Phase II Study for the Evaluation of Efficacy of Pembrolizumab (MK-3475) in Patients With Rare Tumors
Phase: PHASE2
Conditions: Advanced Malignant Solid Neoplasm, Carcinoma of Unknown Primary, Metastatic Adrenal Gland Pheochromocytoma, Metastatic Kidney Medullary Carcinoma, Metastatic Malignant Germ Cell Tumor, Metastatic Malignant Solid Neoplasm, Metastatic Paraganglioma, Metastatic Penile Carcinoma, Metastatic Skin Squamous Cell Carcinoma, Small Cell Carcinoma, Stage III Adrenal Cortex Carcinoma AJCC v7, Stage IV Adrenal Cortex Carcinoma AJCC v7, Stage IV Penile Cancer AJCC v7, Stage IV Renal Cell Cancer AJCC v7, Unresectable Adrenal Gland Pheochromocytoma, Unresectable Paraganglioma, Unresectable Skin Squamous Cell Carcinoma, Unresectable Solid Neoplasm, Vascular Neoplasm
Sponsor: M.D. Anderson Cancer Center

Product:  MK-3475 
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MD Anderson IND Sponsor Cover Sheet 
Protocol ID 
2015-0948 
Protocol Title 
Phase II Study for the Evaluation of Efficacy of Pembrolizumab (MK-
3475) in Patients with Rare Tumors 
Protocol Phase 
Phase II 
Protocol Version 
17 
Version Date 
01/27/2023 
Protocol PI 
Aung Naing, MD 
Department 
Investigational Cancer Therapeutics 
IND Sponsor 
MD Anderson Cancer Center 
IND # 
130086 
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TITLE: Phase II Study for the Evaluation of Efficacy of Pembrolizumab (MK-3475) in 
Patients with Rare Tumors 
 
PRINCIPAL INVESTIGATOR: Aung Naing, MD 
 
SUPPORTER and DRUG SUPPLY:  
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.  
(hereafter referred to as the Supporter or Merck)  
One Merck Drive 
P.O. Box 100 
Whitehouse Station, NJ 08889-0100, U.S.A. 
 
SPONSOR (IND Holder):   
The University of Texas MD Anderson Cancer Center 
(hereafter referred to as the MDACC IND or Sponsor)  
Aman Buzdar, M.D. 
Vice President for Clinical Research Administration 
University of Texas M. D. Anderson Cancer Center 
1515 Holcombe Blvd., Unit 1636 
Houston, TX 77030 
  
IND NUMBER: 130086 
 
 
Protocol Version History: 
 
Version 00, Dated 11-Dec-2015 
Version 01, Dated 04-Jan-2016 
Version 02, Dated 06-Jan-2016 
Version 03, Dated 19-Jan-2016 
Version 04, Dated 12-Feb-2016 
Version 05, Dated 13-May-2016 
Version 06, Dated 15-Jul-2016 
Version 07, Dated 24-Aug-2016 
Version 08, Dated 28-Nov-2016 
Version 09, Dated 30-Jan-2017 
Version 10, Dated 23-Mar-2017 
Version 11, Dated 14-Dec-2017 
Version 12, Dated 11-Sep-2018 
Version 13, Dated 02-Apr-2019 
Version 14, Dated 17-Jul-2020 
Version 15, Dated 29-Jan-2021 
Version 16, Dated 06-Jan-2022 
Version 17, Dated 27-Jan-2023 
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TABLE OF CONTENTS 
1.0 
TRIAL SUMMARY.................................................................................................... 8 
2.0 
TRIAL DESIGN........................................................................................................ 10 
 
Trial Design ........................................................................................................... 10 
 
Trial Diagram ........................................................................................................ 13 
3.0 
OBJECTIVES & HYPOTHESES ........................................................................... 14 
 
Primary Objective ................................................................................................. 14 
3.1.1 Secondary Objectives .......................................................................................... 14 
3.1.2 Exploratory Objectives: ...................................................................................... 14 
 
Hypotheses: ............................................................................................................ 15 
4.0 
BACKGROUND & RATIONALE .......................................................................... 15 
 
Background ........................................................................................................... 15 
4.1.1 Pharmaceutical and Therapeutic Background .................................................... 15 
4.1.2 Preclinical and Clinical Trial Data ...................................................................... 16 
 
Rationale ................................................................................................................ 17 
4.2.1 Rationale for the Trial and Selected Subject Population .................................... 17 
4.2.2 Rationale for Dose Selection/Regimen/Modification ......................................... 18 
4.2.3 Rationale for Endpoints ...................................................................................... 19 
 
Study Updates ....................................................................................................... 23 
5.0 
SUBJECT ELIGIBILITY ........................................................................................ 24 
 
Study Population ................................................................................................... 24 
5.1.1 Diagnosis/Condition for Entry into the Trial ...................................................... 24 
5.1.2 Subject Inclusion Criteria.................................................................................... 24 
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5.1.3 Subject Exclusion Criteria .................................................................................. 26 
 
Trial Treatments ................................................................................................... 28 
5.2.1 Dose Selection/Modification .............................................................................. 28 
5.2.2 Timing of Dose Administration .......................................................................... 34 
5.2.3 Continuing Study Drug Administration after Initial Evidence of Radiologic 
Disease Progression ............................................................................................ 34 
5.2.4 Trial Blinding/Masking ....................................................................................... 35 
 
Randomization or Treatment Allocation ............................................................ 35 
 
Stratification .......................................................................................................... 36 
 
Concomitant Medications/Vaccinations (Allowed & Prohibited) .................... 36 
5.5.1 Acceptable Concomitant Medications ................................................................ 36 
5.5.2 Prohibited Concomitant Medications.................................................................. 36 
 
Rescue Medications & Supportive Care ............................................................. 37 
5.6.1 Supportive Care Guidelines ................................................................................ 37 
 
Diet/Activity/Other Considerations ..................................................................... 40 
5.7.1 Diet ...................................................................................................................... 40 
5.7.2 Contraception ...................................................................................................... 40 
5.7.3 Use in Pregnancy ................................................................................................ 41 
5.7.4 Use in Nursing Women ....................................................................................... 41 
 
Subject Withdrawal/Discontinuation Criteria ................................................... 41 
5.8.1 Discontinuation of Study Therapy after CR ....................................................... 43 
 
Subject Replacement Strategy ............................................................................. 43 
 
Clinical Criteria for Early Trial Termination ................................................... 43 
6.0 
TRIAL FLOW CHART ........................................................................................... 44 
 
Study Flow Chart .................................................................................................. 44 
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7.0 
TRIAL PROCEDURES ........................................................................................... 48 
 
Trial Procedures ................................................................................................... 48 
7.1.1 Administrative Procedures .................................................................................. 48 
7.1.2 Clinical Procedures/Assessments ........................................................................ 51 
7.1.3 Laboratory Procedures/Assessments .................................................................. 60 
7.1.4 Other Procedures ................................................................................................. 62 
7.1.5 Visit Requirements .............................................................................................. 62 
 
Assessing and Recording Adverse Events .......................................................... 65 
7.2.1 Definition of an Overdose for This Protocol and Reporting of Overdose to the 
IND Sponsor and to Merck ................................................................................. 66 
7.2.2 Reporting of Pregnancy and Lactation to the IND Sponsor and to Merck ......... 67 
7.2.3 Immediate Reporting of Adverse Events to the IND Sponsor and to Merck ..... 67 
7.2.4 Evaluating Adverse Events ................................................................................. 70 
7.2.5 Sponsor Responsibility for Reporting Adverse Events ...................................... 73 
8.0 
STATISTICAL ANALYSIS PLAN ........................................................................ 73 
 
Statistical Analysis Plan Summary ..................................................................... 73 
8.1.1 General Analyses ................................................................................................ 73 
8.1.2 Efficacy Analyses ............................................................................................... 73 
8.1.3 Safety Analysis ................................................................................................... 74 
8.1.4 Power and Sample Size ....................................................................................... 75 
8.1.5 Interim Analyses ................................................................................................. 75 
 
Statistical Analysis Plan ....................................................................................... 76 
8.2.1 Responsibility for Analyses ................................................................................ 76 
 
Study Objectives ................................................................................................... 76 
8.3.1 Primary Objective ............................................................................................... 76 
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8.3.2 Secondary Objectives .......................................................................................... 76 
8.3.3 Exploratory Objectives: ...................................................................................... 76 
 
Hypotheses: ............................................................................................................ 77 
 
Analysis Endpoints ............................................................................................... 77 
8.5.2 Analysis Populations ........................................................................................... 79 
8.5.3 Statistical Methods .............................................................................................. 79 
9.0 
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ................................................................................................................. 80 
 
Investigational Product ........................................................................................ 80 
 
Packaging and Labeling Information ................................................................. 80 
 
Clinical Supplies Disclosure ................................................................................. 81 
 
Storage and Handling Requirements .................................................................. 81 
 
Returns and Reconciliation .................................................................................. 81 
10.0 
ADMINISTRATIVE AND REGULATORY DETAILS ....................................... 81 
 
Confidentiality ....................................................................................................... 81 
10.1.1 Confidentiality of Data ....................................................................................... 81 
10.1.2 Confidentiality of Subject Records ..................................................................... 82 
10.1.3 Confidentiality of Investigator Information ........................................................ 82 
10.1.4 Data Sharing ........................................................................................................ 82 
 
Compliance with Financial Disclosure Requirements ....................................... 84 
 
Compliance with Law, Audit and Debarment ................................................... 84 
 
Compliance with Trial Registration and Results Posting Requirements ........ 86 
 
Quality Management System ............................................................................... 86 
 
Data Management ................................................................................................. 86 
11.0 
APPENDICES ........................................................................................................... 88 
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ECOG Performance Status .................................................................................. 88 
 
Common Terminology Criteria for Adverse Events V4.03 (CTCAE) ............. 89 
 
Response Evaluation Criteria in Solid Tumors (RECIST) ............................... 90 
12.0 
REFERENCES .......................................................................................................... 91 
 
 
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1.0 TRIAL SUMMARY 
Abbreviated Title 
Phase II Pembrolizumab (MK-3475) in Rare Tumors 
Trial Phase 
II 
Clinical Indication 
Subjects will be enrolled into one of the following 10 tumor cohorts: 
1) Squamous cell carcinoma of the skin 
2) Small cell malignancies of non-pulmonary origin 
3) Adrenocortical carcinoma 
4) Medullary renal cell carcinoma 
5) Carcinoma of unknown primary 
6) Penile carcinoma 
7) Vascular sarcoma 
8) Germ Cell Tumor 
9) Paraganglioma-pheochromocytoma 
10) Other rare tumor histologies 
Trial Type 
Interventional 
Type of control 
No Treatment Control 
Route of administration 
Intravenous 
Trial Blinding 
Unblinded, Open-Label 
Treatment Groups  
Pembrolizumab (MK-3475) 200 milligrams intravenous infusion every 3 
weeks 
Number of trial subjects 
250 Subjects 
Estimated enrollment period 
March 2016-December 2021 
Estimated duration of trial 
The investigator estimates that the trial will require approximately 24 
months from the time the first subject signs the informed consent until 
the last subject’s last visit 
Duration of Participation 
Each subject will participate in the trial from the time the subject signs 
the Informed Consent Form (ICF) through the final protocol-specified 
contact. After a screening phase of 28 days, eligible subjects will receive 
treatment on Day 1 of each 21 day dosing cycle. Treatment with 
pembrolizumab (MK-3475) will continue until documented confirmed 
radiological disease progression or clinical progression, unacceptable 
adverse event(s), intercurrent illness that prevents further administration 
of treatment, investigator’s decision to withdraw the subject, subject 
withdraws consent, pregnancy of the subject, noncompliance with trial 
treatment or procedure requirements; subject receives 24 months of 
study medication, or administrative reasons.  Subjects who attain a 
complete response may consider stopping trial treatment if they meet 
criteria for holding therapy.  Subjects who stop trial treatment after 
receiving 24 months of study medication for reasons other than disease 
progression or intolerability or who attain a complete response and stop 
trial treatment may be eligible for up to one year of retreatment after 
experiencing disease progression.  The decision to retreat will be at the 
discretion of the investigator only if they meet the criteria for retreatment 
and the trial is ongoing.  After the end of treatment, each subject will be 
followed for 30 days for adverse event monitoring (study drug-related 
serious adverse events will be collected for 90 days after the end of 
treatment).  Subjects who discontinue for reasons other than disease 
progression will have post-treatment follow-up for disease status until 
disease 
progression, 
initiating 
a 
non-study 
cancer 
treatment, 
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withdrawing consent, or becoming lost to follow-up.  Investigators will 
collect survival data for patients after progression of disease unless 
patient fully withdrew consent to participate in the study using 
information from a chart review, patient visit, or telephone call.  
 
 
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2.0 TRIAL DESIGN 
 
Trial Design 
This is a single-center, open-label, phase II trial of pembrolizumab (MK-3475) in patients with 
and without programmed death-ligand 1 (PD-L1) positive advanced tumors to be conducted at 
the University of Texas MD Anderson Cancer Center. 
 
Participation in this trial will be dependent upon pathology or histologic confirmation of an 
advanced tumor type.  Subjects will be enrolled into one of the following 10 tumor cohorts: 
 
1) Squamous cell carcinoma of the skin 
2) Small cell malignancies of non-pulmonary origin 
3) Adrenocortical carcinoma 
4) Medullary renal cell carcinoma 
5) Carcinoma of unknown primary 
6) Penile carcinoma 
7) Vascular sarcoma 
8) Germ Cell Tumor 
9) Paraganglioma-pheochromocytoma 
10) Other rare tumor histologies. 
 
In Cohort 10, “Other rare tumor histologies,” the following tumor types will be excluded: 
melanoma, non-small cell lung cancer, hepatocellular carcinoma, Merkel cell carcinoma, colon 
or rectal adenocarcinoma, anal canal squamous cell carcinoma, pancreas adenocarcinoma, 
esophageal squamous cell carcinoma or adenocarcinoma (including GE junction), biliary tract 
adenocarcinoma (gallbladder and biliary tree but excluding ampulla of vater cancers), 
carcinoid tumors, neuroendocrine carcinomas (well or moderately differentiated pancreatic 
neuroendocrine tumor), ER-positive HER2-negative breast cancer, triple negative breast 
cancer, ovarian epithelial, fallopian tube or primary peritoneal carcinoma, endometrial 
carcinoma, cervical squamous cell cancer, vulvar squamous cell carcinoma, small cell lung 
cancer, malignant pleural mesothelioma, thyroid cancer (papillary or follicular subtype), 
salivary 
gland 
carcinoma, 
nasopharyngeal 
carcinoma, 
glioblastoma 
multiforme, 
leiomyosarcoma, prostate adenocarcinoma, gastric adenocarcinoma, and small bowel 
malignancy. 
 
Patients will be enrolled regardless of their PD-L1 expression status. Patients will supply tissue 
from an archival tissue sample or newly obtained biopsy (if archival tissue is not available) of 
a tumor lesion not previously irradiated (tumors progressing in a prior site of radiation are 
allowed for PD-L1 characterization, other exceptions may be considered after PI consultation).  
This specimen will be evaluated at a central laboratory for expression status of PD-L1 by 
immunohistochemistry (IHC).   
 
Toxicities will be graded according to National Cancer Institute (NCI) Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.03.  Subjects will be evaluated every 3 cycles 
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= every 9 weeks (63 days ±7 days) with radiographic imaging to assess response to treatment. 
After 6 months, at the physician’s discretion, if patients have had complete response (CR), 
partial response (PR) or stable disease (SD) > 27 weeks, then radiographic imaging may be 
performed every 12 weeks (4 cycles or 84 days ± 7 days). Response Evaluation Criteria in 
Solid Tumors (RECIST) 1.11 or immune-related RECIST (irRECIST) or method of tumor 
evaluation criteria best suitable and accepted for the tumor type evaluated will be used as 
the primary and secondary efficacy endpoint of response rate. 
 
Treatment with pembrolizumab (MK-3475) will continue until documented radiological 
disease  progression or clinical progression, unacceptable adverse event(s), intercurrent 
illness that prevents further administration of treatment, investigator’s decision to withdraw 
the subject, subject withdraws consent, pregnancy of the subject, noncompliance with trial 
treatment or procedure requirements, completion of 24 months of treatment with 
pembrolizumab (MK-3475), or administrative reasons. Subjects who attain an investigator-
determined confirmed complete response (CR) may consider stopping trial treatment after 
receiving at least 27 weeks (9 cycles) of treatment. In addition, subjects who discontinue 
after at least 24 months of therapy for reasons other than disease progression or intolerability, 
or who discontinue after attaining a CR and had at least 2 treatments beyond initial CR, may 
be eligible for up to one year of retreatment if they subsequently experience radiographic 
disease progression. The decision to retreat will be at the discretion of the investigator only 
if no cancer treatment was administered since the last dose of pembrolizumab (MK-3475), 
the subject still meets the safety parameters listed in the Inclusion/Exclusion criteria and the 
trial remains open. After the end of treatment, each subject will be followed for 30 days 
for adverse event monitoring (study drug-related serious adverse events will be collected 
for 90 days after the end of treatment). Subjects who discontinue treatment for reasons 
other than disease progression will have post-treatment follow-up of disease status until 
disease progression, o r  initiating a non-study cancer treatment, or withdrawing consent, or 
becoming lost to follow-up. Investigators will collect survival data for patients after progression 
of disease unless patient fully withdrew consent to participate in the study using information 
from a chart review, patient visit, or telephone call. The telephone call will be less than five 
minutes to obtain information regarding survival status. 
 
Immunotherapeutic agents such as pembrolizumab (MK-3475) may produce antitumor effects 
by potentiating endogenous cancer-specific immune responses.  The response patterns seen 
with such an approach may extend beyond the typical time course of responses seen with 
cytotoxic agents, and can manifest as a clinical response after an initial increase in tumor 
burden or even the appearance of new lesions.  If initial radiologic imaging shows progressive 
disease (PD), tumor assessment should be repeated ≥4 weeks later in order to confirm PD with 
the option of continuing treatment per below while awaiting radiologic confirmation of 
progression.  If repeat imaging shows a reduction in the tumor burden compared to the initial 
scan demonstrating PD, treatment may be continued as per treatment calendar.  If repeat 
imaging confirms progressive disease, subjects will be discontinued from study therapy. In 
determining whether or not the tumor burden has increased or decreased, Investigators should 
consider all target lesions as well as non-target lesions. 
 
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The primary objective of the trial is to evaluate efficacy by evaluation of non-progression 
rate (NPR) at 27 weeks (9 cycles) as defined as the percentage of patients who are alive and 
progression-free at 27 weeks (9 cycles) as assessed by RECIST v1.1 or irRECIST or method 
of tumor evaluation criteria best suitable and accepted for the tumor type evaluated, of 
pembrolizumab (MK-3475) in subjects with or without PD-L1 positive advanced tumors.  
Secondary objectives include evaluating safety and tolerability of pembrolizumab 
(MK-3475); correlating efficacy, non-progression rate (NPR) at 27 weeks (9 cycles), 
objective response (CR or PR), clinical benefit (CR, PR, or stable disease [SD] 
>/=4 months), progression-free survival (PFS), overall survival (OS) and duration of response 
(DOR) to PD-L1 status; and identifying imaging characteristics associated with immunological 
changes in tumor following treatment with pembrolizumab.  
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Trial Diagram 
The trial design is depicted in Figure 1. 
  
 
Figure 1: Dosing and Correlative Schema 
Patients may be co-enrolled on other protocols in which the PBMC and tissue samples will be utilized for analyses. 
 

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3.0 OBJECTIVES & HYPOTHESES 
 
Primary Objective  
Objective:  To obtain early indication of efficacy by evaluation of non-progression rate (NPR) 
at 27 weeks as defined as the percentage of patients who are alive and progression-free at 27 
weeks as assessed by RECIST v1.1 or irRECIST or method of tumor evaluation criteria best 
suitable and accepted for the tumor type evaluated in patients with advanced tumor types 
receiving pembrolizumab. 
3.1.1 Secondary Objectives  
(1) Objective:  To correlate efficacy by evaluation of tumor size to PD-L1 status among 
patients with advanced tumor types receiving pembrolizumab.  
(2) Objective:  To evaluate safety and tolerability of pembrolizumab in patients with advanced 
tumors. 
(3) Objective:  To evaluate the percentage of patients with objective response (CR or PR), 
clinical benefit (CR, PR, or stable disease [SD] >/=4 months), progression free survival 
(PFS), overall survival (OS), and duration of response (DOR) as assessed by RECIST v1.1 
in patients with advanced tumor types receiving pembrolizumab. 
(4) Objective: To evaluate the percentage of patients with objective response (CR or PR), 
clinical benefit (CR, PR, or SD >/=4 months), PFS, and DOR as assessed by irRECIST in 
patients with advanced tumor types receiving pembrolizumab. 
(5) Objective:  To correlate the NPR at 27 weeks (9 cycles), objective response (CR or PR), 
clinical benefit (CR, PR, or SD >/=4 months), PFS, OS, and DOR to PD-L1 status among 
patients with advanced tumor types receiving pembrolizumab.  
3.1.2 Exploratory Objectives: 
(1) Objective:  To evaluate the potential role of tumor-associated immune biomarkers for 
prediction of therapy effectiveness in patients with advanced tumor types receiving 
pembrolizumab.  
(2) Objective:  To correlate the potential role of tumor-associated immune biomarkers for 
prediction of therapy effectiveness to PD-L1 status among patients with advanced 
tumor types receiving pembrolizumab. 
(3) Objective: To identify imaging characteristics associated with immunological changes 
in tumor following treatment with pembrolizumab. 
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(4) Objective:  To compare tumor mutation burden and serial assessment of mutation 
status in biopsies obtained at baseline and progression in patients with advanced tumor 
types receiving pembrolizumab. 
(5) Objective: To evaluate patient-reported outcomes (PRO) utilizing the National Cancer 
Institute (NCI) Patient-Reported Outcomes of the Common Terminology Criteria for 
Adverse Events (PRO-CTCAE) questionnaires. 
(6) Objective: For patients that experience dermatologic irAEs, to compare the skin 
microbiome of normal (non-rash) skin to skin microbiome of area with rash. 
(7) Objective: For patients that experience oral irAEs, to assess the oral microbiome at 
baseline, at onset of toxicity, and time of tumor restaging 
(8) Objective: For patients that experience gut irAEs, to assess the gut microbiome at 
baseline, onset of toxicity, time of tumor restaging, and End of Treatment visit per the 
parent treatment protocol. 
(9) Objective: To analyze tumor-infiltrating lymphocytes using H&E (hematoxylin and 
eosin) stained whole slide images. 
 
Hypotheses: 
Intravenous administration of single agent pembrolizumab (MK-3475) to subjects with a 
given PD-L1 positive advanced tumor type will result in an NPR at 27 weeks (9 cycles) 
greater than 20% based on RECIST v1.1 or irRECIST criteria or according to tumor 
evaluation criteria best suitable and accepted for the tumor type evaluated.  
 
4.0 BACKGROUND & RATIONALE 
 
Background 
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background 
information on pembrolizumab (MK-3475).2 
 
4.1.1 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+ 
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effector T-cells / FoxP3+ regulatory T-cells seems to correlate with improved prognosis and 
long-term survival in many solid tumors. 
The programmed death 1 (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 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. 
 
4.1.2 Preclinical and Clinical Trial Data 
Refer to the Investigator’s Brochure for Preclinical and Clinical data.2 
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Rationale 
4.2.1 Rationale for the Trial and Selected Subject Population 
Intact immune surveillance plays a significant role in controlling development of neoplastic 
transformation.3  PD-1 is an immune-checkpoint receptor expressed by T cells.  PD-L1 is 
expressed in the tumor microenvironment of various cancers.  Upon binding to either of its 
ligands, PD-L1 or PD-L2, the PD-1 pathway negatively regulates T-cell effector functions.  
Increased expression of PD-L1 and an immunosuppressive microenvironment are associated 
with ineffective host immune response and subsequent disease progression in multiple tumor 
malignancies.  There is a strong correlation between presence of effective lymphocytes and 
favorable prognosis in different types of malignancies.4-6  Tumors take advantage of immune 
check points such as the PD-1/PD-L1 pathway to evade immune destruction, resulting in 
disease progression.7,8  To overcome tumor immune suppression and to establish an effective 
antitumor immune response, it is necessary to overcome multiple immunosuppressive 
mechanisms.9,10  Anti-PD1, anti-PD-L1, and anti-CTLA-4 are designed to block immune 
checkpoints.  These checkpoint inhibitors thereby decrease immune suppression and increase 
the antitumor effect.  
Pembrolizumab (also known as lambrolizumab and previously known as MK-3475) 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.  
The t1/2 of pembrolizumab is approximately 2-3 weeks (14-21 days), and with no indication 
of dose dependency of half-life among three dose groups (1, 3, and 10 mg/kg), which supports 
a dosing interval of every 2 or 3 weeks.11  Steady-state trough concentrations were 20% greater 
in patients receiving 10 mg/kg every 2 weeks than in those receiving the same dose every 3 
weeks.  Pembrolizumab has shown overall response rates of approximately 38% in patients 
with melanoma and ~20% in patients with non-small cell lung cancer. In September 2014, the 
FDA granted early approval for pembrolizumab in melanoma patients with BRAF V600 
mutation following ipilimumab therapy.12  
Currently, a single agent pembrolizumab trial is being conducted in over 20 PD-L1 expressing 
tumors including:  colon or rectal adenocarcinoma,  anal canal squamous cell carcinoma, 
pancreas adenocarcinoma, esophageal squamous cell carcinoma, adenocarcinoma (including 
GE junction), biliary tract adenocarcinoma (gallbladder and biliary tree but excluding ampulla 
of vater cancers), carcinoid tumors, neuroendocrine carcinomas (well or moderately 
differentiated pancreatic neuroendocrine tumor), ER+/HER2-negative breast cancer, ovarian 
epithelial, fallopian tube or primary peritoneal carcinoma, endometrial carcinoma, cervical 
squamous cell cancer, vulvar squamous cell carcinoma, small cell lung cancer, mesothelioma 
(malignant pleural mesothelioma), thyroid cancer (papillary or follicular subtype), salivary 
gland carcinoma, nasopharyngeal carcinoma, glioblastoma multiforme, leiomyosarcoma, 
prostate adenocarcinoma (NCT02054806).   
Progress is unfolding in the understanding of how the immune system can modulate tumor 
progression or effective responses against cancer.13  In some studies, the levels of PD-L1 
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expression have correlated with clinical outcome.14-16  However, the prognostic impact of 
PD-L1 expression still needs to be defined in rare tumor types. 
Our strategy for this study is to focus on advanced rare types with and without PD-L1-
expressing tumors. We will exclude all types of tumors that are enrolled in the current 
Phase1B study of MK-3475-028 (NCT02054806).  In this study, our goal is to characterize 
the presence of PD-L1 expression in advanced tumor tissues and to correlate levels of PD-L1 
expression with clinico-pathological features as well as survival outcomes. 
4.2.2 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.2  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 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. 
 
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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. 
 
4.2.3 Rationale for Endpoints 
4.2.3.1 Efficacy Endpoints 
The primary objective of this study is to evaluate the efficacy by evaluation of non-progression 
rate (NPR) at 27 weeks as defined as the percentage of patients who are alive and progression-
free at 27 weeks as assessed by RECIST v1.1 or irRECIST or method of tumor evaluation 
criteria best suitable and accepted for the tumor type evaluated, of pembrolizumab (MK-
3475) in subjects with and without PD-L1 positive advanced tumors. Response rates per 
RECIST v1.1 or irRECIST will be evaluated.   The same method of assessment used to 
characterize each identified and reported lesion at baseline must be used in all subsequent 
imaging assessments. Response assessments determined by irRECIST will be compared with 
those of derived using RECIST v1.1. 
 
RECIST v1.1 or irRECIST will be adapted to account for the unique tumor response 
characteristics seen with treatment of pembrolizumab (MK-3475). Immunotherapeutic agents 
such as pembrolizumab (MK-3475) may produce antitumor effects by potentiating 
endogenous cancer-specific immune responses. The response patterns seen with such an 
approach may extend beyond the typical time course of responses seen with cytotoxic 
agents, and can manifest a clinical response after an initial increase in tumor burden or even 
the appearance of new lesions. Standard RECIST may not provide an accurate response 
assessment of immunotherapeutic agents such as pembrolizumab (MK-3475). Therefore, 
RECIST v1.1 will be used with the following adaptations: 
• If radiologic imaging shows initial PD, tumor assessment should be repeated ≥4 
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weeks later in order to confirm PD with the option of continuing treatment per 
below while awaiting radiologic confirmation of progression. If repeat imaging 
shows a reduction in the tumor burden compared to the initial scan demonstrating 
PD, treatment may be continued / resumed. If repeat imaging confirms progressive 
disease, subjects will be discontinued from study therapy (exception noted in 
Section 7.1.2.6). In determining whether or not the tumor burden has increased 
or decreased, investigators should consider all target lesions as well as non-target 
lesions. 
 
In subjects who have initial evidence of radiological PD, it is at the discretion of the treating 
physician whether to continue a subject on study treatment until repeat imaging is obtained a 
minimum of 4 weeks later. This clinical judgment decision should be based on the subject’s 
overall clinical condition, including performance status, clinical symptoms, and laboratory 
data. Subjects may receive pembrolizumab (MK-3475) treatment while waiting for 
confirmation of PD if they are clinically stable as defined by the following criteria: 
• Absence of signs and symptoms indicating disease progression 
• No decline in ECOG performance status 
• Absence of rapid progression of disease 
• Absence of progressive tumor at critical anatomical sites (e.g., cord compression) 
requiring urgent alternative medical intervention. 
 
When feasible, subjects should not be discontinued until progression is confirmed. This 
allowance to continue treatment despite initial radiologic progression takes into account the 
observation that some subjects can have a transient tumor flare in the first few months after 
the start of immunotherapy, but with subsequent disease response. Subjects that are deemed 
clinically unstable are not required to have repeat imaging for confirmation of progressive 
disease. 
 
4.2.3.2 Safety Endpoints 
The secondary safety objective of this study is to characterize the safety and tolerability of 
pembrolizumab (MK-3475) in subjects with or without PD-L1 positive advanced tumors. 
The safety analysis will be based on subjects who experienced toxicities as defined by 
CTCAE criteria.  Safety will be assessed by quantifying the toxicities and grades 
experienced by subjects who have received pembrolizumab (MK-3475), including serious 
adverse events (SAEs) and events of clinical interest (ECIs). 
 
Safety will be assessed by reported adverse experiences using CTCAE, Version 4.03. The 
attribution to drug, time-of-onset, duration of the event, its resolution, and any concomitant 
medications administered will be recorded. AEs will be analyzed including but not limited to 
all AEs, SAEs, fatal AEs, and laboratory changes. Furthermore, specific immune-related 
adverse events (irAEs) will be collected and designated as immune-related events of clinical 
interest (ECIs) as described in Section 7.2.3.2. 
 
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Patients enrolled on this study will be approached for co-enrollment on PA15-0315 prospective 
study to assess immune-related adverse events when receiving immunotherapy at the University 
of Texas MD Anderson Cancer Center (Aung Naing, MD).  All samples and scans will be 
collected using procedures characterized in this protocol, and all patients will be consented for 
procedures done under this optional protocol separately. 
4.2.3.3 Biomarker Research 
Additional biomarker research to identify factors important for pembrolizumab (MK-3475) 
therapy will also be pursued.  For example, tumor and blood samples from this study may 
undergo proteomic, genomic and transcriptional analyses.  Additional research may evaluate 
factors important for predicting responsiveness or resistance to pembrolizumab (MK-3475) 
therapy and other immunologic targets. 
 
Participation in this trial will be dependent upon supplying tissue from an archival tissue sample 
or newly obtained biopsy (if archival tissue is not available) of a tumor lesion not previously 
irradiated (tumors progressing in a prior site of radiation are allowed for PD-L1 characterization, 
other exceptions may be considered after PI consultation).  This specimen will be evaluated at 
a central laboratory for expression status of PD-L1 by immunohistochemistry (IHC).  Baseline, 
on-treatment and time of progression (if patients have had CR/PR/or SD for > 27 weeks) 
biopsies will be obtained for evaluation of the potential role of tumor-associated immune 
biomarkers for prediction of therapy effectiveness. Biopsies will be performed provided that 
there is technically biopsiable tumor, and it is safe for patient to undergo biopsy. In Cohort 9: 
Paraganglioma-pheochromocytoma or Cohort 10, where there is prominent bony disease, 
biopsies may not be possible due to the nature of the disease. 
 
Peripheral blood mononuclear cell (PBMC) will be collected at baseline, tumor restaging, in 
conjunction with biopsies, and time of progression (if patients have had CR/PR/or SD for > 27 
weeks).  These samples will be analyzed for the NanoString assay that will evaluate immune-
related gene expression signatures and the potential to predict benefit from pembrolizumab. 
 
Patients enrolled in this study will be approached for co-enrollment on PA11-0852 
Clearinghouse protocol at the University of Texas MD Anderson Cancer Center (Funda Meric-
Bernstam, MD) to assess tumor mutation burden and genomic alterations detected in cfDNA.  
As per the PA11-0852 Clearinghouse protocol, the optional tumor biopsies from baseline and 
the time of progression (if progression after response or unexpected rapid progression), and 
serial plasma samples will be analyzed.  Development of new mutations or reversal of the 
mutations will be analyzed and correlated with clinical response. This will be our exploratory 
objective and no formal statistical analysis will be done. 
 
4.2.3.4 Patient-Reported Outcomes 
In collaboration with the Department of Symptom Research, we will use pre-specified selected 
items from the National Cancer Institute (NCI) Patient-Reported Outcomes version 1.0 of the 
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Common Terminology Criteria for Adverse Events (PRO-CTCAE) library of items. The NCI 
PRO-CTCAE provides a systematic yet flexible tool for descriptive reporting of symptomatic 
treatment side effects in cancer clinical trials.  
Capturing symptomatic toxicity is challenging since the onset and character of adverse events 
varies within and across trials based on the distinct, on- and off-target toxicity profile of a 
specific therapy. Thus the approach to measuring symptomatic toxicity must be flexible within 
and across studies. 
The National Cancer Institute’s PRO-CTCAE measurement system was developed as a 
companion to the CTCAE, the standard lexicon for adverse event reporting in cancer trials. It 
is not intended to be used as a stand alone patient-reported outcome. 
The PRO-CTCAE measurement system includes an item library of 124 discrete items 
representing 78 symptomatic toxicities drawn from the CTCAE. It provides a systematic yet 
flexible approach to capture symptomatic treatment side effects in trials of new cancer 
therapies. 
For this study, the 20 symptomatic toxicities including oral (dry mouth), gastrointestinal 
(decreased appetite, nausea, diarrhea, and abdominal pain), respiratory (shortness of breath), 
cardio/circulatory (swelling), cutaneous (rash, skin dryness, and itchiness), visual/perception 
(blurred vision), pain (generalized pain, headache, muscle pain, joint pain), sleep/wake 
(fatigue), sexual (decreased libido), and miscellaneous (chills, increased sweating, and hot 
flashes) will be used.  
PRO-CTCAE responses will be rated using a one-week recall period on a 4-point scale, with 
0=“Never” or “Never” and 4=“Very severe” or “Very much” or “Almost constantly.”  PRO-
CTCAE responses are scored from 0 to 4, and there are no standardized scoring rules yet 
established for how to combine attributes into a single score or how best to analyze PRO-
CTCAE data longitudinally. PRO-CTCAE scores for each attribute (frequency, severity and/or 
interference) should be presented descriptively (e.g. summary statistics or graphical 
presentations).  The proportion of missing PRO-CTCAE data should also be summarized to 
aid interpretation. 
We will rely on well-established electronic data-capture methods for the PRO-CTCAE. 
Depending on patient preference, the PRO-CTCAE can be delivered by a computerized, 
telephone-based interactive voice response (IVR) system at the patient’s preferred time and 
days of the week or electronically through web-based platforms. 
The purpose of this project is to estimate the incidence of treatment-emergent irAEs and 
conduct serial PRO assessments.  We will evaluate how these patients were managed and 
investigate the outcome.  By utilizing the PRO-CTCAE questionnaires, we will examine the 
relationships of longitudinal patient-reported symptoms with disease progression and clinical 
outcomes of severe irAEs on patients treated with immunotherapy.   These results will provide 
information that is imperative to providing the most effective patient care. 
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Study Updates 
As of Protocol Version 14, cohorts of this study were closed due to lack of efficacy or difficulty 
in accrual.  
• Cohort 2: Small cell malignancies of non-pulmonary origin; 
• Cohort 4: Medullary renal cell carcinoma; 
• Cohort 6: Penile carcinoma; 
• Cohort 8: Germ cell tumor. 
 
In summary, Cohort 2 Small cell malignancies of non-pulmonary origin was closed after 12 
patients were treated and none were alive and progression-free at 27 weeks (primary-endpoint 
of the study) (June 2019). 
Cohort 4 Medullary renal cell carcinoma was closed after 5 patients were treated and none 
were alive and progression-free at 27 weeks (primary-endpoint of the study) (April 2019).  
Cohort 6 Penile carcinoma was closed after 3 patients were treated (August 2019). Cohort 6 
was difficult to accrue due to eligibility, and 2 of the 3 patients progressed rapidly within 2 
months of treatment. 
Cohort 8 Germ cell tumor was closed after 12 patients were treated (June 2018). Only 1 patient 
was alive and progression free at 27 weeks (primary-endpoint of the study). 
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5.0 SUBJECT ELIGIBILITY 
 
Study Population 
5.1.1 Diagnosis/Condition for Entry into the Trial 
Male and female subjects with or without PD-L1 positive advanced tumor (as specified in 
Section 5.1.2)  of at least 18 years will be enrolled in this trial. 
 
5.1.2 Subject Inclusion Criteria 
In order to be eligible for participation in this trial, the subject must: 
1. Be willing and able to provide written informed consent/assent for the trial. 
2. Be  18 years of age on day of signing informed consent. 
3. Have measurable disease based on RECIST 1.1 or irRECIST. Only Cohort 9 and 
Cohort 10 can have evaluable disease (non-measureable lesions).  Tumor lesions 
situated in a previously irradiated area are considered measurable if progression has 
been demonstrated in such lesions. Patients may have bone metastatic disease evaluable 
according to tumor evaluation criteria best suitable and accepted for the tumor type 
evaluated. 
4. Have one of the following advanced (unresectable and/or metastatic) solid tumor 
indications, that has progressed following standard therapies, where standard 
therapies are available: 
• Squamous cell carcinoma of the skin 
• Adrenocortical carcinoma 
• Carcinoma of unknown primary 
• Vascular sarcoma 
• Paraganglioma-pheochromocytoma 
• Other rare tumor histologies (except those tumor types listed in 5.1.3.) 
 
5. Have failed prior treatment within 6 months of consent date. 
6. Have biopsiable disease. Subjects must have at least one lesion amenable to biopsy. 
Tumor lesions used for biopsy should not be lesions used as target lesions for response 
evaluation. In Cohort 9: Paraganglioma-pheochromocytoma or Cohort 10, where there 
is prominent bony disease, biopsies may not be possible due to the nature of the disease. 
7. Be willing to provide archival tissue. If archival tissue is not available, a newly obtained 
core or excisional biopsy of a tumor lesion will be obtained.  Newly-obtained is defined 
as a specimen obtained up to 6 weeks (42 days) prior to initiation of treatment on Day 
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1.  In Cohort 9: Paraganglioma-pheochromocytoma or Cohort 10, where there is 
prominent bony disease, biopsies may not be possible due to the nature of the disease. 
8. Have a performance status of 0 or 1 on the ECOG Performance Scale. 
9. Demonstrate adequate organ function as defined in Table 1, all screening labs should 
be performed within 28 days of treatment initiation.   
Table 1  Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
Hematological 
 
Absolute neutrophil count (ANC) 
≥1,000 /mcL 
Platelets 
≥75,000 / mcL 
Hemoglobin 
≥9 g/dL or ≥5.6 mmol/L without transfusion or EPO dependency 
(within 7 days of assessment) 
Renal 
 
Serum creatinine OR 
Measured or calculateda creatinine 
clearance 
(GFR can also be used in place of 
creatinine or CrCl) 
≤1.5 X upper limit of normal (ULN) OR 
 
≥60 mL/min for subject with creatinine levels > 1.5 X 
institutional ULN 
Hepatic 
 
Serum total bilirubin 
≤ 1.5 X ULN OR 
 
Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 
1.5 ULN 
AST (SGOT) and ALT (SGPT) 
≤ 2.5 X ULN  OR 
≤ 5 X ULN for subjects with liver metastases 
Albumin 
>2.5 mg/dL 
Coagulation 
International Normalized Ratio (INR) or 
Prothrombin Time (PT) 
 
Activated Partial Thromboplastin Time 
(aPTT) 
≤1.5 X ULN unless subject is receiving anticoagulant therapy 
as long as PT or PTT is within therapeutic range of intended use 
of anticoagulants 
≤1.5 X ULN unless subject is receiving anticoagulant therapy 
as long as PT or PTT is within therapeutic range of intended use 
of anticoagulants 
aCreatinine clearance should be calculated per institutional standard. 
 
10. 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.   
11. 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 (Section 5.7.2).  
Subjects of childbearing potential are those who have not been surgically sterilized or 
have not been free from menses for > 1 year.  
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12. 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. 
13. For subjects in Cohort 2 (Small cell malignancies of non-pulmonary origin), 
confirmation of no brain metastases via imaging.  
5.1.3 Subject Exclusion Criteria 
The subject must be excluded from participating in the trial if the subject: 
1. Is currently participating and receiving study therapy or concurrent chemotherapy, 
immunotherapy, biologic, or hormonal therapy for cancer treatment at the time of 
administration of first dose of trial treatment. Continuation of hormone replacement 
therapy is permitted. Stable regimens of hormonal therapy i.e. for prostate cancer (e.g. 
leuprolide, a GnRH agonist), ovarian, or breast cancer are not exclusionary. 
2. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any 
other form of immunosuppressive therapy within 7 days prior to the first dose of trial 
treatment. 
 
3. Has a known history of active TB (Bacillus Tuberculosis). 
 
4. Hypersensitivity to pembrolizumab or any of its excipients. 
 
5. 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.   
6. 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, and 
diseases for which the treatment could reasonably include Pembrolizumab and are not 
part of the excluded tumor type list or not eligible for the phase I trial. 
7. 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 four 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 
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steroids for at least 7 days prior to trial treatment.  This exception does not include 
carcinomatous meningitis which is excluded regardless of clinical stability. 
8. Has active autoimmune disease that has required systemic treatment in the past 2 years 
(i.e. with use of disease modifying agents, corticosteroids or immunosuppressive 
drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid 
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form 
of systemic treatment. Immunosuppressive corticosteroid doses (>10 mg prednisone 
daily or equivalent) within 4 weeks prior to the first dose of Pembrolizumab. Note: 
corticosteroids given within 24 hours of an imaging study for purposes of pre-
medication in patients with hypersensitivity to radiologic contrast agents are allowed. 
9. Has known history of, or any evidence of active, non-infectious pneumonitis. 
10. Has an active infection requiring systemic therapy. 
11. 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.   
12. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 
13. 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. 
14. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent. 
15. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 
16. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected). 
17. 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. 
18.  Is participating in Cohort 10 and has melanoma; non-small cell lung cancer; 
hepatocellular carcinoma; Merkel cell carcinoma; colon or rectal adenocarcinoma; anal 
canal squamous cell carcinoma; pancreas adenocarcinoma; esophageal squamous cell 
carcinoma or adenocarcinoma (including GE junction); biliary tract adenocarcinoma 
(gallbladder and biliary tree but excluding ampulla of vater cancers); carcinoid tumors; 
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neuroendocrine 
carcinomas 
(well 
or 
moderately 
differentiated 
pancreatic 
neuroendocrine tumor); ER-positive HER2-negative breast cancer; triple negative 
breast cancer; ovarian epithelial, fallopian tube or primary peritoneal carcinoma; 
endometrial carcinoma; cervical squamous cell cancer; vulvar squamous cell 
carcinoma; small cell lung cancer; mesothelioma (malignant pleural mesothelioma); 
thyroid cancer (papillary or follicular subtype); salivary gland carcinoma; 
nasopharyngeal carcinoma; glioblastoma multiforme; leiomyosarcoma; prostate 
adenocarcinoma; gastric adenocarcinoma; or small bowel malignancy. 
 
 
Trial Treatments 
The treatment to be used in this trial is outlined below in Table 2.  One treatment cycle consists 
of 3 weeks (21 days) of treatment.  Pembrolizumab will be given via intravenous (IV) infusion 
on Day 1 of every cycle.  Patients will be restaged at the end of every three cycles (9 weeks).  
Patients may be allowed to continue treatment after restaging if there is continued clinical 
response or disease stabilization and patients do not have significant toxicities. 
Table 2  Trial Treatment 
Drug 
Dose/Potency 
Dose 
Frequency 
Route of 
Administration 
Regimen/Treatment 
Period 
Use 
Pembrolizumab 
(MK-3475) 
200 mg 
Q3W 
IV Infusion 
Day 1 of each 21-
Day Cycle 
Experimental 
The pembrolizumab (MK-3475) dosing interval may be withheld due to toxicity as described in Section 5.2.1.2. 
 
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 trial 
treatments in accordance with the protocol and any applicable laws and regulations. 
 
5.2.1 Dose Selection/Modification 
5.2.1.1 Dose Selection 
The rationale for selection of doses to be used in this trial is provided in Section 4.0 – 
Background and Rationale.   
 
Details on preparation and administration of pembrolizumab (MK-3475) are provided in the 
Pharmacy Manual.   
 
5.2.1.2 Dose Modification  
Adverse events (both non-serious and serious) associated with pembrolizumab exposure may 
represent an immunologic etiology.  These adverse events may occur shortly after the first dose 
or several months after the last dose of treatment. Pembrolizumab must be withheld for drug-
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related toxicities and severe or life-threatening AEs as per Table 3 below. See Section 5.6.1 
for supportive care guidelines, including use of corticosteroids. 
 
For subjects whose dose was withheld due to toxicity, subjects may resume pembrolizumab 
(MK-3475) upon resolution of toxicity to Grade 0-1 or baseline. This dose would be 
considered Day 1 of the next cycle and should be in alignment with the new schedule. 
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Table 3 Dose Modification Guidelines for Drug-Related Adverse Events 
General Instructions: 
1. Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks. 
2. For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to Grade 1 or 0 and 
corticosteroid has been tapered. Pembrolizumab should be permanently discontinued if AE does not resolve within 12 weeks of last dose or 
corticosteroids cannot be reduced to ≤10 mg prednisone or equivalent per day within 12 weeks.  
3. For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other immunosuppressive treatment 
should be initiated if irAEs cannot be controlled by corticosteroids. 
 
Immune-related 
AEs 
Toxicity grade or 
conditions 
(CTCAEv4.0) 
Action taken to 
pembrolizumab 
irAE management with 
corticosteroid and/or other 
therapies  
Monitor and follow-up  
Pneumonitis  
Grade 2 
Withhold  
• Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper 
 
• 
Monitor participants for signs and 
symptoms of pneumonitis 
• 
Evaluate participants with suspected 
pneumonitis with radiographic imaging and 
initiate corticosteroid treatment 
• 
Add prophylactic antibiotics for 
opportunistic infections 
Grade 3 or 4, or 
recurrent Grade 2 
Permanently 
discontinue 
Diarrhea / Colitis  Grade 2 or 3 
Withhold 
• Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper 
 
• 
Monitor participants for signs and symptoms 
of enterocolitis (ie, diarrhea, abdominal 
pain, blood or mucus in stool with or 
without fever) and of bowel perforation 
(ie, peritoneal signs and ileus). 
• 
Participants with ≥ Grade 2 diarrhea 
suspecting colitis should consider GI 
consultation and performing endoscopy to 
rule out colitis.  
• 
Participants with diarrhea/colitis should be 
advised to drink liberal quantities of clear 
fluids.  If sufficient oral fluid intake is not 
feasible, fluid and electrolytes should be 
substituted via IV infusion. 
Grade 4 
Permanently 
discontinue 

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General Instructions: 
1. Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks. 
2. For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to Grade 1 or 0 and 
corticosteroid has been tapered. Pembrolizumab should be permanently discontinued if AE does not resolve within 12 weeks of last dose or 
corticosteroids cannot be reduced to ≤10 mg prednisone or equivalent per day within 12 weeks.  
3. For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other immunosuppressive treatment 
should be initiated if irAEs cannot be controlled by corticosteroids. 
 
Immune-related 
AEs 
Toxicity grade or 
conditions 
(CTCAEv4.0) 
Action taken to 
pembrolizumab 
irAE management with 
corticosteroid and/or other 
therapies  
Monitor and follow-up  
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 
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 -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  
• 
Monitor for signs and symptoms of thyroid 
disorders.  

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General Instructions: 
1. Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks. 
2. For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to Grade 1 or 0 and 
corticosteroid has been tapered. Pembrolizumab should be permanently discontinued if AE does not resolve within 12 weeks of last dose or 
corticosteroids cannot be reduced to ≤10 mg prednisone or equivalent per day within 12 weeks.  
3. For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other immunosuppressive treatment 
should be initiated if irAEs cannot be controlled by corticosteroids. 
 
Immune-related 
AEs 
Toxicity grade or 
conditions 
(CTCAEv4.0) 
Action taken to 
pembrolizumab 
irAE management with 
corticosteroid and/or other 
therapies  
Monitor and follow-up  
Grade 3 or 4  
Withhold or  
permanently 
discontinue1 
• Treat with non-selective beta-
blockers (eg, propranolol) or 
thionamides as appropriate  
 
Hypothyroidism 
Grade 2-4 
Continue  
• Initiate thyroid replacement 
hormones (eg, levothyroxine or 
liothyroinine) per standard of care 
• 
Monitor for signs and symptoms of thyroid 
disorders.  
 
Nephritis and 
Renal 
dysfunction 
Grade 2 
Withhold  
• Administer corticosteroids 
(prednisone 1-2 mg/kg or 
equivalent) followed by taper. 
• 
Monitor changes of renal function 
 
Grade 3 or 4  
Permanently 
discontinue 
Myocarditis 
Grade 1 or 2 
Withhold 
• Based on severity of AE 
administer corticosteroids 
• 
Ensure adequate evaluation to confirm 
etiology and/or exclude other causes 
 
Grade 3 or 4 
Permanently 
discontinue 
All other 
immune-related 
AEs 
Intolerable/ 
persistent Grade 2 
Withhold 
• Based on type and severity of AE 
administer corticosteroids  
• 
Ensure adequate evaluation to confirm 
etiology and/or exclude other causes 
 
Grade 3 
Withhold or 
discontinue based 
on the type of 
event.  Events that 
require 
discontinuation 

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General Instructions: 
1. Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks. 
2. For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to Grade 1 or 0 and 
corticosteroid has been tapered. Pembrolizumab should be permanently discontinued if AE does not resolve within 12 weeks of last dose or 
corticosteroids cannot be reduced to ≤10 mg prednisone or equivalent per day within 12 weeks.  
3. For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other immunosuppressive treatment 
should be initiated if irAEs cannot be controlled by corticosteroids. 
 
Immune-related 
AEs 
Toxicity grade or 
conditions 
(CTCAEv4.0) 
Action taken to 
pembrolizumab 
irAE management with 
corticosteroid and/or other 
therapies  
Monitor and follow-up  
include and not 
limited to:  
Gullain-Barre 
Syndrome, 
encephalitis 
Grade 4 or 
recurrent Grade 3  
Permanently 
discontinue 
1. Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician.   
NOTE:  
For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, pembrolizumab may be resumed 
when AE resolves to ≤ Grade 2 and is controlled with hormonal replacement therapy or achieved metabolic control (in case of T1DM).   
 
 

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Dosing interruptions are permitted in the case of medical / surgical events or logistical reasons 
not related to study therapy (e.g., elective surgery, unrelated medical events, patient vacation, 
and/or holidays). Subjects should be placed back on study therapy within 3 weeks of the 
scheduled interruption, unless due to socio-economic reasons (e.g. insurance-related issues) 
and unless otherwise discussed with the IND Sponsor. The reason for interruption should be 
documented in the patient's study record. 
 
5.2.2 Timing of Dose Administration 
Trial treatment should be administered on Day 1 of each 21-day cycle after all 
procedures/assessments have been completed as detailed on the Trial Flow Chart (Section 6.0).  
Trial treatment may be administered up to 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. 
 
Pembrolizumab (MK-3475) 200 mg will be administered as a 30 minute IV infusion every 3 
weeks (21 days).  Sites should make every effort to target infusion timing to be as close to 30 
minutes as possible.  However, given the variability of infusion pumps from site to site, a 
window of -5 minutes and +10 minutes is permitted (i.e., infusion time is 30 minutes: -5 
min/+10 min). 
 
The Pharmacy Manual contains specific instructions for the preparation of the pembrolizumab 
infusion fluid and administration of infusion solution. 
 
 
5.2.3 Continuing Study Drug Administration after Initial Evidence of Radiologic 
Disease Progression 
Immunotherapeutic agents such as pembrolizumab (MK-3475) may produce antitumor effects 
by potentiating endogenous cancer-specific immune responses. The response patterns seen 
with such an approach may extend beyond the typical time course of responses seen with 
cytotoxic agents, and can manifest as a clinical response after an initial increase in tumor 
burden or even the appearance of new lesions. 
 
If initial radiologic imaging shows PD, tumor assessment should be repeated ≥4 weeks later 
in order to confirm PD with the option of continuing treatment per below while awaiting 
radiologic confirmation of progression. If repeat imaging shows a reduction in the tumor 
burden compared to the initial scan demonstrating PD, treatment may be continued as per 
treatment calendar. If repeat imaging confirms progressive disease, subjects will be 
discontinued from study therapy (exception noted in Section 7.1.2.5.1). In determining 
whether or not the tumor burden has increased or decreased, Investigators should consider all 
target lesions as well as non-target lesions (please refer to the Procedures Manual). 
 
When feasible, subjects should not be discontinued until progression is confirmed; however, 
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the decision to continue study treatment after the 1st evidence of disease progression is at the 
Investigator’s discretion based on the clinical status of the subject as described in Table 4 
below. Subjects may receive study treatment while waiting for confirmation of PD if they 
are clinically stable as defined by the following criteria: 
• Absence of signs and symptoms (including worsening of laboratory values) 
indicating disease progression 
• No decline in ECOG performance status 
• Absence of rapid progression of disease 
• Absence of progressive tumor at critical anatomical sites (e.g., cord 
compression) requiring urgent alternative medical intervention. 
 
Table 4 Imaging and Treatment After 1st Radiologic Evidence of PD 
Clinically Stable 
Clinically Unstable 
Imaging 
Treatment 
Imaging 
Treatment 
1st radiologic 
evidence of PD 
Repeat imaging 
at >4 weeks to 
confirm PD 
May continue 
study treatment at 
the Investigator’s 
discretion while 
awaiting 
confirmatory scan 
Repeat imaging 
at >4 weeks to 
confirm PD if 
possible 
Discontinue 
treatment 
Repeat scan 
confirms PD 
No additional 
imaging 
required 
Discontinue 
treatment 
(exception noted 
in Section 
7.1.2.5) 
No additional 
imaging required 
N/A 
Repeat scan 
shows SD, PR 
or CR 
Continue 
regularly 
scheduled 
imaging 
assessments 
every 9 weeks 
 
Continue study 
treatment at the 
Investigator’s 
discretion 
Continue 
regularly 
scheduled 
imaging 
assessments 
every 9 weeks 
 
May restart 
study treatment 
if condition has 
improved and/or 
clinically stable 
per 
Investigator’s 
discretion 
 
5.2.4 Trial Blinding/Masking 
This is an open-label trial; therefore, the IND Sponsor, investigator and subject will know the 
treatment administered. 
 
 
Randomization or Treatment Allocation 
Subjects participating in this trial will be allocated by non-random assignment. 
 
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Stratification 
No stratification based on age, gender, or other characteristics will be used in this trial. 
 
 
Concomitant Medications/Vaccinations (Allowed & Prohibited) 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for one of these or other medications 
or vaccinations specifically prohibited during the trial, discontinuation from trial therapy or 
vaccination may be required.  The investigator should discuss any questions regarding this 
with the Merck Clinical team.  The final decision on any supportive therapy or vaccination 
rests with the investigator and/or the subject's primary physician.  
 
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. 
 
5.5.1 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 electronic medical record 
(EMR) including all prescription, over-the-counter (OTC), 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 EMR. 
 
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 if associated 
with SAEs and ECIs as defined in Section 7.2. 
 
5.5.2 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  
• 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.   
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• 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 IND Sponsor. 
• Herbal products. 
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. 
 
Rescue Medications & Supportive Care 
5.6.1 Supportive Care Guidelines 
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Suggested supportive care measures for the management of adverse 
events with potential immunologic etiology are outlined below. Where appropriate, these 
guidelines include the use of oral or intravenous treatment with corticosteroids as well as 
additional anti-inflammatory agents if symptoms do not improve with administration of 
corticosteroids.   Note that several courses of steroid tapering may be necessary as symptoms 
may worsen when the steroid dose is decreased. For each disorder, attempts should be made to 
rule out other causes such as metastatic disease or bacterial or viral infection, which might 
require additional supportive care. The treatment guidelines are intended to be applied when 
the investigator determines the events to be related to pembrolizumab.  
Note: if after the evaluation the event is determined not to be related, the investigator does not 
need to follow the treatment guidance (as outlined below). Refer to Section 5.2.1 for dose 
modification.  
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event.  
• Pneumonitis:  
o For Grade 2 events, treat with systemic corticosteroids. When symptoms 
improve to Grade 1 or less, steroid taper should be started and continued over 
no less than 4 weeks. 
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o For Grade 3-4 events, immediately treat with intravenous steroids.  
Administer additional anti-inflammatory measures, as needed. 
o Add prophylactic antibiotics for opportunistic infections in the case of 
prolonged steroid administration. 
• Diarrhea/Colitis:  
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such 
as diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of 
bowel perforation (such as peritoneal signs and ileus).   
o All subjects who experience diarrhea/colitis should be advised to drink liberal 
quantities of clear fluids.  If sufficient oral fluid intake is not feasible, fluid and 
electrolytes should be substituted via IV infusion.  For Grade 2 or higher 
diarrhea, consider GI consultation and endoscopy to confirm or rule out colitis. 
o For Grade 2 diarrhea/colitis that persists greater than 3 days, administer oral 
corticosteroids.  
o For Grade 3 or 4 diarrhea/colitis that persists > 1 week, treat with intravenous 
steroids followed by high dose oral steroids.   
o When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 
 
• Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) or 
≥ Grade 3 Hyperglycemia, if associated with ketosis (ketonuria) or metabolic 
acidosis (DKA) 
o For T1DM or Grade 3-4 Hyperglycemia 
▪ Insulin replacement therapy is recommended for Type I diabetes 
mellitus and for Grade 3-4 hyperglycemia associated with metabolic 
acidosis or ketonuria.  
▪ Evaluate patients with serum glucose and a metabolic panel, urine 
ketones, glycosylated hemoglobin, and C-peptide.  
 
• Hypophysitis: 
o For Grade 2 events, treat with corticosteroids. When symptoms improve to 
Grade 1 or less, steroid taper should be started and continued over no less than 
4 weeks. Replacement of appropriate hormones may be required as the steroid 
dose is tapered. 
o For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed 
by oral corticosteroids. When symptoms improve to Grade 1 or less, steroid 
taper should be started and continued over no less than 4 weeks. Replacement 
of appropriate hormones may be required as the steroid dose is tapered. 
 
• Hyperthyroidism or Hypothyroidism:  
Thyroid disorders can occur at any time during treatment. Monitor patients for changes 
in thyroid function (at the start of treatment, periodically during treatment, and as 
indicated based on clinical evaluation) and for clinical signs and symptoms of thyroid 
disorders. 
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o Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism): 
▪ In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are 
suggested as initial therapy. 
▪ In hypothyroidism, thyroid hormone replacement therapy, with 
levothyroxine or liothyroinine, is indicated per standard of care. 
o Grade 3-4 hyperthyroidism  
▪ Treat with an initial dose of IV corticosteroid followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid 
taper should be started and continued over no less than 4 weeks. 
Replacement of appropriate hormones may be required as the steroid 
dose is tapered. 
 
• Hepatic: 
o For Grade 2 events, monitor liver function tests more frequently until returned 
to baseline values (consider weekly). 
▪ Treat with IV or oral corticosteroids 
o For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 hours.  
o When symptoms improve to Grade 1 or less, a steroid taper should be started 
and continued over no less than 4 weeks. 
 
• Renal Failure or Nephritis: 
o For Grade 2 events, treat with corticosteroids. 
o For Grade 3-4 events, treat with systemic corticosteroids. 
o When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks.  
 
Management of Infusion Reactions: Signs and symptoms usually develop during or 
shortly after drug infusion and generally resolve completely within 24 hours of 
completion of infusion. 
 
Table 5 below shows treatment guidelines for subjects who experience an infusion 
reaction associated with administration of pembrolizumab (MK-3475). 
 
Table 5 Infusion Reaction Treatment Guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
Grade 1 
Mild reaction; infusion interruption 
not indicated; intervention not 
indicated 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
None 
Grade 2 
Requires infusion interruption but 
responds promptly to symptomatic 
treatment (e.g., antihistamines, 
NSAIDS, narcotics, IV fluids); 
prophylactic medications indicated for 
< =24 hrs 
Stop Infusion and monitor symptoms. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Subject may be premedicated 1.5h 
(± 30 minutes) prior to infusion of 
pembrolizumab (MK-3475) with: 
 
Diphenhydramine 50 mg po (or 
equivalent dose of antihistamine). 
 
Acetaminophen 500-1000 mg po 
(or equivalent dose of antipyretic). 
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NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
If symptoms resolve within one hour of stopping 
drug infusion, the infusion may be restarted at 
50% of the original infusion rate (e.g., from 100 
mL/hr to 50 mL/hr).  Otherwise dosing will be 
held until symptoms resolve and the subject 
should be premedicated for the next scheduled 
dose. 
Subjects who develop Grade 2 toxicity despite 
adequate premedication should be 
permanently discontinued from further trial 
treatment administration. 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly responsive 
to symptomatic medication and/or 
brief interruption of infusion); 
recurrence of symptoms following 
initial improvement; hospitalization 
indicated for other clinical sequelae 
(e.g., renal impairment, pulmonary 
infiltrates) 
Grade 4: 
Life-threatening; pressor or ventilatory 
support indicated 
Stop Infusion. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine 
 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
Hospitalization may be indicated. 
Subject is permanently discontinued from 
further trial treatment administration. 
No subsequent dosing 
Appropriate resuscitation equipment should be available in the room and a physician readily available during the period of drug 
administration. 
 
 
 
 
Diet/Activity/Other Considerations 
5.7.1 Diet 
Subjects should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea or vomiting. 
5.7.2 Contraception 
Pembrolizumab may have adverse effects on a fetus in utero.  Furthermore, it is not known if 
pembrolizumab has transient adverse effects on the composition of sperm.  Non-pregnant, non-
breast-feeding women may be enrolled if they are willing to use 2 methods of birth control or 
are considered highly unlikely to conceive.  Highly unlikely to conceive is defined as 1) 
surgically sterilized, or 2) postmenopausal (a woman who is ≥45 years of age and has not had 
menses for greater than 1 year will be considered postmenopausal), or 3) not heterosexually 
active for the duration of the study.  The two birth control methods can be either two barrier 
methods or a barrier method plus a hormonal method to prevent pregnancy. Subjects should 
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start using birth control from study Visit 1 throughout the study period up to 120 days after the 
last dose of study therapy.  
 
The following are considered adequate barrier methods of contraception: diaphragm, condom 
(by the partner), copper intrauterine device, sponge, or spermicide.  Appropriate hormonal 
contraceptives will include any registered and marketed contraceptive agent that contains an 
estrogen and/or a progestational agent (including oral, subcutaneous, intrauterine, or 
intramuscular agents). 
 
Subjects should be informed that taking the study medication may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the study.  In order to participate in 
the study they must adhere to the contraception requirement (described above) for the duration 
of the study and during the follow-up period defined in Section 7.2.2-Reporting of Pregnancy 
and Lactation to the IND Sponsor and to Merck.  If there is any question that a subject will not 
reliably comply with the requirements for contraception, that subject should not be entered into 
the study. 
 
 
5.7.3 Use in Pregnancy 
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab, the 
subject will immediately be removed from the study.  The site will contact the subject at least 
monthly and document the subject’s status until the pregnancy has been completed or 
terminated.  The outcome of the pregnancy will be reported to the IND Sponsor and to Merck 
without delay and within 24 hours to the IND Sponsor 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 IND 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 IND Sponsor and to Merck and followed as 
described above and in Section 7.2.2. 
5.7.4 Use in Nursing Women 
It is unknown whether pembrolizumab is excreted in human milk.  Since many drugs are 
excreted in human milk, and because of the potential for serious adverse reactions in the 
nursing infant, subjects who are breast-feeding are not eligible for enrollment. 
 
Subject Withdrawal/Discontinuation Criteria 
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur.  In addition, a subject may be 
withdrawn by the investigator if enrollment into the trial is inappropriate, the trial plan is 
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violated, or for administrative and/or other safety reasons.  Specific details regarding 
discontinuation or withdrawal are provided in Section 7.1.4 – Other Procedures. Subjects who 
have attained a confirmed CR that have been treated for at least 27 weeks (9 cycles) with 
pembrolizumab and had at least two treatments with pembrolizumab beyond the date when the 
initial CR was declared may also consider discontinuation of treatment, details for which are 
provided in Section 5.8.1. 
A subject must be discontinued from the trial for any of the following reasons: 
• The subject or legal representative (such as a parent or legal guardian) withdraws 
consent. 
• Confirmed radiographic disease progression 
Note: For unconfirmed radiographic disease progression, please see Section 7.1.2.5. 
Note: A subject may be granted an exception to continue on treatment with 
confirmed radiographic progression if clinically stable or clinically improved, 
please see Section 7.1.2.5. 
• Clinical progression as determined by PI or treating physician. 
• Unacceptable adverse experiences as described in Section 5.2.1.2 
• 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 34 
administrations of study medication, whichever is later. A patient may continue past 24 
months (or 34 administrations) after discussion with Merck on a case by case basis. 
Note: 24 months of study medication is calculated from the date of first dose. Subjects 
who stop pembrolizumab after 24 months may be eligible for up to one year of 
additional study treatment if they progress after stopping study treatment provided they 
meet the requirements detailed in Section 7.1.5.5 
• Administrative reasons 
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The End of Treatment and Follow-up visit procedures are listed in Section 6 (Protocol Flow 
Chart) and Section 7.1.5 (Visit Requirements).  After the end of treatment, each subject will 
be followed for 30 days for adverse event monitoring (serious adverse events will be collected 
for 90 days after the end of treatment as described in Section 7.2.3.1).  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 by telephone or chart review for overall survival until death, withdrawal of 
consent, or the end of the study, whichever occurs first. 
5.8.1 Discontinuation of Study Therapy after CR  
Discontinuation of treatment may be considered for subjects who have attained a confirmed 
CR that have been treated for at least 27 weeks (9 cycles) with pembrolizumab and had at least 
two treatments with pembrolizumab beyond the date when the initial CR was declared.  
Subjects who then experience radiographic disease progression may be eligible for up to one 
year of additional treatment with pembrolizumab via the Second Course Phase at the discretion 
of the investigator if no cancer treatment was administered since the last dose of 
pembrolizumab, the subject meets the safety parameters listed in the Inclusion/Exclusion 
criteria, and the trial is open.  Subjects will resume therapy at the same dose and schedule at 
the time of initial discontinuation.  Additional details are provided in Section 7.1.5.5. 
 
Subject Replacement Strategy 
Patients will not be replaced on study. However, if a patient is considered to be non-evaluable 
for primary efficacy assessment (alive and progression free at 27 weeks), additional subjects 
may be enrolled in a given cohort to ensure that the required number of evaluable subjects in 
each cohort is achieved. 
 Clinical Criteria for Early Trial Termination 
Early trial termination will be the result of the criteria specified below: 
1. Quality or quantity of data recording is inaccurate or incomplete 
2. Poor adherence to protocol and regulatory requirements 
3. Incidence or severity of adverse drug reaction in a particular cohort or other studies 
indicates a potential health hazard to subjects 
4. Plans to modify or discontinue the development of the study drug 
In the event of Merck decision to no longer supply study drug, ample notification will be 
provided so that appropriate adjustments to subject treatment can be made. 
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6.0 TRIAL FLOW CHART 
 
Study Flow Chart 
Trial Period: 
Screening 
Phase 
Treatment Cyclesa 
End of 
Treatment 
Post-Treatment 
Treatment
Cycle/Title:
Screening 
(Visit 1) 
1 
2 
3 
4 
To be repeated beyond 
8 cyclesa 
Discon 
Safety 
Follow-
up 
Follow-up 
Visitsc 
Survival 
Follow-up 
5 
6 
7 
8 
Scheduling Window
(Days):
-28 to -1 
Day 1 
(-3 
days) 
Day 
1 
(± 3 
days) 
Day 
1 
(± 3 
days) 
Day 
1 
(± 3 
days) 
Day 
1 
(± 3 
days 
Day 
1 
(± 3 
days) 
Day 
1 
(± 3 
days) 
Day 
1 
(± 3 
days) 
At time 
of 
Discon 
30 days 
from 
last 
dose 
(± 7 days) 
Post 
discon 
(± 7 days) 
Every 
12 
weeks 
(± 4 weeks) 
Administrative Procedures 
Informed Consentb 
Xb 
Inclusion/Exclusion Criteria 
X 
Demographics and Medical History 
X 
Concomitant Medication Review 
Xd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xd 
X 
Trial Treatment Administrationa 
 
X 
X 
X 
X 
X 
X 
X 
X 
Post-study Anticancer Therapy Status 
 
X 
X 
Survival Status 
 
XX 
Clinical Procedures/Assessments 
Review Adverse Eventse 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xe 
Xe 
Physical Examinationf 
X 
X 
X 
X 
X 
X
X 
X 
X 
X 
X 
X 
Vital Signs and Weight g 
X 
Xg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG Performance Status 
X 
X 
X 
X 
X 
X 
Xh 
Xh 
Xh 
X 
X 
X 
Laboratory Procedures/Assessments: analysis performed by LOCAL laboratory 
Pregnancy Test – Urine or Serum -HCGi 
Xi 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PT/INR and aPTT 
Xj 
As Clinically Indicated 
CBC with Differentialk 
Xj 
Xk 
X 
X 
X 
X 
X 
X 
X 
X 
Xn 
X 

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Trial Period: 
Screening 
Phase 
Treatment Cyclesa 
End of 
Treatment 
Post-Treatment 
Treatment
Cycle/Title:
Screening 
(Visit 1) 
1 
2 
3 
4 
To be repeated beyond 
8 cyclesa 
Discon 
Safety 
Follow-
up 
Follow-up 
Visitsc 
Survival 
Follow-up 
5 
6 
7 
8 
Scheduling Window
(Days):
-28 to -1 
Day 1 
(-3 
days) 
Day 
1 
(± 3 
days) 
Day 
1 
(± 3 
days) 
Day 
1 
(± 3 
days) 
Day 
1 
(± 3 
days 
Day 
1 
(± 3 
days) 
Day 
1 
(± 3 
days) 
Day 
1 
(± 3 
days) 
At time 
of 
Discon 
30 days 
from 
last 
dose 
(± 7 days) 
Post 
discon 
(± 7 days) 
Every 
12 
weeks 
(± 4 weeks) 
Comprehensive Chemistry Panelk 
Xj 
Xk 
X 
X 
X 
X 
X 
X 
X 
X 
Xn 
X 
Urinalysisk,l 
Xj 
 
Xl 
 
 
Xl 
Xn 
T3, FT4 and TSHk 
Xj 
 
Xl 
 
 
Xl 
Xn 
Tumor Marker Assessment (if available) m 
X j 
 
Xm 
 
 
Xm 
Xm 
Xm 
Efficacy Measurements 
Tumor Imaginga,o, p, q 
XW 
 
X 
 
 
X 
 
Xq 
Xc 
Correlative Studies 
Tissue Collection for PD-L1 Characterizationr 
Xr 
Tumor Biopsy Tissue Collection 
Xs 
Xs 
 
Xs 
PBMC Collectiont 
X 
Xt 
 
X 
 
 
X 
Xt 
Immune-related Imaging 
Xu 
 
 
 
Xu 
 
 
Xu 
 
Xu 
Patient-Reported Outcomes 
PRO-CTCAE Questionnairesv 
X 
Weekly for 9 Weeks 
Every 2 Weeks until Week 54, 
then every 4 Weeks 
X 
a. Treatment cycles are 3 weeks (21 days). Radiographic imaging should be performed every 9 weeks (3 cycles or 63 days ± 7 days) regardless of any treatment delays (i.e. 
Screening visit, after to Cycle 3, Cycle 6, Cycle 9 and then every 3 cycles (9 weeks)). However, after 6 months, at the physician’s discretion, if patients have had CR, PR or 
SD > 27 weeks, then radiographic imaging may be performed every 12 weeks (4 cycles or 84 days ± 7 days). 
b. Written consent must be obtained prior to performing any protocol specific procedure. Results of a test performed prior to the subject signing consent as part of routine 
clinical management are acceptable in lieu of a screening test if performed within the specified time frame (e.g., within 28 days prior to the first dose of trial treatment). 
Baseline number will be assigned when the study informed consent is signed. 
c. The Follow-Up Visits post discontinuation may be performed every 9 weeks, 12 weeks, or at the discretion of the treating physician. In subjects who discontinue study 

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Trial Period: 
Screening 
Phase 
Treatment Cyclesa 
End of 
Treatment 
Post-Treatment 
Treatment
Cycle/Title:
Screening 
(Visit 1) 
1 
2 
3 
4 
To be repeated beyond 
8 cyclesa 
Discon 
Safety 
Follow-
up 
Follow-up 
Visitsc 
Survival 
Follow-up 
5 
6 
7 
8 
Scheduling Window
(Days):
-28 to -1 
Day 1 
(-3 
days) 
Day 
1 
(± 3 
days) 
Day 
1 
(± 3 
days) 
Day 
1 
(± 3 
days) 
Day 
1 
(± 3 
days 
Day 
1 
(± 3 
days) 
Day 
1 
(± 3 
days) 
Day 
1 
(± 3 
days) 
At time 
of 
Discon 
30 days 
from 
last 
dose 
(± 7 days) 
Post 
discon 
(± 7 days) 
Every 
12 
weeks 
(± 4 weeks) 
therapy without documented disease progression, every effort should be made to continue monitoring their disease status by radiologic imaging every 9 weeks (± 7 days) 
until (1) the start of new anti-cancer treatment, (2) documented radiological or clinical disease progression, (3) death, or (4) the end of the study, whichever occurs first.  
d. Prior medications – Record all medications taken 28 days before the first dose of trial treatment. Concomitant medications – Enter new medications started during the trial 
and 30 days after last dose of trial treatment regardless of when the Safety Follow-up visit occurs. 
e. Patients enrolled on this study will be approached for co-enrollment on PA15-0315 prospective study to assess immune-related adverse events when receiving immunotherapy 
All samples and scans will be collected using procedures characterized in this protocol and all patients will be consented for procedures done under this optional protocol 
separately. Record all AEs occurring within 30 days after the last dose of trial treatment regardless of when the Safety Follow-up visit occurs. After 30 days, record all 
SAEs (related and unrelated to trial treatment) / ECIs occurring up to 90 days after the last dose of trial treatment or the start of new anti-cancer treatment, whichever 
comes first. Afterwards, any drug related AE regardless of seriousness occurring outside of any reporting timeframes must be reported 
f. Physical exams are to be completed at screening, Day 1 of every Cycle, End of Treatment, Safety Follow-up and every 9 –week Follow-up visits. 
g. Height will be measured at visit 1 only. 
h. Following Cycle 8, the ECOG performance status should be determined only in conjunction with a protocol-specified full or directed physical exam (Cycle 9, 11, 13, 15, 
17, 19 and every 2 cycles thereafter. 
i. 
For women of reproductive potential, a urine pregnancy test should be performed within 72 hours prior to first dose of trial treatment. If urine pregnancy results cannot 
be confirmed as negative, a serum pregnancy test performed by the local study site laboratory will be required. Pregnancy tests (serum and/or urine tests) should be repeated 
if required by local guidelines. 
j. 
Laboratory tests for screening are to be performed within 28 days prior to the first dose of trial treatment.  
k. After Cycle 1, lab samples can be collected up to 72 hours (3 days) prior to the scheduled time point.  
l. 
Urinalysis and T3, FT4 and TSH are to be repeated every 3 cycles at the time of restaging. If the urinalysis is abnormal, a microscopic urinalysis will be performed.  
m. Tumor marker assessment is not an additional study-related laboratory evaluation. The purpose is to collect information that may be a part of standard clinical 
assessment for certain tumor types.  Data collection (if applicable and if available) should occur every 9 weeks (3 cycles or 63 days ± 7 days) regardless of any treatment 
delays (i.e. Screening visit, after to Cycle 3, Cycle 6, Cycle 9 and then every 3 or 4 cycles (9 or 12 weeks) thereafter coinciding with imaging visits). Upon discontinuation, 
tumor marker data collection will occur every 9 or 12 weeks coinciding with post-treatment imaging follow-up visits.   
n. Unresolved abnormal labs that are drug related AEs should be followed until resolution. 
o. The initial tumor imaging will be performed within 28 days prior to the first dose of trial treatment. Scans performed as part of routine clinical management are acceptable for 
use as the screening scan if they are of diagnostic quality and performed within 28 days prior to the first dose of trial treatment. On-study imaging will be performed every 9
weeks (± 7 days) after the first dose of trial treatment and should follow calendar days and should not be adjusted for delays in cycle starts or withholding of pembrolizumab 
(MK-3475) cycle frequencies. However, after 6 months, at the physician’s discretion, if patients have had CR, PR or SD > 27 weeks, then radiographic imaging may be 
performed every 12 weeks (4 cycles or 84 days ± 7 days). The same imaging technique should be used in a subject throughout the trial. Local reading (investigator assessment 

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Trial Period: 
Screening 
Phase 
Treatment Cyclesa 
End of 
Treatment 
Post-Treatment 
Treatment
Cycle/Title:
Screening 
(Visit 1) 
1 
2 
3 
4 
To be repeated beyond 
8 cyclesa 
Discon 
Safety 
Follow-
up 
Follow-up 
Visitsc 
Survival 
Follow-up 
5 
6 
7 
8 
Scheduling Window
(Days):
-28 to -1 
Day 1 
(-3 
days) 
Day 
1 
(± 3 
days) 
Day 
1 
(± 3 
days) 
Day 
1 
(± 3 
days) 
Day 
1 
(± 3 
days 
Day 
1 
(± 3 
days) 
Day 
1 
(± 3 
days) 
Day 
1 
(± 3 
days) 
At time 
of 
Discon 
30 days 
from 
last 
dose 
(± 7 days) 
Post 
discon 
(± 7 days) 
Every 
12 
weeks 
(± 4 weeks) 
with site radiology reading) will be used to determine eligibility and for subject management.  Tumor imaging and assessment per local standard of care should be performed 
for patient management, and may include additional imaging (e.g. bone scan for prostate cancer patients) and appropriate tumor markers.  
p. Per the modified RECIST 1.1 or irRECIST used in this protocol, if imaging shows progressive disease, the imaging assessment should be repeated at a minimum of 4 
weeks later in order to confirm progressive disease. 
q. If a scan was obtained within 4 weeks prior to the date of discontinuation, then a scan at treatment discontinuation isn’t mandatory. In subjects who discontinue study 
therapy without confirmed disease progression, a radiological evaluation should be repeated at the time of treatment discontinuation (i.e. date of discontinuation ± 4 week 
window). 
r. Mandatory archived or newly obtained (within 42 days (6 weeks)) FFPE (formalin-fixed paraffin embedded) for 5 unstained (4 or 5 micron, 4 micron preferred) slides 
must be submitted for characterization at a central lab for PD-L1 characterization. Newly-obtained is defined as a specimen obtained up to 6 weeks (42 days) prior to 
initiation of treatment on Day 1.  Tumor lesions not previously irradiated must be provided (tumors progressing in a prior site of radiation are allowed for PD-L1 
characterization). 
s. Tumor tissue will be obtained pre- treatment (baseline), between Cycle 1 Day 15 and Cycle 1 Day 21, and at progression (if patient had CR, PR or SD > 27 weeks) provided 
there is technically biopsiable tumor, and it is safe for patient to undergo biopsy.  In Cohort 9: Paraganglioma-pheochromocytoma or Cohort 10, where there is prominent 
bony disease, biopsies may not be possible due to the nature of the disease. 
t. 
Peripheral blood mononuclear cell (PBMC) will be collected at baseline, tumor restaging, in conjunction with biopsies, and time of progression (if patients have had 
CR/PR/or SD for > 27 weeks).  PBMC collections at tumor restaging and in conjunction with biopsies will have a +/- 1 day window. 
u. The CT or MRI tumor scans for tumor assessment will be utilized for immune-related imaging correlatives. Additional scans will not be required. 
v. Baseline questionnaires will be performed in person with the study team. Subsequent questionnaires will be issued weekly for 9 weeks and every 2 week until Week 54, 
and every 4 weeks thereafter until the End of Treatment or up to Week 81. All questionnaires will have a +/-2 day window. 
w. Subjects in Cohort 2 (small cell malignancies of non-pulmonary origin) are required to have confirmation of no brain metastases via imaging at screening. 
x. Investigators will collect survival data for patients after progression of disease unless patient fully withdrew consent to participate in the study using information from a 
chart review, patient visit, or telephone call. 
 

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7.0 TRIAL PROCEDURES 
 
Trial Procedures 
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to perform 
these procedures at unscheduled time points if deemed clinically necessary by the investigator. 
Furthermore, additional evaluations/testing may be deemed necessary by the IND Sponsor 
and/or Merck for reasons related to subject safety. In some cases, such evaluation/testing may 
be potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations may 
require that additional informed consent be obtained from the subject.  In these cases, such 
evaluations/testing will be performed in accordance with those regulations. 
7.1.1 Administrative Procedures 
7.1.1.1 Informed Consent 
The Investigator must obtain documented consent from each potential subject prior to 
participating in a clinical trial. 
7.1.1.1.1 General Informed Consent 
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature 
of the person conducting the consent discussion.  
A copy of the signed and dated consent form should be given to the subject before participation 
in the trial. 
The initial informed consent form, any subsequent revised written informed consent form and 
any written information provided to the subject must receive the IRB/ERC’s 
approval/favorable opinion in advance of use.  The subject or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available 
that may be relevant to the subject’s willingness to continue participation in the trial.  The 
communication of this information will be provided and documented via a revised consent 
form or addendum to the original consent form that captures the subject’s dated signature or 
by the subject’s legally acceptable representative’s dated signature. 
Specifics about a trial and the trial population will be added to the consent form template at 
the protocol level.   
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations 
and IND Sponsor requirements. 
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For patients enrolled on this study prior to approval of Protocol Version 13, the baseline blood 
samples collected for correlative research studies may be used for the germline DNA testing 
under the Waiver of Consent.  All patients consent to the blood collection for the correlative 
blood testing. Patients off-study prior to Version 13 would not be able to be reconsented. The 
purpose of Protocol Version 13 was to specify an additional type of testing.  Under the Waiver 
of Consent, samples from patients no longer on the study will be used for the specific germline 
DNA testing.  Samples from patients that withdrew consent will not be used. 
For patients enrolled on this study prior to approval of Protocol Version 14 that cannot be 
reconsented, survival data, de-identified clinical data and RNA sequencing data output, 
imaging, and baseline plasma samples collected for translational research studies may be used 
under the Waiver of Consent for entities listed in the 10.1.4 Data Sharing section of the 
protocol.  All patients consented to the collection of data and blood for translational research. 
Patients off-study prior to Version 14 would not be able to be reconsented.  Under the Waiver 
of Consent, samples from patients no longer on the study will be used for testing conducted by 
entities listed in 10.1.4 Data Sharing. Samples and data from patients that withdrew consent 
will not be used for these purposes. 
 
7.1.1.2 Inclusion/Exclusion Criteria 
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the trial.  
7.1.1.3 Medical History 
A medical history will be obtained by the investigator or qualified designee.  Medical history 
will include all active conditions, and any condition diagnosed within the prior 10 years that 
are considered to be clinically significant by the Investigator.  Details regarding the disease for 
which the subject has enrolled in this study will be recorded separately and not listed as medical 
history.   
7.1.1.4 Prior and Concomitant Medications Review 
7.1.1.4.1 Prior Medications 
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the subject 
within 28 days before starting the trial.  Treatment for the disease for which the subject has 
enrolled in this study will be recorded separately and not listed as a prior medication.  
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7.1.1.4.2 Concomitant Medications 
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial.  All medications related to reportable SAEs and ECIs should be recorded as 
defined in Section 7.2. 
7.1.1.5 Disease Details and Treatments 
7.1.1.5.1 Disease Details 
The investigator or qualified designee will obtain prior and current details regarding disease 
status.  
7.1.1.5.2 Prior Treatment Details 
The investigator or qualified designee will review all prior cancer treatments including 
systemic treatments, radiation and surgeries. 
7.1.1.5.3 Subsequent Anti-Cancer Therapy Status 
The investigator or qualified designee will review all new anti-neoplastic therapy initiated after 
the last dose of trial treatment.  If a subject initiates a new anti-cancer therapy within 30 days 
after the last dose of trial treatment, the 30 day Safety Follow-up visit must occur before the 
first dose of the new therapy.  Once new anti-cancer therapy has been initiated the subject will 
move into survival follow-up.  
7.1.1.6 Assignment of Screening Number 
Consented subjects will not be given a unique screening number for randomization or 
allocation. All patients who meet eligibility criteria and are enrolled in this trial will be 
registered in Clinical Oncology Research Database (CORe) at the University of Texas MD 
Anderson Cancer Center at Houston.  Each patient will have a CORe accession number. 
 
 
 
7.1.1.7 Assignment of Randomization Number 
Subjects participating in this trial will be allocated by non-random assignment; therefore, a 
randomization number will not be assigned to patients. 
7.1.1.8 Trial Compliance (Medication/Diet/Activity/Other) 
Interruptions from the protocol specified treatment plan for greater than 12 weeks between 
pembrolizumab (MK-3475) doses due to toxicity require consultation between the investigator 
and the IND Sponsor and written documentation of the collaborative decision on subject 
management. 
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Administration of trial medication will be witnessed by the investigator and/or trial staff. 
The total volume of trial treatment infused will be compared to the total volume prepared to 
determine compliance with each dose administered. 
 
The instructions for preparing and administering pembrolizumab (MK-3475) will be 
provided in the Pharmacy Manual. 
 
 
7.1.2 Clinical Procedures/Assessments 
7.1.2.1 Adverse Event (AE) Monitoring 
The investigator or qualified designee will assess each subject to evaluate for potential new or 
worsening AEs as specified in the Trial Flow Chart and more frequently if clinically indicated.  
Adverse experiences will be graded and recorded throughout the study and during the follow-
up period according to NCI CTCAE Version 4.03 (see Section 11.2).  Toxicities will be 
characterized in terms regarding seriousness, causality, toxicity grading, and action taken with 
regard to trial treatment.  
For subjects receiving treatment with pembrolizumab all AEs of unknown etiology associated 
with pembrolizumab exposure should be evaluated to determine if it is possibly an event of 
clinical interest (ECI) of a potentially immunologic etiology (termed immune-related adverse 
events, or irAEs).   
Please refer to Section 7.2 for detailed information regarding the assessment and recording of 
AEs.   
7.1.2.2 Physical Exam 
The investigator or qualified designee will perform a complete physical exam during the 
screening period.  Clinically significant abnormal findings should be recorded as medical 
history.  A physical exam should be performed during screening, Day 1 of every Cycle, End 
of Treatment, Safety Follow-Up, and every 9-week Follow-up Visit. After the first dose of trial 
treatment, new clinically significant abnormal findings should be recorded as AEs. 
7.1.2.3 Vital Signs 
The investigator or qualified designee will take vital signs at screening, prior to the 
administration of each dose of trial treatment and at treatment discontinuation as specified in 
the Trial Flow Chart (Section 6.0).  Vital signs should include temperature, pulse, respiratory 
rate, weight and blood pressure.  Height will be measured at screening only. 
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7.1.2.4 Eastern Cooperative Oncology Group (ECOG) Performance Scale 
The investigator or qualified designee will assess ECOG status (Section 11.1) at screening, 
prior to the administration of each dose of trial treatment and discontinuation of trial treatment 
as specified in the Trial Flow Chart.   
7.1.2.5 Tumor Imaging and Assessment of Disease 
RECIST v1.1 or irRECIST or method of tumor evaluation criteria best suitable and accepted 
for the tumor type evaluated will be applied by the site as the primary measure for assessment 
of tumor response and as a basis for all protocol guidelines related to disease status (e.g., 
discontinuation of study therapy).   
 
RECIST v1.1 or irRECIST will be adapted as follows to account for the unique tumor 
response seen in this class of therapeutics. If imaging shows PD, tumor assessment should 
be repeated ≥4 weeks later in order to confirm PD with the option of continuing treatment 
for clinically stable subjects as discussed below in Table 6. Clinically stable is defined by the 
following criteria: 
• Absence of signs and symptoms indicating disease progression 
• No decline in ECOG performance status 
• Absence of rapid progression of disease 
• Absence of progressive tumor at critical anatomical sites (e.g., cord compression) 
requiring urgent alternative medical intervention. 
 
Table 6 Imaging and Treatment after 1st Radiologic Evidence of PD 
Clinically Stable 
Clinically Unstable 
Imaging 
Treatment 
Imaging 
Treatment 
1st radiologic 
evidence of PD 
Repeat imaging 
at  4 weeks to 
confirm PD 
May continue 
study treatment 
at the 
Investigator’s 
discretion while 
awaiting 
confirmatory 
scan 
Repeat imaging 
at  4 weeks to 
confirm PD if 
possible 
Discontinue 
treatment 
Repeat scan 
confirms PD 
No additional 
imaging required 
Discontinue 
treatment 
(exception noted 
in Section 
7.1.2.5.) 
No additional 
imaging required 
N/A 
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Repeat scan 
shows SD, PR 
or CR 
Continue 
regularly 
scheduled 
imaging 
assessments 
every 9 weeks 
 
Continue study 
treatment at the 
Investigator’s 
discretion 
Continue 
regularly 
scheduled 
imaging 
assessments 
every 9 weeks 
 
 
May restart study 
treatment if 
condition has 
improved and/or 
clinically stable 
per Investigator’s 
discretion 
 
In determining whether or not the tumor burden has increased or decreased, Investigators 
should consider all target lesions as well as non-target lesions (please refer to the Procedures 
Manual). Subjects that are deemed clinically unstable are not required to have repeat imaging 
for confirmation. If radiologic progression is confirmed, then the subject will be 
discontinued from trial treatment. If radiologic progression is not confirmed, then the subject 
should resume/continue trial treatment and have their next scan according to the every 9 
weeks (63 days ±7 days). 
 
NOTE: If a subject with confirmed radiographic progression (i.e. 2 scans at least 28 days 
apart demonstrating progressive disease) is clinically stable or clinically improved, and there 
is no further increase in the tumor dimensions at the confirmatory scan, an exception may be 
considered to continue treatment upon consultation with the IND Sponsor. Clinically stable 
subjects should also have at the confirmatory scan no further increase in the target lesions, no 
unequivocal increase in non-target lesions, and no additional new lesions develop (non- 
worsening PD) to continue study treatment. 
 
 
Local reading (investigator assessment with site radiology reading) based on RECIST v1.1 
or irRECIST will be used to determine subject eligibility and for subject management. 
Tumor imaging and assessment per local standard of care should be performed for patient 
management, and may include additional imaging (e.g. bone scan for prostate cancer patients) 
and appropriate tumor markers. 
 
7.1.2.5.1 Initial Tumor Imaging 
Initial tumor imaging must be performed within 28 days prior to the first dose of trial 
treatment. The site study team must review pre-trial images to confirm the subject has 
measurable disease per RECIST v1.1 or irRECIST or method of tumor evaluation criteria 
best suitable and accepted for the tumor type evaluated. The baseline imaging scan should 
be submitted to the central imaging vendor for a possible retrospective analysis of this 
eligibility criterion. 
 
Scans performed as part of routine clinical management are acceptable for use as the screening 
scan if they are of diagnostic quality and performed within 28 days prior to the first dose of 
trial treatment. The same imaging technique should be used in a subject throughout the study. 
 
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7.1.2.5.2 Tumor Imaging During Trial 
Tumor imaging may be performed by CT or magnetic resonance imaging (MRI), but the 
same imaging technique should be used in a subject throughout the trial. Imaging should be 
performed every 9 weeks (63 days ± 7 days) from the first dose of trial treatment or more 
frequently if clinically indicated. Imaging should not be delayed for delays in cycle starts or 
withholding of pembrolizumab (MK-3475) cycle intervals. After 6 months, at the physician’s 
discretion, if patients have had CR, PR or SD > 27 weeks, then radiographic imaging may be 
performed every 12 weeks (4 cycles or 84 days ± 7 days). 
 
Per RECIST 1.1 or irRECIST, response should be confirmed by a repeat radiographic 
assessment not less than 4 weeks from the date the response was first documented. The scan 
for confirmation of response may be performed at the earliest 4 weeks after the first indication 
of response, or at the next scheduled scan, whichever is clinically indicated. 
 
Imaging should continue to be performed until documented disease progression, the start of 
new anti-cancer treatment, withdrawal of consent, death, or the end of the study, whichever 
occurs first. Disease progression should be confirmed at least 4 weeks after the first scan 
indicating progressive disease in clinically stable subjects. Subjects who have unconfirmed 
disease progression may continue on treatment until progression is confirmed provided they 
have met the conditions detailed in Section 7.1.2.5. 
 
7.1.2.5.3 Tumor Imaging During Follow-Up 
 
Imaging during the follow-up period is to be repeated every 9 weeks or 12 weeks or at 
the discretion of the attending physician for subjects who discontinue trial treatment for 
reasons other than disease progression documented disease progression, the start of new anti-
cancer treatment, withdrawal of consent, death, or the end of the study, whichever occurs first. 
 
7.1.2.6 Tumor Tissue Collection and Correlative Studies Blood Sampling 
7.1.2.6.1 Tumor Tissue Collection 
Mandatory tumor tissue (archival or newly obtained lesion) is required at screening.  If archival 
tissue is not available, a newly obtained core or excisional biopsy of a tumor lesion will be 
obtained.  The screening biopsy must be newly-obtained, which is defined as a specimen 
obtained up to 6 weeks (42 days) prior to initiation of treatment on Day 1.  Tumor lesions not 
previously irradiated must be provided (tumors progressing in a prior site of radiation are 
allowed for PD-L1 characterization). PD-L1 characterization is not required prior to Cycle 1 
Day 1. The PD-L1 characterization will be performed retrospectively. 
Tumor tissue will be obtained pre- treatment (baseline), between C1D15 and C1D21, and at 
progression (if patient had complete response (CR), partial response (PR) or stable disease 
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(SD) > 27 weeks) provided there is technically biopsiable tumor, and it is safe for patient to 
undergo biopsy.   
Core needle biopsies should be performed utilizing an 18 gauge needle or thicker whenever 
feasible or as directed by institutional standards.  It is recommended that a minimum of 3 and 
up to 5 passes are required to ensure adequate tissue is obtained. Alternative biopsy procedures 
(e.g. cup, punch, excisional, incisional) that are expected to produce a tissue sample greater to 
or equal than a core biopsy with an 18 gauge core biopsies will also be acceptable. Four fine 
needle aspirates (FNAs) will also be obtained when feasible for additional exploratory 
molecular analysis (DNA, RNA, protein). The biopsy approach, number and size may be 
modified as needed based on tumor size and accessibility. 
At screening, archived or newly obtained FFPE (formalin-fixed paraffin embedded) for 5 
unstained (4 or 5 micron, 4 micron preferred) slides must be submitted for characterization at 
a central lab for PD-L1 characterization.  
 
A fine needle aspirate, frozen sample, plastic embedded sample, cell block, clot, bone, bone 
marrow, cytologic specimen or formalin fixed samples frozen at any point will not be 
acceptable for IHC analysis.  These samples will be sent to a central laboratory at Merck. 
7.1.2.6.2 Correlative Studies Blood Sampling 
Peripheral blood mononuclear cell (PBMC) will be collected at baseline, tumor restaging, in 
conjunction with biopsies, and time of progression (if patients have had CR/PR/or SD for > 27 
weeks).  PBMC collections at tumor restaging and in conjunction with biopsies will have a +/- 
1 day window. Up to six (6) Cell Preparation Tubes (CPT) will be collected at each time point. 
These samples will be analyzed for the NanoString assay that will evaluate immune-related 
gene expression signatures and using RNA sequencing, HD peptide analyses, autoantibody 
profiling analyses and other correlative studies to characterize the molecular phenotype of the 
tumor and the tumor microenvironment, which have the potential to predict benefit from 
pembrolizumab. 
If subjects are retreated per Section 7.1.5.5, then the PBMC schedule in Section 6.1 will be 
followed. 
 
Blood samples obtained at baseline or any time point will be used for germline DNA analysis. 
The analysis of next generation sequencing data for DNA somatic mutations is optimal when 
germline data is available to ensure that mutation calling is for somatic alterations.  
 
7.1.2.7 Tumor Imaging for Correlative Studies 
The correlative study imaging will incorporate the standard CT scan parameters or, in the case 
of MRI, the conventional MRI (T1 pre and post-contrast images, T2-weighted images (T2WI), 
Fluid attenuating inversion recovery (FLAIR) images) and other standard sequences routinely 
used. In the case of GBM tumors, additional advanced MRI (MR perfusion [dynamic 
susceptibility contrast (DSC), dynamic contrast enhancement (DCE) and arterial spin labeling 
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(ASL)], MR- diffusion, and MR spectroscopy) sequences will be obtained. The CT or MRI 
tumor scans from tumor assessments at baseline, every 9 or 12 weeks (restaging), and at the 
end-of-treatment will be utilized for these correlative studies.  Additional scans or time points 
will not be required.  Imaging post-processing will include but not be limited to RECIST v1.1, 
irRECIST, advanced quantitative imaging and volume tumor metrics, and voxel-by-voxel 
radiome sequencing (texture, heterogeneity, energy, etc) imaging analysis. Image analyses will 
include non-invasive assessments of cell death (apoptosis), active tumor proliferation, tumor 
invasion, tumor density, vascularity, vascular permeability, microvascular density and 
metabolite profiles. Exploratory analyses will utilize quantitative imaging tumor metrics and 
radiome sequencing for texture maps to assess gene signatures of tumor cell apoptosis, 
invasion and immune cell infiltration. Exploratory analysis using quantitative imaging tumor 
metrics and texture maps will also be used to assess pseudoprogression, progression and 
response. These analyses will be compared to a retrospective cohort of patients that have been 
dichotomously analyzed for lack of inflammatory response versus robust intratumoral 
inflammatory responses to prospectively validate the sensitivity and specificity of this 
approach. 
7.1.2.8 Serial Mutation Assessment 
Patients enrolled on this study will be approached for co-enrollment on PA11-0852 
Clearinghouse protocol for germline testing for the MD Anderson Cancer Center Personalized 
Cancer Therapy Program.  We expect most patients enrolled will have had hot spot mutation 
testing or targeted exome profiling performed through the Clearinghouse protocol.  If evidence 
of clinical activity is seen, targeted exome sequencing on a 200-400 gene platform or larger 
will be performed in patients with objective responses and prolonged stable disease > 27 weeks 
as well as any patients with rapid progression (this would be done as part of a Institute of 
Personalized Cancer Therapy Unusual Responder Program.  In addition patients who have a 
mixed response of response with subsequent progression will be approached for optional 
biopsies for molecular characterization as well as generation of patient-derived xenografts and 
conditionally-reprogrammed cells. This evaluation will determine the evolution of the 
mutation and will facilitate functional characterization. Plasma mutations may be assessed with 
digital PCR or next generation sequencing. 
 
As per the PA11-0852 Clearinghouse protocol, the optional tumor biopsies from baseline and 
the time of progression (if progression after response or unexpected rapid progression) will be 
analyzed.  Development of new mutations or reversal of the mutations will be analyzed and 
correlated with clinical response. This will be our exploratory objective and no formal 
statistical analysis will be done. 
 
7.1.2.9 Microbiome Assessment 
7.1.2.9.1 Skin Microbiome 
Samples will be obtained for skin microbiome testing. Samples may be collected at baseline, 
at onset of toxicity, and time of tumor restaging.  For dermatologic toxicity, samples will be 
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obtained from normal tissue and from area of dermatitis (or inflamed skin condition), samples 
will be obtained from normal tissue and from area of resolved dermatitis (or inflamed skin 
condition). Up to 11 samples (for culture and DNA) may be collected at each time point. In 
cases where dermatitis (or inflamed skin condition) occurs in regions that are not designated 
for skin sample collection, additional skin swab samples may be collected on a case by case 
basis.  Per the laboratory manual, one sample will be used for environmental control. 
 
Patients will be advised to cleanse with only non-antibacterial cleansers during the 7 days 
before sample collection. To maximize microbial load, no bathing, shampooing or 
moisturizing will be advised within 24 hours of sample collection, which previously observed 
produces no discernible shifts in the overall diversity and structures of skin communities.  
Collection and shipping procedures will be described in the laboratory manual.  
 
Clinical data regarding personal history of atopic dermatitis, family history of atopic 
dermatitis, current use of topical or antibiotics and date of initiation, past use (within one 
month) of oral antibiotics with start and end dates, time of last shower, use of antibacterial 
soap, history of Accutane usage with start and end dates, and history of topical retinoid usage 
with start and end dates, will be collected.  
 
De-identified samples and de-identified clinical data will be sent to Jackson Laboratory (Julia 
Oh, PhD) for analyses.  The de-identified clinical data will be coded to the samples. The code 
will only be available to the PI and MDACC study team.  Analyzed patient data will be returned 
to this trial, 2015-0948. 
 
7.1.2.9.2 Gut Microbiome 
In order to evaluate the gut microbiome, fecal samples will be collected from patients at 
baseline, onset of toxicity, time of tumor restaging, and End of Treatment visit per the parent 
treatment protocol.  
 
Sequencing of the V4 region of the 16S bacterial gene will be performed on fecal samples. 
Whole genome shotgun sequencing may be done on smaller subset of samples on the extreme 
(e.g. best and worst responders, most toxic vs least toxic). As an initial assessment of 
microbiome samples; richness, evenness and α-diversity will be assessed. Alpha-diversity is 
measure of intra-sample diversity and will be reported as a continuous variable that is 
calculated based the number and distribution of operational taxonomic units (OTUs refers to 
classification of microbes into phylum, genus, species, etc.). Indices such as Chao1, Simpson, 
and Shannon will be used for the determination of alpha-diversity.  
 
Beta-diversity is a measure of inter-sample diversity and will be assessed by the UniFrac 
method, which calculates the phylogenetic distance between communities. UniFrac distances 
will be calculated in a weighted or unweighted fashion based on presence or absence of OTUs. 
In the weighted strategy, the bacterial taxa that are more abundant will get the higher weight. 
 
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Sequencing reads that result in OTU classification will be normalized across the entire dataset 
by determining the point at which the variance in observed unique OTUs reaches a constant 
value independent of the sequencing depth. These OTUs will be used determine the relative 
abundances of bacterial taxa within a sample. 
 
Only de-identified samples will be sent to Jackson Laboratory (Julia Oh, PhD) for analyses. 
Analyzed patient data will be returned to this trial, 2015-0948. 
 
7.1.2.9.3 Oral Microbiome 
Samples will be obtained for oral microbiome testing. Samples will be collected at baseline, at 
onset of toxicity, and time of tumor restaging.  For oral toxicity, samples will be obtained at 
onset. Collection and shipping procedures will be described in the laboratory manual. 
 
Only de-identified samples will be sent to Jackson Laboratory (Julia Oh, PhD) for analyses. 
Analyzed patient data will be returned to this trial, 2015-0948. 
 
 
 
7.1.2.10 Patient-Reported Outcomes 
Patient-reported outcomes (PROs) will be collected using select PRO-CTCAE items.  Patients 
will have the baseline PRO-CTCAE completed in clinic on paper.  At baseline, patients will 
specify the preference of delivery of subsequent questionnaires on study- computerized, 
telephone-based interactive voice response (IVR) system at the patient’s preferred time and 
days of the week or electronically through web-based platforms with RedCap (Research 
Electronic Data Capture) via an email push. 
 
Subsequent PRO-CTCAE questionnaires will be issued weekly for the first 9 weeks, every 2 
weeks until week 54, and every 4 weeks thereafter until End of Treatment or up to Week 81. 
All questionnaires will have a +/- 2 day window. Questionnaires will be completed at each 
time point if the patient can be contacted and is willing and able to complete. 
 
7.1.2.10.1 PRO Electronic Data Collection and Storage 
Symptom data may be collected and managed using REDCap electronic data capture tools 
hosted at MD Anderson. REDCap (www.project-redcap.org) is a secure, web-based 
application with controlled access designed to support data capture for research studies, 
providing: 1) an intuitive interface for validated data entry; 2) audit trails for tracking data 
manipulation and export procedures; 3) automated export procedures for seamless downloads 
to common statistical packages; and 4) procedures for importing data from external sources.  
 
REDCap (https://redcap.mdanderson.org) is hosted on a secure server by MD Anderson 
Cancer Center's Department of Research Information Systems & Technology Services. 
REDCap has undergone a Governance Risk & Compliance Assessment (05/14/14) by MD 
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Anderson's Information Security Office and found to be compliant with HIPAA, Texas 
Administrative Codes 202-203, University of Texas Policy 165, federal regulations outlined in 
21CFR Part 11, and UTMDACC Institutional Policy #ADM0335. Those having access to the 
data file include the study PI and research team personnel. Users are authenticated against 
MDACC's Active Directory system. External collaborators are given access to projects once 
approved by the project sponsor. The application is accessed through Secure Socket Layer 
(SSL). 
 
All protected health information (PHI) will be removed from the data when it is exported from 
REDCap for analysis. All dates for a given patient will be shifted by a randomly generated 
number between 0 and 364, thus preserving the distance between dates. Dates for each patient 
will be shifted by a different randomly generated number. After publication, study data will be 
archived in REDCap. 
 
7.1.2.10.2 IVR system  
We will use paper or a secure electronic method when the patient is in the clinic, and use an 
interactive voice response (IVR) system, phone calls by field coordinators, secure web access, 
or regular mail when patients are away from the clinic. The method of collecting the PRO-
CTCAE assessments will be based on patient preference and may be varied throughout the 
study based on patient request. An IVR system can greatly facilitate the longitudinal tracking 
of symptoms in patients. IVR systems are programmed to call patients at home for symptom 
assessment. The IVR system asks patients to rate each symptom and interference item on the 
PRO-CTCAE numeric scales using the keypad of a touchtone telephone.  
 
Participants electing to use the IVR system may be provided with an informational brochure 
outlining the steps to complete an IVR call. A telephone number will be provided in the event 
of questions or problems. Patients will also be given a Patient Identification Number (PIN) for 
access to the system. IVR calls will be scheduled at a time that is convenient for the patient.  
 
Completion or failure of calls will be monitored by the research staff. In the event of missed 
calls, a notification screen will appear in the IVR system to alert the research staff. The research 
staff will then contact the patient, check on their status and, if possible, complete the 
assessment with the patient during the telephone interview. The system will continue calling 
the patient at the preset schedule. 
 
The IVR symptom and interference data will be available on an MD Anderson intranet site 
with access limited to authorized project staff only. Patient data will be identified by subject 
study number. 
 
 
 
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7.1.3 Laboratory Procedures/Assessments 
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below. Laboratory tests for hematology, chemistry, urinalysis, and others are 
specified in Table 7.   
 
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Table 7 Laboratory Tests 
Hematology 
Chemistry 
Urinalysis 
Other 
Hematocrit 
Albumin 
Blood 
Serum β-human chorionic gonadotropin† 
Hemoglobin 
Alkaline phosphatase 
Glucose 
  (β-hCG)† 
Platelet count 
Alanine aminotransferase (ALT) 
Protein 
PT (INR) 
WBC (total and differential) 
Aspartate aminotransferase (AST) 
Specific gravity  
aPTT 
Red Blood Cell Count 
Lactate dehydrogenase (LDH) 
Microscopic exam (If abnormal)  
Total thriiodothyronine (T3) 
Absolute Neutrophil Count 
Carbon Dioxide ‡ 
results are noted 
Free thyroxine (T4) 
Absolute Lymphocyte Count 
  (CO2 or biocarbonate) 
Urine pregnancy test † 
Thyroid stimulating hormone (TSH) 
 
Uric Acid 
 
 
 
Calcium 
 
 
 
Chloride 
 
Blood for correlative studies 
 
Glucose 
 
  
 
Phosphorus 
 
  
 
Potassium   
 
  
 
Sodium 
 
  
 
Magnesium 
 
  
 
Total Bilirubin 
 
  
 
Direct Bilirubin (If total bilirubin is 
elevated above the upper limit of 
normal) 
 
 
 
Total protein 
 
 
 
Blood Urea Nitrogen 
 
 
† Perform on women of childbearing potential only. If urine pregnancy results cannot be confirmed as negative, a serum pregnancy test will be required.   
‡ If considered standard of care in your region. 
 
 
 

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Laboratory tests for screening or entry into the Second Course Phase should be performed 
within 28 days prior to the first dose of treatment.  After Cycle 1, pre-dose laboratory 
procedures can be conducted up to 72 hours (3 days) prior to each dosing on Day 1 of each 
subsequent cycle.  Results must be reviewed by the investigator or qualified designee and 
found to be acceptable prior to each dose of trial treatment.  
7.1.4 Other Procedures 
7.1.4.1 Withdrawal/Discontinuation 
When a subject discontinues/withdraws prior to trial completion, all applicable activities 
scheduled for the final trial visit should be performed at the time of discontinuation.  Any 
adverse events which are present at the time of discontinuation/withdrawal should be followed 
in accordance with the safety requirements outlined in Section 7.2 - Assessing and Recording 
Adverse Events.  Subjects who a) attain a CR or b) complete 24 months of treatment with 
pembrolizumab may discontinue treatment with the option of restarting treatment if they meet 
the criteria specified in Section 7.1.5.5.  After discontinuing treatment following assessment 
of CR, these subjects should return to the site for a Safety Follow-up Visit (described in Section 
7.1.5.3) and then proceed to the Follow-Up Period of the study (described in Section 7.1.5.4). 
If a patient withdraws consent for further study treatment, the patient should still be followed 
for progression and survival.  If a patient withdraws consent for further participation in the 
study, follow-up assessments will be discontinued. 
 
7.1.4.2 Blinding/Unblinding 
This is an open label trial; there is no blinding for this trial. 
7.1.5 Visit Requirements 
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.   Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures. 
7.1.5.1 Screening Period 
Approximately 28 days prior to enrollment, potential subjects will be evaluated to determine 
that they fulfill the entry requirements as set forth in Section 5.1. Visit requirements are 
outlined in Section 6.0 – Trial Flow Chart. 
 
After providing main study consent, subjects will undergo the screening period. Results of 
a test performed prior to the subject signing consent as part of routine clinical management 
are acceptable in lieu of a screening test if performed within the specified time frame. 
Screening procedures are to be completed within 28 days prior to the first dose of trial 
treatment except for the following: 
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• 
Laboratory tests are to be performed within 28 days prior to the first dose of trial 
treatment 
• 
For women of reproductive potential, a urine pregnancy test will be performed within 
72 hours (3 days) prior to the first dose of trial treatment. If urine pregnancy results 
cannot be confirmed as negative, a serum pregnancy test will be required 
(performed by the local study site laboratory) 
• 
Archival tissue collection for PD-L1 characterization are not required to be completed 
within 28 days prior to the first dose of trial treatment 
 
Subjects may be rescreened after initially failing to meet the inclusion/exclusion criteria. 
Results from assessments performed during the initial screening period are acceptable in lieu 
of a repeat screening test if performed within the specified time frame and the 
inclusion/exclusion criteria is met. 
 
7.1.5.2 Treatment Period 
Visit requirements are outlined in Section 6.0 – Trial Flow Chart. 
 
7.1.5.3 Post-Treatment Visits 
7.1.5.3.1 Safety Follow-Up Visit 
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days (± 7 days) 
after the last dose of trial treatment or before the initiation of a new anti-cancer treatment, 
whichever comes first.  All AEs that occur prior to the Safety Follow-Up Visit should be 
recorded.  Subjects with an AE of Grade > 1 will be followed until the resolution of the AE to 
Grade 0-1 or until the beginning of a new anti-neoplastic therapy, whichever occurs first.  SAEs 
that occur within 90 days of the end of treatment or before initiation of a new anti-cancer 
treatment should also be followed and recorded.  Subjects who are eligible for retreatment with 
pembrolizumab (as described in Section 7.1.5.5) may have up to two safety follow-up visits, 
one after the Treatment Period and one after the Second Course Phase. 
 
7.1.5.4 Follow-up Visits 
Subjects who discontinue trial treatment for a reason other than disease progression will move 
into the Follow-Up Phase. Post discontinuation, subjects will be assessed every 9 weeks, 12 
weeks, or at the discretion of the treating physician (± 7 days) by radiologic imaging to monitor 
disease status.  Every effort should be made to collect information regarding disease status 
until the start of new anti-neoplastic therapy, disease progression, death, end of the study or if 
the subject begins retreatment with pembrolizumab as detailed in Section 7.1.5.5.  Information 
regarding post-study anti-neoplastic treatment will be collected if new treatment is initiated. 
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Subjects who are eligible to receive retreatment with pembrolizumab according to the criteria 
in Section 7.1.5.5 will move from the follow-up phase to the Second Course Phase when they 
experience disease progression.  Details are provided in Section 6.1 – Trial Flow Chart for 
Retreatment.    
7.1.5.4.1 Survival Follow-up 
Once a subject experiences confirmed disease progression or starts a new anti-cancer therapy, 
the subject moves into the survival follow-up phase, and survival data will be collected from a 
chart review, patient visit, or by telephone every 12 weeks (± 4 weeks) to assess for survival 
status until death, withdrawal of consent, or the end of the study, whichever occurs first.  
7.1.5.5 Second Course Phase (Retreatment Period) 
Subjects who stop pembrolizumab with SD or better may be eligible for up to one year of 
additional pembrolizumab therapy if they progress after stopping study treatment.  This 
retreatment is termed the Second Course Phase of this study and is only available if the study 
remains open and the subject meets the following conditions: 
• Either  
o Stopped initial treatment with pembrolizumab after attaining an investigator-
determined confirmed CR according to RECIST v1.1 or irRECIST or method 
of tumor evaluation criteria best suitable and accepted for the tumor type 
evaluated, and 
▪ Was treated for at least 27 weeks (9 cycles) with pembrolizumab before 
discontinuing therapy 
▪ Received at least two treatments with pembrolizumab beyond the date when 
the initial CR was declared 
 
 
OR 
o Had SD, PR or CR and stopped pembrolizumab treatment after 24 months of study 
therapy for reasons other than disease progression or intolerability 
AND 
• Experienced an investigator-determined confirmed radiographic disease progression 
after stopping their initial treatment with pembrolizumab 
• Did not receive any anti-cancer treatment since the last dose of pembrolizumab 
• Has a performance status of 0 or 1 on the ECOG Performance Scale 
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• Demonstrates adequate organ function as detailed in Section 5.1.2 
• Female subject of childbearing potential should have a negative serum or urine 
pregnancy test within 72 hours prior to receiving retreatment with study medication.   
• Female subject 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 (Reference Section 
5.7.2).  Subjects of child bearing potential are those who have not been surgically 
sterilized or have been free from menses for > 1 year.  
• Male subject 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.   
• Does not have a history or current evidence of any condition, therapy, or laboratory 
abnormality that might 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. 
Subjects who restart treatment will be retreated at the same dose and dose interval as when 
they last received pembrolizumab.  Treatment will be administered for up to one additional 
year. 
Visit requirements are outlined in Section 6.1 – Trial Flow Chart. 
 
 
Assessing and Recording Adverse Events 
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol-
specified procedure, whether or not considered related to the medicinal product or protocol-
specified procedure.  Any worsening (i.e., any clinically significant adverse change in 
frequency and/or intensity) of a preexisting condition that is temporally associated with the use 
of the Merck’s product, is also an adverse event. 
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  Examples 
of this may include, but are not limited to, teething, typical crying in infants and children and 
onset of menses or menopause occurring at a physiologically appropriate time. 
Merck product includes any pharmaceutical product, biological product, device, diagnostic 
agent or protocol-specified procedure, whether investigational (including placebo or active 
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comparator medication) or marketed, manufactured by, licensed by, provided by or distributed 
by Merck for human use. 
Adverse events may occur during the course of the use of Merck product in clinical trials or 
within the follow-up period specified by the protocol, or prescribed in clinical practice, from 
overdose (whether accidental or intentional), from abuse and from withdrawal. 
Adverse events may also occur in screened subjects during any pre-allocation baseline period 
as a result of a protocol-specified intervention, including washout or discontinuation of usual 
therapy, diet, placebo treatment or a procedure. 
Progression of the cancer under study is not considered an adverse event unless it is considered 
to be drug related by the investigator. 
All adverse events will be recorded from the time the consent form is signed through 30 days 
following cessation of treatment and at each examination on the Adverse Event case report 
forms/worksheets. The reporting timeframe for adverse events meeting any serious criteria is 
described in section 7.2.3.1. 
The study drug-related adverse event data will be collected and stored in the Investigational 
Cancer Therapeutics database, Molecular and Clinical Data Integrated Platform (MOCLIP). 
The PI or designee will be responsible for determining attribution for all events, and this will 
be documented in the electronic medical record. 
 
 
7.2.1 Definition of an Overdose for This Protocol and Reporting of Overdose to the 
IND Sponsor 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. Appropriate supportive treatment should be provided 
if clinically indicated. 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.” 
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All reports of overdose with and without an adverse event must be reported within 24 hours to 
the IND Sponsor and within 2 working days hours to Merck Global Safety. (Attn: Worldwide 
Product Safety; FAX 215 993-1220) 
7.2.2 Reporting of Pregnancy and Lactation to the IND Sponsor and to 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), including the pregnancy of a male subject's female partner that occurs during 
the trial or within 120 days of completing the trial completing the trial, or 30 days following 
cessation of treatment if the subject initiates new anticancer therapy, whichever is earlier.  All 
subjects and female partners of male subjects who become pregnant must be followed to the 
completion/termination of the pregnancy.  Pregnancy outcomes of spontaneous abortion, 
missed abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, 
miscarriage and stillbirth must be reported as serious events (Important Medical Events).  If 
the pregnancy continues to term, the outcome (health of infant) must also be reported. 
Such events must be reported within 24 hours to the IND Sponsor and within 2 working days 
to Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220) 
7.2.3 Immediate Reporting of Adverse Events to the IND Sponsor and to Merck 
7.2.3.1 Serious Adverse Events 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of either 
the investigator or the sponsor, it results in any of the following outcomes: 
• Death 
• A life-threatening adverse drug experience – any adverse experience that places the 
patient, in the view of the initial reporter, at immediate risk of death from the adverse 
experience as it occurred. It does not include an adverse experience that, had it occurred 
in a more severe form, might have caused death. 
• Inpatient hospitalization or prolongation of existing hospitalization 
• A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions. 
• A congenital anomaly/birth defect. 
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
Examples of such medical events include allergic bronchospasm requiring intensive treatment 
in an emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse (21 CFR 
312.32). 
 
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• Important medical events as defined above, may also be considered serious 
adverse events. Any important medical event can and should be reported as an 
SAE if deemed appropriate by the Principal Investigator or the IND Sponsor, IND 
Office. 
• All events occurring during the conduct of a protocol and meeting the definition of a 
SAE must be reported to the IRB in accordance with the timeframes and procedures 
outlined in “The University of Texas M. D. Anderson Cancer Center Institutional 
Review Board Policy for Investigators on Reporting Unanticipated Adverse Events for 
Drugs and Devices”.  Unless stated otherwise in the protocol, all SAEs, expected or 
unexpected, must be reported to the IND Office, regardless of attribution (within 5 
working days of knowledge of the event). 
• All life-threatening or fatal events, that are unexpected, and related to the study drug, 
must have a written report submitted within 24 hours (next working day) of knowledge 
of the event to the Safety Project Manager in the IND Office.   
• Unless otherwise noted, the electronic SAE application (eSAE) will be utilized for 
safety reporting to the IND Office and MDACC IRB.  
• Serious adverse events will be captured from the time of the first protocol-specific 
intervention, until 90 days after the last dose of drug, unless the participant 
withdraws consent. Serious adverse events must be followed until clinical recovery 
is complete and laboratory tests have returned to baseline, progression of the 
event has stabilized, or there has been acceptable resolution of the event. 
• Additionally, any serious adverse events that occur after the 90 day time period 
that are related to the study treatment must be reported to the IND Office. This 
may include the development of a secondary malignancy. 
 
Reporting to FDA: 
 
• Serious adverse events will be forwarded to FDA by the IND Sponsor (Safety Project 
Manager IND Office) according to 21 CFR 312.32. 
 
It is the responsibility of the PI and the research team to ensure serious adverse events 
are reported according to the Code of Federal Regulations, Good Clinical Practices, the 
protocol guidelines, the sponsor’s guidelines, and Institutional Review Board policy. 
 
Any serious adverse event, or follow up to a serious adverse event, including death due to any 
cause other than progression of the cancer under study that occurs to any subject from the time 
the consent is signed through 90 days following cessation of treatment, or the initiation of new 
anti-cancer therapy, whichever is earlier, whether or not related to Merck product, must be 
reported within 2 working days to Merck Global Safety.  
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to Merck product that is brought to the attention of the investigator at 
any time following consent through the end of the specified safety follow-up period specified 
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in the paragraph above, or at any time outside of the time period specified in the previous 
paragraph also must be reported immediately to the IND Sponsor and to Merck. 
SAE reports and any other relevant safety information are to be forwarded to the Merck 
Global Safety facsimile number:  +1-215-993-1220 
A copy of all 15 Day Reports and Annual Progress Reports is submitted as required by FDA, 
European Union (EU), Pharmaceutical and Medical Devices agency (PMDA) or other local 
regulators. Investigators will cross reference this submission according to local regulations to 
the Merck Investigational Compound Number (IND, CSA, etc.) at the time of submission.  
Additionally investigators will submit a copy of these reports to Merck & Co., Inc. (Attn: 
Worldwide Product Safety; FAX 215 993-1220) at the time of submission to FDA. 
All subjects with serious adverse events must be followed up for outcome. 
7.2.3.2 Events of Clinical Interest 
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be recorded as such on the Adverse Event case report forms/worksheets and 
reported within 24 hours to the IND Sponsor and within 2 working days to Merck Global 
Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220). 
For the time period beginning when the consent form is signed until treatment, any ECI, or 
follow up to an ECI, that occurs to any subject must be reported within 24 hours to the IND 
Sponsor and within 2 working days to Merck Global Safety if it causes the subject to be 
excluded from the trial, or is the result of a protocol-specified intervention, including but not 
limited to washout or discontinuation of usual therapy, diet, placebo treatment or a procedure. 
For the time period beginning at treatment through 90 days following cessation of treatment, 
or 30 days following cessation of treatment if the subject initiates new anticancer therapy, 
whichever is earlier, any ECI, or follow up to an ECI, whether or not related to Merck product, 
must be reported within 24 hours to the IND Sponsor and within 24 hours to Merck Global 
Safety. 
Events of clinical interest for this trial include: 
1.  An overdose of Merck product, as defined in Section 7.2.1 - Definition of an Overdose for 
This Protocol and Reporting of Overdose to the IND 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.* 
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*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.  This is a recommendation; however, 
the clinical decision will be made by the PI and consulting/treating physician. 
7.2.3.3 Protocol-Specific Exceptions to Serious Adverse Event Reporting  
Efficacy endpoints as outlined in this section will not be reported to Merck as described in 
Section 7.2.3- Immediate Reporting of Adverse Events to the IND Sponsor and to Merck, 
unless there is evidence suggesting a causal relationship between the drug and the event. Any 
such event will be submitted to the IND Sponsor within 24 hours and to Merck Global Safety 
within 2 working days either by electronic or paper media. 
Specifically, the suspected/actual events covered in this exception include any event that is 
disease progression of the cancer under study. 
The IND Sponsor will monitor unblinded aggregated efficacy endpoint events and safety data 
to ensure the safety of the subjects in the trial. Any suspected endpoint which upon review is 
not progression of the cancer under study will be forwarded to Merck Global Safety as a SAE 
within 2 working days of determination that the event is not progression of the cancer under 
study 
Hospitalization related to convenience (e.g. transportation issues etc.) will not be considered a 
SAE. 
 
 
7.2.4 Evaluating Adverse Events 
An investigator who is a qualified physician will evaluate all adverse events according to the 
NCI Common Terminology for Adverse Events (CTCAE), version 4.03. Any adverse event 
which changes CTCAE grade over the course of a given episode will have each change of 
grade recorded on the adverse event case report forms/worksheets. 
All adverse events regardless of CTCAE grade must also be evaluated for seriousness. 
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Table 8 Evaluating Adverse Events 
An investigator who is a qualified physician, will evaluate all adverse events as to: 
V4.03 CTCAE 
Grading 
Grade 1 
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention not indicated. 
 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL. 
 
Grade 3 
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation or hospitalization indicated; 
disabling; limiting self-care ADL. 
 
Grade 4 
Life threatening consequences; urgent intervention indicated. 
 
Grade 5 
Death related to AE 
Seriousness 
A serious adverse event is any adverse event occurring at any dose or during any use of Merck product that: 
 
†Results in death; or 
 
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred (Note: This does not include an 
adverse event that, had it occurred in a more severe form, might have caused death.); or 
 
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or 
 
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation. (Note: Hospitalization [including hospitalization for an elective procedure] for a preexisting 
condition which has not worsened does not constitute a serious adverse event.); or 
 
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis);or 
 
Is a new cancer; (that is not a condition of the study) or 
 
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event. An overdose that is not 
associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24 hours. 
 
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes 
listed previously (designated above by a †). 
Duration 
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units 
Action taken  
Did the adverse event cause the Merck product to be discontinued? 
Relationship to 
test drug  
Did the Merck product cause the adverse event? The determination of the likelihood that the Merck product caused the adverse event will be provided by an 
investigator who is a qualified physician. The investigator’s signed/dated initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialed document must be retained for the required regulatory time frame. The 
criteria below are intended as reference guidelines to assist the investigator in assessing the likelihood of a relationship between the test drug and the adverse event 
based upon the available information.  
The following components are to be used to assess the relationship between the Merck product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the Merck product caused the adverse event (AE): 
 
Exposure 
Is there evidence that the subject was actually exposed to the Merck product such as: reliable history, acceptable compliance assessment (pill 
count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen? 
 
Time Course 
Did the AE follow in a reasonable temporal sequence from administration of the Merck product?  
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal product)? 
 
Likely Cause 
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or environmental 
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Relationship 
The following components are to be used to assess the relationship between the test drug and the AE: (continued) 
to Merck 
product 
(continued)  
Dechallenge 
Was the Merck product discontinued or dose/exposure/frequency reduced? 
If yes, did the AE resolve or improve? 
If yes, this is a positive dechallenge. If no, this is a negative dechallenge. 
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the AE resolved/improved despite continuation 
of the Merck product; or (3) the trial is a single-dose drug trial); or (4) Merck product(s) is/are only used one time.) 
 
Rechallenge 
Was the subject re-exposed to the Merck product in this study? 
If yes, did the AE recur or worsen? 
If yes, this is a positive rechallenge. If no, this is a negative rechallenge. 
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, or (2) the trial is a single-dose drug trial); or 
(3) Merck product(s) is/are used only one time). 
NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN 
CAUSED BY THE MERCK PRODUCT, OR IF REEXPOSURE TO THE MERCK PRODUCT POSES ADDITIONAL POTENTIAL 
SIGNIFICANT RISK TO THE SUBJECT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE U.S. CLINICAL 
MONITOR AS PER DOSE MODIFICATION GUIDELINES IN THE PROTOCOL. 
 
Consistency 
with Trial 
Treatment 
Profile 
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the Merck product or drug class pharmacology 
or toxicology? 
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to his/her best clinical judgment, including 
consideration of the above elements. 
Record one of the following 
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of a Merck product relationship). 
Yes, there is a reasonable 
possibility of Merck product 
relationship. 
There is evidence of exposure to the Merck product.  The temporal sequence of the AE onset relative to the administration of the Merck product 
is reasonable.  The AE is more likely explained by the Merck product than by another cause. 
No, there is not a reasonable 
possibility Merck product 
relationship 
Subject did not receive the Merck product OR temporal sequence of the AE onset relative to administration of the Merck product is not reasonable 
OR there is another obvious cause of the AE.  (Also entered for a subject with overdose without an associated AE.) 

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7.2.5 Sponsor Responsibility for Reporting Adverse Events 
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations.  
8.0 STATISTICAL ANALYSIS PLAN 
This section outlines the statistical analysis strategy and procedures for the study. If, after 
the study has begun, changes are made to primary and/or key secondary hypotheses, or the 
statistical methods related to those hypotheses, then the protocol will be amended (consistent 
with ICH Guideline E-9).  
 
 
Statistical Analysis Plan Summary 
This section contains a brief summary of the statistical analyses for this trial. There will be 10 
cohorts included in the overall population of different cancer types. All patients who have 
received at least 1 dose of study medication with at least one adequate on-study tumor 
assessment will be included in the efficacy analysis. If a patient discontinued the study before 
the first radiological assessment due to progression of disease, either radiological or clinical, 
they will be considered evaluable and will be included in the efficacy analysis. However, if the 
patient discontinued the study before 27 weeks due to reasons other than progression of disease 
or death, they will be considered non evaluable for assessment of primary efficacy endpoint 
(alive and progression-free at 27 weeks). All patients who received at least 1 dose of study 
medication will be considered for the toxicity analysis.  
 
8.1.1 General Analyses 
Tabulations will be produced for appropriate demographic, baseline, efficacy and safety 
parameters.  For categorical variables, summary tabulations of the number and percentage of 
subjects within each category (with a category for missing data) of the parameter will be 
presented, as well as two-sided 95% confidence intervals, unless otherwise stated. For 
continuous variables, the number of subjects, mean, median, standard deviation (SD), 
minimum, and maximum values will be presented.  Time-to-event data will be summarized 
using Kaplan-Meier methodology using 25th, 50th (median), and 75th percentiles with 
associated 2-sided 95% confidence intervals, as well as percentage of censored observations. 
 
 
8.1.2 Efficacy Analyses 
Clinical efficacy will be measured by non-progression rate (NPR) at 27 weeks as defined as 
the percentage of patients who are alive and progression-free at 27 weeks as assessed by 
RECIST v1.1 criteria or irRECIST or method of tumor evaluation criteria best suitable and 
accepted for the tumor type evaluated.  A 95% confidence interval of response rate will be 
estimated based on a binomial distribution. Other efficacy parameters such as percentage of 
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patients with objective response, clinical benefit (CR, PR, SD >/=4 months), PFS, OS and 
DOR and their correlation to PD-L1 status will also be analyzed. 
 
8.1.3 Safety Analysis 
For the objective of describing the toxicity profile, descriptive statistics will be provided on 
the grade and type of toxicity by dose level.   
 
8.1.3.1 Adverse Events 
Adverse Events (AEs) will be coded using the NCI-CTCAE (4.03) dictionary and displayed 
for all study patients combined.  Analyses of AEs will be performed for those events that are 
considered treatment emergent, where treatment-emergent is defined as any AE with onset or 
worsening of a pre-existing condition on or after the first administration of study medication 
through 30 days following last dose or any event considered drug-related by the investigator 
through the end of the study. AEs with partial dates will be assessed using the available date 
information to determine if treatment-emergent; AEs with completely missing dates will be 
assumed to be treatment-emergent.  
 
AEs will be summarized by patient incidence rates, therefore, in any tabulation, a patient 
contributes only once to the count for a given AE preferred term.  The number and percentage 
of patients with any treatment-emergent AE will be summarized for all study patients 
combined. The number and percentage of patients with treatment-emergent AEs assessed by 
the Investigator as at least possibly related to treatment will also be tabulated. The number and 
percentage of patients with any grade ≥ 3 treatment-emergent AE will be tabulated in the same 
manner. In the event a patient experiences repeated episodes of the same AE, then the event 
with the highest severity and/or strongest causal relationship to study treatment will be used 
for purposes of tabulations.  Serious AEs will also be tabulated.  
 
No formal hypothesis-testing analysis of AE incidence rates will be performed.  All AEs 
(treatment emergent and post-treatment) will be listed in patient data listings.  By-patient 
listings will be provided for the following: patient deaths; serious AEs; and AEs leading to 
withdrawal.  
 
8.1.3.2 Laboratory Data  
The actual value and change from baseline to each on study evaluation will be summarized for 
each clinical laboratory parameter, including hematology and clinical chemistry, for all study 
patients combined. In the event of repeat values, the last non-missing value per study day/time 
will be used. Severity of select clinical lab measures will be determined using CTCAE criteria 
(e.g. those measures that have a corresponding CTCAE grade classification). Labs with 
CTCAE grades greater than or equal to 3 will be presented in a data listing. Shift tables that 
present changes from baseline to worst on-study values relative to CTCAE classification 
ranges will be produced.  
 
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8.1.4 Power and Sample Size 
The sample size for this study is based on the Simon’s optimal two-stage design.17  
 
This trial has futility interim analyses for the well-defined expansion cohorts of Cohorts 1-9, 
and the endpoint is 27-week PFS (referred to as non-progression rate, NPR).  Cohorts 1-9 will 
follow a two-stage design with 12 patients in the first stage and 13 in the second stage. If among 
the 12 evaluable patients enrolled in the first stage, 3 or more patients are alive and progression-
free at 27 weeks, enrollment into the second stage will begin. If more than 7 of the 25 total 
evaluable patients in a cohort are alive and progression-free at 27 weeks, the drug will be 
considered worthy of further study in that cohort. The null success rate is set at 20% and the 
alternative at 40% for each cohort. This design has a 10% Type I error rate, 82% power and 
56% probability of stopping after the first stage if the true 27-week PFS rate is 20%.  
 
The maximum accrual will be 250 patients (25 patients x 10 cohorts). In order to get 250 
evaluable patients, up to 275 patients may need to be enrolled. 
 
In Cohort 10, there will not be a two-step design since the cohort will be composed of a 
heterogeneous tumor population. If one patient of a tumor type experiences success defined as 
subjects being alive and progression-free at 27 weeks, then that tumor type may be expand to 
an additional 14 patients. 
 
8.1.5 Interim Analyses 
For Cohorts 1-9, in accordance with the Simon two-stage study design described in Section 
8.1.4, there will be a preliminary assessment of efficacy for each cohort after the first 12 
evaluable patients enrolled in that cohort have 27-week data available to assess efficacy.  Note 
that this initial analysis for a cohort may take place sooner than when the 12th patient has 
available data, should there be 3 or more responders after fewer than 12 patients are enrolled. 
Should the trial be terminated at the first stage, all efficacy and safety analyses as noted above 
will be performed. Patient enrollment will be suspended pending observation of the needed 
numbers of responses. 
 
Response Monitoring: 
• STAGE 1: 
A Futility Summary will be submitted to the IND Medical Monitor after 12 subjects 
are evaluable for response (at 27 weeks) per cohort. 
• STAGE 2: 
A final Response Summary will be submitted to the IND Medical Monitor after there 
are 25 evaluable patients for response per cohort. 
 
The final analysis for each cohort will take place after there are 25 patients evaluable for 
analysis of efficacy. Additional data summarization may take place after all available survival 
data are collected, or after investigator decision, as appropriate.   
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Statistical Analysis Plan 
8.2.1 Responsibility for Analyses 
The statistical analysis of the data obtained from this study will be the responsibility of the 
University of Texas MD Anderson Cancer Center, Biostatistics department. A detailed analysis 
plan has been developed and will be implemented. 
 
Study Objectives  
8.3.1 Primary Objective  
Objective:  To obtain early indication of efficacy by evaluation of non-progression rate (NPR) 
at 27 weeks as defined as the percentage of patients who are alive and progression-free at 27 
weeks, as assessed by RECIST v1.1 or irRECIST or method of tumor evaluation criteria best 
suitable and accepted for the tumor type evaluated in patients with advanced tumor types 
receiving pembrolizumab. 
8.3.2 Secondary Objectives  
(1) Objective:  To correlate efficacy by evaluation of tumor size to PD-L1 status among 
patients with advanced tumor types receiving pembrolizumab.  
(2) Objective:  To evaluate safety and tolerability of pembrolizumab in patients with advanced 
tumors. 
(3) Objective:  To evaluate the percentage of patients with objective response (CR or PR), 
clinical benefit (CR, PR, stable disease [SD] >/=4 months), progression free survival 
(PFS), overall survival (OS), and duration of response (DOR) as assessed by RECIST v1.1 
in patients with advanced tumor types receiving pembrolizumab.  
(4) Objective: To evaluate the percentage of patients with objective response (CR or PR), 
clinical benefit (CR, PR, or SD >/=4 months), PFS, and DOR as assessed by irRECIST in 
patients with advanced tumor types receiving pembrolizumab. 
(5) Objective:  To correlate the NPR at 27 weeks (9 cycles), objective response (CR or PR), 
clinical benefit (CR, PR, or SD >/=4 months), PFS, OS, and DOR to PD-L1 status among 
patients with advanced tumor types receiving pembrolizumab.  
8.3.3 Exploratory Objectives: 
(1) Objective:  To evaluate the potential role of tumor-associated immune biomarkers for 
prediction of therapy effectiveness in patients with advanced tumor types receiving 
pembrolizumab.  
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(2) Objective:  To correlate the potential role of tumor-associated immune biomarkers for 
prediction of therapy effectiveness to PD-L1 status among patients with advanced tumor 
types receiving pembrolizumab. 
(3) Objective:  To identify imaging characteristics associated with immunological changes in 
tumor following treatment with pembrolizumab. 
(4) Objective:  To compare tumor mutation burden and serial assessment of mutation status 
in biopsies obtained at baseline and progression in patients with advanced tumor types 
receiving pembrolizumab. 
(5) Objective: To evaluate PRO utilizing the NCI PRO-CTCAE items. 
(6) Objective: For patients that experience dermatologic irAEs, to compare the skin 
microbiome of normal (non-rash) skin to skin microbiome of area with rash.  
(7) Objective: For patients that experience oral irAEs, to assess the oral microbiome at 
baseline, at onset of toxicity, and time of tumor restaging  
(8) Objective: For patients that experience gut irAEs, to assess the gut microbiome at baseline, 
onset of toxicity, time of tumor restaging, and End of Treatment visit per the parent treatment 
protocol. 
(9) Objective: To analyze tumor-infiltrating lymphocytes using H&E stained whole slide 
images. 
 
Hypotheses: 
Intravenous administration of single agent pembrolizumab (MK-3475) to subjects with a 
given PD-L1 positive advanced tumor type will result in an NPR at 27 weeks greater than 
20% based on RECIST v1.1 criteria or irRECIST or according to tumor evaluation criteria 
best suitable and accepted for the tumor type evaluated.  
 
Analysis Endpoints 
Efficacy endpoints will be evaluated as aggregate and between PD-L1 and non-PD-L1 
expressing tumor types within and across tumor types.  
8.5.1.1 Efficacy Endpoints 
The primary efficacy endpoint is NPR at 27 weeks, defined as the proportion of subjects in 
the analysis population who have has no progression of disease by 27 weeks.  Response for 
the primary analysis will be determined by the investigator assessment, and a confirmation 
assessment is required per RECIST v1.1 or irRECIST or according to tumor evaluation 
criteria best suitable and accepted for the tumor type evaluated. 
 
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Secondary efficacy endpoints include: objective response (CR, PR); clinical benefit (CR, PR 
or SD >/=4 months)  according to RECIST, v1.1 or irRECIST;; progression-free survival 
(PFS), defined as the time from allocation to the first documented disease progression 
according to RECIST v1.1  or irRECIST or death due to any cause, whichever occurs first; 
and overall survival (OS). The duration of overall response is measured from the time 
measurement criteria are first met for CR/PR (whichever is first recorded) until the first date 
that progressive disease is objectively documented. The duration of overall complete response 
is measured from the time measurement criteria are first met for CR until the first date that 
recurrent disease is objectively documented. Stable disease is measured from the start of the 
treatment until the criteria for progression are met. 
 
 
Per RECIST 1.1 or irRECIST, response should be confirmed by a repeat radiographic 
assessment not less than 4 weeks from the date the response was first documented. The scan for 
confirmation of response may be performed at the earliest 4 weeks after the first indication of 
response, or at the next scheduled scan, whichever is clinically indicated. 
 
Disease progression should be confirmed at least 4 weeks after the first scan indicating 
progressive disease in clinically stable subjects. Subjects who have unconfirmed disease 
progression may continue on treatment until progression is confirmed provided they have met 
the conditions detailed in Section 7.1.2.5. Symptomatic deterioration may indicate progressive 
disease (PD). However, radiological confirmation of PD is strongly recommended. 
 
8.5.1.2 Safety Endpoints 
The primary safety endpoints are AEs graded using CTCAE (Version 4.03) criteria. Safety 
will be assessed by quantifying the toxicities and grades experienced by subjects who have 
received pembrolizumab (MK-3475), including serious adverse events (SAEs), events of 
clinical interest (ECIs), and immune-related adverse experiences (irAEs). Other safety 
endpoints include laboratory safety assessments, ECOG performance status, vital signs and 
physical examinations. 
8.5.1.3 Exploratory Endpoints 
Image analyses will include non-invasive assessments of cell death (apoptosis), active tumor 
proliferation, tumor invasion, tumor density, vascularity, vascular permeability, microvascular 
density and metabolite profiles. Exploratory analyses will utilize quantitative imaging tumor 
metrics and radiome sequencing for texture maps to assess gene signatures of tumor cell 
apoptosis, invasion and immune cell infiltration. Exploratory analysis using quantitative 
imaging tumor metrics and texture maps will also be used to assess pseudoprogression, 
progression and response. These analyses will be compared to a retrospective cohort of patients 
that have been dichotomously analyzed for lack of inflammatory response versus robust 
intratumoral inflammatory responses to prospectively validate the sensitivity and specificity of 
this approach. 
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Analysis results of Tumor-infiltrating lymphocytes will be summarized using descriptive 
statistics. 
Patient responses to the select items of the PRO-CTCAE will be examined over time using 
descriptive statistics to capture the patient symptom toxicity.  
Microbiome analyses will utilize (1) gene expression for a variety of genes in normal skin vs. 
skin area with rash for patients that experience dermatologic irAEs, (2) gene expression for a 
variety of genes at baseline, at onset of toxicity, and time of tumor restaging for patients that 
experience oral irAEs, and (3) gene expression for a variety of genes at baseline, at onset of 
toxicity, time of tumor restaging, and end of treatment visit for patients that experience gut 
irAEs. These analyses will explore differentially expressed genes between normal skin and 
skin with rash and will explore differentially expressed genes at onset of toxicity comparing to 
baseline for patients that experience oral irAEs and for patients that experience gut irAEs. The 
threshold of absolute fold change≥1.3 and Benjamini-Hochberg adjusted p<0.2 will be used to 
identify biologically meaningful sets of differentially expressed genes.18 Due to exploratory 
nature of this analysis, we may use different significant criteria. 
8.5.2 Analysis Populations 
The population analysis will be evaluated as aggregate data, by tumor indication, and between 
PD-L1 and non-PD-L1 expressing tumor types.  
 
8.5.2.1 Efficacy Analysis Populations 
There will be 10 cohorts included in the overall population of different cancer types.  The 
safety population will be the main population for all analyses (demographics, efficacy and 
safety) unless otherwise stated.  The modified intent-to-treat (ITT) population will include all 
patients enrolled in the study that received at least one dose of drug. 
 
8.5.3 Statistical Methods 
Tabulations will be produced for appropriate demographic, baseline, efficacy and safety 
parameters.  For categorical variables, summary tabulations of the number and percentage of 
subjects within each category (with a category for missing data) of the parameter will be 
presented, as well as two-sided 95% confidence intervals, unless otherwise stated. For 
continuous variables, the number of subjects, mean, median, standard deviation (SD), 
minimum, and maximum values will be presented.  Time-to-event data will be summarized 
using Kaplan-Meier methodology using 25th, 50th (median), and 75th percentiles with 
associated 2-sided 95% confidence intervals, as well as percentage of censored observations. 
 
No imputation of missing efficacy data is planned.  For time to event analyses, patients who 
have no efficacy evaluations for disease recurrence will be considered censored at time 0.   
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For adverse events (AEs), missing dates will not be imputed, however, if partial dates are 
available, they will be used to assess if the AE occurred during the treatment period.  Missing 
severities of AEs will not be imputed and will be considered missing in any tabulations of AE 
severity.  If an AE is missing a response to the question regarding relationship to treatment, 
the event will be considered to be related.  
 
No adjustments for multiple testing will be performed. All inferences beyond those involved 
in the Simon design will be considered exploratory.  Unless otherwise stated, all statistical tests 
will be conducted at the α=0.05 (2-sided) level. 
 
The statistical analysis of the data obtained from the PRO-CTCAE questionnaires will be 
performed. We will use primarily descriptive statistics to describe how patients rated 
symptoms over time. We will construct lowess curves for each symptom to graphically display 
how symptom changes over time.  
 
 
9.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES 
 
Investigational Product  
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and 
regulations. 
Clinical Supplies will be provided by Merck as summarized in Table 9. 
Table 9 Product Descriptions 
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. 
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Clinical Supplies Disclosure 
This trial is open-label; therefore, the subject, the trial site personnel, the IND 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.   
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. 
10.0 ADMINISTRATIVE AND REGULATORY DETAILS 
 Confidentiality 
10.1.1 Confidentiality of Data 
By signing this protocol, the investigator affirms to the IND Sponsor that information 
furnished to the investigator by the IND Sponsor will be maintained in confidence, and 
such information will be divulged to the institutional review board, ethics review committee 
(IRB/ERC) or similar or expert committee; affiliated institution and employees, only 
under an appropriate understanding of confidentiality with such board or committee , 
affiliated institution and employees. Data generated by this trial will be considered 
confidential by the investigator, except to the extent that it is included in a publication as 
provided in the Publications section of this protocol. 
 
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10.1.2 Confidentiality of Subject Records 
By signing this protocol, the investigator agrees that the IND Sponsor (or Sponsor 
representative), IRB/ERC, or regulatory authority representatives may consult and/or copy 
trial documents in order to verify worksheet/case report form data. By signing the consent 
form, the subject agrees to this process. If trial documents will be photocopied during the 
process of verifying worksheet/case report form information, the subject will be identified 
by unique code only; full names/initials will be masked prior to transmission to the IND 
Sponsor. 
 
By signing this protocol, the investigator agrees to treat all subject data used and disclosed 
in connection with this trial in accordance with all applicable privacy laws, rules and 
regulations. 
 
10.1.3 Confidentiality of Investigator Information  
By signing this protocol, the investigator recognizes that certain personal identifying 
information with respect to the investigator, and all subinvestigators and trial site personnel, 
may be used and disclosed for trial management purposes, as part of a regulatory 
submissions, and as required by law. This information may include: 
 
1. Name, address, telephone number and e-mail address; 
2. Hospital or clinic address and telephone number; 
3. Curriculum vitae or other summary of qualifications and credentials; and 
4. Other professional documentation. 
 
Consistent with the purposes described above, this information may be transmitted to the 
IND Sponsor, and subsidiaries, affiliates and agents of the Merck, in your country and 
other countries, including countries that do not have laws protecting such  information. 
Additionally, the investigator’s name and business contact information may be included 
when reporting certain serious adverse events to regulatory authorities or to other 
investigators. By signing this protocol, the investigator expressly consents to these uses and 
disclosures. 
 
If this is a multicenter trial, in order to facilitate contact between investigators, the IND 
Sponsor may share an investigator’s name and contact information with other participating 
investigators upon request. 
 
10.1.4 Data Sharing 
Study data, imaging, and samples will not be shared with any individuals or entities unless 
specified in a clinical trial agreement or data or material transfer agreement. 
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De-identified data, including, but not limited to tumor type, tumor response, and toxicity, and 
de-identified scans and imaging will be reviewed by the collaborator, Rivka Colen at 
University of Pittsburgh, to provide expertise in the statistical analyses for the relationship of 
immune cell metabolism and radiomics. A waiver of consent will be utilized for patients that 
cannot be reconsented.  Results from the analysis will be sent to the PI. 
De-identified data output from RNA sequencing performed on tumor samples will be reviewed 
by the collaborator, Daniel Lee, MD, PhD, at InSilico Genomics to provide expertise in the 
statistical analyses for the relationship of epigenetic signatures and provide a score for clinical 
outcomes and markers. No clinical data will be sent to Dr. Lee. All clinical data and epigenetics 
scoring will be correlated here at MDACC. A waiver of consent will be utilized for patients 
that cannot be reconsented.  
De-identified data, including, but not limited to tumor type, tumor response, toxicity, 
translational data, and baseline plasma samples will be sent to the collaborator, Stephen 
Johnston, PhD at Arizona State University to perform HD peptide analyses. A waiver of 
consent will be utilized for patients that cannot be reconsented.  Results from the analysis will 
be sent to the PI. 
De-identified data, including, but not limited to personal hygiene, antibiotic use, medication 
use, tumor type, tumor response, and toxicity, and de-identified samples will be reviewed by 
the collaborator, Julia Oh, PhD at Jackson Laboratory to provide expertise in the skin, stool, 
and oral microbiome analyses for the relationship microbiome and immune-related toxicity. 
De-identified clinical data will be coded to the samples; however, the code will only be 
available to the PI and MDACC study team. A waiver of consent will be utilized for patients 
that cannot be reconsented.  Results from the analysis will be sent to the PI. 
De-identified data, including, but not limited to tumor type, tumor response, toxicity, 
translational data, and two (baseline and on-treatment) samples (plasma or serum) for up to 
130 patients will be sent to the collaborator, Ronan McDaid, at Oncimmune to perform 
autoantibody profiling analyses. A waiver of consent will be utilized for patients that cannot 
be reconsented.  Results from the analysis will be sent to the PI. 
H&E stained whole slide images will be uploaded to the webpage of collaborator, Chan-Young 
Ock, MD, PhD at Lunit Inc. to analyze tumor-infiltrating lymphocytes. A waiver of consent 
will be utilized for patients that cannot be reconsented. Results from the analysis will be sent 
to the PI. Lunit SCOPE IO is an artificial intelligence (AI)-powered spatial tumor-infiltrating 
lymphocytes analyzer. Lunit SCOPE IO classifies Immune Phenotype (IP) of each region of 
interest (ROI) in the tumor microenvironment: inflamed immune phenotype as high TIL 
density within the cancer area; immune-excluded immune phenotype as high TIL density 
exclusively in the cancer stroma; immune-desert immune phenotype as low TIL density in both 
the cancer area and cancer stroma. The Inflamed Score (IS) or Immune-Excluded Score (IES) 
are defined as the proportion of all tumor-containing tiles within a WSI classified as being of 
the inflamed IP or immune-excluded IP. Lunit SCOPE IO will be accessed via a web interface 
for slide image analysis and return of results. H&E stained whole slide images will be uploaded 
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to the webpage of collaborator, Chan-Young Ock, MD, PhD at Lunit Inc. to analyze tumor-
infiltrating lymphocytes. A waiver of consent will be utilized for patients that cannot be 
reconsented.  Results from the analysis will be sent to the PI. 
Data sent outside of MDACC will not have identifying patient information included. 
 Compliance with Financial Disclosure Requirements 
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the 
IND Sponsor's responsibility to determine, based on these regulations, whether a request 
for Financial Disclosure information is required. It is the investigator's/subinvestigator's 
responsibility to comply with any such request. 
 
The investigator/subinvestigator(s) agree, if requested by the IND Sponsor in accordance with 
21 CFR Part 54, to provide his/her financial interests in and/or arrangements with the IND 
Sponsor to allow for the submission of complete and accurate certification and disclosure 
statements. The investigator/subinvestigator(s) further agree to provide this information on 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the IND Sponsor or through a secure password-protected electronic portal provided by the 
IND Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the IND Sponsor in the United States for these purposes. This may involve 
the transmission of information to countries that do not have laws protecting personal data. 
 
 Compliance with Law, Audit and Debarment 
By signing this protocol, the investigator agrees to conduct the trial in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of Good 
Clinical Practice (e.g., International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use Good Clinical Practice: 
Consolidated Guideline and other generally accepted standards of good clinical practice); and 
all applicable federal, state and local laws, rules and regulations relating to the conduct of the 
clinical trial. 
 
The investigator also agrees to allow monitoring, audits, IRB/ERC review and regulatory 
authority inspection of trial-related documents and procedures and provide for direct access 
to all trial-related source data and documents. 
 
The investigator agrees not to seek reimbursement from subjects, their insurance providers or 
from government programs for procedures included as part of the trial reimbursed to the 
investigator by the Sponsor. 
 
The investigator shall prepare and maintain complete and accurate trial documentation in 
compliance with Good Clinical Practice standards and applicable federal, state and local 
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laws, rules and regulations; and, for each subject participating in the trial, provide all data, 
and, upon completion or termination of the clinical trial, submit any other reports to the 
IND Sponsor as required by this protocol or as otherwise required pursuant to any agreement 
with the IND Sponsor. 
 
Trial documentation will be promptly and fully disclosed to the IND Sponsor by the 
investigator upon request and also shall be made available at the trial site upon request for 
inspection, copying, review and audit at reasonable times by representatives of the IND 
Sponsor or any regulatory authorities. The investigator agrees to prompt ly take any reasonable 
steps that are requested by the IND Sponsor as a result of an audit to cure deficiencies in the 
trial documentation and worksheets/case report forms. 
 
The investigator must maintain copies of all documentation and records relating to the 
conduct of the trial in compliance with all applicable legal and regulatory requirements. This 
documentation includes, but is not limited to, the protocol, worksheets/case report forms, 
advertising for subject participation, adverse event reports, subject 
source data, 
correspondence with regulatory authorities and IRBs/ERCs, consent forms, investigator’s 
curricula vitae, monitor visit logs, laboratory reference ranges, laboratory certification or 
quality control procedures and laboratory director curriculum vitae. By signing this protocol, 
the investigator agrees that documentation shall be retained until at least 2 years after the last 
approval of a marketing application in an ICH region or until there are no pending or 
contemplated marketing applications in an ICH region or until at least 2 years have elapsed 
since the formal discontinuation of clinical development of the investigational product. 
Because the clinical development and marketing application process is variable, it is 
anticipated that the retention period can be up to 15 years or longer after protocol database 
lock. The IND Sponsor will determine the minimum retention period and notify the 
investigator when documents may be destroyed. The IND Sponsor also recognizes that 
documents may need to be retained for a longer period if required by local regulatory 
requirements. All trial documents shall be made available if required by relevant regulatory 
authorities. The investigator must consult with and obtain written approval by the IND Sponsor 
prior to discarding trial and/or subject files. 
 
ICH Good Clinical Practice guidelines recommend that the investigator inform the subject’s 
primary physician about the subject’s participation in the trial if the subject has a primary 
physician and if the subject agrees to the primary physician being informed. 
 
The investigator will promptly inform the IND Sponsor of any regulatory authority 
inspection conducted for this trial. 
 
Persons debarred from conducting or working on clinical trials by any court or regulatory 
authority will not be allowed to conduct or work on this IND Sponsor’s trials. The 
investigator will immediately disclose in writing to the IND Sponsor if any person who is 
involved in conducting the trial is debarred or if any proceeding for debarment is pending or, 
to the best of the investigator’s knowledge, threatened. 
 
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In the event the IND Sponsor prematurely terminates a particular trial site, the IND 
Sponsor will promptly notify that trial site’s IRB/IEC. 
 
According to European legislation, a IND Sponsor must designate an overall coordinating 
investigator for a multi-center trial (including multinational). When more than one trial site 
is open in an EU country, Merck, as the IND Sponsor, will designate, per country, a 
national principal coordinator (Protocol CI), responsible for coordinating the work of the 
principal investigators at the different trial sites in that Member State, according to national 
regulations. For a single-center trial, the Protocol CI is the principal investigator. In addition, 
the IND Sponsor must designate a principal or coordinating investigator to review the trial 
report that summarizes the trial results and confirm that, to the best of his/her knowledge, 
the report accurately describes the conduct and results of the trial [Clinical Study Report (CSR) 
CI]. The IND Sponsor may consider one or more factors in the selection of the individual 
to serve as the Protocol CI and or CSR CI (e.g., availability of the CI during the anticipated 
review process, thorough understanding of clinical trial methods, appropriate enrollment 
of subject cohort, timely achievement of trial milestones). The Protocol CI must be a 
participating trial investigator. 
 
 Compliance with Trial Registration and Results Posting Requirements 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the Sponsor of the trial is solely 
responsible for determining whether the trial and its results are subject to the requirements for 
submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov.  Information posted 
will allow subjects to identify potentially appropriate trials for their disease conditions and 
pursue participation by calling a central contact number for further information on appropriate 
trial locations and trial site contact information.     
 Quality Management System 
By signing this protocol, the IND Sponsor agrees to be responsible for implementing and 
maintaining a quality management system with written development procedures and 
functional area standard operating procedures (SOPs) to ensure that trials are conducted 
and data are generated, documented, and reported in compliance with the protocol, 
accepted standards of Good Clinical Practice, and all applicable federal, state, and local 
laws, rules and regulations relating to the conduct of the clinical trial. 
 
 Data Management 
The investigator or qualified designee is responsible for recording and verifying the 
accuracy of subject data. By signing this protocol, the investigator acknowledges that 
his/her electronic signature is the legally binding equivalent of a written signature. By 
entering his/her electronic signature, the investigator confirms that all recorded data have 
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been verified as accurate. 
 
This study will be monitored by the University of Texas MD Anderson IND Office, and a 
protocol-specific monitoring plan will be followed.  
 
All patients who meet eligibility criteria and are enrolled in this trial will be registered in 
Clinical Oncology Research Database (CORe) at the University of Texas MD Anderson 
Cancer Center at Houston.  Data will be collected and stored in the Investigational Cancer 
Therapeutics database, Molecular and Clinical Data Integrated Platform (MOCLIP). 
 
 
 
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11.0 APPENDICES 
 ECOG Performance Status 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, but 
unable to carry out any work activities. Up and about more than 50% 
of waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. 
Totally confined to bed or chair. 
5 
Dead. 
* As published in Am. J. Clin. Oncol.:  Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., 
McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology 
Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative Oncology Group, Robert Comis 
M.D., Group Chair. 
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 Common Terminology Criteria for Adverse Events V4.03 (CTCAE) 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.03 will be utilized for adverse event reporting. 
(http://ctep.cancer.gov/reporting/ctc.html)
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 Response Evaluation Criteria in Solid Tumors (RECIST)   
RECIST version 1.1* or irRECIST will be used in this study for assessment of tumor response. 
While either CT or MRI may be utilized, as per RECIST 1.1 or irRECIST, CT is the preferred 
imaging technique in this study. 
* As published in the European Journal of Cancer: 
 
E.A. Eisenhauer, P. Therasse, J. Bogaerts, L.H. Schwartz, D. Sargent, R. Ford, J. 
Dancey, S. Arbuck, S. Gwyther, M. Mooney, L. Rubinstein, L. Shankar, L. Dodd, R. Kaplan, 
D. Lacombe, J. Verweij. New response evaluation criteria in solid tumors: Revised RECIST 
guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47. 
Bohnsack O, Hoos A, Ludajic K. Adaptation of the immune related response criteria: 
irRECIST Ann Oncol 2014;25(suppl 4):11 Abstract 1070. 
 
In addition, volumetric analysis will be explored by central review for response assessment. 
 
 
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12.0 REFERENCES 
 
1. 
Eisenhauer EA, Therasse P, Bogaerts J, et al: New response evaluation criteria 
in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45:228-47, 2009 
 
2. 
Corp. MSD: Pembrolizumab Investigator's Brochure, 2015 
 
3. 
Disis ML: Immune regulation of cancer. J Clin Oncol 28:4531-8, 2010 
 
4. 
Yang I, Tihan T, Han SJ, et al: CD8+ T-cell infiltrate in newly diagnosed 
glioblastoma is associated with long-term survival. J Clin Neurosci 17:1381-5, 2010 
 
5. 
Dong H, Strome SE, Salomao DR, et al: Tumor-associated B7-H1 promotes T-
cell apoptosis: a potential mechanism of immune evasion. Nat Med 8:793-800, 2002 
 
6. 
Sharpe AH, Freeman GJ: The B7-CD28 superfamily. Nat Rev Immunol 2:116-
26, 2002 
 
7. 
Blackburn SD, Crawford A, Shin H, et al: Tissue-specific differences in PD-1 
and PD-L1 expression during chronic viral infection: implications for CD8 T-cell exhaustion. 
J Virol 84:2078-89, 2010 
 
8. 
Blank C, Brown I, Peterson AC, et al: PD-L1/B7H-1 inhibits the effector phase 
of tumor rejection by T cell receptor (TCR) transgenic CD8+ T cells. Cancer Res 64:1140-5, 
2004 
 
9. 
Bronte V, Mocellin S: Suppressive influences in the immune response to 
cancer. J Immunother 32:1-11, 2009 
 
10. 
Hodi FS, O'Day SJ, McDermott DF, et al: Improved survival with ipilimumab 
in patients with metastatic melanoma. N Engl J Med 363:711-23, 2010 
 
11. 
Hamid O, Robert C, Daud A, et al: Safety and Tumor Responses with 
Lambrolizumab (Anti-PD-1) in Melanoma. New England Journal of Medicine 369:134-144, 
2013 
 
12. 
DiGiulio S: Keytruda Approved by FDA for Advanced Melanoma, Called 
‘Game Changer’. Oncology Times, 2014 
 
13. 
Francisco LM, Sage PT, Sharpe AH: The PD‐1 pathway in tolerance and 
autoimmunity. Immunol Rev 236:219-242, 2010 
 
14. 
Thompson RH, Dong H, Kwon ED: Implications of B7-H1 expression in clear 
cell carcinoma of the kidney for prognostication and therapy. Clinical cancer research 13:709s-
715s, 2007 
 
15. 
Ohigashi Y, Sho M, Yamada Y, et al: Clinical significance of programmed 
death-1 ligand-1 and programmed death-1 ligand-2 expression in human esophageal cancer. 
Clinical cancer research 11:2947-2953, 2005 
 
16. 
McDermott DF, Atkins MB: PD‐1 as a potential target in cancer therapy. 
Cancer medicine 2:662-673, 2013 
 
17. 
Simon R: Optimal two-stage designs for phase II clinical trials. Control Clin 
Trials 10:1-10, 1989 
 
18. 
Huggins CE, Domenighetti AA, Ritchie ME, et al: Functional and metabolic 
remodelling in GLUT4-deficient hearts confers hyper-responsiveness to substrate intervention. 
J Mol Cell Cardiol 44:270-80, 2008 
 
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