-randomized with subjects receiving 
200mg Pembrolizumab to assess response rate in patients 
with NEC. 
Study Duration 
Accrual anticipated over 30 months, time to complete 42 
months 
Study Center(s) 
This trial will open as a multi-site study conducted at the 
Huntsman Cancer Institute-University of Utah (including 
various other satellite sites and Intermountain Healthcare).  
Objectives 
To assess overall response rate, clinical benefit rate, 
progression free survival and overall survival in patients 
that receive Pembrolizumab using irRECIST  
Number of Subjects 
30 – 40 total  
Diagnosis and Main 
Eligibility Criteria 
High grade (Grade 3 defined by Ki-67 >20% or >20 
mitoses/10 hpf) non-pulmonary neuroendocrine 
carcinoma. 
Patients must have failed at least one line of therapy but 
no maximum number of therapies is exclusionary (i.e. 
second-line therapy and beyond) 
Study Product, Dose, 
Route, Regimen 
Pembrolizumab 200 mg IV q3weeks 
Duration of administration 24 months 
Reference therapy 
none 
Statistical Methodology 
Simon two-stage design based on expected RR of 25%.  
 
 


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SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Consent and Screening 
 
• Patients with high grade non pulmonary neuroendocrine carcinoma 
• Previously received at least one line of therapy prior to study 
enrollment 
 
Open label, non-randomized 
Pembrolizumab 200mg IV q 3 weeks 
CT of the abdomen/chest/pelvis must be repeated every 6 weeks through C12 
(24 weeks), then every 12 weeks until disease progression 
Patients may remain on treatment pembrolizumab for up to 2 years as long as they 
are receiving clinical benefit (SD, PR, CR), or until irRECIST progressive disease 
(PD) is confirmed 


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1 OBJECTIVES 
1.1 
Primary Objectives and Endpoint 
To evaluate overall response rate of pembrolizumab (irPR + irCR) using immune related 
(ir)RECIST in patients with non-pulmonary, high grade neuroendocrine carcinoma. 
1.2 
Secondary Objectives and Endpoint 
 To evaluate clinical benefit rate of pembrolizumab (irPR + irCR + irSD) using 
irRECIST in this setting. 
 To evaluate progression free survival of patients treated with pembrolizumab in this 
setting. 
 To evaluate the median overall survival (OS) of patients treated with pembrolizumab 
in this setting 
 To evaluate safety and tolerability of the pembrolizumab in this setting. 
1.3 
Exploratory Objectives and Endpoint 
 To evaluate the correlation of response to tumor mutational burden.  
 To evaluate the correlation of response to PD-L1 expression in primary tumor.  
 To evaluate the correlation of response to proliferative rate in Grade 3 NECs (Ki-67 
20-55% vs. Ki-67 >55%). 
2 BACKGROUND 
2.1 
Hypothesis 
Pembrolizumab will be clinically active in patients with high grade NECs as demonstrated by 
clinical response 
2.2 
Neuroendocrine carcinoma (NECs) / Neuroendocrine Tumors (NETs) 
Neuroendocrine tumors (NETs) make up a relatively rare but heterogeneous family of 
neoplasms. Historically considered rare, the incidence of NETs has been steadily increasing 
since the 1970s, with SEER registry data suggesting an increase in incidence of almost 500% 
over this period of time in the United States (1). These tumors arise from neuroendocrine 
cells that are found primarily in the gut and make up the largest group of hormone-producing 
cells in the body. The hallmark of NETs is evidence of predominant neuroendocrine 
differentiation; namely, they have distinctive morphologic characteristics and expression of 
specific tissue markers including chromogranin A, synaptophysin, and neoron-specific 
enolase. These tumors commonly arise in the lung, intestine and pancreas but can arise in 
various anatomic locations including the larynx, thymus, kidneys, cervix, prostate, ovaries, 
and other sites. No primary site is identified in approximately 10 – 15% of metastatic NET 
cases (1). 


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2.3 
NET / NEC Classification and Grading 
The pathologic classification of non-pulmonary neuroendocrine malignancies is complex and 
continually evolving. Low grade, well-differentiated neuroendocrine neoplasms are 
commonly referred to as “neuroendocrine tumors” (NETs) whereas high grade, poorly 
differentiated neuroendocrine neoplasms are commonly referred to as “neuroendocrine 
carcinoma” (NECs). Pathologic specimens are distinguished based on morphologic evidence 
of differentiation. Well-differentiated NETs show a solid, trabecular, gyriform, or glandular 
pattern with uniform nuclei, salt-and-pepper chromatin, and finely granular cytoplasm. 
Poorly differentiated NECs resemble small cell or large cell neuroendocrine carcinoma of the 
lung. Small cell NECs are comprised of small round cells with small amounts of cytoplasm 
with hyperchromatic nuclei; large cell NEC cells are arranged in organoid, trabecular, or 
palisading patterns with prominent necrosis.  
The 2010 WHO classifications of gastroenteropancreatic neuroendocrine tumors (GEP-
NETs) adopted a classification system previously endorsed by the European Neuroendocrine 
Tumour Society (ENETS). Namely, well-differentiated tumors are separated into low-grade 
and intermediate-grade with poorly-differentiated tumors generally classified as high grade 
depending on mitotic count and/or Ki-67 proliferation indices (Table 1). The WHO Grade 3 
(G3) of NECs is somewhat heterogenous. Namely, the majority of NECs exhibit a poorly 
differentiated morphology and will fall in the range of G3 tumors based on mitotic or 
proliferative indices; however, a subset of patients will exhibit a well- or moderately-
differentiated histology but higher grade based on mitotic and proliferative indices. These 
tumors are considered “grade discordant.” Their clinical behavior generally falls somewhere 
between lower grade NETs and poorly differentiated, G3 NECs.  
Table 1: 2010 WHO tumor grading for gastrointestinal neuroendocrine tumors 
Grading of GEP-NETs 
Mitotic Index 
Ki-67 labelling index 
Grade 1 (G1) 
<2 mitoses/10 hpf 
≤2% 
Grade 2 (G2) 
2-10 mitoses/10 hpf 
3-20% 
Grade 3 (G3) 
>20 mitoses / 10 hpf 
>20% 
Well-differentiated NETs are frequently associated with clinical syndromes depending on 
hormone secretion. Namely, NETs arising in the small bowel are often associated with 
“carcinoid syndrome,” manifest by diarrhea, flushing, palpitations, wheezing and other 
symptoms predominantly due to excess serotonin secretion. Similarly, pancreatic NETs may 
secrete insulin, glucagon, gastrin, vasoactive intestinal peptide (VIP), somatostatin, or other 
hormones with clinical syndromes directly related to this hormone secretion. On the other 
hand, poorly differentiated NECs do not closely resemble non-neoplastic neuroendocrine 
cells and are not generally associated with specific clinical syndromes due to excessive 
hormone secretion. Like SCLC, however, poorly differentiated are relatively frequently 
associated with other paraneoplastic syndromes (e.g. hypercalcemia, hyponatremia, venous 
thromboembolism, etc.). 
2.4 
Prognosis and Treatment  
While most NETs are relatively slow-growing (G1 or G2) with a median survival of many 
years, the prognosis of patients with poorly differentiated G3 NECs is dismal with a median 


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survival of approximately 12 months (2). Common sites of metastases include liver, lung, 
bones, and brain. Histologically, poorly differentiated NECs can be classified as either “small 
cell” or “large cell” NEC. Clinically these entities behave very similarly and standard 
treatment for both large and small cell NEC is usually identical, although some practitioners 
favor temozolomide-based chemotherapy regimens over platinum-based regimens in patients 
with poorly differentiated NEC with Ki-67 <55% (2). 
As this is a relatively rare patient population, large-scale, randomized phase III trials have 
been very difficult to perform. Standard accepted therapies have been extrapolated from 
experience in the treatment of SCLC or are based on smaller phase II trials in this specific 
population. First-line treatment generally involves chemotherapy, either platinum-based (e.g. 
carboplatin or cisplatin in combination with etoposide) or temozolomide-based (e.g. single-
agent temozolomide, capecitabine + temozolomide). Response rates range from 10 – 70% but 
are generally not durable with no standard second-line treatment (2-4). Extrapolating from 
treatment algorithms used in small cell lung cancer (SCLC), chemotherapy is often 
administered in the second-line setting with disappointingly low response rates and early 
clinical progression (5-7).  
3 DRUG INFORMATION 
3.1 
Pembrolizumab 
Refer to the Investigator’s Brochure (IB) for detailed background information on MK-3475 
(Pembrolizumab). 
 Pharmaceutical and Therapeutic Background 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades. Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in 
various malignancies. In particular, the presence of CD8+ T-cells and the ratio of CD8+ 
effector T-cells / FoxP3+ regulatory T-cells 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). The structure of 
murine PD-1 has been resolved. 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, 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. The mechanism by which PD-1 down modulates T-cell responses is similar 


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to, but distinct from that of CTLA-4 as both molecules regulate an overlapping set of signaling 
proteins. 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. Expression has also been 
shown during thymic development on CD4-CD8- (double negative) T-cells as well as subsets 
of macrophages and dendritic cells. 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. 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. 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). 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. 
 Preclinical and Clinical Trial Data 
Refer to the Investigator’s Brochure for Preclinical and Clinical data. 
3.2 
Rationale for the Trial and Selected Subject Population 
 Rationale for anti-PD-1 therapy in high grade (G3) NET/NECs  
Immunotherapy, in particular therapy with immune checkpoint inhibitors such as anti-PD-1 
antibody therapy, has recently shown significant efficacy in a wide variety of tumors with 
FDA approved indications for anti-PD-1 antibody therapy includes melanoma, non-small cell 
lung cancer, squamous cell carcinoma of the head and neck, renal cell cancer, and Hodgkin 
lymphoma. Additionally, phase II trials have demonstrated activity in other cancer types 
including small cell lung (SCLC), merkel cell, bladder, gastric, hepatobiliary, breast and 
prostate cancers. Included in this list of cancers where activity has been demonstrated are two 
aggressive neuroendocrine cancers:  Merkel cell carcinoma and small cell lung cancer. 
The multicenter, phase 2 clinical trial leading to wide acceptance of pembrolizumab therapy 
in patients with advanced Merkel cell carcinoma demonstrated an objective response rate of 
56% with a response duration ranging from 2.2 months to at least 9.7 months and a 6-month 
progression-free survival rate of 67% (9). Similarly, trials demonstrating activity of anti-PD-
1 antibody therapy in SCLC include the KEYNOTE-028 trial and the CHECKMATE-032 
trial. In the KEYNOTE-028 trial, patients with metastatic SCLC with evidence of PD-L1 


Protocol name: Pembrolizumab for the treatment of recurrent high grade neuroendocrine 
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expression by immunohistochemistry who were previously treated with platinum-based 
chemotherapy were treated with pembrolizumab. Early data suggest a 25% response rate 
with response duration lasting > 4 months (10). The CHECKMATE-032 trial enrolled a 
similar patient population. Patients were treated with nivolumab either alone or in 
combination with ipilumumab with response rates of 13% and 31% respectively and duration 
of responses lasting > 6 months (11). With this encouraging data, multiple ongoing trials are 
evaluating the role of anti-PD-1 therapy and other immune checkpoint inhibitors in the 
treatment of patients with Merkel cell carcinoma and SCLC. These trials all support the 
rationale for treatment with immune checkpoint blockade in patients with high grade 
NET/NECs. 
Among biologic correlates evaluated with anti-PD-1 therapies, none have defined a clear 
subset to definitively predict clinical efficacy. However, some correlates have emerged as 
strong predictors for clinical benefit. Three leading correlative markers predictive of benefit 
include:  1) mutation burden (namely, cancers with higher mutation burden tend to be more 
likely to respond to anti-PD-1 therapy, likely due to an increase in neoantigen expression) 
(12); 2) PD-L1 expression (13-14); and, 3) tumor T cell infiltration, associated with PD-L1 
expression by infiltrating immune cells (15-16). High grade NECs have been shown to have 
a high mutation burden (17-18). Similarly, NECs have been found to express PD-L1, which 
is more commonly expressed in G3 NECs (19). Lastly, the majority of extra-pulmonary 
higher grade NETs have also been shown to exhibit intratumoral T cell infiltration on 
histopathologic review (20). Together, these features suggests a higher likelihood of clinical 
benefit in this patient population. 
 Rationale for Dose Selection/Regimen/Modification  
An open-label Phase I trial (Protocol 001) is being conducted to evaluate the safety and 
clinical activity of single agent MK-3475. 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 MK-3475 showed evidence of 
target engagement and objective evidence of tumor size reduction at all dose levels (1 mg/kg, 
3 mg/kg and 10 mg/kg Q2W). No MTD has been identified to date. 10.0 mg/kg Q2W, the 
highest dose tested in PN001, will be the dose and schedule utilized in Cohorts A, B, C and 
D of this protocol to test for initial tumor activity. Recent data from other clinical studies 
within the MK-3475 program has shown that a lower dose of MK-3475 and a less frequent 
schedule may be sufficient for target engagement and clinical activity. 
PK data analysis of MK-3475 administered Q2W and Q3W showed slow systemic clearance, 
limited volume of distribution, and a long half-life (refer to IB). Pharmacodynamic data (IL-2 
release assay) suggested that peripheral target engagement is durable (>21 days). This early 
PK and pharmacodynamic data provides scientific rationale for testing a Q2W and Q3W 
dosing schedule.  
A population pharmacokinetic analysis has been performed using serum concentration time 
data from 476 patients. Within the resulting population PK model, clearance and volume 
parameters of MK-3475 were found to be dependent on body weight. The relationship 
between clearance and body weight, with an allometric exponent of 0.59, is within the range 
observed for other antibodies and would support both body weight normalized dosing or a 


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fixed dose across all body weights. MK-3475 has been found to have a wide therapeutic 
range based on the melanoma indication. The differences in exposure for a 200 mg fixed 
dose regimen relative to a 2 mg/kg Q3W body weight based regimen are anticipated to 
remain well within the established exposure margins of 0.5 – 5.0 for MK-3475 in the 
melanoma indication. The exposure margins are based on the notion of similar efficacy and 
safety in melanoma at 10 mg/kg Q3W vs. the proposed dose regimen of 2 mg/kg Q3W (i.e. 
5-fold higher dose and exposure). 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 indication settings. 
The rationale for further exploration of 2 mg/kg and comparable doses of pembrolizumab in 
solid tumors is based on: 1) similar efficacy and safety of pembrolizumab when dosed at either 
2 mg/kg or 10 mg/kg Q3W in melanoma patients, 2) the flat exposure-response relationships 
of pembrolizumab for both efficacy and safety in the dose ranges of 2 mg/kg Q3W to 10 mg/kg 
Q3W, 3) the lack of effect of tumor burden or indication on distribution behavior of 
pembrolizumab (as assessed by the population PK model) and 4) the assumption that the 
dynamics of pembrolizumab target engagement will not vary meaningfully with tumor type. 
The choice of the 200 mg Q3W as an appropriate dose for the switch to fixed dosing is based 
on simulations performed using the population PK model of pembrolizumab showing that the 
fixed dose of 200 mg every 3 weeks will provide exposures that 1) are optimally consistent 
with those obtained with the 2 mg/kg dose every 3 weeks, 2) will maintain individual patient 
exposures in the exposure range established in melanoma as associated with maximal efficacy 
response and 3) will maintain individual patients exposure in the exposure range established 
in melanoma that are well tolerated and safe.  
A fixed dose regimen will simplify the dosing regimen to be more convenient for physicians 
and to reduce potential for dosing errors. A fixed dosing scheme will also reduce complexity 
in the logistical chain at treatment facilities and reduce wastage. 
4 STUDY DESIGN 
4.1 
Description 
This is an open label, non-randomized phase 2 study to assess overall response rate (ORR), 
clinical benefit rate (CBR), overall survival (OS) and progression free survival (PFS) in 
patients with high grade neuroendocrine tumors treated with pembrolizumab 200mg Q 3 
Weeks.   
Simon Optimum Two-Stage designs will be used. A Type I error rate alpha equal to 0.10 and 
a Type II error rate beta equal to 0.20 will be used. Null and alternative hypotheses are 
associated with treatments. See Section 12 for additional details  
4.2 
Number of Patients 
A total of 34-40 subjects will be recruited to one treatment arm in this study with the goal of 
enrolling 34 evaluable patients (defined in sections 11.1 and 11.3).  


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4.3 
Number of Study Centers 
This trial will open as a multi-site study conducted at the Huntsman Cancer Institute 
including various other satellite sites and Intermountain Healthcare.  
4.4 
Study Duration  
We would anticipate that on average, patients will remain on treatment approximately 24 
weeks (range of 2 to 52 weeks comparatively). However, patients may remain on treatment 
pembrolizumab for up to 2 years as long as they are receiving clinical benefit (SD, PR, CR), 
or until irRECIST progressive disease (PD) is confirmed. Confirmation of progression will 
occur 4-6 weeks after first detection prior to subject coming off study.  
Accrual is anticipated to take 24-30 months. Estimated duration of accrual and patient 
participation is approximately three and half years. 
 
 


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5 ELIGIBILITY CRITERIA 
This eligibility checklist is used to determine patient eligibility and filed with signature in the 
patient research chart.  
Patient No. ______________________ 
Patient’s Initials: (L,F,M) _________________ 
5.1 
Inclusion Criteria 
Yes/No (Response of “no” = patient ineligible) 
 _____ Histologically confirmed, metastatic or unresectable neuroendocrine 
carcinoma of non-pulmonary origin, high grade as indicated by Ki-67 >20% and/or > 
20 mitoses/10 hpf. Patients must have existing Ki-67 results from archival tissue or 
available tissue for Ki-67 testing. If no archival tissue is available the subject must 
agree to a fresh biopsy for testing to qualify for the study. 
 _____ Patients must have progressed during or after first-line treatment for metastatic 
or unresectable disease with either a platinum-based regimen (e.g. carboplatin + 
VP16, cisplatin + VP-16, FOLFOX) OR temozolomide-based regimen. Patients must 
have failed at least one line of therapy but no maximum number of therapies is 
exclusionary (i.e. second-line therapy and beyond). 
 _____ Have measurable disease based on irRECIST. 
 _____ Be ≥ 18 years of age on day of signing informed consent.  
 _____ Have a performance status of 0 or 1 on the ECOG Performance Scale.  
 _____ Demonstrate adequate organ function as defined in Table 2, all screening labs 
should be performed within 14 days of treatment initiation.  
Table 2: Adequate Organ Function Laboratory Values: 
System 
Laboratory Value 
 Hematological:  
 
Absolute Neutrophil Count 
ANC 
> 1,500/uL 
Platelets > 100,000/uL 
Hemoglobin > 9 g/dL 
 Renal 
 
Serum Creatinine OR measured 
calculated creatinine clearance 
(GFR may also be used in place 
of creatinine or CrCl)  
< 1.5 upper limit of normal (ULN) 
OR  
> 60 mL/min for subject with 
creatinine levels > 1.5 X 
institutional ULN 
 Hepatic 
 


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Serum total bilirubin < 1.5 X ULN OR  
Direct bilirubin < ULN for 
subjects with total bilirubin > 1.5 
ULN 
AST or ALT  < 2.5 X ULN OR 
< 5 X ULN for subjects with liver 
metastases 
 Coagulation 
 
International Normalized Ratio 
(INR) or Prothrombin Time 
(PT) 
Activated Partial 
Thromboplastin Time (aPTT) 
≤1.5 X ULN 
If on active anticoagulants prior to 
study treatment, levels must be 
within standard therapeutic ranges 
per investigator. 
 _____ Subjects with a history of known central nervous system (CNS) metastases 
must have documentation of stable or improved brain imaging for at least 2 weeks 
after completion of definitive treatment. Definitive treatment may include surgical 
resection, whole brain irradiation, and/or stereotactic radiation therapy. 
 _____ Female subject of childbearing potential should have a negative urine or serum 
pregnancy within 72 hours prior to receiving the first dose of study medication. If the 
urine test is positive or cannot be confirmed as negative, a serum pregnancy test will 
be required.   
 _____ Female subjects of childbearing potential should be willing to use 2 methods 
of birth control or be surgically sterile, or abstain from heterosexual activity for the 
course of the study through 120 days after the last dose of study medication Subjects 
of childbearing potential are those who have not been surgically sterilized or have not 
been free from menses for > 1 year (according to Section 8.4.2). 
 _____ Male subjects should agree to use an adequate method of contraception starting 
with the first dose of study therapy through 120 days after the last dose of study 
therapy (according to Section 8.4.2). 
 _____ Must have recovered from adverse effects of any prior surgery, radiotherapy or 
other antineoplastic therapy. 
 _____ Last dose of any antineoplastic therapy ≥ 2 weeks (including chemotherapy, 
small molecule inhibitors, radiation, and/or other investigational anticancer agents). 
Patients receiving hormone manipulation (e.g. SERMs, aromatase inhibitors, LHRH 
agonist, etc.) for reasons other than treatment of metastatic breast cancer may 
continue this treatment at the discretion of the investigator. 
 _____ Able to provide informed consent and willing to sign an approved consent 
form that conforms to federal and institutional guidelines. 


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5.2 
Exclusion Criteria 
Yes/No (Response of “yes” = patient ineligible) 
 _____ Is currently participating and receiving study therapy or has participated in a 
study of an investigational agent and received study therapy or used an investigational 
device within 2 weeks of the first dose of treatment. 
 _____ Has a diagnosis of immunodeficiency or receiving steroid therapy of any other 
form of immunosuppressive therapy within 7 days prior to first dose of trial 
treatment. Subjects who receive daily steroid replacement therapy serve as an 
exception to this rule. Daily prednisone at doses of 5 to 7.5 mg (or hydrocortisone 
equivalent doses) is an example of replacement therapy. 
 _____ Has a known history of active TB (Bacillus Tuberculosis).  
 _____ Hypersensitivity to pembrolizumab or any of its excipients. 
 _____ Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior 
to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse 
events due to agents administered more than 4 weeks earlier.  
 _____ Has had prior chemotherapy, targeted small molecule therapy, or radiation 
therapy within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 
or at baseline) from adverse events due to a previously administered agent. Note:  
Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify 
for the study. Note:  If subject received major surgery, they must have recovered 
adequately from the toxicity and/or complications from the intervention prior to 
starting therapy. Patients receiving hormone manipulation (e.g. tamoxifen, aromatase 
inhibitors, LHRH agonist, etc.) for reasons other than treatment of metastatic breast 
cancer may continue this treatment at the discretion of the investigator.  
 _____ Has a known additional malignancy that is progressing or requires active 
treatment. Exceptions include basal cell carcinoma of the skin or squamous cell 
carcinoma of the skin that has undergone potentially curative therapy or in situ 
cervical cancer. Patients on long-term adjuvant therapy with no evidence of disease 
are not excluded if felt appropriate by investigator. 
 _____ Has known active central nervous system (CNS) metastases and/or 
carcinomatous meningitis. Subjects with previously treated brain metastases may 
participate provided they are stable (without evidence of progression by imaging for 
at least 2 weeks prior to the first dose of trial treatment and any neurologic symptoms 
have returned to baseline), have no evidence of new or enlarging brain metastases, 
and are not using steroids for at least 7 days prior to trial treatment. This exception 
does not include carcinomatous meningitis which is excluded regardless of clinical 
stability.  


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 _____ Has active autoimmune disease that has required systemic treatment in the past 
2 years (i.e. with use of disease modifying agents, Replacement therapy (e.g. 
thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or 
pituitary insufficiency, etc.) is not considered a form of systemic treatment.  
 _____ Has known history of (non-infectious) pneumonitis that required steroids or 
has current pneumonitis. 
 _____ Has an active infection requiring systemic therapy.  
 _____ 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 treating investigator.   
 _____ Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial.  
 _____ Is 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.  
 _____ Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 
agent.  
 _____ Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 
antibodies).  
 _____ Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV 
RNA [qualitative] is detected).  
 _____ Has received a live vaccine within 30 days of 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.  
 
I certify that this patient meets all inclusion and exclusion criteria for enrollment onto 
this study.  
______________________________ 
 
_________ 
_______ 
Investigator Signature   
 
 
Date  
Time 
 
 


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6 STRATIFICATION FACTORS 
Not applicable – all patients will be enrolled on one arm 
7 TREATMENT PLAN 
Treatment should be administered on Day 1 of each cycle after all procedures and assessments 
have been completed as detailed on the Study Calendar (Section 9). Trial treatment may be 
administered up to 3 days before or after the scheduled Day 1 of each cycle due to administrative 
reasons.  
All trial treatments will be administered on an outpatient basis. 
7.1 
Administration Schedule 
Pembrolizumab 200 mg will be administered as a 30 minute IV infusion every 3 weeks. Sites 
should make every effort to target infusion timing to be as close to 30 minutes as possible. 
However, given the variability of infusion pumps from site to site, a window of -5 minutes 
and +10 minutes is permitted (i.e., infusion time is 30 minutes: -5 min/+10 min). 
7.2 
Pembrolizumab (MK-3475) Treatment  
 How Supplied, Stored, Packaged and Labeled 
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and 
regulations. 
Clinical Supplies will be provided by Merck as summarized in the table below. 
Product Name & Potency 
Dosage Form 
Pembrolizumab 50 mg 
Lyophilized Powder for Injection 
Pembrolizumab 100 mg/ 4mL 
Solution for Injection 
 Packaging and Labeling Information 
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements. 
 Clinical Supplies Disclosure 
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or 
designee are not blinded to treatment. Drug identity (name, strength) is included in the label 
text; random code/disclosure envelopes or lists are not provided. 
 Storage and Handling Requirements 
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.  


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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. 
 Returns and Reconciliation 
The investigator is responsible for keeping accurate records of the clinical supplies received 
from Merck or designee, the amount dispensed to and returned by the subjects and the 
amount remaining at the conclusion of the trial.  
Upon completion or termination of the study, all unused and/or partially used 
investigational product will be destroyed at the site per institutional policy. It is the 
Investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, 
local and institutional guidelines and procedures, and provided that appropriate records of 
disposal are kept. 
 Preparation and Administration 
Pembrolizumab (MK-3475) Solution for Infusion, 100 mg/ 4 mL vial:  pembrolizumab 
(MK-3475) Solution for Infusion vials should be stored at refrigerated conditions (2 – 8 °C) 
and protected from light. 
Note: vials should be stored in the original box to ensure the drug product is protected from 
light. 
Pembrolizumab (MK-3475) infusion solutions should be prepared in 0.9% Sodium Chloride 
Injection, USP (normal saline) or regional equivalent or 5% Dextrose Injection, USP (5% 
dextrose) or regional equivalent and the final concentration of pembrolizumab (MK-3475) in 
the infusion solutions should be between 1 mg/mL and 10 mg/mL.  
Please note, the preferred diluent is 0.9% Sodium Chloride and 5% dextrose is only permissible 
if normal saline is not available. 
Local guidelines should be followed for collection of diluent information such as manufacturer, 
lot and expiry. When the diluent is provided by Merck, the drug accountability log should be 
used for collection of diluent information. 
Pembrolizumab (MK-3475) SHOULD NOT BE MIXED WITH OTHER DILUENTS.  
Pembrolizumab (MK-3475) solutions may be stored at room temperature for a cumulative time 
of up to 4 hours. This includes room temperature storage of admixture solutions in the IV bags 
and the duration of infusion 
In addition, IV bags may be stored under refrigeration at 2 °C to 8 °C (36 °F to 46 °F) for up 
to 20 hours. If refrigerated, allow the IV bags to come to room temperature prior to use.  
Parenteral drug products should be inspected visually for particulate matter and discoloration 
prior to administration. Discard the drug product vial if extraneous particulate matter other 
than translucent to white proteinaceous particles is observed. 
Sites should follow their SOPs for drug transport and delivery, with all possible   effort to 
minimize agitation of the drug product between the pharmacy and the clinic 


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DO NOT USE PEMBROLIZUMAB (MK-3475) IF DISCOLORATION IS OBSERVED. 
DO NOT SHAKE OR FREEZE THE VIAL(S). 
DO NOT ADMINISTER THE PRODUCT AS AN (INTRAVENOUS (IV) PUSH OR 
BOLUS). 
DO NOT COMBINE, DILUTE OR ADMINISTER IT AS AN INFUSION WITH 
OTHER MEDICINAL PRODUCTS. 
Any departure from the guidance listed in this protocol, must be discussed with sponsor 
7.3 
Dose Calculation 
200 mg Fixed Dose 
• 2 vials (100 mg/4 mL) 
•  8 mL total  
7.4 
Preparation of Infusion Solution 
Aseptic technique must be strictly observed throughout the preparation procedure preferably 
in a biologic safety cabinet or hood since no anti-microbial preservative is present in the 
solutions.  
Equilibrate required number of pembrolizumab MK-3475 vials to room temperature 
The preferred method of dose preparation is the volumetric method, gravimetric method is not 
permitted.  
Choose a suitable infusion bag size so that the following conditions are met: 
• Concentration of pembrolizumab MK-3475 is between 1 mg/mL and 10 mg/mL 
• The infusion volume to bag capacity ratio should not be less than 0.3. In other words, 
the bag must be filled to at least 30% of its capacity.  
Choose a suitable infusion bag material. The bag may be empty or it may contain normal saline. 
The following infusion bag materials are compatible with pembrolizumab (MK-3475):  
• 
PVC plasticized with DEHP 
• 
Non-PVC (polyolefin) 
• 
EVA 
• 
PE lined polyolefin 
Contact Sponsor for materials not listed above 
Calculate the volume of pembrolizumab (MK-3475) and normal saline required to prepare the 
infusion (admixture) bag 
Volume of pembrolizumab (MK-3475) (mL) = required dose amount (mg) / 25 (mg/mL) 
Volume of normal saline = total infusion volume – volume of pembrolizumab (MK-3475) from 
above 
If a bag pre-filled with normal saline is being used, remove the excess volume of normal saline 
using a sterile syringe (Polypropylene, latex-free) attached to a suitable needle.  


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Keep in consideration the excess bag fill volume as well as the volume of pembrolizumab 
(MK-3475) to be added to the bag to prepare the infusion solution. This helps ensure that the 
concentration in the bag can be accurately calculated and falls within the acceptable range of 
1 mg/mL to 10 mg/mL. If the site would like to proceed without removing excess saline they 
must ensure that the concentration of MK-3475 would still fall within acceptable range. 
If an empty bag is being used, withdraw the necessary volume of normal saline from another 
appropriate bag and inject into the empty bag. Keep in consideration the volume of 
pembrolizumab (MK-3475) to be added to the bag to prepare the infusion solution. 
Withdraw the required volume of pembrolizumab (MK-3475) from the vial(s) (up to 4 mL 
from each vial) using a sterile syringe attached to a suitable needle. The vial(s) may need to be 
inverted to remove solution. 
Volume of pembrolizumab (MK-3475) (mL) = required dose amount (mg) / 25 (mg/mL) 
Note: If it is necessary to use several vials, it is advisable to withdraw from several vials into 
a suitable size single use syringe using a new needle for each vial.  
Add the required pembrolizumab (MK-3475) into the infusion IV bag containing normal saline 
and gently invert the bag 10-15 times to mix the solution. 
Pembrolizumab (MK-3475) solutions may be stored at room temperature for a cumulative time 
of up to 4 hours. This includes room temperature storage of admixture solutions in the IV bags 
and the duration of infusion.  
In addition, IV bags may be stored under refrigeration at 2 °C to 8 °C (36 °F to 46 °F) for up 
to 20 hours. If refrigerated, allow the IV bags to come to room temperature prior to use.  
DO NOT FREEZE THE PEMBROLIZUMAB (MK-3475) INFUSION SOLUTION. 
Discard any unused portion left in the vial as the product contains no preservative 
7.5 
Administration 
Pembrolizumab (MK-3475) infusions should be administered in 30 minutes, with a window of 
-5 and +10 minutes, using an infusion pump. A central catheter is not required for infusion; 
however if a subject has a central venous catheter in place, it is recommended that it be used 
for the infusion.  
The following infusion set materials are compatible with (pembrolizumab) MK-3475: 
• PVC Infusion set that is plasticized using DEHP 
• PVC and tri-(2-ethylhexyl) trimellitate (TOTM) infusion set 
• Polyethylene lined PVC infusion set 
• PVC Infusion set that is plasticized using Di-2-ethylhexyl Terephthalate (DEHT) 
• Polyurethane set 
Contact Sponsor for materials not listed above 
A sterile, non-pyrogenic, low-protein binding 0.2 to 5 µm in-line filter made of 
polyethersulfone (PES) must be used during administration to remove any adventitious 
particles. If the infusion set does not contain 0.2 to 5 µm in-line filter, it is recommended to 


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use 0.2 to 5 µm add-on filter which may contain an extension line (Note: the materials of the 
extension line and filter should be as mentioned above). 
Attach the infusion line to the pump and prime the line, either with normal saline (at least 25 
mL) or with infusion solution as per local SOP, before starting the infusion. 
Infuse pembrolizumab (MK-3475) over approximately 30 minutes, with a window of -5 and 
+10 minutes, through a peripheral line or indwelling catheter.  
Ensure the entire contents of the bag are dosed and all remaining drug solution in the line is 
administered according to institutional guidelines for saline flushing.  
Document volume administered according to data entry guidelines. 
In case of infusion reactions, infusion rate may differ; refer to protocol section 8.2 for specific 
instructions.  
Whenever possible, the lowest infusion rate should be used that will allow completion of the 
infusion within the 30 minutes.  
Maximum rate of infusion should not exceed 6.7 mL/min. through a peripheral line or 
indwelling catheter. However, when it is necessary to infuse a larger volume (i.e. 250 mL), the 
flow rate may go as high as 10 mL/min (maximum) in order to keep the infusion within the 
window as defined above.  
DO NOT CO-ADMINISTER OTHER DRUGS THROUGH THE SAME INFUSION 
LINE. 
UNUSED INFUSION SOLUTION FOR INJECTION SHOULD NOT BE USED FOR 
ANOTHER INFUSION OF THE SAME SUBJECT OR DIFFERENT SUBJECT. 
7.6 
Accountability and Compliance 
The investigator is responsible for keeping accurate records of the clinical supplies received 
from Merck or designee, the amount dispensed to and returned by the subjects and the 
amount remaining at the conclusion of the trial.  
Upon completion or termination of the study, all unused and/or partially used investigational 
product will be destroyed at the site per institutional policy. It is the Investigator’s 
responsibility to arrange for disposal of all empty containers, provided that procedures for 
proper disposal have been established according to applicable federal, state, local and 
institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept 
7.7 
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 investigator should discuss any questions regarding this 
with the study sponsor (principal investigator). The final decision on any supportive therapy 
or vaccination rests with the investigator and/or the subject's primary physician.  


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 Acceptable Concomitant Medications 
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the 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 after 30 days after the last dose of trial treatment should be 
recorded for SAEs and ECIs as defined in Section 7.2. 
 Prohibited Concomitant Medications 
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase (including retreatment for post-complete response relapse) of this trial: 
• Antineoplastic systemic chemotherapy or biological therapy. Hormonal therapies or 
other long-term adjuvant therapies may be approved after discussion with the 
principal investigator. 
• Immunotherapy not specified in this protocol 
• Chemotherapy not specified in this protocol 
• Investigational agents other than pembrolizumab 
• Radiation therapy  
o Note: Radiation therapy to a symptomatic solitary lesion or to the brain may be 
allowed at the investigator’s discretion.  
• Live vaccines within 30 days prior to the first dose of 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, yellow fever, rabies, BCG, and 
typhoid vaccine.  
• Systemic glucocorticoids for any purpose other than to modulate symptoms from an 
event of clinical interest of suspected immunologic etiology. The use of physiologic 
doses of corticosteroids may be approved after consultation with the study sponsor 
(principal investigator). 
Subjects who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial. 
Subjects may receive other medications that the investigator deems to be medically 
necessary. 
The Exclusion Criteria describes other medications which are prohibited in this trial. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
7.8 
Duration of Therapy 
A subject must be discontinued from the trial for any of the following reasons: 


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• The subject or legal representative (such as a parent or legal guardian) withdraws 
consent. 
• Radiographic disease progression by irRECIST (progression must be confirmed with 
follow up scan no less than 4 weeks and no more than 8 weeks after the first scan shows 
disease progression)  
• Unacceptable adverse experiences as described in Section 8.1 
• Intercurrent illness that prevents further administration of treatment 
• Investigator’s decision to withdraw the subject 
• The subject has a confirmed positive serum pregnancy test 
• Noncompliance with trial treatment or procedure requirements 
• The subject is lost to follow-up 
• Completed 24 months of uninterrupted treatment with pembrolizumab or 35 
administrations of study medication, whichever is later. 
Note: 24 months of study medication is calculated from the date of first dose.  
• Administrative reasons 
The End of Treatment and Follow-up visit procedures are listed in Section 9 (Protocol 
Calendar). 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 
or until a new cancer treatment is started, if sooner). 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, withdrawal of consent, or the end of the study, whichever occurs first. 
8 TOXICITIES AND DOSAGE MODIFICATION 
This study will utilize the CTCAE (NCI Common Terminology Criteria for Adverse Events) 
Version 4.0 for adverse event and serious adverse event reporting.  
8.1 
Dose modification and toxicity management guidelines for pembrolizumab 
 Dose modification and toxicity management for immune-related AEs associated 
with Pembrolizumab 
AEs associated with pembrolizumab exposure may represent an immunologic etiology. 
These immune-related AEs (irAEs) may occur shortly after the first dose or several months 
after the last dose of pembrolizumab treatment and may affect more than one body system 
simultaneously. Therefore, early recognition and initiation of treatment is critical to reduce 
complications. Based on existing clinical trial data, most irAEs were reversible and could be 
managed with interruptions of pembrolizumab, administration of corticosteroids and/or other 
supportive care. For suspected irAEs, ensure adequate evaluation to confirm etiology or 
exclude other causes. Additional procedures or tests such as bronchoscopy, endoscopy, skin 
biopsy may be included as part of the evaluation. Based on the severity of irAEs, withhold or 
permanently discontinue pembrolizumab and administer corticosteroids. Dose modification 


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and toxicity management guidelines for irAEs associated with pembrolizumab are provided 
in Table 3. 
Table 3: Dose modification and toxicity management guidelines for immune-related 
AEs associated with Pembrolizumab. 
General instructions: 
1. Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over 
at least 4 weeks. 
2. For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has 
been reduced to Grade 1 or 0 and corticosteroid has been tapered. Pembrolizumab should be permanently 
discontinued if AE does not resolve within 12 weeks of last dose or corticosteroids cannot be reduced to 
≤10 mg prednisone or equivalent per day within 12 weeks.  
3. For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. 
Other immunosuppressive treatment should be initiated if irAEs cannot be controlled by corticosteroids. 
Immune-related 
AEs 
Grade 
CTCAE v4 
Action taken 
with pembro 
irAE 
managements 
Monitor and follow-up 
Pneumonitis  
Grade 2 
Withhold  
Administer 
corticosteroids 
(initial dose of 1-
2 mg/kg 
prednisone or 
equivalent) 
followed by 
taper 
• Monitor participants for signs 
and symptoms of pneumonitis 
• Evaluate participants with 
suspected pneumonitis with 
radiographic imaging and 
initiate corticosteroid 
treatment 
• Add prophylactic antibiotics 
for opportunistic infections 
Grade 3 or 4, 
or recurrent 
Grade 2 
Permanently 
discontinue 
Diarrhea / Colitis  Grade 2 or 3 
Withhold 
Administer 
corticosteroids 
(initial dose of 1-
2 mg/kg 
prednisone or 
equivalent) 
followed by 
taper 
• Monitor participants for signs 
and symptoms of enterocolitis 
(ie, diarrhea, abdominal pain, 
blood or mucus in stool with 
or without fever) and of bowel 
perforation (ie, peritoneal 
signs and ileus). 
• Participants with ≥ Grade 2 
diarrhea suspecting colitis 
should consider GI 
consultation and performing 
endoscopy to rule out colitis.  
• Participants with 
diarrhea/colitis should be 
advised to drink liberal 
quantities of clear fluids. If 
sufficient oral fluid intake is 
not feasible, fluid and 
electrolytes should be 
substituted via IV infusion. 
Grade 4 
Permanently 
discontinue 
AST / ALT 
elevation or 
Increased 
bilirubin 
Grade 2 
Withhold 
Administer 
corticosteroids 
(initial dose of 
0.5- 1 mg/kg 
prednisone or 
equivalent) 
followed by 
taper 
Monitor with liver function tests 
(consider weekly or more 
frequently until liver enzyme 
value returned to baseline or is 
stable 


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


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Grade 3 
Withhold or 
discontinue 
based on the 
type of event. 
Events that 
require 
discontinuatio
n include and 
not limited to: 
Gullain-Barre 
Syndrome, 
encephalitis 
AE administer 
corticosteroids  
Grade 4 or 
recurrent 
Grade 3  
Permanently 
discontinue 
Notes:  
1. Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating 
physician. 
2. For subjects with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is 
required, pembrolizumab may be resumed when AE resolves to ≤ Grade 2 and is controlled with 
hormonal replacement therapy or achieved metabolic control (in case of T1DM). 
8.2 
Dose modification and toxicity management of infusion-reactions related to 
pembrolizumab 
Pembrolizumab may cause severe or life threatening infusion-reactions including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after 
drug infusion and generally resolve completely within 24 hours of completion of infusion. 
Dose modification and toxicity management guidelines on pembrolizumab associated 
infusion reaction are provided in Table 4.  
Table 4 Pembrolizumab Infusion Reaction Dose modification and Treatment Guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at 
Subsequent Dosing 
Grade 1 
Mild reaction; infusion 
interruption not 
indicated; intervention 
not indicated 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
None 
Grade 2 
Requires therapy or 
infusion interruption but 
responds promptly to 
symptomatic treatment 
(e.g., antihistamines, 
NSAIDs, narcotics, IV 
fluids); prophylactic 
medications indicated 
for ≤24 hrs 
Stop Infusion. 
Additional appropriate medical therapy may 
include but is not limited to: 
• IV fluids 
• Antihistamines 
• NSAIDs 
• Acetaminophen 
• Narcotics 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
If symptoms resolve within 1 hour of stopping 
drug infusion, the infusion may be restarted at 
Subject may be 
premedicated 1.5h (± 30 
minutes) prior to infusion of 
pembrolizumab with: 
• Diphenhydramine 50 
mg po (or equivalent 
dose of antihistamine). 
• Acetaminophen 500-
1000 mg po (or 
equivalent dose of 
analgesic). 


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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 study 
drug treatment 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not 
rapidly responsive to 
symptomatic medication 
and/or brief interruption 
of infusion); recurrence 
of symptoms following 
initial improvement; 
hospitalization indicated 
for other clinical 
sequelae (e.g., renal 
impairment, pulmonary 
infiltrates) 
Grade 4: 
Life-threatening; pressor 
or ventilatory support 
indicated 
Stop Infusion. 
Additional appropriate medical therapy may 
include but is not limited to: 
• Epinephrine** 
• IV fluids 
• Antihistamines 
• NSAIDs 
• Acetaminophen 
• Narcotics 
• Oxygen 
• Pressors 
• Corticosteroids 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
Hospitalization may be indicated. 
**In cases of anaphylaxis, epinephrine should be 
used immediately. 
Subject is permanently discontinued from 
further study drug treatment. 
No subsequent dosing 
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the 
period of drug administration. 
For further information, please refer to the Common Terminology Criteria for Adverse Events v4.0 (CTCAE) at 
http://ctep.cancer.gov 
8.3 
Other allowed dose interruption for pembrolizumab  
Pembrolizumab may be interrupted for situations other than treatment-related AEs such as 
medical / surgical events or logistical reasons not related to study therapy. Subjects should be 
placed back on study therapy within 3 weeks of the scheduled interruption, unless otherwise 
discussed with the study sponsor (principal investigator). The reason for interruption should 
be documented in the patient's study record. 
8.4 
Diet/Activity/Other Considerations:  
 Diet 
Subjects should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea or vomiting. 


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 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.  
For this trial, male subjects will be considered to be of non-reproductive potential if they 
have azoospermia (whether due to having had a vasectomy or due to an underlying medical 
condition).  
Female subjects will be considered of non-reproductive potential if they are either:  
(1) Postmenopausal (defined as at least 12 months with no menses without an alternative 
medical cause; in women < 45 years of age a high follicle stimulating hormone (FSH) 
level in the postmenopausal range may be used to confirm a post-menopausal state in 
women not using hormonal contraception or hormonal replacement therapy. In the 
absence of 12 months of amenorrhea, a single FSH measurement is insufficient.);  
OR  
(2) Have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or 
bilateral tubal ligation/occlusion, at least 6 weeks prior to screening;  
OR  
(3) Has a congenital or acquired condition that prevents childbearing. 
Female and male subjects of reproductive potential must agree to avoid becoming pregnant 
or impregnating a partner, respectively, while receiving study drug and for 120 days after the 
last dose of study drug by complying with one of the following: 
(1) Practice abstinence† from heterosexual activity;  
OR  
(2) Use (or have their partner use) acceptable contraception during heterosexual activity.  
Acceptable methods of contraception are‡: 
Single method (one of the following is acceptable): 
• Intrauterine device (IUD) 
• Vasectomy of a female subject’s male partner 
• Contraceptive rod implanted into the skin 
Combination method (requires use of two of the following): 
• Diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide) 
• Cervical cap with spermicide (nulliparous women only)   
• Contraceptive sponge (nulliparous women only)  
• Male condom or female condom (cannot be used together) 
• Hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or progestin-
only pill), contraceptive skin patch, vaginal contraceptive ring, or subcutaneous 
contraceptive injection 


Protocol name: Pembrolizumab for the treatment of recurrent high grade neuroendocrine 
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†Abstinence (relative to heterosexual activity) can be used as the sole method of 
contraception if it is consistently employed as the subject’s preferred and usual lifestyle and 
if considered acceptable by local regulatory agencies and ERCs/IRBs. Periodic abstinence 
(e.g., calendar, ovulation, sympto-thermal, post-ovulation methods, etc.) and withdrawal are 
not acceptable methods of contraception.  
‡ If a contraceptive method listed above is restricted by local regulations/guidelines, then it 
does not qualify as an acceptable method of contraception for subjects participating at sites in 
this country/region. 
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 subjects of childbearing potential must adhere to the contraception requirement 
(described above) from the day of study medication initiation (or 14 days prior to the 
initiation of study medication for oral contraception) throughout the study period up to 120 
days after the last dose of trial therapy. If there is any question that a subject of childbearing 
potential will not reliably comply with the requirements for contraception, that subject should 
not be entered into the study. 
 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 the Sponsor, IRB/DSMC and 
Merck without delay and within 24 hours to the Sponsor and DSMC and within 2 working 
days to Merck if the outcome is a serious adverse experience (e.g., death, abortion, 
congenital anomaly, or other disabling or life-threatening complication to the mother or 
newborn).  
The study investigator will make every effort to obtain permission to follow the outcome of 
the pregnancy and report the condition of the fetus or newborn to the Sponsor.  If a male 
subject impregnates his female partner the study personnel at the site must be informed 
immediately and the pregnancy reported to the Sponsor, IRB/ DSMC and Merck and 
followed as described above and in Section 16.8. 
 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. 
 


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9 STUDY CALENDAR 
CYCLE Calendar: 1 cycle = 21 days (± 3 days) 
Examination 
Screening1 
C113 
C2 
C3 
C4 
C5 
C6 
C7 and 
beyond 
End of 
Treatment 
Follow-up12 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Medical history/baseline AE 
X 
 
 
 
 
 
 
 
 
 
Eligibility criteria 
X 
 
 
 
 
 
 
 
 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Physical examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG performance status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Hematology2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Chemistry3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Urinalysis 
X 
 
 
 
 
 
 
 
X 
 
T3, free T4, TSH4 
X 
 
 
 
X 
 
 
X4 
 
 
PT, PTT, INR 
X 
 
 
 
 
 
 
 
 
 
Pregnancy test5 
X 
 
 
 
 
 
 
 
 
 
Review Adverse events and events 
of clinical interest 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Review of concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Archival tissue for PD-L1 analysis6 
X 
 
 
 
 
 
 
 
 
 
Archival tissue for TMB analysis7 
X 
 
 
 
 
 
 
 
 
 
Archival tissue for Ki-67 analysis8 
X 
 
 
 
 
 
 
 
 
 
ECG9  
X 
 
 
 
 
 
 
 
 
 
CT scans (c/a/p)10 
X 
 
 
X 
 
X 
 
X10 
X 
X10 
Disease Assessment (irRECIST)10 
X 
 
 
X 
 
X 
 
X 
X 
X 
MRI14 
 
 
 
 
 
 
 
 
 
 
Study drug11 
 
X 
X 
X 
X 
X 
X 
X 
 
 


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Page 37 of 52 
1 
ALL Pre-study/Screening procedures should be completed within 4 weeks of study enrollment - with the exception of laboratory tests which need to be 
completed within 14 days prior to study enrollment.  
2 
Hematology includes CBC with differential and platelets 
3 
Chemistry includes Albumin, Alkaline Phosphatase, Aspartate Aminotransferase, Alanine Aminotransferase, Total Bilirubin, Calcium, Carbon Dioxide, 
Creatinine, Chloride, Glucose, Potassium, Protein, Sodium, and Urea Nitrogen 
4 
T3, free T4, TSH to be performed at screening and every 9 weeks (every third cycle) while on treatment 
5 
Pregnancy test must be done at screening and within 72 hours of starting study treatment for all women of childbearing potential and repeated as clinically 
indicated. Serum or urine tests may be used. If urine pregnancy is positive, confirm with serum.  
6 
If the patient consented to the optional testing and tissue is available (either from archival tissue or fresh biopsy tissue), PD-L1 analysis will be performed at 
central lab. If fresh tissue is being used, it should be obtained during screening window prior to study treatment. See section 15. 
7 
If clinically indicated, and not previously performed, tumor mutation burden analysis will be performed at central lab. If performed, results should be 
collected for the study. See section 15.  
8 
Patients must have existing Ki-67 results from archival tissue or available tissue for Ki-67 testing. If no archival tissue is available the subject must agree to 
a fresh biopsy for testing to qualify for the study. Ki-67 analysis will be performed at local lab if not previously performed. See section 15. 
9 
ECG will be done if medically indicated 
10 CT of the abdomen/chest/pelvis must be repeated every 6 weeks through C12 (36 weeks), then every 12 weeks until disease progression. Progression must 
be confirmed no earlier than 4 weeks and no later than 8 weeks. Scans must be completed within 7 days prior to the next dosing cycle. 
11 Pembrolizumab 200 mg IV q3weeks 
12 Follow-up should occur no less than every 6 months for 4 years following study enrollment  
13 Baseline procedures do not need to be repeated if screening procedures have been done within 7 days of start of treatment 
14 MRI may be required at baseline for subjects with previously treated brain metastases 
 


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10 STUDY PROCEDURES  
10.1 
Screening Evaluations 
• Informed Consent 
• Physical examination with vital signs and ECOG Performance Status 
• Review of medical history/baseline symptoms 
• Review baseline concomitant medications 
• Laboratory assessments: 
 
o CBC with differential 
o CMP to include sodium, potassium, chloride, carbon dioxide or bicarbonate, blood 
urea nitrogen (BUN), creatinine, glucose, total protein, albumin, calcium, AST, ALT, 
alkaline phosphatase, total bilirubin 
o Coagulation to include PT/INR and aPTT  
o Thyroid function tests to include TSH, total T3, and free T4  
o Serum or urine pregnancy test (for women of childbearing potential) within 72 hours 
of starting study treatment 
o Urinalysis 
• 12-lead ECG if clinically indicated 
• CT scans and disease assessments for baseline irRECIST 
• MRI only for subjects with previously treated brain metastases  
• Archival tissue or fresh tissue biopsy (if archival tissue is not available) for Ki-67 testing 
(see footnote #8 in calendar)  
• Archival tissue or fresh biopsy for central PD-L1 analysis if patients consent to optional 
testing.   
10.2 
On-Treatment Evaluations (every three weeks unless otherwise noted)  
• Physical examination with vital signs and ECOG Performance Status 
• Laboratory assessments (do not need to be repeated if screening labs were performed 
within 7 days of C1D1): 
o CBC with differential 
o CMP to include sodium, potassium, chloride, carbon dioxide or bicarbonate, blood 
urea nitrogen (BUN), creatinine, glucose, total protein, albumin, calcium, AST, ALT, 
alkaline phosphatase, total bilirubin 
o Coagulation to include PT/INR and aPTT  
o Thyroid function tests to include TSH, total T3, and free T4 at the beginning of every 
third cycle (C4D1, C7D1, C10D1, etc.)  
o Serum or urine pregnancy test (for women of childbearing potential) only on C1D1 if 
not performed during screening and within 72 hours of C1D1. Testing during 
treatment is required as clinically indicated 
• Safety assessment: monitoring and recording of all adverse events and serious adverse 
events. 
• Review of concomitant medications 


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• CT scans and review of response every 6 weeks through C12 (36 weeks), then every 12 
weeks until disease progression. 
• Treatment with pembrolizumab 200 mg 
10.3 
End of Treatment Assessments: 
• Physical examination with vital signs and ECOG Performance Status 
• Laboratory assessments: 
o CBC with differential 
o CMP to include sodium, potassium, chloride, carbon dioxide or bicarbonate, blood 
urea nitrogen (BUN), creatinine, glucose, total protein, albumin, calcium, AST, ALT, 
alkaline phosphatase, total bilirubin 
o Thyroid function tests to include TSH, total T3, and free T4 at the beginning of every 
third cycle (C4D1, C7D1, C10D1, etc.)  
o Urinalysis 
• Safety assessment: monitoring and recording of all adverse events and serious adverse 
events. 
10.4 
Follow-up Assessments 
After coming off treatment patients will be followed per standard of care practice for 
progression free survival. For patients who come off trial prior to disease progression, 
disease assessments should continue every 12 weeks. Follow-up should occur no less than 
every 6 months for 4 years following study enrollment.  
11 CRITERIA FOR EVALUATION AND ENDPOINT 
11.1 
Efficacy 
Disease assessments will be measured by CT or MRI scan and assessed according to Immune 
related RECIST (irRECIST) based on Nishino et. al. (21) 
Response rate is the primary response objective. Generally, evaluable patients should have 
baseline scans and one 6 week follow-up scan to be evaluable for response assessment. 
Patients should also have received at least 2 cycles of Pembrolizumab to be considered 
evaluable for response. 
 irRECIST  
Measurable disease/non-measurable and target/non-target criteria- using one-dimensional 
measurements (simulating RECIST 1.1): 
The following definitions and criteria (irRECIST) should be used for the baseline evaluations 
of existing disease, and for the ongoing evaluation of tumor measurements according to 
Nishino, an adaptation of Wolchok (22).  
Measurable lesions - lesions that can be accurately measured in at least one dimension with 
longest diameter (LD) ≥ 10 mm using CT, MRI, or caliper measurements or ≥20 mm with x-


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ray. Lymph nodes which are defined as measurable at baseline must meet the criterion of a 
short axis > 15mm by CT scan.  
Non-measurable lesions - all other lesions including small lesions (LD < 10 mm with CT, 
MRI, or caliper measurements or <20 mm with x-ray). 
Target Lesions - all measurable lesions, up to a maximum of five lesions, should be 
identified as target lesions to be measured and recorded on the medical record at Screening. 
The target lesions should be representative of all involved organs. In addition, target  lesions 
should be selected based on their size (lesions with the longest diameters), their suitability for 
accurate repeat assessment by imaging techniques, and how representative they are of the 
patient’s tumor burden. At screening, a sum of the products of diameters (SPD) for all target 
lesions will be calculated and considered the baseline sum of the products of diameters. 
Response criteria to be followed are listed below. The baseline sum will be used as the 
reference point to determine the objective tumor response of the target lesions at tumor 
assessment (TA). 
Non-Target Lesions - measurable lesions, other than target lesions, and all sites of non-
measurable disease, will be identified as non-target lesions. Non-target lesions will be 
recorded on the medical record and should be evaluated at the same assessment time points 
as the target lesions. In subsequent assessments, non-target lesions will be recorded as 
“stable or decreased disease,” “absent,” or “progression.” 
New Lesions and non-target lesions - In irRECIST a new lesion does not automatically 
indicate progressive disease 
New measurable lesions are added to the sum of the longest diameters of the previously 
existing target lesions, and the sum of the longest diameters is followed at each subsequent 
tumor assessment 
New measurable lesions are defined using the same criteria as for baseline target lesions in 
RECIST 1.1. New measurable lesions shall be prioritized according to size and the largest 
lesions shall be selected as new measured lesion up to 2 lesions per organ and 5 new lesions 
total.  
Non-target lesions (baseline and new non measurable) are used for determination of 
Complete Response. The RECIST 1.1 definitions for the assessment of non-target lesions 
apply. 
Response Categories: 
• Complete Response (irCR):  disappearance of all not-nodal target lesions and non-target 
lesions in two consecutive observations not less than 4 weeks apart. In addition, any 
pathological lymph nodes assigned as target lesions must have a reduction in short axis to 
<10mm (sum of diameters may be greater than zero at the time of CR, if nodal lesion are 
including as target lesions).  
• Partial Response (irPR): at least a 30% decrease in the sum of diameters of all target 
lesions including new target lesion in two consecutive observations not less than 4 weeks 
apart, taking as reference the baseline sum of diameters. 


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• Progressive Disease (irPD): at least a 20% increase in the sum of diameters of all measured 
target lesions including new measurable lesions. The reference for irPD will be the smallest 
sum of diameter of all target lesions recorded at original baseline or subsequent. 
Progression must be confirmed with a follow up scan no less than 4 weeks and no more 
than 8 weeks after the first scan that shows disease progression.  
• Stable Disease (irSD): neither a sufficient shrinkage to qualify of irPR or irCR, or an 
increase in the sum of target lesions which would qualify for irPD.  
 Evaluation of Best Overall Response 
The best overall response is the best response observed until progression/recurrence and is 
determined as indicated in the table below: 
Target Lesions 
Non-Target 
Lesions 
Evaluation of New 
Lesions 
Best Overall 
Response 
CR 
CR 
No 
CR 
CR 
SD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 Progression Free Survival 
Time to progression (TTP), progression-free (PFS) survival, and overall survival (OS) will be 
determined, but are not primary study endpoints. Patients will be followed for progression 
free survival beginning with C1D1 of pembrolizumab on this trial through the date of 
progression, or death, whichever comes earlier. Progression will be assessed by irRECIST. 
Patients will be followed for survival endpoints every 6 months for 4 years following study 
enrollment.  
11.2 
Safety 
Routine safety and tolerability will be evaluated from the results of reported signs and 
symptoms, scheduled physical examinations, vital sign measurements, and clinical laboratory 
test results. More frequent safety evaluations may be performed if clinically indicated or at 
the discretion of the investigator.  
Physical Examination: 
Complete and symptom-directed physical examinations will be performed by a licensed 
physician (or physician’s assistant or nurse practitioner). 
Vital Signs:  
Vital signs (blood pressure, respiratory rate, pulse rate and temperature) will be obtained. 


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Safety Laboratory Determinations:  
Laboratory evaluations will be performed as noted in the flow chart.  
11.3 
Stopping Rules 
Up to a total of 34 response evaluable patients are required. Generally, evaluable patients 
should have baseline scans and one 6 week follow-up scan to be evaluable for response 
assessment. Patients should also have received at least 2 cycles of Pembrolizumab to be 
considered evaluable for response. Enrollment and evaluation of response based on irRECIST.  
An initial analysis will be done on the first 13 response evaluable patients enrolled to the 
Pembrolizumab treatment regimen. Recruitment will be terminated (stopped) if there are only 
0 – 1 responses (irCR/irPR). If there are 2+ responses in 13 evaluable patients, recruitment will 
be expanded with this treatment regimen to up to an additional 21 evaluable patients.  
12 STATISTICAL CONSIDERATIONS 
A Simon Optimum Two-Stage design will be used with a Type I error rate alpha equal to 0.10 
and a Type II error rate beta equal to 0.20. The null hypothesis is an objective response rate 
(irCR + irPR) of 10% or lower. The alternative hypothesis is an objective response rate of 25% 
or higher. With these design parameters, the first stage will consist of 13 patients. If there are 2 
or more responses in 13 patients, up to an additional 21 evaluable patients will be recruited for a 
maximum sample size of 34 evaluable patients. If there are 6 or more responses in up to 34 
evaluable patients the null hypothesis will be rejected. If there are 5 or fewer responses 34 
evaluable patients the null hypothesis will not be rejected. It is estimated that it may be necessary 
to enroll up to 40 patients to accrue 34 response evaluable patients. 
Kaplan-Meier methods and associated confidence intervals will be used to analyze PFS and OS. 
All subjects assessed for progression will contribute to this analysis. The clinical benefit rates 
(irCR + irPR + irSD) will be analyzed by tabulating the observed counts and proportions 
together with exact binomial confidence intervals.  
Tumor tissue will be analyzed for the correlation of biomarkers to response rate.  
1) Tissues analyzed for correlation of tumor mutational burden will be categorized as high, 
medium and low burden.  
2) Tissues analyzed for correlation of PD-L1 expression will be categorized as high or low.  
3) Tissues analyzed for correlation to proliferative index will be categorized as Ki-67 20-
55% or Ki-67 > 55%. 
Fisher’s exact test will be used to analyze each of these biomarkers. Two sided p-values < 0.05 
will be regarded as statistically significant.  
Safety will analyzed by tabulating adverse events. 
13 REGISTRATION GUIDELINES 
When the clinical research coordinator (CRC) or study coordinator (SC) identifies a potential study 
patient, they MUST contact the Research Compliance Office at the Huntsman Cancer Institute (by 


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email at compliance@hci.utah.edu) to confirm that a slot is available prior to initiating the consent 
process. 
After a patient has consented to participate in the study and all screening procedures have been 
completed, the CRC/SC will review eligibility with the properly delegated enrolling physician who 
will sign a copy of the eligibility checklist (section 5). This, along with all de-identified 
documentation supporting eligibility, will be sent to the RCO at HCI for verification.  
Eligible patients will be registered on study at the University of Utah – Huntsman Cancer Institute 
and applicable subsites via the OnCore system by the CRC/SC. Patients must meet all of the 
eligibility requirements listed in Section 5 prior to registration.  
Following registration, patients should begin protocol treatment within 5 days. Issues that would 
cause treatment delays should be discussed with the principal investigator. If a patient does not 
receive protocol therapy following registration, the patient’s registration on the study may be 
canceled. The CRC/SC and Research Compliance Office should be notified of cancellations as 
soon as possible. 
Once the RCO confirms the patient’s eligibility and notifies the CRC/SC, the patient can be 
registered by emailing a completed Clinical Trials Office Patient Registration Form to the RCO at 
CTORegistrations@hci.utah.edu. The RCO will then return the completed form (including patient 
number and cohort/dose level) to the coordinator after which time the patient can begin treatment. 
Patients must meet all of the eligibility requirements listed in Section 5 prior to registration.  
Study related screening procedures can only begin once the patient has signed a consent 
form. Patients must not begin protocol treatment prior to registration. 
14 DATA SUBMISSION SCHEDULE 
The Case Report Forms (CRFs) are a set of (electronic or paper) forms for each patient that 
provides a record of the data generated according to the protocol. CRF’s should be created prior 
to the study being initiated and updated (if applicable) when amendments to the protocol are IRB 
approved. These forms will be completed on an on-going basis during the study. The medical 
records will be source of verification of the data. During the study, the CRFs will be monitored 
for completeness, accuracy, legibility and attention to detail by a member of the Research 
Compliance Office. The CRFs will be completed by the Investigator or a member of the study 
team as listed on the Delegation of Duties Log. The data will be reviewed no less than annually 
by the Data and Safety Monitoring Committee. The Investigator will allow the Data and Safety 
Monitoring Committee or Research Compliance Office personnel access to the patient source 
documents, clinical supplies dispensing and storage area, and study documentation for the above-
mentioned purpose. The Investigator further agrees to assist the site visitors in their activities.  
Data capture should be restricted to endpoints and relevant patient information required for 
planned manuscripts. 


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15 SPECIAL INSTRUCTIONS  
15.1 
Pathology review for PD-L1 analysis at central laboratory 
Formalin fixed paraffin embedded (FFPE) tissue samples will be sent for PD-L1 IHC 
analysis at screening if samples are available. Fine needle aspirate, frozen sample, plastic 
embedded sample, cell block, clot, bone, bone marrow or cytologic specimens will not be 
accepted for PD-L1 IHC analysis. If a patient does not have archival tissue available and a 
fresh biopsy is required for Ki-67 testing (see 15.3), tissue will be sent for PD-L1 analysis if 
adequate tissue is available after Ki-67 testing has been performed. This is optional when 
tissue is available for evaluation. 
If the patient consents to this testing, screening tissue samples will be sent to QualTek 
Molecular Laboratories.  
Please reference the Qualtek lab manual for more information.   
15.2 
Pathology review for tumor mutational burden analysis 
Screening tissue analyzed for correlation of tumor mutational burden will be performed 
locally per treatment center’s standard protocol. If not performed previously and not 
clinically indicated at the time of screening, TMB will not be required.   
15.3 
Pathology review for Ki-67 antibody staining  
Patients must have existing Ki-67 results from archival tissue or available tissue for Ki-67 
testing. If no archival tissue is available the subject must agree to a fresh biopsy for testing to 
qualify for the study. 
Screening tissue Ki-67 immunohistochemistry will be performed locally per treatment 
center’s standard protocol.  
15.4 
Correlative Studies 
 Tissue Specimens for PD-L1 IHC analysis 
• 5 unstained slides cut at 4 microns thickness. 
15.4.1.1 Fresh tissue biopsy (if archival tissue is not available for Ki-67 testing) 
• 1-2 cores with an 18 gauge needle. 
• .  
16 ETHICAL AND REGULATORY CONSIDERATIONS 
16.1 
Recruitment Strategies  
Potential patients will be identified by Investigators in the setting of their outpatient clinics. 


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16.2 
Informed consent  
Informed consent will be obtained from all research participants prior to performing any 
study procedures using the most recent IRB approved version.  
16.3 
Human Subjects Protections 
 Participation of Children 
Patients must be at least 18 years of age to participate. 
 Participation of Subjects Unable To Give Consent 
Patients unable to give consent will be allowed to participate if a legally authorized 
representative (as defined by Utah state laws and the policy of the IRB) consents on their 
behalf.  
16.4 
Institutional Review 
Study will be approved by the Institutional Review Board of University of Utah. 
16.5 
 Data and Safety Monitoring Plan 
A Data and Safety Monitoring Committee (DSMC) is established at Huntsman Cancer 
Institute (HCI) and approved by the NCI to assure the well-being of patients enrolled on 
Investigator Initiated Trials that do not have an outside monitoring review. Roles and 
responsibilities of the DSMC are set forth in the NCI approved plan. The activities of this 
committee include a quarterly review of adverse events including SAEs, important medical 
events, significant revisions or amendments to the protocol, and approval of cohort/dose 
escalations. If the DSMC and/or the PI have concerns about unexpected safety issues, the 
study will be stopped and will not be resumed until the issues are resolved. The DSMC also 
reviews and approves audit reports generated by the Research Compliance Office.  
All phase II studies are reviewed by the full committee at each quarterly DSMC meeting. This 
includes a review of all serious adverse events (SAEs) occurring in patients treated at HCI or 
its affiliates as well as toxicities for patients on treatment and within a 30 day follow-up 
window.  
16.6 
Adverse Events / Serious Adverse Events 
This study will utilize the CTCAE (NCI Common Terminology Criteria for Adverse Events) 
Version 4.0 for AE and SAE reporting.  
 Adverse Events (AEs) 
An adverse event is the appearance or worsening of any undesirable sign, symptom, or 
medical condition occurring after starting the study drug even if the event is not considered 
to be related to study drug. For the purposes of this study, the terms toxicity and adverse 
event are used interchangeably. Medical conditions/diseases present before starting study 
drug are only considered adverse events if they worsen after starting study drug. Abnormal 
laboratory values or test results constitute adverse events only if they induce clinical signs or 
symptoms, are considered clinically significant, or require therapy. 


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The collection of adverse events will begin after the first dose of study treatment and end 30 
days post the last dose of study treatment.  
Information about all adverse events, whether volunteered by the subject, discovered by 
investigator questioning, or detected through physical examination, laboratory test or other 
means, will be collected and recorded and followed as appropriate. 
The occurrence of adverse events should be sought by non-directive questioning of the 
patient at each visit or phone contact during the study. Adverse events also may be detected 
when they are volunteered by the patient during or between visits or through physical 
examination, laboratory test, or other assessments. As far as possible, each adverse event 
should be evaluated to determine: 
1. The severity grade based on CTCAE v.4 (grade 1-5) 
2. Its relationship to the study drug(s) (definite, probable, possible, unlikely, not related)  
3. Its duration (start and end dates or if continuing at final exam) 
4. Action taken (no action taken; study drug dosage adjusted/temporarily interrupted; 
study drug permanently discontinued due to this adverse event; concomitant 
medication taken; non-drug therapy given; hospitalization/prolonged hospitalization) 
5. Whether it constitutes an SAE 
All adverse events will be treated appropriately. Such treatment may include changes in 
study drug treatment as listed in the dose modification section of this protocol (see section 8 
for guidance). Once an adverse event is detected, it should be followed until its resolution, 
and assessment should be made at each visit (or more frequently, if necessary) of any 
changes in severity, the suspected relationship to the study drug, the interventions required to 
treat it, and the outcome. 
Information about common side effects already known about the investigational and 
commercial drugs are described in the Drug Information (section 3) and the most recent 
Investigator Brochure or the FDA-approved product labels. This information will be included 
in the patient informed consent and will be discussed with the patient during the study as 
needed. 
All adverse events will be immediately recorded in the patient research chart.  
 Serious Adverse Event (SAE) 
Information about all serious adverse events will be collected and recorded. A serious 
adverse event is an undesirable sign, symptom or medical condition which: 
• Is fatal or life-threatening 
• Results in persistent or significant disability/incapacity 
• Is medically significant, i.e., defined as an event that jeopardizes the patient or may 
require medical or surgical intervention to prevent one of the outcomes listed above 
• Causes congenital anomaly or birth defect 
• Requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 


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o Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition (procedures such as central line placements, 
paracentesis, pain control) 
o Elective or pre-planned treatment for a pre-existing condition that is unrelated to 
the indication under study and has not worsened since the start of study drug 
o Treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 
o Social reasons and respite care in the absence of any deterioration in the patient’s 
general condition 
Collection of serious adverse events will begin after the first dose and end 90 days after the 
last dose of study treatment or until a new cancer treatment is initiated, whichever happens 
the soonest. 
Any death from any cause while a patient is receiving treatment on this protocol or up to 30 
days after the last dose of protocol treatment, or any death which occurs more than 30 days 
after protocol treatment has ended but which is felt to be treatment related, must be reported. 
Toxicities which fall within the definitions listed above must be reported as an SAE 
regardless if they are felt to be treatment related or not. Toxicities unrelated to treatment that 
do NOT fall within the definitions above, must simply be documented as AEs in the patient 
research chart.  
16.7 
SAE Reporting Requirements 
SAEs must be reported to the DSMC, the FDA, the IRB, and LSK BioPartners, Inc., 
according to the requirements described below: 
A MedWatch 3500A form must be completed and submitted to compliance@hci.utah.edu as 
soon as possible, but no later than 1 working day of first knowledge or notification of event. 
DSMC Notifications: 
• An HCI Research Compliance Officer (RCO) will process and submit the MedWatch 
form to the proper DSMC member as necessary for each individual study.  
• The RCO will summarize and present all reported SAEs according to the Data and Safety 
Monitoring Plan at the quarterly DSMC meeting. 
For multisite studies: the HCI DSMC will notify all participating sites of all unexpected and 
related SAEs via the Research Compliance Office. The RCO will also notify all investigators 
at remote clinical sites participating in a multisite trial of any other safety update, including 
external safety reports, manufacturer’s reports and updates to the investigator’s brochure. 
FDA Notifications: 
Adverse events occurring during the course of a clinical study that meet the following criteria 
will be promptly reported to the FDA: 
• Serious 
• Unexpected 


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• Definitely, Probably or Possibly Related to the investigational drug 
Fatal or life-threatening events that meet the criteria above will be reported within 7 calendar 
days after first knowledge of the event by the investigator; followed by as complete a report 
as possible within 8 additional calendar days. 
All other events that meet the criteria above will be reported within 15 calendar days after 
first knowledge of the event by the investigator. 
The RCO will review the MedWatch report for completeness, accuracy and applicability to 
the regulatory reporting requirements. The RCO will also ensure the complete, accurate, and 
timely reporting of the event to the FDA. 
The Regulatory Coordinator will submit the report as an amendment to the IND application. 
All other adverse events and safety information not requiring expedited reporting that occur 
or are collected during the course of the study will be summarized and reported to the FDA 
through the IND Annual Report. 
IRB Notification: 
Events meeting the University of Utah IRB reporting requirements 
(http://www.research.utah.edu/irb/) will be submitted through the IRB’s electronic reporting 
system within 10 working days. 
External sites should abide by local IRB requirements for submission of SAEs  
Drug Manufacturer Notifications: 
SAEs should be reported to Merck Global Safety within 2 working days of first knowledge or 
notification of event.  
SAE reports and any other relevant safety information are to be forwarded to the Merck Global 
Safety facsimile number: +1-215-993-1220.  
A copy of all 15 Day Reports and Annual Progress Reports is submitted by HCI as required 
by FDA, European Union (EU), Pharmaceutical and Medical Devices agency (PMDA) or other 
local regulators. Investigators will cross reference this submission according to local 
regulations to the Merck Investigational Compound Number (IND, CSA, etc.) at the time of 
submission. Additionally investigators will submit a copy of these reports to Merck & Co., Inc. 
(Attn: Worldwide Product Safety; FAX 215 993-1220 or AER_mailbox@merck.com) at the 
time of submission to FDA. 
Non-serious Events of Clinical Interest will be forwarded to Merck Global Safety and will be 
handled in the same manner as SAEs. 
16.8 
Events of Clinical Interest (ECI)  
Selected non-serious and serious adverse events thought to be related to Pembrolizumab are 
also known as Events of Clinical Interest (ECI) and must be recorded as such on the Adverse 
Event case report forms/worksheets and reported within 24 hours to the HCI Principal 
Investigator and research compliance office and within 2 working days of first knowledge or 
notification of event to Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 
993-1220 or AER_mailbox@merck.com) 


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Events of clinical interest for this trial include: 
1. An overdose of Merck product, as defined in Section 16.7 - Definition of an Overdose 
for This Protocol and Reporting of Overdose to the Sponsor, that is not associated 
with clinical symptoms or abnormal laboratory results.  
2. An elevated AST or ALT lab value that is greater than or equal to 3X the upper limit 
of normal and an elevated total bilirubin lab value that is greater than or equal to 2X 
the upper limit of normal and, at the same time, an alkaline phosphatase lab value that 
is less than 2X the upper limit of normal, as determined by way of protocol-specified 
laboratory testing or unscheduled laboratory testing.* 
*Note: these criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may 
require an additional evaluation for an underlying etiology.  
ECIs that occur in any subject from the date of first dose through 90 days following cessation 
of treatment, or the initiation of a new anticancer therapy, whichever is earlier, whether or 
not related to the Merck’s product, must be reported within 24 hours to the HCI and to Merck 
Global Safety within 2 working days of first knowledge or notification of event 
16.9 
Definition of an Overdose for this Protocol and Reporting of Overdose to HCI 
and to Merck 
For purposes of this trial, an overdose of pembrolizumab will be defined as any dose of 1,000 
mg or greater (≥5 times the indicated dose). No specific information is available on the 
treatment of overdose of pembrolizumab. In the event of overdose, the 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 within 24 hours 
to the Sponsor and within 2 working days hours to Merck Global Safety. (Attn: Worldwide 
Product Safety; FAX 215 993-1220 or AER_mailbox@merck.com) 
16.10 Reporting of Pregnancy and Lactation to HCI Sponsor, IRB, DSMC and Merck 
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them) that occurs during the trial. 
Pregnancies and lactations that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but 


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not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure.  
Pregnancies and lactations that occur from the time of treatment  allocation/randomization 
through 120 days following cessation of Sponsor’s product, or 30 days following cessation of 
treatment if the subject initiates new anticancer therapy, whichever is earlier, must be reported 
by the investigator. All reported pregnancies must be followed to the completion/termination 
of the pregnancy. Pregnancy outcomes of spontaneous abortion, missed abortion, benign 
hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage and stillbirth 
must be reported as serious events (Important Medical Events). If the pregnancy continues to 
term, the outcome (health of infant) must also be reported. 
Such events must be reported within 24 hours to the Sponsor, DSMC and IRB and within 2 
working days to Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220 
or AER_mailbox@merck.com) 
16.11 Protocol Amendments 
Any amendments or administrative changes in the research protocol during the period, for 
which the IRB approval has already been given, will not be initiated without submission of 
an amendment for IRB review and approval.   
These requirements for approval will in no way prevent any immediate action from 
being taken by the investigator in the interests of preserving the safety of all patients 
included in the trial.  
Any amendments to the protocol that significantly affect the safety of subjects, scope of 
the investigation, or the scientific quality of the study are required to submit the 
amendment for FDA review. 
16.12 Protocol Deviations 
A protocol deviation (or violation) is any departure from the defined procedures and 
treatment plans as outlined in the protocol version submitted and previously approved by the 
IRB. Protocol deviations have the potential to place participants at risk and can also 
undermine the scientific integrity of the study thus jeopardizing the justification for the 
research. Protocol deviations are unplanned and unintentional events.  
Because some protocol deviations pose no conceivable threat to participant safety or 
scientific integrity, reporting is left to the discretion of the PI within the context of the 
guidelines below. The IRB requires the prompt reporting of protocol deviations which are: 
• 
Exceptions to eligibility criteria. 
• 
Intended to eliminate apparent immediate hazard to a research participant or  
• 
Harmful (caused harm to participants or others, or place them at increased risk of 
harm - including physical, psychological, economic, or social harm), or  
• 
Possible serious or continued noncompliance  
16.13 FDA Annual Reporting  
An annual progress report will be submitted to the FDA within 60 days of the anniversary of 
the date that the IND went into effect. (21 CFR 312.33).  


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16.14 Clinical Trials Data Bank  
The study will be registered on http://clinicaltrials.gov and the NCI CTRP (Clinical Trials 
Reporting Program) by the Clinical Trials Office. 
16.15 Record Keeping 
Per 21 CFR 312.57, Investigator records shall be maintained for a period of 2 years following 
the date a marketing application is approved; or, if no application is filed or the application is 
not approved, until 2 years after the investigation is discontinued and the FDA is notified. 
 
 


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