Conditions: Anaplastic Thyroid Cancer
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 6
Healthy volunteers: no

Brief summary:
This study is being done because there are currently no approved and no commonly working targeted therapies in anaplastic thyroid cancer (ATC). This is an area of urgent need for patients, not just for approved treatments but also rationally-designed clinical trials designed specifically for ATC. Patients diagnosed with anaplastic thyroid cancer have a very high likelihood of dying because of their disease. As such there is a clear need for improving therapy for ATC.

Detailed description:
The goal of this multi-center, open-label trial is to measure the impact of treating metastatic anaplastic thyroid cancer patients with immune checkpoint therapy. This trial will potentially lead to the development of new therapy for anaplastic thyroid cancer. The drug to be administered, pembrolizumab is FDA approved with known side effects and is active in many tumor types.

Programmed death 1 or (PD-1) PD-1/PD-L1 expression will be measured and reported for patients undergoing therapy with pembrolizumab. This will help determine if there PD-1 or PD-L1 are predictive biomarkers for anti-PD-1 therapy. It will also add to the data regarding their frequency in aggressive thyroid cancer. Where available, genomic profiling data will be analyzed to determine if there is a correlation between response and mutational status.

Arms:
arm 1: 200 milligrams of Pembrolizumab will be given intravenously every 3 weeks.

Interventions: intervention 1: Pembrolizumab
Intervention descriptions: intervention 1: 200 mg IV once every 3 weeks

Protocol document:
Prot_SAP_000.pdf: 
ClinicalTrials.gov cover page 
UTSW Protocol STU012016-019 
NCT02688608 
“Phase II Trial of Pembrolizumab in Metastatic or Locally Advanced 
Anaplastic/Undifferentiated Thyroid Cancer” 
aka “Pembrolizumab in Anaplastic/Undifferentiated Thyroid Cancer” 
28 September 2019 (version 3) 


 
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CONFIDENTIAL 
This material is the property of the UTSW Simmons Cancer Center. Do not disclose or use except as authorized in writing by the 
study sponsor. 
 
Template Updated: 12/2012; 9/2013; 8/2014; 4/2015; 10/2015 
Protocol Version 3.0, September 28, 2019 
 
Phase II Trial of Pembrolizumab in Metastatic or Locally Advanced Anaplastic/Undifferentiated 
Thyroid Cancer 
 
Principal Investigator: Saad A. Khan, MD 
UT Southwestern Medical Center Medical Oncology 
5323 Harry Hines Boulevard, Dallas, TX 75390-8852 
Telephone: (214) 648-4180. Fax: (214) 648-1955 
Email: Saad.Khan@UTSouthwestern.edu 
 
Sub-Investigator(s): 
Randall Hughes, MD  
 
 
 
 
 
UTSW Medical Oncology  
 
 
 
  
5323 Harry Hines Boulevard, Dallas, TX 75390  
 
Telephone: (214) 648-4180. Fax: (214) 648-1955 
 
 
 
 
Email: Randall.Hughes@UTSouthwestern.edu 
 
 
 
 
 
 
 
 
David Gerber, MD 
 
 
 
 
 
UTSW Medical Oncology 
 
 
 
 
5323 Harry Hines Boulevard, Dallas, TX 75390                 
Telephone: (214)648-4180. Fax: (214) 648-1955  
 
 
 
 
Email: David.Gerber@UTSouthwestern.edu 
 
 
 
 
Baran Sumer, MD 
 
 
 
UTSW ENT 
 
 
 
5323 Harry Hines Boulevard, Dallas, TX 75390 
 
 
 
Telephone: (214)648-2904. Fax (214)648-9122 
 
 
 
Email: Baran.Sumer@UTSouthwestern.edu 
 
Biostatistician: 
Hong Zhu, PhD  
University of Texas, Southwestern Medical Center 
Department of Clinical Science 
5323 Harry Hines Boulevard, Dallas, TX 75390 
Phone:(214) 648-7438. Fax: (214) 648-5120 
Email: Hong.Zhu@UTSouthwestern.edu  
 
Study Drug: 
 
 
Pembrolizumab 
 
IND Number: 
 
 
Pending 
 
IND Holder Name: 
 
Dr. Saad Khan, UT Southwestern Medical Center 
 
Funding Source:  
Merck – funding and investigational agent 
 
 
Initial version: 
Version 2.0, July 20,2016 
 
Amended: 
 
Protocol Version 3.0, September 28, 2019 
 
 
UT Southwestern Medical Center (UTSW) 
Harold C. Simmons Cancer Center 
Attn: Clinical Research Office 
5323 Harry Hines Blvd. MC 9179 
Dallas, Texas 75390-9179 
 


 
STU012016-019, Khan, FormA3-ResearchProtocol-V3.0-09.28.19, Mod_21, 03-16-20 
 
 
CONFIDENTIAL 
This material is the property of the UTSW Simmons Cancer Center. Do not disclose or use except as authorized in writing by the 
study sponsor. 
 
Template Updated: 12/2012; 9/2013; 8/2014; 4/2015; 10/2015 
Protocol Version 3.0, September 28, 2019 
 
 
Signature Page 
                                                       
Protocol Version 3.0, September 28, 2019  
 
The signature below constitutes the approval of this protocol and the attachments, and provides the 
necessary assurances that this trial will be conducted according to all stipulations of the protocol, including 
all statements regarding confidentiality, and according to local legal and regulatory requirements and 
applicable U.S. federal regulations and ICH guidelines. 
 
 
 
Principal Investigator (PI) Name:_____________________________ 
 
 
 
PI Signature: _____________________________ 
 
 
 
Date:____________________ 
 


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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ............................................................................................................. 5 
STUDY SCHEMA ............................................................................................................................. 7 
STUDY SUMMARY .......................................................................................................................... 8 
1.0 
BACKGROUND AND RATIONALE ....................................................................................... 9 
1.1 
Disease Background........................................................................................................ 9 
1.2 
Study Agent(s) Background and Associated Known Toxicities ..................................... 11 
1.3 
Other Agents .................................................................................................................. 12 
1.4 
Rationale ........................................................................................................................ 14 
1.5 
Correlative Studies ........................................................................................................ 14 
2.0 
STUDY OBJECTIVES .......................................................................................................... 14 
2.1 
Primary Objectives ......................................................................................................... 14 
2.2 
Secondary Objectives .................................................................................................... 14 
2.3 
Exploratory Objectives ................................................................................................... 14 
2.4 
Endpoints ....................................................................................................................... 14 
3.0 
SUBJECT ELIGIBILITY ....................................................................................................... 15 
3.1 
Inclusion Criteria ............................................................................................................ 15 
3.2 
Exclusion Criteria ........................................................................................................... 15 
4.0 
TREATMENT PLAN ............................................................................................................. 18 
4.1 
Treatment Dosage and Administration .......................................................................... 18 
4.2 
Toxicities and Dosing Delays/Dose Modifications ......................................................... 18 
4.3 
Concomitant Medications/Treatments ........................................................................... 20 
 
 
  a. 
Rescue Medications & Supportive……………………………………………………21 
4.4 
Diet/Activity/Other Considerations ................................................................................. 24 
4.5 
Subject Withdrawal/Discontinuation Criteria ............................................................... 204 


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4.6 
Duration of Therapy ....................................................................................................... 20 
4.7 
Duration of Follow Up .................................................................................................... 26 
4.8 
Removal of Subjects from Protocol Therapy ................................................................. 26 
 
    4.9 
Subject Replacement…………………………………………………………………………….26 
5.0 
STUDY PROCEDURES ....................................................................................................... 23 
5.1 
Screening/Baseline Procedures .................................................................................... 26 
5.2 
Protocol Flow and Visit Schedule .................................................................................. 26 
5.3 
Trial Procedures ............................................................................................................ 31 
5.4 
Assessment Types ........................................................................................................ 35 
6.0 
MEASUREMENT OF EFFECT ............................................................................................. 39 
6.1 
Antitumor Effect- Solid Tumors ...................................................................................... 39 
6.2 
Safety/Tolerability .......................................................................................................... 42 
7.0 
ADVERSE EVENTS ............................................................................................................. 42 
7.1 
Experimental Therapy.................................................................................................... 42 
7.2 
Assessing and Recording Adverse Events ................................................................... 44 
7.3 
Adverse Event Monitoring ............................................................................................. 46 
7.4 
Steps to Determine if an Adverse Event Requires Expedited Reporting ...................... 49 
8.0 
DRUG INFORMATION ......................................................................................................... 53 
8.1 
Labeling, Packaging, Storage and Return of Clinical Supplies ..................................... 53 
 
    8.2      Investigational Product……………………………………………………………………….53 
 
     8.3     Packaging and Labeling Information……………………………………………………….54 
 
    8.4 
    Clinical Supplies Disclosure…………………………………………………………………..54 
 
    8.5         Storage and Handling Requirements………………………………………………………..54 
 
   8.6          Returns and Reconciliation…………………………………………………………………..54 
9.0 
STATISTICAL CONSIDERATIONS ................................................................................... 54 
9.1 
Study Design/Study Endpoints ...................................................................................... 54 


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Sample Size and Accrual .............................................................................................. 54 
9.3 
Definition of End of the Study ........................................................................................ 55 
 
    9.4 
   Early Termination………………………………………………………………………………55 
 
    9.5 
   Data Confidentiality…………………………………………………………………………….55 
 
   9.6        Statistical Methods and Data Analysis……………………………………………………….55 
 
    9.7       Patient Demographics/Other Baseline Characteristics……………………………………..55 
 
    9.8       Treatments (Pembrolizumab Treatment, Concomitant Therapies, Compliance)………..55   
 
    9.9       Data Analyses Plans……………………………………………………………………………56    
10.0 
STUDY MANAGEMENT .................................................................................................... 56 
10.1 
Regulatory and Ethical Compliance .............................................................................. 56 
10.2 
Informed Consent Procedures ....................................................................................... 56 
10.3 
Discontinuation of the Study .......................................................................................... 56 
10.4 
Publication of the Study and Results ............................................................................. 56 
10.5 
Study Documentation, Record Keeping and Retention of Documents ......................... 56 
10.6 
Confidentiality of Study Documents and Patient Records ............................................. 56 
10.7 
Audits and Inspections .................................................................................................. 57 
10.8 
Conflict of Interest .......................................................................................................... 57 
10.9 
Institutional Review Board (IRB) Approval and Consent ............................................... 57 
 
   10.10    Required Documentation…………………………………………………………………….57 
 
    10.11    Registration Procedures……………………………………………………………………...57 
 
    10.12    Data Management and Monitoring/Auditing………………………………………………..58 
 
    10.13    Adherence to the Protocol……………………………………………………………………59 
 
    10.14    Amendments to the Protocol…………………………………………………………………60 
 
     10.15    Record Retention……………………………………………………………………………..60 
 
     10.16    Obligations of Investigators………………………………………………………………….60 
11.0 
REFERENCES ................................................................................................................... 61 
12.0 
APPENDICES .................................................................................................................... 63 


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      12.1     ECOG Performance Status……………………………………………………………………63 
 
       12.2     Common Terminology Criteria for Adverse Events V4.1 (CTCAE)………………………63 


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LIST OF ABBREVIATIONS (EXAMPLES) 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ALC 
ALK 
ASCO 
Absolute Lymphocyte Count 
Anaplastic lymphoma kinas 
American Society of Clinical Oncology 
AST 
ATC 
Aspartate Aminotransferase 
Anaplastic Thyroid Cancer 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CMP 
Comprehensive Metabolic Panel 
CR 
Complete Response 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
Dose Limiting Toxicity 
DOT 
Disease Oriented Team 
DSMB 
Data and Safety Monitoring Board 
ECOG 
Eastern Cooperative Oncology Group 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
H&P 
History & Physical Exam 
HRPP 
Human Research Protections Program 
IHC 
Immunohistochemistry 
IND 
Investigational New Drug 
IV (or iv) 
Intravenously 
MRI 
Magnetic Resonance Imaging 
MTD 
Maximum Tolerated Dose 
NCI 
National Cancer Institute 
ORR 
Overall Response Rate 
OS 
Overall Survival 
PBMCs 
Peripheral Blood Mononuclear Cells 
pCR 
Pathologic Complete Response 
PD 
Progressive Disease 
PET 
Positron Emission Tomography 
PFS 
Progression Free Survival 
p.o. 
peros/by mouth/orally 
PR 
Partial Response 
RCB 
Residual Cancer Burden 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious Adverse Event 
SCCC 
Simmons Comprehensive Cancer Center 
SD 
Stable Disease 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 


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SPGT 
Serum Glutamic Pyruvic Transaminase 
WBC 
White Blood Cells 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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STUDY SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pembrolizumab 
200 mg IV once every 3 weeks 
 
CR, PR, 
SD 
Disease 
Progression 
Continue study agent Day 1 
 
Continue q3 weeks followed by imaging assessment 
every 2 cycles. 
Repeat until evidence of progression or 
unacceptable toxicity, withdrawal of consent, or 
discontinuation of the trial for any other reason. 
 
 
Discontinue protocol treatment 
unless patient deriving clinical benefit 
and with approval of Principal 
Investigator. 
 
Patient registration 
anaplastic/undifferentiated thyroid cancer 
without curative option 
 
Disease Evaluation by CT/MRI 
 


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STUDY SUMMARY 
Title 
Phase II trial of Pembrolizumab in metastatic or locally advanced 
anaplastic/undifferentiated thyroid cancer 
Short Title 
Pembrolizumab in anaplastic/undifferentiated thyroid cancer 
Protocol Number 
Insert from PRMC Approval Letter 
Phase 
Phase 2 
Methodology 
Open label, non-randomized single agent trial 
Study Duration 
2 years 
Study Center(s) 
Multicenter, additional 3 centers expected 
Objectives 
Response rate of pembrolizumab in anaplastic/undifferentiated thyroid 
cancer 
Number of Subjects 
20 
Diagnosis and Main 
Inclusion Criteria 
Anaplastic/undifferentiated thyroid cancer that is metastatic or locally 
advanced with no curative treatment options. 
Study Product(s), Dose, 
Route, Regimen 
Pembrolizumab (Keytruda-Merck) 200 mg, given IV every 3 weeks. 
Duration of administration 
Until evidence of progression, intolerance of treatment, withdrawal of 
consent or death 
Reference therapy 
Historical controls, no established chemotherapy options in this disease 
proven to show survival benefit 
Statistical Methodology 
Sample size calculated on the basis of tumor response rate of patients 
treated on this protocol compared to published response rates. Kaplan 
Meier Methods will be used to estimate progression-free survival, overall 
survival and response duration. 
 
 
 


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1.0 
BACKGROUND AND RATIONALE 
1.1 
Disease Background 
 
1.1.1 
Anaplastic Thyroid Cancer 
 
Anaplastic thyroid cancer (ATC) is an undifferentiated tumor of thyroidal follicular epithelium. 
Although not as common as differentiated thyroid cancers, ATC has much higher disease 
specific mortality, approaching 100% [1]. In fact, despite accounting for less that 5% of all 
thyroid cancer diagnoses, ATC leads to more than half of the 1200 deaths from thyroid 
cancer every year in the United States [2, 3].  
 
 
Forty six percent of patients present with distant metastases, and almost 70% demonstrate 
metastases at some stage of the disease [3]. All staging for anaplastic thyroid cancer is as 
stage IV [3], given its aggressive nature and propensity for metastasis. Even with the most 
aggressive existing multimodality therapy involving surgery, radiation and chemotherapy, 
most patients do not derive consistent, sustained benefit in outcomes and survival. Median 
overall survival remains 3-4 months, with 90% of patients dead at 1 year from diagnosis [3]. 
Patients often suffer from distant metastases even after local therapy is completed, 
demonstrating the inadequacy of treatment. Lung, brain and bone metastases are common 
as well as significant airway compromise and suffocation even after tracheostomy. 
 
1.1.2 
Treatment for Anaplastic Thyroid Cancer-Chemotherapy 
Doxorubicin is the only approved chemotherapy for anaplastic thyroid cancer [4], and is 
often combined with radiation or surgery as part of multi-modality therapy. No randomized 
trial has demonstrated improved statistically significant survival or better quality of life in 
patients treated with any current therapy [4]. 
 
 
Given the poor prognosis, guidelines from the American Thyroid Association as well as the 
National Comprehensive Cancer Network recommend all patients should be treated as part 
of a clinical trial regardless of stage [4, 5].  
 
 
This treatment protocol aims to offer a new therapy for patients with anaplastic thyroid 
cancer who would otherwise have very poor treatment options and outcome. 
 
1.1.3 
Treatment for Anaplastic Thyroid Cancer-Targeted Therapy and Clinical 
Trials  
There are currently no approved and no commonly employed targeted therapies in 
anaplastic thyroid cancer. This is an area of urgent need for patients, not just for approved 
treatments but also rationally-designed clinical trials designed specifically for ATC. 
 
Newer agents have been tested in patients with ATC, but currently none have been 
approved for any stage of therapy for patients in the US. Fosbretabulin is a novel tubulin 
binding compound that demonstrated activity in ATC [6]. A Phase III trial randomized ATC 
patients to fosbretabulin or placebo. These patients had previously received carboplatin and 
paclitaxel treatment and 55% of them had undergone surgical resection [7]. The arm 
containing the experimental drug had 33.3% survival at one year vs 7% for the carboplatin 
and paclitaxel alone arm. Although not powered to detect differences in survival, the median 
survival for the standard arm was reported as 4 months for the control arm versus 8.4 
months for the fosbretabulin arm. 
 


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Sorafenib has demonstrated some activity in multi-institution, small studies. In 20 patients 
treated with sorafenib, 2 patients demonstrated a partial response [8]. Sorafenib is currently 
not listed as a recommended regimen in the NCCN guidelines for anaplastic thyroid cancer, 
nor in the ATA guidelines for Anaplastic Thyroid Cancer.  
 
 
Clinical trials for this disease are also extremely rare, leaving patients with very limited 
treatment options. Patients diagnosed with anaplastic thyroid cancer have a very high 
likelihood of dying because of their disease. As such there is a clear need for improving 
therapy for anaplastic thyroid cancer. 
 
1.1.4 
Immune checkpoints in cancer 
Cancer cells can evade destruction by the immune system, and can gain the ability to 
circumvent the usual immune checkpoints [9, 10]. The programmed death 1 (PD-1) 
receptor and its ligands appear to play a role in the tumor cells evading immune-
mediated destruction. PD-1 is an immunoinhibitory receptor that is expressed on B/T 
cells, tumor infiltrating lymphocytes, monocytes and NK cells [11].  
 
The binding of PD-1 to one of its ligands PD-L1 or PD-L2 results in inhibition of cytotoxic 
T-cell responses [12]. Pembrolizumab is a monoclonal antibody against PD-1 which 
disrupts ligand binding and T cell inhibitory signals, resulting in increased tumor 
recognition by cytotoxic T-cells[13]. 
 
Higher levels of PD-L1 are associated with an increased response rate of lung cancer to 
anti-PD-1 therapy [13]. PD-L1 overexpression is associated with more aggressive 
disease in papillary thyroid cancer [14], but has not been similarly evaluated in anaplastic 
thyroid cancer. In a small series, PD-L1 expression was seen in 3 out of 13 anaplastic 
thyroid cancer patients [15], though whether this represents the true frequency of PD-L1 
overexpression is unknown. It is also unknown whether PD-L1 expression correlates with 
response to anti-PD-1 agents in thyroid cancer. 
 
1.1.5 
Molecular abnormalities in anaplastic thyroid cancer 
The frequency of mutations in anaplastic thyroid cancer/undifferentiated thyroid cancer is 
not well-defined. The impact of mutations in ATC may be to alter its natural history and 
may also be associated with differential responses to immune based therapy. 
 
Experiments have been done to determine the genetic drivers of malignancy in aggressive 
thyroid cancer. In anaplastic thyroid cancer (ATC) collected from patient samples, 
mutations in the kinase domain of ALK have been characterized in 11% [16]. In this study 
of ATC, two exons in the tyrosine kinase domain were sequenced and novel mutations 
were found in both exon 23 and 25. Both mutations led to increased tyrosine kinase activity 
of ALK. 
 
These mutations were associated with activation of the PI3kinase pathway as well as high 
phosphorylation levels of Akt and ERK, suggesting that they contributed to malignant 
behavior. These novel ALK mutations were transfected into wild type ALK cells, and 
stimulated cell transformation and invasion as possible mechanism of malignancy, the 
frequency of ALK mutations was 11%.  
 
In one 71 year old patient with anaplastic thyroid cancer, ALK overexpression was seen 
[17]. Further analysis demonstrated the presence of a rearrangement and the patient was 
treated with the ALK-inhibitor crizotinib. This resulted in a dramatic response and reduction 
of the lung metastases by 90%. 
 
Other abnormalities have been reported and sporadically targeted in anaplastic thyroid 
cancer. These include braf which is found in 14-25% of anaplastic thyroid cancer [18, 19]. 


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This has also been associated with dramatic responses to targeted therapy in one case 
report. These anecdotal results remain to be confirmed in larger studies. 
 
Other mutations commonly found in ATC include PI3KCA (24%), PTEN (16%), RAS 
(60%) and TP53 (48%) [20]. 
 
Molecular testing is commonly performed in anaplastic thyroid cancer using commercial 
tests such as FoundationOne and Caris. In cases where these results are available, they 
will be collected to determine if there is any correlation between mutations and 
responses. 
 
1.1.5.1 
Concept 
The goal of this multi-center, open-label trial is to measure the impact of treating metastatic 
anaplastic thyroid cancer patients with immune checkpoint therapy. This trial will potentially 
lead to the development of new therapy for anaplastic thyroid cancer. The drug to be 
administered, pembrolizumab is FDA approved with known side effects and is active in 
many tumor types. 
 
PD-1/PD-L1 expression will be measured and reported for patients undergoing therapy 
with pembrolizumab. This will help determine if there PD-1 or PD-L1 are predictive 
biomarkers for anti-PD-1 therapy. It will also add to the data regarding their frequency in 
aggressive thyroid cancer. Where available, genomic profiling data will be analyzed to 
determine if there is a correlation between response and mutational status. 
 
 
1.2 
Study Agent(s) Background and Associated Known Toxicities 
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background 
information on pembrolizumab (MK-3475). 
 
1.2.1 
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+ 
effector T-cells / FoxP3+ regulatory T-cells seems to correlate with improved prognosis 
and long-term survival in many solid tumors. 
 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control.  The normal function of PD-1, expressed on the cell surface of activated 
T-cells under healthy conditions, is to down-modulate unwanted or excessive immune 
responses, including autoimmune reactions.  PD-1 (encoded by the gene Pdcd1) is an Ig 
superfamily member related to CD28 and CTLA-4 which has been shown to negatively 
regulate antigen receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2).  
The structure of murine PD-1 has been resolved.  PD-1 and family members are type I 
transmembrane glycoproteins containing an Ig Variable-type (V-type) domain responsible 
for ligand binding and a cytoplasmic tail which is responsible for the binding of signaling 
molecules.  The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an 
immunoreceptor tyrosine-based inhibition motif (ITIM) and an immunoreceptor tyrosine-
based switch motif (ITSM).  Following T-cell stimulation, PD-1 recruits the tyrosine 
phosphatases SHP-1 and SHP-2 to the ITSM motif within its cytoplasmic tail, leading to 
the dephosphorylation of effector molecules such as CD3ζ, PKCθ and ZAP70 which are 
involved in the CD3 T-cell signaling cascade.  The mechanism by which PD-1 down 
modulates T-cell responses is similar 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 


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Natural Killer cells.  Expression has also been shown during thymic development on CD4-
CD8- (double negative) T-cells as well as subsets of macrophages and dendritic cells.  The 
ligands for PD-1 (PD-L1 and PD-L2) are constitutively expressed or can be induced in a 
variety of cell types, including non-hematopoietic tissues as well as in various tumors.  Both 
ligands are type I transmembrane receptors containing both IgV- and IgC-like domains in 
the extracellular region and contain short cytoplasmic regions with no known signaling 
motifs.  Binding of either PD-1 ligand to PD-1 inhibits T-cell activation triggered through the 
T-cell receptor.  PD-L1 is expressed at low levels on various non-hematopoietic tissues, 
most notably on vascular endothelium, whereas PD-L2 protein is only detectably 
expressed on antigen-presenting cells found in lymphoid tissue or chronic inflammatory 
environments.  PD-L2 is thought to control immune T-cell activation in lymphoid organs, 
whereas PD-L1 serves to dampen unwarranted T-cell function in peripheral tissues.  
Although healthy organs express little (if any) PD-L1, a variety of cancers were 
demonstrated to express abundant levels of this T-cell inhibitor.  PD-1 has been suggested 
to regulate tumor-specific T-cell expansion in subjects with melanoma (MEL).  This 
suggests that the PD-1/PD-L1 pathway plays a critical role in tumor immune evasion and 
should be considered as an attractive target for therapeutic intervention. 
 
Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of 
the IgG4/kappa isotype designed to directly block the interaction between PD-1 and its 
ligands, PD-L1 and PD-L2.  KeytrudaTM (pembrolizumab) has recently been approved in 
the United Stated for the treatment of patients with unresectable or metastatic melanoma 
and disease progression following ipilomumab and, if BRAF V600 mutation positive, a 
BRAF inhibitor. 
 
1.2.2 
Preclinical and Clinical Trial Data 
Refer to the Investigator’s Brochure for Preclinical and Clinical data. 
 
1.3 
Rationale 
 
1.3.1 
Rationale for the Trial and Selected Subject Population 
Currently the therapeutic options for metastatic or locally advanced anaplastic thyroid 
cancer are non-existent. Though many drugs are given in hope of benefitting patients, 
none have been proven to do so. There are no treatment options that prolong survival, 
and as a result new agents are desperately needed.  
 
The identification of immune checkpoint inhibitors has transformed the treatment 
landscape in many different cancers. Where previously there were no good treatment 
options such as melanoma, immune therapy has dramatically altered the outcomes for 
patients [21].  
 
A similar change in outcomes is needed in anaplastic thyroid cancer. The relatively broad 
range of tumor types in which pembrolizumab has shown benefit (breast [22], lymphoma 
[23], urothelial cancer [24], head and neck cancer [25] as well as others) suggests that 
aggressive thyroid cancer may also be sensitive to this therapy. The prevalence of PD-L1 
overexpression in anaplastic thyroid cancer suggests that for a subset of patients, there 
may be a dramatic improvement in outcomes. However the paucity of viable alternative 
treatments means that even modest improvements in PD-L1 low cancers may still have a 
meaningful impact on patients’ lives. 
 
The currently available data does not justify a large randomized study evaluating the 
impact of pembrolizumab in anaplastic thyroid cancer. If a promising signal of 
pembrolizumab activity is identified after this initial study; a larger trial is planned to 


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confirm the results and accurately describe the true impact of pembrolizumab in this 
disease. 
1.4 
Rationale for Dose Selection/Regimen/Modification 
An open-label Phase I trial (Protocol 001) is being conducted to evaluate the safety and 
clinical activity of single agent MK-3475.  The dose escalation portion of this trial 
evaluated three dose levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 
weeks (Q2W) in subjects with advanced solid tumors.  All three dose levels were well 
tolerated and no dose-limiting toxicities were observed.  This first in human study of MK-
3475 showed evidence of target engagement and objective evidence of tumor size 
reduction at all dose levels (1 mg/kg, 3 mg/kg and 10 mg/kg Q2W).  No MTD has been 
identified to date.  10.0 mg/kg Q2W, the highest dose tested in PN001, will be the dose 
and schedule utilized in Cohorts A, B, C and D of this protocol to test for initial tumor 
activity.  Recent data from other clinical studies within the MK-3475 program has shown 
that a lower dose of MK-3475 and a less frequent schedule may be sufficient for target 
engagement and clinical activity. 
 
PK data analysis of MK-3475 administered Q2W and Q3W showed slow systemic 
clearance, limited volume of distribution, and a long half-life (refer to IB).  
Pharmacodynamic data (IL-2 release assay) suggested that peripheral target 
engagement is durable (>21 days).  This early PK and pharmacodynamic data provides 
scientific rationale for testing a Q2W and Q3W dosing schedule.   
 
A population pharmacokinetic analysis has been performed using serum concentration 
time data from 476 patients. Within the resulting population PK model, clearance and 
volume parameters of MK-3475 were found to be dependent on body weight. The 
relationship between clearance and body weight, with an allometric exponent of 0.59, is 
within the range observed for other antibodies and would support both body weight 
normalized dosing or a fixed dose across all body weights.  MK-3475 has been found to 
have a wide therapeutic range based on the melanoma indication.  The differences in 
exposure for a 200 mg fixed dose regimen relative to a 2 mg/kg Q3W body weight based 
regimen are anticipated to remain well within the established exposure margins of 0.5 – 
5.0 for MK-3475 in the melanoma indication. The exposure margins are based on the 
notion of similar efficacy and safety in melanoma at 10 mg/kg Q3W vs. the proposed 
dose regimen of 2 mg/kg Q3W (i.e. 5-fold higher dose and exposure). The population PK 
evaluation revealed that there was no significant impact of tumor burden on exposure. In 
addition, exposure was similar between the NSCLC and melanoma indications. 
Therefore, there are no anticipated changes in exposure between different indication 
settings. 
 
The rationale for further exploration of 2 mg/kg and comparable doses of pembrolizumab 
in solid tumors is based on: 1) similar efficacy and safety of pembrolizumab when dosed 
at either 2 mg/kg or 10 mg/kg Q3W in melanoma patients, 2) the flat exposure-response 
relationships of pembrolizumab for both efficacy and safety in the dose ranges of 2 mg/kg 
Q3W to 10 mg/kg Q3W, 3) the lack of effect of tumor burden or indication on distribution 
behavior of pembrolizumab (as assessed by the population PK model) and 4) the 
assumption that the dynamics of pembrolizumab target engagement will not vary 
meaningfully with tumor type. 
 
The choice of the 200 mg Q3W as an appropriate dose for the switch to fixed dosing is 
based on simulations performed using the population PK model of pembrolizumab showing 
that the fixed dose of 200 mg every 3 weeks will provide exposures that 1) are optimally 
consistent with those obtained with the 2 mg/kg dose every 3 weeks, 2) will maintain 
individual patient exposures in the exposure range established in melanoma as associated 
with maximal efficacy response and 3) will maintain individual patients exposure in the 
exposure range established in melanoma that are well tolerated and safe.  


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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. 
 
1.5 
Correlative Studies 
The diagnosis of anaplastic thyroid cancer is often delayed due to it being a rare 
diagnosis and one without clear pathognomonic pathologic findings. Tissue from patients 
who are enrolled on to this study will be reviewed at UT Southwestern medical center 
pathology by a pathologic specialized in endocrine neoplasia. Central review and 
confirmation of the diagnosis will not be a prerequisite for study eligibility. 
 
Additionally tissue will be tested for PD-L1 expression, as well as other potential 
biomarkers predictive of disease response to the study agent. In studies in squamous 
lung cancer, high PD-L1 expression was associated with an enhanced improved 
outcomes with pembrolizumab therapy[13].  
 
2.0 
STUDY OBJECTIVES 
 
2.1 
Primary Objectives 
2.1.1 
To determine the response rate of pembrolizumab when administered at 200 mg 
IV every 3 weeks in patients with anaplastic thyroid cancer. 
2.2 
Secondary Objectives 
2.2.1 
To describe the median progression free survival in anaplastic thyroid cancer 
patients treated with pembrolizumab compared to previously published values. 
2.2.2 
To describe the median overall survival in anaplastic thyroid cancer patients 
treated with pembrolizumab compared to previously published values. 
 
2.2.3 
To describe the adverse events associated with pembrolizumab when 
administered at a dose of 200 mg IV every 3 weeks. 
 
 
2.3 
Exploratory/biomarker Objectives 
Collection of genomic profiling and PD-L1 status as well as others 
 
 
2.4 
Endpoints 
2.4.1  
Primary endpoint: Best radiographic response of patients who receive 
pembrolizumab. RECIST 1.1 will be used to describe whether patients 
demonstrate a complete response, partial response, stable disease or 
progressive disease. Response rate will be the percentage of patients showing 
complete or partial response.  
 
2.4.2 
(2.2.1) Secondary endpoint: Median time from initiation of pembrolizumab until 
disease progression by RECIST1.1, unacceptable toxicity, withdrawal of consent, 
or discontinuation from the trial for any other reason. 
 
2.4.3 
(2.2.2) Secondary endpoint: Time from initiation of pembrolizumab until death. 
 
2.4.4 
(2.2.3) Secondary endpoint: toxicity and adverse events (CTCAE v.4) 
3.0 
Subject ELIGIBILITY 


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Eligibility waivers are not permitted. Subjects must meet all of the inclusion and exclusion 
criteria to be registered to the study. Study treatment may not begin until a subject is 
registered. 
 
3.1 
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 for the trial. 
 
2. Histologically or cytologically confirmed diagnosis of anaplastic thyroid cancer or 
undifferentiated thyroid cancer. A diagnosis of possible ATC/UTC will be allowed if the 
clinical presentation is consistent with anaplastic or undifferentiated thyroid cancer. 
 
3. Patients will be eligible if they meet either criteria: 
a. Unresectable anaplastic thyroid cancer limited to the neck: Patients must have 
received radiation therapy or surgery to primary tumor and have subsequent 
evidence of ATC. 
 
b. Metastatic anaplastic thyroid cancer: either with entirely surgically removed 
cancer/metastatic only disease, or with disease in the neck not requiring radiation or 
surgery to the neck mass. 
 
 
4. Be  18 years of age on day of signing informed consent. 
 
5. Have measurable disease based on RECIST 1.1.   
 
 
6. Patients with a bulky thyroid/neck mass and those in whom airway obstruction is suspected 
should undergo an evaluation via indirect or direct laryngoscopy to ensure patency of the 
trachea/airway prior to enrollment 
 
7. Have a performance status of 0-1 on the ECOG Performance Scale. 
 
8. Demonstrate adequate organ function as defined in Table 1, all screening labs should be 
performed within 14 days of treatment initiation.   
Table 1:  Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
HEMATOLOGICAL 
Absolute neutrophil count 
(ANC) 
≥1,500 /mcL 
Platelets 
≥75,000 / mcL 
Hemoglobin 
≥8 g/dL 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 


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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. 
 
9. 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.   
 
10. 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 (Reference 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.  
 
11. 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. 
3.2 
Exclusion Criteria 
 
The subject must be excluded from participating in the trial if the subject: 
 
1. Is currently participating and receiving study therapy or has participated in a study of an 
investigational agent and received study therapy or used an investigational device within 4 
weeks of the first dose of treatment. 
 
2. Patients who have received radiation therapy within 7 days prior to the first dose of treatment 
should be excluded.  Treatment-related adverse events must have resolved prior to study 
treatment. 
 
3. 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. 
 
 
4. Has a known history of active TB (Bacillus Tuberculosis). 
 
5. Hypersensitivity to pembrolizumab or any of its excipients. 
 
6. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study  
Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from acute, non- hematological 
adverse events due to agents administered more than 4 weeks earlier  unless otherwise approved 
by the Principal Investigator.  


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- Note: Subjects with ≤ Grade 2 neuropathy, any grade dysphagia, ≤ Grade 2   
pain, ≤ Grade 2 weight loss, any grade hyperpigmentation of skin, any grade  fatigue, any 
grade xerostomia, and any grade dysgeusia, are an exception to this 
criterion and may qualify for the study. Also please note that the presence of a  feeding 
tube to aid with nutrition does not disqualify patients from 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.    
 
Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy   
within 2 weeks prior to the first protocol treatment or who has not recovered (i.e., ≤  Grade 1 or at 
baseline) from acute, non-hematological adverse events due to a   
previously administered agent unless otherwise approved by the Principal Investigator.  
- Note: Subjects with ≤ Grade 2 neuropathy, any grade dysphagia, ≤ Grade 2   
pain, ≤ Grade 2 weight loss, any grade hyperpigmentation of skin, any grade  fatigue, any grade 
xerostomia, and any grade dysgeusia, are an exception to this  criterion and may qualify for 
the study. Also please note that the presence of a  feeding tube to aid with nutrition does not 
disqualify patients from 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.   
- 
 
  
7. 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. 
 
8. 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 steroids for at least 7 days prior to trial 
treatment.  This exception does not include carcinomatous meningitis which is excluded 
regardless of clinical stability.   
 
9. 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 (e.g., thyroxine, insulin, or physiologic corticosteroid replacement 
therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic 
treatment.  
 
10. Has known history of, or any evidence of active, non-infectious pneumonitis. 
 
11. Has an active infection requiring systemic therapy. 
 
12. 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.   
 
13. Has known psychiatric or substance abuse disorders that would interfere with cooperation with 
the requirements of the trial. 


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14. 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. 
15. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent. 
16. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 
17. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] 
is detected). 
18. 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. 
 
4.0 
TREATMENT PLAN 
4.1 
Treatment Dosage and Administration  
The treatment to be used in this trial is outlined below in Table 2. This treatment will be 
administered as an outpatient. 
 
Table 2:  Trial Treatment  
Trial treatment should begin on the day 1 of cycle. 
Drug 
Dose/Potency 
Dose 
Frequency 
Route of 
Administration 
Regimen/Treatment 
Period 
Use 
Pembrolizumab 
200 mg 
Q3W 
IV infusion 
Day 1 of each 3 
week cycle 
Experimental 
4.1.1 
Dose Selection 
The rationale for selection of doses to be used in this trial is provided in Section 1.4– 
Background and Rationale.   
4.2 
Toxicities and Dosing Delays/Dose Modifications 
Any subject who receives treatment on this protocol will be evaluable for toxicity. Each patient 
will be assessed for the development of toxicity according to the Time and Events table 
(Table 3). Toxicity will be assessed according to the NCI Common Toxicity Criteria for 
Adverse Events (CTCAE), version 4.0. Dose adjustments should be made according to the 
system showing the greatest degree of toxicity.  
 
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-related toxicities and severe or life-threatening AEs as per Table 3 below. See Section 
5.6.1 and Events of Clinical Interest Guidance Document for supportive care guidelines, 
including use of corticosteroids. 
 
Table 3:   Dose Modification Guidelines for Drug-Related Adverse Events 


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Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting 
Treatment 
Discontinue Subject 
Diarrhea/Colitis 
2-3 
 
Toxicity resolves to Grade 0-1. 
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
4 
Permanently discontinue 
Permanently discontinue 
AST, ALT, or 
Increased Bilirubin 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose. 
3-4 
Permanently discontinue 
(see exception below)1 
Permanently discontinue 
Type 1 diabetes 
mellitus (if new 
onset) or 
Hyperglycemia 
T1DM or 
3-4 
Hold pembrolizumab for new 
onset Type 1 diabetes mellitus 
or Grade 3-4 hyperglycemia 
associated with evidence of 
beta cell failure. 
 
Resume pembrolizumab when patients are clinically and 
metabolically stable. 
Hypophysitis 
2-3 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
4 
Permanently discontinue 
Permanently discontinue 
Hyperthyroidism 
3 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
4 
Permanently discontinue 
Permanently discontinue 
Hypothyroidism 
2-4 
Therapy with pembrolizumab 
can be continued while 
treatment for the thyroid 
disorder is instituted 
Therapy with pembrolizumab can be continued while 
treatment for the thyroid disorder is instituted. 
Infusion Reaction 
3-4 
Permanently discontinue 
Permanently discontinue 
Pneumonitis 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
3-4 
Permanently discontinue 
Permanently discontinue 
Renal Failure or 
Nephritis 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
3-4 
Permanently discontinue 
Permanently discontinue 
All Other Drug-
Related Toxicity2 
3 or Severe 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
4 
Permanently discontinue 
Permanently discontinue 
Note: Permanently discontinue for any severe or Grade 3 drug-related AE that recurs or any life-threatening event. 
1 For patients with liver metastasis who begin treatment with Grade 2 AST or ALT, if AST or ALT increases by greater than or equal 
to 50% relative to baseline and lasts for at least 1 week then patients should be discontinued. 
2 Patients with intolerable or persistent Grade 2 drug-related AE may hold study medication at physician discretion.  Permanently 
discontinue study drug for persistent Grade 2 adverse reactions for which treatment with study drug has been held, that do not 
recover to Grade 0-1 within 12 weeks of the last dose.   
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 otherwise discussed with the Sponsor. The reason for interruption should be 
documented in the patient's study record. 
4.2.1 
Timing of Dose Administration 
Trial treatment should be administered on Day 1 of each cycle after all 
procedures/assessments have been completed as detailed on the Trial Flow Chart (Section 


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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 200 mg will be administered as a 30 minute IV infusion every 3 weeks.  Sites 
should make every effort to target infusion timing to be as close to 30 minutes as possible.  
However, given the variability of infusion pumps from site to site, a window of -5 minutes and 
+10 minutes is permitted (i.e., infusion time is 30 minutes: -5 min/+10 min). 
 
4.2.2 
Trial Blinding/Masking 
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the 
treatment administered. 
 
4.3 
Concomitant Medications/Treatments 
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.  
 
4.3.1 
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 case report form (CRF) 
including all prescription, over-the-counter (OTC), herbal supplements, and IV medications 
Duration of Therapy and fluids.  If changes occur during the trial period, documentation of drug 
dosage, frequency, route, and date may also be included on the CRF. 
 
All concomitant medications received within 28 days before the first dose of trial treatment and 
30 days after the last dose of trial treatment should be recorded.  Concomitant medications 
administered after 30 days after the last dose of trial treatment should be recorded for SAEs 
and ECIs as defined in Section 7.2. 
 
4.3.2 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.   
 
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 Sponsor. 
 


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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. 
 
a. Rescue Medications & Supportive Care 
i. 
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 and in greater detail in the ECI guidance document. 
Where appropriate, these guidelines include the use of oral or intravenous treatment with 
corticosteroids as well as additional anti-inflammatory agents if symptoms do not improve with 
administration of corticosteroids.   Note that several courses of steroid tapering may be necessary as 
symptoms may worsen when the steroid dose is decreased. For each disorder, attempts should be 
made to rule out other causes such as metastatic disease or bacterial or viral infection, which might 
require additional supportive care. The treatment guidelines are intended to be applied when the 
investigator determines the events to be related to pembrolizumab.  
 
Note: if after the evaluation the event is determined not to be related, the investigator is instructed to 
follow the ECI reporting guidance but does not need to follow the treatment guidance (as outlined in 
the ECI guidance document). 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. Suggested conditional procedures, as appropriate, can 
be found in the ECI guidance document. 
 
Pneumonitis:  
o 
For Grade 2 events, treat with systemic corticosteroids. When symptoms improve to 
Grade 1 or less, steroid taper should be started and continued over no less than 4 
weeks. 
o 
For Grade 3-4 events, immediately treat with intravenous steroids.  Administer 
additional anti-inflammatory measures, as needed. 
o 
Add prophylactic antibiotics for opportunistic infections in the case of prolonged steroid 
administration. 
 
 
Diarrhea/Colitis:  
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such as 
diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of bowel 
perforation (such as peritoneal signs and ileus).   
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) 


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o 
For T1DM or Grade 3-4 Hyperglycemia 
 
Insulin replacement therapy is recommended for Type I diabetes mellitus and 
for Grade 3-4 hyperglycemia associated with metabolic acidosis or ketonuria.  
 
Evaluate patients with serum glucose and a metabolic panel, urine ketones, 
glycosylated hemoglobin, and C-peptide.  
 
 
Hypophysitis: 
o 
For Grade 2 events, treat with corticosteroids. When symptoms improve to Grade 1 or 
less, steroid taper should be started and continued over no less than 4 weeks. 
Replacement of appropriate hormones may be required as the steroid dose is tapered. 
o 
For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid taper should be 
started and continued over no less than 4 weeks. Replacement of appropriate 
hormones may be required as the steroid dose is tapered. 
 
 
Hyperthyroidism or Hypothyroidism:  
Thyroid disorders can occur at any time during treatment. Monitor patients for changes in 
thyroid function (at the start of treatment, periodically during treatment, and as indicated based 
on clinical evaluation) and for clinical signs and symptoms of thyroid disorders. 
o 
Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism): 
 
In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are 
suggested as initial therapy. 
 
In hypothyroidism, thyroid hormone replacement therapy, with 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 4 below shows treatment guidelines for subjects who experience an infusion reaction 
associated with administration of pembrolizumab (MK-3475). 
Table 4:   Infusion Reaction Treatment Guidelines 


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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 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
If symptoms resolve within one hour of stopping 
drug infusion, the infusion may be restarted at 
50% of the original infusion rate (e.g., from 100 
mL/hr to 50 mL/hr).  Otherwise dosing will be 
held until symptoms resolve and the subject 
should be premedicated for the next scheduled 
dose. 
Subjects who develop Grade 2 toxicity 
despite adequate premedication should be 
permanently discontinued from further trial 
treatment administration. 
Subject may be premedicated 1.5h 
(± 30 minutes) prior to infusion of 
pembrolizumab (MK-3475) with: 
 
Diphenhydramine 50 mg po (or 
equivalent dose of antihistamine). 
 
Acetaminophen 500-1000 mg po (or 
equivalent dose of antipyretic). 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief interruption 
of infusion); recurrence of 
symptoms following initial 
improvement; hospitalization 
indicated for other clinical sequelae 
(e.g., renal impairment, pulmonary 
infiltrates) 
Grade 4: 
Life-threatening; pressor or 
ventilatory support indicated 
Stop Infusion. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine 
 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
Hospitalization may be indicated. 
Subject is permanently discontinued from 
further trial treatment administration. 
No subsequent dosing 
Appropriate resuscitation equipment should be available in the room and a physician readily available during the period of drug 
administration. 
 
4.4 
Diet/Activity/Other Considerations 
4.4.1 
Diet 
Subjects should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea or vomiting. 
4.4.2 
Contraception 
Pembrolizumab may have adverse effects on a fetus in utero.  Furthermore, it is not known if 
pembrolizumab has transient adverse effects on the composition of sperm.  Non-pregnant, non-breast-


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feeding women may be enrolled if they are willing to use 2 methods of birth control or are considered 
highly unlikely to conceive.  Highly unlikely to conceive is defined as 1) surgically sterilized, or 2) 
postmenopausal (a woman who is ≥45 years of age and has not had menses for greater than 1 year 
will be considered postmenopausal), or 3) not heterosexually active for the duration of the study.  The 
two birth control methods can be either two barrier methods or a barrier method plus a hormonal method 
to prevent pregnancy. Subjects should start using birth control from study Visit 1 throughout the study 
period up to 120 days after the last dose of study therapy.  
The following are considered adequate barrier methods of contraception: diaphragm, condom (by the 
partner), copper intrauterine device, sponge, or spermicide.  Appropriate hormonal contraceptives will 
include any registered and marketed contraceptive agent that contains an estrogen and/or a 
progestational agent (including oral, subcutaneous, intrauterine, or intramuscular agents). 
Subjects should be informed that taking the study medication may involve unknown risks to the fetus 
(unborn baby) if pregnancy were to occur during the study.  In order to participate in the study they 
must adhere to the contraception requirement (described above) for the duration of the study and during 
the follow-up period defined in section 7.2.2-Reporting of Pregnancy and Lactation to the 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. 
4.4.3 
Use in Pregnancy 
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab, the subject will 
immediately be removed from the study.  The site will contact the subject at least monthly and 
document the subject’s status until the pregnancy has been completed or terminated.  The outcome 
of the pregnancy will be reported to the Sponsor and to Merck without delay and within 24 hours to 
the 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 Sponsor.   If a male subject 
impregnates his female partner the study personnel at the site must be informed immediately and the 
pregnancy reported to the Sponsor and to Merck and followed as described above and in Section 7.2.2. 
4.4.4 
Use in Nursing Women 
It is unknown whether pembrolizumab is excreted in human milk.  Since many drugs are excreted in 
human milk, and because of the potential for serious adverse reactions in the nursing infant, subjects 
who are breast-feeding are not eligible for enrollment. 
4.5 
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 or the Sponsor if enrollment into the trial is inappropriate, the trial plan 
is violated, or for administrative and/or other safety reasons.  Specific details regarding 
discontinuation or withdrawal are provided in Section 7.1.4 – Other Procedures. 
 
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,  
Note: A subject may be granted an exception to continue on treatment with confirmed radiographic 
progression if clinically stable or clinically improved. 


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 
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 35 administrations of 
study medication, whichever is later. 
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 regarding second phase treatment 
 
Administrative reasons 
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 for overall survival until 
death, withdrawal of consent, or the end of the study, whichever occurs first. 
4.5.1 
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 24 weeks 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.   
 
4.6 
Duration of Therapy 
In the absence of treatment delays due to adverse events, treatment may continue until:  
 
Disease progression 
 
Inter-current illness that prevents further administration of treatment 
 
Unacceptable adverse event(s) 
 
Subject  decides to withdraw from the study, OR 
 
General or specific changes in the patient’s condition render the subject 
unacceptable for further treatment in the judgment of the investigator. 


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4.7 
Duration of Follow Up 
Subjects will be followed for 5 years after removal from treatment or until death, whichever 
occurs first. Subjects removed from treatment for unacceptable adverse events will be 
followed until resolution or stabilization of the adverse event. Trial follow up will be with clinic 
visits as indicated, and with a phone call every 3 months if the patient is no longer being seen. 
4.8 
Removal of Subjects from Protocol Therapy 
Subjects will be removed from therapy when any of the criteria listed in Section 5.5 apply. 
Notify the Principal Investigator, and document the reason for study removal and the date the 
subject was removed in the Case Report Form. The subject should be followed-up per 
protocol.  
4.9 
Subject Replacement 
If a patient is enrolled but does not receive pembrolizumab for any reason, they may be 
replaced with another trial participant. Patients that receive at least one dose of 
pembrolizumab will not be replaced. 
5.0 
STUDY PROCEDURES 
5.1 
Screening/Baseline Procedures 
Assessments performed exclusively to determine eligibility for this study will be done 
only after obtaining informed consent. Assessments performed for clinical indications 
(not exclusively to determine study eligibility) may be used for baseline values even if 
the studies were done before informed consent was obtained. 
 
All screening procedures must be performed within 30 days prior to registration 
unless otherwise stated. The screening procedures include: 
 
5.1.1 
Screening assessments to confirm eligibility will be performed as per the schedule of 
assessments. Documented Informed consent must be obtained before any study 
specific procedure will be performed. 
 
For treatment on the trial, the patient must have a documented 
anaplastic/undifferentiated thyroid cancer and meet the remainder of the eligibility 
criteria. If the diagnosis of ATC/UTC is suspected, patients will be allowed to enroll if 
they have a compatible clinical picture such as rapidly enlarging thyroid mass. This 
must be done at the treating center and all study required testing must be completed 
within the 30 day period prior to day of initiating therapy. 
 
Re-screening of patients will be allowed, if all entry criteria are met during the re-
screening phase time period (-30 days to -1 day). 
5.1.2 
Medical history 
Complete medical and surgical history, history of infections, autoimmune disease. 
5.1.3 Demographics 
Data to be collected on patient characteristics at screening include: 
 
- 
Demography (including: date of birth, age, patient initials, gender, childbearing 
potential, race and ethnicity, or as allowed by local regulations) 
 
- 
ATC diagnosis and extent of disease, including: 
• 
Date of diagnosis 
• 
Site of active disease 


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• 
Prior antineoplastic therapies (medications, radiation, surgeries) 
• 
Prior and Concomitant Medications, surgical and medical procedures 
 
All other medications taken within 30 days before the first dose of pembrolizumab treatment is 
administered will be noted in the clinical trial medication record and updated on a continual 
basis if there is new change to the medication. 
5.1.4 Review subject eligibility criteria  
According to section 3. 
5.1.5 Review previous and concomitant medications 
5.1.6 Physical exam including vital signs, height and weight 
Vital signs (temperature, pulse, respirations, blood pressure), height, weight 
5.1.7 Performance status 
Performance status evaluated prior to study entry  
 
5.1.8 Adverse event assessment 
Baseline adverse events will be assessed. See section 7.1 for Adverse Event monitoring and 
reporting. 
 
5.1.9 Hematology 
Hgb, platelets, white blood cells (WBC), red blood cells (RBC), differential (basophils, 
eosinophils, lymphocytes, monocytes, neutrophils (% or absolute)) 
 
5.1.10 Serum chemistries 
Albumin, ALT, AST, calcium, creatinine, total bilirubin, direct bilirubin (only if total bilirubin is ≥ 
grade 2), blood urea nitrogen (BUN) or urea, magnesium, potassium, sodium, alkaline 
phosphatase, TSH, T3, Free T4, Creatinine clearance will be calculated using the serum 
creatinine value. 
5.1.11 Urinalysis 
Macroscopic panel (dipstick) (color, total bilirubin, blood, glucose, ketones, leukocyte 
esterase, nitrite, pH, protein, specific gravity, urobilinogen)  
             Microscopic panel (RBC, WBC, casts, crystals, bacteria, epithelial cells) 
 
5.1.12 ECG 
A standard 12 lead ECG should be used for assessments as clinically indicated. 
5.1.13 Pregnancy test (for females of child bearing potential) 
At screening visit, serum pregnancy test will be performed. Following the screening 
assessment, urine pregnancy tests should be performed. 
5.1.14 Tumor assessment 
To be performed using radiographic imaging according to section 5.3.1. 
5.2 
Time and Events Table  
 
Table 5-1 lists the protocol schedule and assessments and indicates when particular 
assessments will be performed with an “X”. The cycle length is fixed at 21 days, and will be 
maintained regardless of whether there were dose modifications or interruptions in therapy. If 


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treatment with pembrolizumab is interrupted, future visits and assessments will continue as 
listed from cycle 1 day as Day#1 for the purpose of scheduling. 
There will be variation of up to +/-3 days allowed in visits and assessment from Cycle 2 
onwards. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 5-1  
Visit evaluation 
Schedule 
Protocol 
Section 
Screening / 
Baseline 
Day 1 of 
Cycle 1 
(21d) +/-3 
Day 1 of 
Cycle 2 
(21d) +/-3 
Day 1 of 
Subsequent 
cycles 
(21d) +/-3 
End of study treatment (EoT) 
(at last visit, or up to 30 days 
from last dose) 
Visit Number 
 
1 
2 
3 
4, 5.. 
Last 
Day of cycle 
   
-30 to -1 
1 
D29 
D57, D85.. 
Last 
Obtain Informed Consent 
 
ICF 
X 
 
 
 
 
Patient history 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
 
3.2 & 3.3 
X 
 
 
 
 
Documentation of diagnosis of 
anaplastic thyroid cancer, 
undifferentiated thyroid cancer, or 
compatible pathologic appearance 
and clinical presentation 
 
5.1.1.1.1 
X 
 
 
 
 
Diagnosis and extent of cancer 
 
5.1.1.2 
X 
 
 
 
 
Demography 
 
5.1.1.2 
X 
 
 
 
 
Relevant medical history/current 
medical conditions 
 
5.1.1.2 
X 
 
 
 
 
Prior antineoplastic therapy 
(meds, surgery, radiation) 
 
5.1.1.2 
X 
 
 
 
 
Prior/concomitant medications 
 
4.4 
X 
Continuous 
Surgical and Medical Procedures 
 
4.4 
X 
Continuous 
Eligibility Screening  
 
5.1.1.1 
X 
 
 
End of Phase Disposition 
 
5.1.1.
1 and 
5.1.3 
X 
Screening 
Phase 
Disposition  
 
 
 
X 
End of Treatment 
Phase  
Physical examination 
 
5.2.2.1 
X 
 
X 
X 
X 
Performance status (WHO) 
 
5.2.2.4 
X 
X 
X 
X 
X 
Height 
 
5.2.2.3 
X 
 
 
 
 
Weight 
 
5.2.2.3 
X 
X 
X 
X 
X 
Vital signs 
 
5.2.2.2 
X 
X 
X 
X 
X 


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Table 5-1. 
 Visit evaluation Schedule 
(continued) 
 
Protocol 
Section 
Screening / 
Baseline 
Day 1 of Cycle 1 
(21d) +/- 3 
Day 1 of Cycle 
2 (21d) +/- 3 
Day 1 of 
Subsequent 
cycles 
(21d) +/- 3 
End of study treatment (EoT) 
(at last visit, or up to 30 days 
from last dose) 
Visit Number 
 
1 
2 
3 
4, 5,… 
Last 
Day of cycle 
 
-30 to-1 
1 
D29 
D57, D85.. 
Last 
Lab assessments* 
 
 
X 
X 
X 
X 
X 
CBC 
 
5.2.2.5.1 
X 
X 
X 
X 
X 
Chemistry, *T3, *T4, *TSH * Results not 
required prior to Pembrolizumab infusion.  
 
5.2.2.5.2 
X 
X 
X 
X 
X 
Creatinine clearance 
 
5.2.2.5.2 
X 
 
 
 
 
Urinalysis (dipstick) with 
microscopic analysis(Repeat 
anytime during study if clinically 
indicated) 
 
5.2.2.5.4 
X 
 
 
 
 
Pregnancy test  *WOCBP 
 
5.2.2.5.5 
X(Serum)  
 
X(Urine) 
X(Urine) 
X(Urine) 
 
 
 
Imaging 
Standard of care imaging of 
neck/chest/abdomen (CT, MRI) as 
indicated to areas of known/ suspected 
disease 
 
5.2.1 
X 
 
 
X (within 0-7d 
prior to every even 
cycle) 
 
Standard of Care Imaging of the brain at 
baseline and then as clinically indicated 
(MRI/CT) 
 
5.2.1 
X 
 
 
X (if known or 
suspected brain 
metastases) 
 
Safety 
Adverse events 
 
7.1 
X 
Continuous 
Drug administration 
 
4.1 
 
X 
X 
X 
 


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5.3 
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 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. 
 
5.3.1 
Screening/Baseline 
Screening assessments to confirm eligibility will be performed as per the schedule of 
assessments. Documented Informed consent must be obtained before any study specific 
procedure will be performed. After meeting all the eligibility criteria, patients must sign a 
consent form for therapeutic portion of the trial.  
 
For the therapeutic portion of the trial, the patient must meet the remainder of the eligibility 
criteria. This must be done at the treating center and all study required testing must be 
completed within the 30 day period prior to day of initiating therapy. 
 
Re-screening of patients will be allowed, if all entry criteria are met during the re-screening 
phase time period (-30 days to -1 day). 
 
5.3.2 
Administrative Procedures 
 
5.3.2.1 
Informed Consent 
The Investigator must obtain documented consent from each potential subject prior to 
participating in a clinical trial. 
 
5.3.3 
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 Sponsor requirements. 
 


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5.3.3.1 
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.  
 
5.3.3.2 
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.   
 
5.3.3.3 
Patient demographics and other baseline characteristics 
Data to be collected on patient characteristics at screening include: 
 
-Demography (including: date of birth, age, patient initials, gender, childbearing potential, 
race and ethnicity, or as allowed by local regulations) 
 
-Relevant medical history 
 
-ATC diagnosis and extent of disease, including: 
Date of diagnosis 
Site of active disease 
Prior antineoplastic therapies (medications, radiation, surgeries) 
Prior and Concomitant Medications, surgical and medical procedures 
 
All other medications taken within 30 days before the first dose of pembrolizumab treatment is 
administered will be noted in the clinical trial medication record and updated on a continual 
basis if there is new change to the medication. 
 
5.3.3.4 
Information to be collected on screening failures 
A patient who signs an informed consent but fails to satisfy all eligibility criteria for any reason 
will be considered a screen failure. The reason for not entering the treatment protocol will be 
entered on the Screening Phase Disposition Page. The demographic information, informed 
consent, and Inclusion/Exclusion pages will be completed for Screen Failure patients. No other 
data will be entered into the clinical database for patients who are screen failures, unless the 
patient experienced a Serious Adverse Event during the Screening Phase (see Section 7 for 
SAE reporting details). 
 
Subjects who signed ICF but are considered ineligible after signing the study consent will be 
considered as screening failures, and data will be handled in the same manner. 
 
The following information will be recorded for screening failure patients: 
 
- Screening Phase Disposition page (including reason for not satisfying eligibility criteria and   
being started on treatment). 
- Informed consent. 
- Demography. 
- Adverse Events (only if an SAE occurs). 
- Inclusion/Exclusion Criteria. 
5.3.4 
Treatment period 
Following completion of screening procedures and verifying patient eligibility, the patient will 
be approved for treatment per protocol. 
 
The study treatment phase begins on Cycle 1, Day 1 with the first administration of 
pembrolizumab and will continue to receive treatment until disease progression by RECIST, 


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unacceptable toxicity, withdrawal of consent, or discontinuation of the trial for any other reason 
whichever occurs first.  Patients who have RECIST-defined PD as assessed by the investigator 
but who, in the opinion of the investigator, have evidence of continued clinical benefit from 
pembrolizumab may continue to receive the study medication upon approval by the principal 
investigator. In such cases, these patients must continue to be followed for safety and efficacy 
assessments as per the schedule of assessments.  Patients will be assessed as per visit 
schedule in Table 5-1. 
 
Visit windows of ± 3 days from scheduled study assessments will apply during and beyond 
Cycle 2. 
 
5.3.4.1 Treatment phase and duration of treatment  
Patients eligible for treatment will receive pembrolizumab. The first dose of each cycle will be 
administered after evaluation at the study center. Patients will remain on study and receive 
pembrolizumab until there is evidence of disease progression by RECIST, unacceptable 
toxicity, withdrawal of consent, or discontinuation of the trial for any other reason.  Patients who 
have RECIST-defined PD as assessed by the investigator but who, in the opinion of the 
investigator, have evidence of continued clinical benefit from pembrolizumab may continue to 
receive the study medication. In such cases, these patients must continue to be followed for 
safety and efficacy assessments as per the schedule of assessments. 
 
 
5.3.5 
End of treatment visit including study completion and premature withdrawal 
 
5.3.5.1 
End of Phase Disposition 
Patients will be evaluated upon discontinuation of the pembrolizumab by a clinic visit. At that 
time all assessments listed for End Of Treatment will be performed. A note will be entered into 
the clinical trial record will be completed, giving the date and reason for stopping the study 
treatment. 
 
At a minimum, all patients who discontinue study treatment, including those who refuse to 
return for a final visit, will be contacted for safety evaluations during the 30 days following the 
last dose of treatment. 
 
5.3.5.2 
Disease Details and Treatments 
 
5.3.5.2.1 Disease Details 
The investigator or qualified designee will obtain prior and current details regarding disease 
status.  
 
5.3.5.2.2 Prior Treatment Details 
The investigator or qualified designee will review all prior cancer treatments including 
systemic treatments, radiation and surgeries. 
 
5.3.5.2.3 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.  
5.3.5.3 
Criteria for patient withdrawal 
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Patient death will be considered as a withdrawal from the study. Patients may also be withdrawn (the 
physician may decide to remove the patient from any further study activity) if any of the following occur: 
 
Adverse event(s) (see Section 7.1) 
 
Disease progression 
 
Major protocol deviation 
 
Technical problems 
 
Physician decision 
 
Non-compliance with study treatment. 
 
Death 
 
Completed 
 
Patients must be withdrawn if any of the following occur: 
 
Lost to follow-up 
 
Subject/guardian decision 
 
Pregnancy (Pregnancy will be followed for outcome) 
 
Patients lost to follow up should be recorded as such in the clinical trial record. For patients 
who are lost to follow-up, the investigator will record the attempts at “due diligence” by 
documenting in the source documents steps taken to contact the patient, e.g. dates of 
telephone calls, registered letters, etc. 
5.3.5.4 
Replacement policy 
If an eligible patient is unable to start therapy with pembrolizumab, they may be replaced with another 
eligible patient if they have not received any study drug. 
Apart from the above, patients will not be replaced on this study.  
 
5.4 
Assessment types 
5.4.1 
Efficacy assessments 
Efficacy evaluations will be via revised RECIST 1.1 criteria on imaging performed at the conclusion of 
every 2 cycles. Target lesions will be identified prior to initiation of therapy on imaging and will be 
followed on subsequent imaging. Progression must be documented on imaging. 
Imaging exams will be according to standard of care guidelines to areas of known/suspected disease. 
These will include CT of the neck, chest, abdomen and pelvis as well as MRI of the brain. Other tests 
may be clinically indicated, these will be ordered according to disease and patient specific guidelines. 
Imaging of the brain will be required at baseline by CT or MRI per standard of care for anaplastic thyroid 
cancer. 
5.4.2 
Safety and tolerability assessments 
Safety will be monitored by the assessments described below as well as the collection of AEs 
at every visit. For details on AE collection and reporting, refer to Section 7. Significant findings 
that were present prior to the signing of informed consent must be included in the relevant 
medical history/current medical conditions in the clinical trial record. Significant new findings 
that begin or worsen after informed consent must be recorded in the clinical trial record. 
5.4.2.1 
Physical examination 
Physical examinations will include an examination of general appearance, skin, neck (including 
thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, extremities, and 


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a basic nervous system evaluation. Information about the physical examination will be present 
in the source documentation. For the assessment schedule refer to Table 5-1. 
 
Significant findings that were present prior to the signing of informed consent must be included 
in the clinical trial record. Significant new findings that begin or worsen after informed consent 
must be recorded in the clinical trial record. 
5.4.2.2 
Vital signs 
Vital signs include body temperature, blood pressure and pulse measurements. Blood 
pressure (systolic and diastolic) and pulse should be measured. 
For the assessment schedule refer to Table 5-1. 
5.4.2.3 
Height and weight 
Height in centimeters (cm) and body weight (to the nearest 0.1 kilogram [kg]) will be 
measured. Height will be measured at screening only.  
 
For the assessment schedule for weight refer to Table 5-1. 
5.4.2.4 
Performance status 
WHO performance status will be assessed as per the assessment schedule (refer to Table 5-
1). 
 
Assessment of WHO performance status (Table 5-2) will be performed within the time 
windows described above of the scheduled assessment, even if study medication is being 
held. More frequent examinations may be performed at the investigator’s discretion, if 
medically indicated. 
 
Table 5-2:   WHO Performance status scale 
Score 
Performance Status 
1 
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 
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 
Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair 
5 
Dead 
 
5.4.2.5 Laboratory evaluations 
Local site laboratories will be used for the analysis of scheduled hematology, biochemistry, 
urine, and other blood specimens collected as part of safety monitoring. All unscheduled 
blood testing will be performed locally, with exceptions for emergency conditions. The time 
windows granted for laboratory evaluations are identical to the corresponding visit time 
windows for each visit (refer to Section 5.1). 
 
Laboratory abnormalities that are considered clinically significant, induce clinical signs or 
symptoms, require concomitant therapy or require changes in pembrolizumab treatment  
constitute an adverse event (AE) and must be reported as an AE in the clinical trial record. 
Laboratory values obtained at the screening visit will be used to assess eligibility to meet 
inclusion criteria. In addition, eligible patients must have baseline laboratory assessments 
performed on Cycle 1 Day 1 or within 24 hours prior to dosing. 


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5.3.2.5.1 Hematology 
Hematology assessments of the parameters listed in Table 5-3 will be tested as per the 
schedule of assessments (Table 5-1). 
 
Table 5-3:  Local Clinical laboratory parameters collection plan 
Test 
Category 
Test Name 
*Normal ranges based on local laboratory standard of care parameters  
Hematology 
Hgb, platelets, white blood cells (WBC), red blood cells (RBC), differential 
(basophils, eosinophils, lymphocytes, monocytes, neutrophils (% or 
absolute)) 
Chemistry 
Albumin, ALT, AST, calcium, creatinine, total bilirubin, direct bilirubin (only 
if total bilirubin is ≥ grade 2), blood urea nitrogen (BUN) or urea, TSH, T3, 
Free T4, potassium, sodium, alkaline phosphatase,  
Creatinine 
clearance 
             Creatinine clearance 
Urinalysis 
Macroscopic panel (dipstick)(color, total bilirubin, blood, glucose, ketones, 
leukocyte esterase, nitrite, pH, protein, specific gravity, urobilinogen)  
Microscopic panel (RBC, WBC, casts, crystals, bacteria, epithelial cells) 
Pregnancy 
test 
For women of childbearing potential(WOCBP) : 
At screening visit, serum pregnancy test 
At subsequent cycles, urinary pregnancy test. 
If local requirements dictate otherwise, local regulations should be 
followed 
5.4.2.5.1 
Hematology 
Hematology assessments of the parameters listed in Table 5-3 will be tested as per the 
schedule of assessments (Table 5-1). 
5.4.2.5.2 
Clinical chemistry and Creatinine clearance 
Clinical chemistry and Creatinine clearance assessments of the parameters listed in Table 5-
3 will be tested as per the schedule of assessments (Table 5-1). 
5.4.2.5.3 
Urinalysis 
Dipstick measurements will be performed as per Table 5-3 and according to the schedule of 
assessments (Table 5-1). Any significant findings on dipstick will be followed up with 
microscopic evaluation as per Table 5-3. Urinalysis after baseline will be performed only if 
clinically indicated, it is not mandatory. 
5.4.2.5.4 
Pregnancy and assessments of fertility 
During screening, a serum pregnancy test will be completed. Starting on day 1 of Cycle 2, and 
at EOT, urinary pregnancy test (dipstick) will be performed. The time windows granted for 
pregnancy testing are identical to the corresponding visit time windows for each visit. If local 
requirements dictate otherwise, local regulations should be followed. 
Women who are determined not to be of child bearing potential before the study will only be tested at 
screening. When non-child bearing potential status is determined during the study, further pregnancy 
testing will not be continued. Women are considered post-menopausal if they have had 12 months of 
natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of 
vasomotor symptoms), and otherwise not of child bearing potential if they have had surgical bilateral 
oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks ago. In the case of 
oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up 
hormone level assessment is she considered not of child bearing potential. 


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The time windows granted for pregnancy testing are identical to the corresponding visit time windows 
for each visit.  
If a positive pregnancy test is performed in between study visits, the patients must immediately notify 
the investigator. 
5.4.2.6 
Cardiac assessments 
5.4.2.6.1 
Electrocardiogram (ECG) 
A standard 12 lead ECG should be used for assessments. ECG’s will be performed as 
clinically indicated. All ECGs will be performed locally and reviewed by investigator. 
Interpretation of the tracing must be made by a qualified physician and documented. Clinically 
significant abnormalities present when the patient signs the informed consent should be reported. New 
or worsened clinically significant findings occurring after informed consent must be recorded. 
 
5.4.3 
Safety Follow-Up Visit 
The mandatory Safety Follow-Up Visit should be conducted approximately 30 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 may have up to two safety follow-up visits, one after the Treatment 
Period and one after the Second Course Phase. 
 
5.4.3.1 
Follow-up Visits 
Subjects who discontinue trial treatment for a reason other than disease progression will 
move into the Follow-Up Phase and should be assessed every 6 weeks (42 ± 7 days) by 
radiologic imaging to monitor disease status.  After 1 year, the imaging time point will occur 
every 9 weeks (± 7 days). 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. Information regarding 
post-study anti-neoplastic treatment will be collected if new treatment is initiated. 
 
Subjects who are eligible to receive retreatment with pembrolizumab according to the criteria 
in will move from the follow-up phase to the Second Course Phase when they experience 
disease progression.  Details are provided in Section 6.2 – Trial Flow Chart for Retreatment.    
 
5.4.3.1.1 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 should be contacted by telephone every 12 weeks 
to assess for survival status until death, withdrawal of consent, or the end of the study, whichever 
occurs first.  
5.4.3.2 
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: 


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 
Either  
o 
Stopped initial treatment with pembrolizumab after attaining an investigator-determined 
confirmed CR according to RECIST 1.1, and 
 
Was treated for at least 24 weeks 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 
 
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 Trial Flow Chart. 
6.0 
Measurement of Effect 
6.1 
Antitumor Effect- Solid Tumors 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee [JNCI 
92(3):205-216, 2000]. Changes in only the largest diameter (unidimensional measurement) of 
the tumor lesions are used in the RECIST v1.1 criteria. 


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6.1.1 
Definitions 
Evaluable for toxicity. All subjects will be evaluable for toxicity from the time of their first 
treatment with study drug. 
 
Evaluable for objective response.  Only those subjects who have measurable disease 
present at baseline, have received at least one cycle of therapy, and have had their disease 
re-evaluated will be considered evaluable for response. These subjects will have their 
response classified according to the definitions stated below. (Note: Subjects who exhibit 
objective disease progression prior to the end of cycle 1 will also be considered evaluable.) 
 
6.1.2 
Disease Parameters 
Measurable disease. Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as >20 mm with 
conventional techniques (CT, MRI, x-ray) or as >10 mm with spiral CT scan. All tumor 
measurements must be recorded in millimeters (or decimal fractions of centimeters). 
 
 
 
Note: Previously irradiated lesions are non-measurable except in cases of documented 
progression of the lesion since the completion of radiation therapy. 
 
Non-measurable disease. All other lesions (or sites of disease), including small lesions 
(longest diameter <20 mm with conventional techniques or <10 mm using spiral CT scan), 
are considered non-measurable disease. Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, 
abdominal masses (not followed by CT or MRI), and cystic lesions are all non-measurable. 
 
Target lesions. All measurable lesions up to a maximum of 3 lesions per organ and 6 lesions 
in total, representative of all involved organs, should be identified as target lesions and 
recorded and measured at baseline. Target lesions should be selected on the basis of their 
size (lesions with the longest diameter) and their suitability for accurate repeated 
measurements (either by imaging techniques or clinically). A sum of the longest diameter 
(LD) for all target lesions will be calculated and reported as the baseline sum LD. The 
baseline sum LD will be used as reference by which to characterize the objective tumor 
response. 
 
Non-target lesions. All other lesions (or sites of disease) including any measurable lesions 
over and above the 6 target lesions should be identified as non-target lesions and should 
also be recorded at baseline. Measurements of these lesions are not required, but the 
presence or absence of each should be noted throughout follow-up.  
6.1.3 
Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or calipers. 
All baseline evaluations should be performed as closely as possible to the beginning of 
treatment and never more than 28 days before the beginning of the treatment. 
 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination when both methods have been 
used to assess the antitumor effect of a treatment. 
 
Provide each method and note timeframe for when each will be done (e.g., every 6 weeks, 
every 2 cycles, etc.). Examples include: 
 


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Conventional CT and MRI. These techniques should be performed with cuts of 10 mm or less 
in slice thickness contiguously. Spiral CT should be performed using a 5 mm contiguous 
reconstruction algorithm. This applies to tumors of the chest, abdomen, and pelvis.  
 
CT scans of the neck, chest, abdomen and pelvis will be performed at baseline and every two 
cycles according to standard of care. Other imaging of these areas such as PET/MRI will be 
allowed if CT cannot be performed. 
MRI of the brain will be performed at baseline and as clinically indicated. Wherever it can be 
safely given, radiographic contrast agents should be given for the imaging studies. 
 
6.1.4 
Response Criteria 
6.1.4.1 Evaluation of Target Lesions 
Complete Response (CR): Disappearance of all target lesions, determined by two separate 
observations conducted not less than 4 weeks apart. There can be no appearance of new 
lesions. 
Partial Response (PR): At least a 30% decrease in the sum of the longest diameter (LD) of 
target lesions, taking as reference the baseline sum LD. There can be no appearance of new 
lesions. 
 
Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, 
taking as reference the smallest sum LD recorded since the treatment started, or the 
appearance of one or more new lesions. 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum LD since the treatment started. 
6.1.4.2 Evaluation of Non-Target Lesions 
Complete Response (CR): Disappearance of all non-target lesions and normalization of 
tumor marker level. 
 
Incomplete Response/Stable Disease (SD): Persistence of one or more non-target lesion(s) 
and/or maintenance of tumor marker level above the normal limits. 
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions 
6.1.4.3 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started). The subjects best response 
assignment will depend on the achievement of both measurement and confirmation criteria. 
 
 
 
 
 
 
 
 
 
 
 
 


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Target 
Lesions 
Non-
Target 
Lesions 
New Lesions 
Overall 
Response 
Best Response 
for this Category 
Also Requires: 
CR 
CR 
No 
CR 
>4 wks. 
confirmation 
CR 
Non-
CR/Non-
PD 
No 
PR 
 
>4 wks. 
confirmation 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
documented at 
least once >4 wks. 
from baseline 
PD 
Any 
Yes or No 
PD 
 
no prior SD, PR or 
CR 
Any 
PD* 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
* 
In exceptional circumstances, unequivocal progression in non-target 
lesions may be accepted as disease progression. 
 
Note: 
Subjects with a global deterioration of health status requiring 
discontinuation of treatment without objective evidence of disease 
progression at that time should be reported as “symptomatic 
deterioration”. Every effort should be made to document the 
objective progression even after discontinuation of treatment. 
Note: If subjects respond to treatment and are able to have their disease resected, the 
patient’s response will be assessed prior to the surgery. 
6.1.5 
Duration of Response 
Duration of overall response: The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date 
that recurrent or progressive disease is objectively documented (taking as reference for 
progressive disease the smallest measurements recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met for 
CR until the first date that recurrent disease is objectively documented. 
 
 
Duration of stable disease: Stable disease is measured from the start of the treatment until 
the criteria for progression are met, taking as reference the smallest measurements recorded 
since the treatment started.  
6.1.6 
Progression-Free Survival 
Progression-free survival (PFS) is defined as the duration of time from start of treatment to 
time of progression. 
6.2 
Safety/tolerability 
 
Analyses will be performed for all subjects having received at least one dose of study drug. 
The study will use the CTCAE version 4.0 for reporting of non-hematologic adverse events 
(http://ctep.cancer.gov/reporting/ctc.html) and modified criteria for hematologic adverse 
events. 
7.0 
ADVERSE EVENTS 


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7.1 
Experimental Therapy 
For the most recent safety update, please refer to the current Investigator’s Brochure or 
Study Agent Prescribing Information. 
7.1.1 
Contraindications 
Pembrolizumab is approved by the FDA for use in melanoma. In its current labeling, there are 
no contraindications listed. Based on currently available data, there are no absolute 
contraindications to its usage in patients. 
7.1.2 
Special Warnings and Precautions for Use 
There are concerns about pembrolizumab side effects, often immune-related. Always refer to 
the package insert, any immune related toxicity should be carefully evaluated and considered 
serious. The relevant section from Lexicomp is provided below. 
 
• Gastrointestinal toxicity: Immune-mediated colitis (including microscopic colitis) has occurred, 
including cases of grade 2 or 3 colitis. The median time to onset of colitis was 6.5 months (range: ~2 
to 10 months) and the mediation duration was 2.6 months (range: 4 days to 3.6 months). Grade 2 or 3 
colitis was managed with high-dose systemic corticosteroids (prednisone ≥40 mg/day [median initial 
dose 70 mg/day] or equivalent) with a median duration of initial corticosteroid therapy of 7 days (range: 
4 to 41 days), followed by a corticosteroid taper. Patients with colitis experienced complete resolution. 
May require treatment interruption, systemic corticosteroid therapy, or permanent discontinuation. 
Monitor for signs and symptoms of colitis; administer systemic corticosteroids for grade 2 or higher 
colitis. 
• Hepatotoxicity: Hepatitis, including autoimmune hepatitis, occurred (case reports, including 1 case of 
grade 4 hepatitis). The median onset for grade 4 hepatitis was 22 days; the duration was 1.1 months. 
Grade 4 hepatitis was managed with high-dose systemic corticosteroids (prednisone ≥40 mg/day or 
equivalent), followed a corticosteroid taper. Monitor for liver function changes. May require treatment 
interruption, systemic corticosteroids (for grade 2 or higher toxicity), or permanent discontinuation. 
• Hypophysitis: Immune-mediated hypophysitis occurred (1 case of grade 2 and one case of grade 4). 
The time to onset was 1.3 and 1.7 months, respectively. Hypophysitis was managed with high-dose 
systemic corticosteroids (prednisone ≥40 mg/day or equivalent), followed by a corticosteroid taper. 
Patients then remained on physiologic corticosteroid replacement. Monitor for signs/symptoms of 
hypophysitis. May require treatment interruption, systemic corticosteroids (for grade 2 or higher 
toxicity), or permanent discontinuation. 
• Nephrotoxicity: Nephritis, including autoimmune nephritis (1 case) and interstitial nephritis with renal 
failure (2 cases), has occurred. The onset for autoimmune nephritis was 11.6 months after the first 
dose and 5 months after the last dose, and duration was 3.2 months. Acute interstitial nephritis was 
confirmed by renal biopsy in 2 patients with grades 3/4 renal failure. These cases were managed with 
high-dose systemic corticosteroids (prednisone ≥40 mg/day equivalent, followed by a corticosteroid 
taper), with full recovery. Monitor for renal function changes. May require treatment interruption, 
systemic corticosteroids (for grade 2 or higher toxicity), or permanent discontinuation. 
• Pulmonary toxicity: Immune-mediated pneumonitis has been observed, including cases which were 
grade 2 and 3. The median time to development was 5 months (range: ~2 days to ~10 months) and 
the median duration was ~5 months (range: 1 week to 14.4 months). Some patients required initial 
management with high-dose systemic corticosteroids (median initial prednisone dose of 63.4 mg/day 


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or equivalent), the median duration of initial corticosteroid therapy was 3 days (range: 1 to 34 days) 
followed by a corticosteroid taper. Most patients with grade 2 or 3 pneumonitis had complete resolution. 
May require treatment interruption, corticosteroid therapy, or permanent discontinuation. Monitor for 
signs and symptoms of pneumonitis; if pneumonitis is suspected, evaluate with radiographic imaging 
and administer systemic corticosteroids for grade 2 or higher pneumonitis. 
• Thyroid disorders: Immune-mediated hyperthyroidism and hypothyroidism have occurred. The 
median onset for hyperthyroidism was 1.5 months (range: 2 to 8 weeks), and the median duration was 
2.8 months (range: 1 to 6 months). May require management with high-dose systemic corticosteroids 
(prednisone ≥40 mg/day or equivalent), followed by a corticosteroid taper. Hyperthyroidism resolved in 
all cases observed in the clinical trial. Hypothyroidism occurred with a median onset of 3.5 months 
(range: 5 days to 19 months). Hypothyroidism was generally managed with long-term thyroid hormone 
replacement therapy, although some patients only required short-term replacement therapy. 
Hypothyroidism did not require systemic corticosteroid therapy or discontinuation. Thyroid disorders 
may occur at any point in pembrolizumab therapy. Monitor for changes in thyroid function (at baseline, 
periodically during treatment and as clinically indicated). Administer systemic corticosteroids (for grade 
3 or higher hyperthyroidism); may require treatment interruption or permanent discontinuation. Isolated 
hypothyroidism may be managed with replacement therapy (without corticosteroids and treatment 
interruption). 
• Other immune-mediated toxicities: Other clinically relevant immune-mediated disorders have been 
observed, including exfoliative dermatitis, uveitis, arthritis, myositis, pancreatitis, hemolytic anemia, 
partial seizure (in a patient with inflammatory foci in brain parenchyma), and adrenal insufficiency. 
Myasthenic syndrome, optic neuritis, and rhabdomyolysis have also been observed in patients 
receiving pembrolizumab. If an immune-mediated adverse event is suspected, evaluate appropriately; 
withhold treatment and administer systemic corticosteroids based on severity of reaction. Upon 
resolution to grade 0 or 1, initiate corticosteroid taper (continue tapering over at least 1 month). If 
reaction remains at grade 1 or less during taper may reinitiate pembrolizumab. Discontinue 
permanently for severe or grade 3 immune-mediated adverse event that is recurrent or life-threatening. 
 
7.1.3 
Interaction with other medications 
Refer to the package insert for possible interactions. There are currently no known 
interactions with other drugs. 
7.1.4 
Adverse Reactions 
 
7.1.4.1 
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 4.0 (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); see the 


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separate ECI guidance document in Appendix 4 regarding the identification, evaluation and 
management of potential irAEs.   
 
Please refer to section 7.2 for detailed information regarding the assessment and recording of AEs.  
  
7.2 
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 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. A planned hospitalization is not considered reportable; however, if a serious 
adverse event occurs during the course of the hospitalization, then the event is reportable.  The 
reporting timeframe for adverse events meeting any serious criteria is described in section 7.2.3.1. 
 
 
7.2.1 
Definition of an Overdose for This Protocol and Reporting of Overdose to the 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. 
 


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If an adverse event(s) is associated with (“results from”) the overdose of a Merck product, the 
adverse event(s) is reported as a serious adverse event, even if no other seriousness criteria are met. 
If a dose of Merck’s product meeting the protocol definition of overdose is taken without any 
associated clinical symptoms or abnormal laboratory results, the overdose is reported as a non-
serious Event of Clinical Interest (ECI), using the terminology “accidental or intentional overdose 
without adverse effect.” 
 
All reports of overdose with and without an adverse event must be reported within 24 hours to the 
Sponsor and within 2 working days hours to Merck Global Safety. (Attn: Worldwide Product Safety; 
FAX 215 993-1220). 
 
7.2.2 
Reporting of Pregnancy and Lactation to the 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 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 Sponsor and to Merck 
7.2.3.1 
Serious Adverse Events 
A serious adverse event is any adverse event occurring at any dose or during any use of 
Merck’s product that: 
 
Results in death; 
 
Is life threatening; 
 
Results in persistent or significant disability/incapacity; 
 
Results in or prolongs an existing inpatient hospitalization; 
 
Is a congenital anomaly/birth defect; 
 
Is a new cancer (that is not a condition of the study); 
 
Is associated with an overdose; 
 
Is another important medical event  
Refer to Table 6 for additional details regarding each of the above criteria. 
 
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 24 
hours to the Sponsor and within 2 working days to Merck Global Safety.  
 
Non-serious Events of Clinical Interest will be forwarded to Merck Global Safety and will be handled in 
the same manner as SAEs.  
 


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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 outside of 
the time period specified in the previous paragraph also must be reported immediately to the 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. 
7.3 
Adverse Event Monitoring 
Adverse event data collection and reporting, which are required as part of every 
clinical trial, are done to ensure the safety of subjects enrolled in the studies as well 
as those who will enroll in future studies using similar agents. Adverse events are 
reported in a routine manner at scheduled times during a trial. Additionally, certain 
adverse events must be reported in an expedited manner to allow for optimal 
monitoring of subject  safety and care.  
 
All subjects experiencing an adverse event, regardless of its relationship to study 
drug, will be monitored until:  
 the adverse event resolves or the symptoms or signs that constitute the 
adverse event return to baseline;  
 any abnormal laboratory values have returned to baseline;  
 there is a satisfactory explanation other than the study drug for the changes 
observed; or 
 death. 
 
7.3.1 
Definition  
Adverse Events will be reported as indicated by the appropriate following table (see 
below).    
An adverse event is defined as any untoward or unfavorable medical occurrence in a 
human research study participant, including any abnormal sign (for example, 
abnormal physical exam or laboratory finding), symptom, clinical event, or disease, 
temporarily associated with the subject’s participation in the research, whether or not 
it is considered related to the subject’s participation in the research. 
Adverse events encompass clinical, physical and psychological harms. Adverse 
events occur most commonly in the context of biomedical research, although on 
occasion, they can occur in the context of social and behavioral research. Adverse 
events may be expected or unexpected. 
Severity  
Adverse events will be graded by a numerical score according to the defined NCI 
Common Terminology Criteria for Adverse Events (NCI CTCAE) and version number 


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specified in the protocol. Adverse events not specifically defined in the NCI CTCAE 
will be scored on the Adverse Event log according to the general guidelines provided 
by the NCI CTCAE and as outlined below.   
 
Grade 1: Mild  
 
Grade 2: Moderate 
 
Grade 3: Severe or medically significant but not immediately life threatening 
 
Grade 4: Life threatening consequences 
 
Grade 5: Death related to the adverse event 
 
Serious Adverse Events  
ICH Guideline E2A and the UTSW IRB define serious adverse events as those 
events, occurring at any dose, which meets any of the following criteria:  
 
Results in death   
 
Immediately life-threatening  
 
Results in inpatient hospitalization or prolongation of existing hospitalization  
 
Results in persistent or significant disability/incapacity  
 
Results in a congenital anomaly/birth defect  
 
Based upon appropriate medical judgment, may jeopardize the subject’s 
health and may require medical or surgical intervention to prevent one of the other 
outcomes listed in this definition. 
Note: A “Serious adverse event” is by definition an event that meets any of the above 
criteria. Serious adverse events may or may not be related to the research project. A 
serious adverse event determination does not require the event to be related to the 
research. That is, both events completely unrelated to the condition under study and 
events that are expected in the context of the condition under study may be serious 
adverse events, independent of relatedness to the study itself. As examples, a car 
accident requiring overnight hospitalization would be a serious adverse event for any 
research participant; likewise, in a study investigating end-stage cancer care, any 
hospitalization or death would be a serious adverse event, even if the event observed 
is a primary clinical endpoint of the study. Refer to the UTSW IRB website at 
http://www.utsouthwestern.net/intranet/research/research-administration/irb/study-
management/adverse-events.html to determine when a serious adverse event 
requires reporting to the IRB. 
7.3.2 
Unanticipated Problems: 
The term “unanticipated problem” is found, but not defined in the regulations for the 
Protection of Human Subjects at 45 CFR 46, and the FDA regulations at 21 CFR 56. 
Guidance from the regulatory agencies considers unanticipated problems to include 
any incident, experience, or outcome that meets each of the following criteria: 
• 
Unexpected (in terms of nature, severity or frequency) AND 
• 
Definitely, probably, or possibly related to participation in the research AND  
• 
Serious or a possible unexpected problem in that the research places 
subjects or others at greater risk of harm than was previously known or recognized. 
Note: Any serious adverse event would always suggest a greater risk of harm. 
 
Follow-up  
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7.3.3 
Reporting 
 
7.3.3.1 Local unanticipated problems require expedited reporting, and are submitted to the UTSW IRB 
through the UTSW eIRB and to the SCC DSMC Coordinator.  Hardcopies or electronic versions 
of the eIRB report; FDA Form #3500A forms, or other sponsor forms, if applicable; and/or any 
other supporting documentation available should be forwarded to the DSMC Coordinator.  The 
DSMC Coordinator forwards the information onto the DSMC Chairman who determines if 
immediate action is required.  Follow-up eIRB reports, and all subsequent SAE documentation 
that is available are also submitted to the DSMC Chair who determines if further action is 
required. (See Appendix IV of the SCC DSMC Plan for a template Serious Adverse Event Form 
which may be utilized when a sponsor form is unavailable and SAE submission to the eIRB in 
not required). 
  
All local serious adverse events which occur on research subjects on protocols for 
which the SCC is the DSMC of record require reporting to the DSMC regardless of 
whether IRB reporting is required. Hardcopies or electronic versions of the FDA Form 
#3500A forms, or other sponsor forms, if applicable; and/or any other supporting 
documentation available should be forwarded to the DSMC Coordinator.   
 
If the event occurs on a multi-institutional clinical trial coordinated by the Cancer 
Center, the DOT Manager or lead coordinator ensures that all participating sites are 
notified of the event and resulting action, according to FDA guidance for expedited 
reporting. DSMC Chairperson reviews all serious adverse events within upon receipt 
from the DSMC Coordinator.  The DSMC Chairperson determines whether action is 
required and either takes action immediately, convenes a special DSMC session 
(physical or electronic), or defers the action until a regularly scheduled DSMC 
meeting.  
  
Telephone reports to: 
(Investigator: Saad Khan, office # 214- 648- 4180, pager 972- 229- 4270) 
 
UTSW SCC Data Safety Monitoring Committee Coordinator (if fax report is not 
available) within 1 working day to 214-648-7097. 
 
Written reports to: 
(Investigator: Saad Khan, office fax # 214 648-1955, 5323 Harry Hines Blvd, 
Dallas, TX 75390-8852) 
 
UTSW SCC Data Safety Monitoring Committee Coordinator 
Email: SCCDSMC@utsouthwestern.edu 
Fax: 214-648-5949 or deliver to BLB.306 
 
UTSW Institutional Review Board (IRB) 
Submit via eIRB with a copy of the final sponsor report as attached supporting 
documentation 
 
1. 
SAEs 
Local serious adverse events (SAEs) for studies where SCC DSMC is the DSMC of 
record require reporting to the DSMC coordinator within 2 working days of PI 
awareness, or as described in the protocol.   
2. 
Unanticipated Problems  
 


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Local unanticipated problems require reporting to the UTSW IRB within 2 working 
days of PI awareness of the event.   
Unanticipated problems, including those that occur as non-local events, require 
reporting to the UTSW IRB within 10 working days of PI awareness of the event. 
For further guidance for Investigators regarding safety reporting requirements for 
INDs and BA/BE studies, refer to FDA Draft Guidance document: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Gui
dances/UCM227351.pdf 
7.4 
Steps to Determine If an Adverse Event Requires Expedited Reporting 
Step 1: Identify the type of adverse event using the NCI Common Terminology 
Criteria for Adverse Events (CTCAE v4).  
 
Step 2: Grade the adverse event using the NCI CTCAE v4. 
 
Step 3: Determine whether the adverse event is related to the protocol therapy  
Attribution categories are as follows: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
Note: This includes all events that occur within 30 days of the last dose of protocol 
treatment. Any event that occurs more than 30 days after the last dose of treatment 
and is attributed (possibly, probably, or definitely) to the agent(s) must also be 
reported accordingly. 
 
Step 4: Determine the prior experience of the adverse event.  
Expected events are those that have been previously identified as resulting from 
administration of the agent. An adverse event is considered unexpected, for 
expedited reporting purposes only, when either the type of event or the severity of 
the event is not listed in: 
 
the current known adverse events listed in the Agent Information Section of 
this protocol; 
 
the drug package insert; 
 
the current Investigator’s Brochure 
7.4.1.1 
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 Sponsor and within 2 working days to 
Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220)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 Sponsor, that is not associated with clinical 
symptoms or abnormal laboratory results.  
2.  an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the upper 
limit of normal and, at the same time, an alkaline phosphatase lab value that is less than 2X 
the upper limit of normal, as determined by way of protocol-specified laboratory testing or 
unscheduled laboratory testing.* 
*Note:  These criteria are based upon available regulatory guidance documents. The purpose of 
the criteria is to specify a threshold of abnormal hepatic tests that may require an additional 


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evaluation for an underlying etiology.  The trial site guidance for assessment and follow up of 
these criteria can be found in the Investigator Trial File Binder (or equivalent). 
1. Additional adverse events: 
 
A separate guidance document has been provided entitled “Event of Clinical Interest Guidance 
Document” (previously entitled, “Event of Clinical Interest and Immune-Related Adverse Event 
Guidance Document”).  This document can be found in Appendix 4 and provides guidance 
regarding identification, evaluation and management of ECIs and irAEs.   
 
ECIs (both non-serious and serious adverse events) identified in this guidance document from the 
date of first dose through 90 days following cessation of treatment, or 30 days after the initiation 
of a new anticancer therapy, whichever is earlier, need to be reported within 24 hours to the 
Sponsor and within 2 working days to Merck Global Safety. (Attn: Worldwide Product Safety; FAX 
215 993-1220), regardless of attribution to study treatment, consistent with standard SAE 
reporting guidelines. 
 
 
Subjects should be assessed for possible ECIs prior to each dose.  Lab results should be 
evaluated and subjects should be asked for signs and symptoms suggestive of an immune-
related event.  Subjects who develop an ECI thought to be immune-related should have 
additional testing to rule out other etiologic causes.  If lab results or symptoms indicate a possible 
immune-related ECI, then additional testing should be performed to rule out other etiologic 
causes.  If no other cause is found, then it is assumed to be immune-related. 
 
 
7.4.2 
Evaluating Adverse Events 
An investigator who is a qualified physician will evaluate all adverse events according to the 
NCI Common Terminology for Adverse Events (CTCAE), version 4.0. Any adverse event 
which changes CTCAE grade over the course of a given episode will have each change of 
grade recorded on the adverse event case report forms/worksheets. 
All adverse events regardless of CTCAE grade must also be evaluated for seriousness. 
 
 
 
 


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Table 6:  Evaluating Adverse Events 
An investigator, who is a qualified physician, will evaluate all adverse events as to: 
V4.0 CTCAE 
Grading 
Grade 1 
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental ADL. 
 
Grade 3 
Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation or hospitalization indicated; disabling; limiting self-care ADL. 
 
Grade 4 
Life threatening consequences; urgent intervention indicated. 
 
Grade 5 
Death related to AE 
Seriousness 
A serious adverse event is any adverse event occurring at any dose or during any use of Merck product that: 
 
†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 factors 


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Relationship 
The following components are to be used to assess the relationship between the 
test drug and the AE: (continued) 
to Merck 
product 
(continued)  
Dechallenge 
Was the Merck product discontinued or dose/exposure/frequency 
reduced? 
If yes, did the AE resolve or improve? 
If yes, this is a positive dechallenge. If no, this is a negative 
dechallenge. 
(Note: This criterion is not applicable if: (1) the AE resulted in death or 
permanent disability; (2) the AE resolved/improved despite 
continuation of the Merck product; or (3) the trial is a single-dose drug 
trial); or (4) Merck product(s) is/are only used one time.) 
 
Rechallenge 
Was the subject re-exposed to the Merck product in this study? 
If yes, did the AE recur or worsen? 
If yes, this is a positive rechallenge. If no, this is a negative 
rechallenge. 
(Note: This criterion is not applicable if: (1) the initial AE resulted in 
death or permanent disability, or (2) the trial is a single-dose drug 
trial); or (3) Merck product(s) is/are used only one time). 
NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE 
EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN 
CAUSED BY THE MERCK PRODUCT, OR IF REEXPOSURE TO 
THE MERCK PRODUCT POSES ADDITIONAL POTENTIAL 
SIGNIFICANT RISK TO THE SUBJECT, THEN THE RECHALLENGE 
MUST BE APPROVED IN ADVANCE BY THE U.S. CLINICAL 
MONITOR AS PER DOSE MODIFICATION GUIDELINES IN THE 
PROTOCOL. 
 
Consistency 
with Trial 
Treatment 
Profile 
Is the clinical/pathological presentation of the AE consistent with 
previous knowledge regarding the Merck product or drug class 
pharmacology or toxicology? 
The assessment of relationship will be reported on the case report forms /worksheets by 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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8.0 DRUG INFORMATION  
8.1 
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL SUPPLIES 
8.1.1 
Agent Pembrolizumab 
 
 
Other names for the drug: Keytruda, MK-3475 
 
 
Classification - type of agent: monoclonal antibody 
 
 
Mode of action: monoclonal antibody to PD-1 
 
 
Storage and stability: Store vials under refrigeration at 2°C to 8°C (36°F to 46°F). 
  
 
Protocol dose: 200 mg every 3 weeks 
 
 
Route of administration for this study: intravenous 
 
 
Incompatibilities: none 
 
 
Availability: provided by Merck free of charge to patients on this study. 
 
 
Side effects:  Please refer to the pembrolizumab package insert for a 
comprehensive list of adverse events. 
 
Common side effects include peripheral edema, fatigue, pruritus, hypoglycemia, 
elevated AST, cough, arthralgia, diarrhea. Some potentially serious side effects 
include hypothyroidism, sepsis, pneumonitis, colitis. 
 
 
Nursing implications: none 
8.1.2 
Return and Retention of Study Drug 
The study drug pembrolizumab will be destroyed by the UT Southwestern 
designated investigational drug service pharmacy in accordance with 
institutional protocols. No patient returned drug will be re-assigned to other 
patients or diverted to another person. 
 
8.1.2 
Study Drug compliance  
 
Drug will be administered by intravenous infusion, with full documentation of 
administration in the medical record and study records. 
 
8.2 
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 7. 
 
 
 
 
 


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Table 7  Product Descriptions 
Product Name & Potency 
Dosage Form 
Pembrolizumab 50 mg 
Lyophilized Powder for Injection 
Pembrolizumab 100 mg/ 4mL 
Solution for Injection 
 
8.3 
Packaging and Labeling Information 
Clinical supplies will be affixed with a clinical label in accordance with regulatory requirements. 
8.4 
Clinical Supplies Disclosure 
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or 
designee are not blinded to treatment. Drug identity (name, strength) is included in the label text; 
random code/disclosure envelopes or lists are not provided. 
8.5 
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. 
8.6 
Returns and Reconciliation 
The investigator is responsible for keeping accurate records of the clinical supplies received 
from Merck or designee, the amount dispensed to and returned by the 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. 
 
9.0 
STATISTICAL CONSIDERATIONS 
9.1 
Study Design/Study Endpoints 
It is an open-label, multi-institution trial designed to evaluate the activity of pembrolizumab therapy 
in anaplastic thyroid cancer in patients with no curative alternative therapy. The primary endpoint 
is the overall response rate of patients with unresectable or metastatic anaplastic thyroid cancer. 
The secondary endpoint is the progression free survival, overall survival, safety and toxicity of 
patients with unresectable or metastatic anaplastic thyroid cancer. The exploratory objective is to 
determine whether any tissue biomarkers or mutations noted on Next Generation Sequencing with 
FoundationOne Panel correlate for enhanced or impaired response to pembrolizumab therapy, in 
patients with unresectable or metastatic anaplastic thyroid cancer. 
 
9.2 
Sample Size and Accrual 
 


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9.2.1 
Using the exact binomial test, a sample size of 21 patients would provide 80% power to 
detect a difference in the response rate from 5% for historical control to a target rate of 
25%, with a one-sided significant level of 0.05. The sample size is calculated using PASS 
13 software.  
9.3 
Definition of end of the Study 
The arm will be completed when 21 patients have evidence of disease progression by RECIST, 
unacceptable toxicity, withdrawal of consent, or discontinuation of the trial for any other reason.  Patients 
who have RECIST-defined PD as assessed by the investigator but who, in the opinion of the investigator, 
have evidence of continued clinical benefit from pembrolizumab may continue to receive the study 
medication. In such cases, these patients must continue to be followed for safety and efficacy assessments 
as per the schedule of assessments.  
At the completion or discontinuation of study medication, all patients will be seen within 30 days for an end 
of therapy evaluation. This will include a safety assessment for AE’s SAE’s. Any unused medication will 
be returned. 
9.4 
Early Termination 
Treatment on protocol may be terminated early if the Principal investigator or institution assess that the 
safety of the enrolled subjects will be compromised by continuation of the trial. The procedure followed will 
be that of the premature withdrawal patient and any patients on treatment will be seen as soon as possible. 
9.5 
Data confidentiality 
Information about protocol subjects will be kept confidential and managed under the applicable 
laws and regulations. Those regulations require a signed subject authorization informing the 
subject of the following: 
 
- What protected health information (PHI) will be collected from subjects in this protocol 
- Who will have access to that information and why 
- Who will use or disclose that information 
- The rights of a research subject to revoke their authorization for use of their PHI. 
 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization. For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect follow-up safety information (e.g. has the subject 
experienced any new or worsened AEs) at the end of their scheduled protocol treatment period. 
9.6 
Statistical methods and data analysis 
9.6.1 
Full Analysis Set 
The Full Analysis Set (FAS) comprises all consented patients. 
9.6.2 
Safety Set 
The Safety Set includes all patients who received at least one dose of pembrolizumab 
medication. 
9.7 
Patient demographics/other baseline characteristics 
Demographic, disease characteristics and other baseline data will be summarized descriptively 
for the FAS. 
9.8 
Treatments (pembrolizumab treatment, concomitant therapies, compliance) 
All analyses from this section will be performed on all patients from the safety set. Duration of 
pembrolizumab treatment exposure will be summarized. 


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9.9 
Data Analyses Plans 
The rate of overall response and its 95% confidence interval will be estimated using exact binomial 
method. Kaplan-Meier methods will be used to estimate the progression free survival and overall 
survival. Response duration will be summarized for patients who responded. Descriptive summary 
statistics like median, 25% and 75% percentiles will be used. Toxicities will be dichotomized as 
none versus any adverse event, or none and mild versus moderate to severe adverse event. 
Summary tables for adverse events (AEs) will be produced. 
 
 
10.0 
STUDY MANAGEMENT 
10.1 
Regulatory and ethical compliance 
This clinical study was designed, shall be implemented and reported in accordance with the ICH 
Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local regulations 
(including European Directive 2001/20/EC and US Code of Federal Regulations Title 21), and 
with the ethical principles laid down in the Declaration of Helsinki. 
10.2 
Informed consent procedures 
Eligible patients will only be included on this after providing written (witnessed, where 
required by law or regulation), IRB/IEC/REB-approved informed consent. 
Informed consent must be obtained before conducting any protocol-specific procedures (i.e. all of 
the procedures described in the protocol). The process of obtaining informed consent should be 
documented in the patient source documents. The date when a subject’s Informed Consent 
was actually obtained will be captured in the clinical trial record. The informed consent 
document will be approved by the IRB. 
10.3 
Discontinuation of the study 
This study will discontinue if terminated by the Institutional Review Board or at the discretion of the 
Principal Investigator. 
10.4 
Publication of the study and results 
The results of this study will be updated and posted per regulatory requirements, including (but not 
limited) to databases such as clinicaltrials.gov.  
10.4.1 
Communication and Publication of Clinical Trial Results 
All submitted manuscripts will comply with institutional guidelines and with authorship guidelines of 
the International Committee of Medical Journal Editors. 
 
10.5 
Study documentation, record keeping and retention of documents 
The investigator/institution should maintain the trial documents as specified in Essential Documents 
for the Conduct of a Clinical Trial (ICH E6 Section 8) and as required by applicable regulations 
and/or guidelines. The investigator/institution should take measures to prevent accidental or 
premature destruction of these documents. 
10.6 
Confidentiality of study documents and patient records 
The investigator must ensure anonymity of the patients; patients must not be identified by names 
in any trial documents. Signed informed consent forms and patient enrollment log must be kept 
strictly confidential to enable patient identification. 


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10.7 
Audits and inspections 
Source data/documents must be available to inspections by Health Authorities. 
10.8 
Conflict of Interest 
 
Any investigator who has a conflict of interest with this study (patent ownership, 
royalties, or financial gain greater than the minimum allowable by their institution, etc.) 
must have the conflict reviewed by the UTSW COI Committee and IRB according to 
UTSW Policy on Conflicts of Interest.  All investigators will follow the University conflict 
of interest policy. 
 
10.9 
Institutional Review Board (IRB) Approval and Consent 
It is expected that the IRB will have the proper representation and function in 
accordance with federally mandated regulations. The IRB must approve the consent 
form and protocol. 
 
In obtaining and documenting informed consent, the investigator should comply with the 
applicable regulatory requirement(s), and should adhere to Good Clinical Practice 
(GCP) and to ethical principles that have their origin in the Declaration of Helsinki. 
 
 
Before recruitment and enrollment onto this study, the subject will be given a full 
explanation of the study and will be given the opportunity to review the consent form. 
Each consent form must include all the relevant elements currently required by the FDA 
Regulations and local or state regulations. Once this essential information has been 
provided to the subject and the investigator is assured that the subject understands the 
implications of participating in the study, the subject will be asked to give consent to 
participate in the study by signing an IRB-approved consent form. 
 
Prior to a patient’s participation in the trial, the written informed consent form should be 
signed and personally dated by the subject  and by the person who conducted the 
informed consent discussion. 
10.10 
Required Documentation  
Before the study can be initiated at any site, the following documentation must be 
provided to the Clinical Research Office. 
 
 
A copy of the official IRB approval letter for the protocol and informed consent 
 
IRB membership list or Federal wide Assurance letter 
 
CVs and medical licensure for the principal investigator and any associate 
investigators who will be involved in the study 
 
Form FDA 1572 appropriately filled out and signed with appropriate documentation 
(NOTE: this is required if {institution} holds the IND. Otherwise, the affiliate 
Investigator’s signature on the protocol is sufficient to ensure compliance) 
 
A copy of the IRB-approved consent form 
 
CAP and CLIA Laboratory certification numbers and institution lab normal values 
 
Executed clinical research contract 
10.11 
Registration Procedures 
All subjects must be registered with the Clinical Research Office before enrollment to 
study. Prior to registration, eligibility criteria must be confirmed with the Research Office 
Study Coordinator. To register a subject, call Pamela Kurian at 214-648-5874 Monday 
through Friday, 9:00AM-5:00PM.  


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New subjects will receive a number beginning with 001 upon study consent such that 
the first subject consented is numbered 001, the second subject consented receives the 
number 002, etc.  
 
Upon confirmation of eligibility and enrollment as per the afore-mentioned instructions, 
the subject will maintain the assigned number. For example, subject 001 will remain as 
subject 001 upon enrollment.  
 
For all sites outside of UTSW, the first patient consented and enrolled at the first site will 
be subject 01-001. The second subject enrolled at the second site might be 02-003. 
 
Each newly consented subject should be numbered using the schema provided above. 
Upon registration, the registrar will assign the additional registration/randomization code 
according to the numbering schema outlined above, which should then be entered as 
the patient study id in Velos upon updating the status to enrolled. 
 
The numbering schema should clearly identify the site number; the sequential number of 
the subject enrolled as well as the status of the subjects enrolled so that the number of 
subjects consented versus the number of subjects actually enrolled may be easily 
identified.   
 
 
10.12 
Data Management and Monitoring/Auditing 
REDCap is the UTSW SCC institutional choice for the electronic data capture of case 
report forms for this and all SCC Investigator Initiated Trials. REDCap will be used for 
electronic case report forms in accordance with Simmons Cancer Center requirements. 
 
Other institutions participating in this trial as sub-sites will be expected to enter data into 
REDCap and upload de-identified source materials when instructed by the Simmons 
Cancer Center study team to facilitate remote source to case report form verification.  
 
Trial monitoring will be conducted no less than annually and refers to a regular interval 
review of trial related activity and documentation performed by the DOT, which includes 
but is not limited to accuracy of case report forms, protocol compliance, timeless and 
accuracy of Velos entries and AE/SAE management and reporting. Documentation of 
trial monitoring will be maintained along with other protocol related documents and will 
be reviewed during internal audit. 
 
Toxicity and dose escalation reviews will be performed through the duration of the trial.  
These reviews will be documented by the Clinical Research Office and the reports will 
be distributed to the SCC-DSMC, if needed. 
 
 
The UTSW Simmons Cancer Center (SCC) Data Safety Monitoring Committee (DSMC) 
is responsible for monitoring data quality and patient safety for all UTSW SCC clinical 
trials.  As part of that responsibility, the DSMC reviews all local serious adverse events 
and unanticipated problems in real time as they are reported and reviews adverse 
events on a quarterly basis.  The quality assurance activity for the Clinical Research 
Office provides for periodic auditing of clinical research documents to ensure data 
integrity and regulatory compliance.  A copy of the DSMC plan is available upon 
request. 
 
The SCC DSMC meets quarterly and conducts annual comprehensive reviews of 
ongoing clinical trials, for which it serves as the DSMC of record. The QAC works as 


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part of the DSMC to conduct regular audits based on the level of risk. Audit findings are 
reviewed at the next available DSMC meeting.  In this way, frequency of DSMC 
monitoring is dependent upon the level of risk.  Risk level is determined by the DSMC 
Chairman and a number of factors such as the phase of the study; the type of 
investigational agent, device or intervention being studied; and monitoring required to 
ensure the safety of study subjects based on the associated risks of the study. Protocol-
specific DSMC plans must be consistent with these principles.  
10.13 
Adherence to the Protocol 
Except for an emergency situation in which proper care for the protection, safety, and 
well-being of the study subject requires alternative treatment, the study shall be 
conducted exactly as described in the approved protocol.  
10.13.1 Emergency Modifications 
Investigators may implement a deviation from, or a change of, the protocol to 
eliminate an immediate hazard(s) to trial subjects without prior IRB approval.  
 
For any such emergency modification implemented, an IRB modification form 
must be completed within five (5) business days of making the change. 
10.13.2 Other Protocol Deviations/Violations 
All other planned deviations from the protocol must have prior approval by the 
Principal Investigator and the IRB. According to the IRB, a protocol deviation is 
any unplanned variance from an IRB approved protocol that:  
 
Is generally noted or recognized after it occurs 
 
Has no substantive effect on the risks to research participants 
 
Has no substantive effect on the scientific integrity of the research plan or 
the value of the data collected  
 
Did not result from willful or knowing misconduct on the part of the 
investigator(s).  
 
An unplanned protocol variance is considered a violation if the variance: 
 
Has harmed or increased the risk of harm to one or more research 
participants. 
 
Has damaged the scientific integrity of the data collected for the study. 
 
Results from willful or knowing misconduct on the part of the investigator(s). 
 
Demonstrates serious or continuing noncompliance with federal regulations, 
State laws, or University policies. 
 
If a deviation or violation occurs without prior approval from the Principal 
Investigator, please follow the guidelines below: 
 
 
Protocol Deviations: Personnel will report to any sponsor or data and safety 
monitoring committee in accordance with their policies. Deviations should be 
summarized and reported to the IRB at the time of continuing review. 
 
Protocol Violations: Study personnel should report violations within two (2) 
week of the investigator becoming aware of the event using the same IRB 
online mechanism used to report Unanticipated Problems.  


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10.14 
Amendments to the Protocol 
Should amendments to the protocol be required, the amendments will be originated and 
documented by the Principal Investigator.  A summary of changes document outlining 
proposed changes as well as rationale for changes, when appropriate, is highly 
recommended.  When an amendment to the protocol substantially alters the study 
design or the potential risk to the patient, a revised consent form might be required.  
 
The written amendment, and if required the amended consent form, must be sent to the 
IRB for approval prior to implementation.  
 
10.15 
Record Retention 
Study documentation includes all Case Report Forms, data correction forms or queries, 
source documents, Sponsor-Investigator correspondence, monitoring logs/letters, and 
regulatory documents (e.g., protocol and amendments, IRB correspondence and 
approval, signed patient consent forms). 
 
Source documents include all recordings of observations or notations of clinical activities 
and all reports and records necessary for the evaluation and reconstruction of the 
clinical research study. 
 
Government agency regulations and directives require that the study investigator retain 
all study documentation pertaining to the conduct of a clinical trial. In the case of a study 
with a drug seeking regulatory approval and marketing, these documents shall be 
retained for at least two years after the last approval of marketing application in an 
International Conference on Harmonization (ICH) region. In all other cases, study 
documents should be kept on file until three years after the completion and final study 
report of this investigational study. 
10.16 
Obligations of Investigators 
The Principal Investigator is responsible for the conduct of the clinical trial at the site in 
accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of 
Helsinki. The Principal Investigator is responsible for personally overseeing the 
treatment of all study patients. The Principal Investigator must assure that all study site 
personnel, including sub-investigators and other study staff members, adhere to the 
study protocol and all FDA/GCP/NCI regulations and guidelines regarding clinical trials 
both during and after study completion. 
 
The Principal Investigator at each institution or site will be responsible for assuring that 
all the required data will be collected and entered onto the Case Report Forms. 
Periodically, monitoring visits may be conducted and the Principal Investigator will 
provide access to his/her original records to permit verification of proper entry of data. At 
the completion of the study, all case report forms will be reviewed by the Principal 
Investigator and will require his/her final signature to verify the accuracy of the data. 
 
 
 
 
 
 
 
 


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11.0 
REFERENCES 
 
1. 
Are, C. and A.R. Shaha, Anaplastic thyroid carcinoma: biology, pathogenesis, prognostic factors, 
and treatment approaches. Ann Surg Oncol, 2006. 13(4): p. 453-64. 
2. 
Hundahl, S.A., et al., A National Cancer Data Base report on 53,856 cases of thyroid carcinoma 
treated in the U.S., 1985-1995 [see comments]. Cancer, 1998. 83(12): p. 2638-48. 
3. 
McIver, B., et al., Anaplastic thyroid carcinoma: a 50-year experience at a single institution. 
Surgery, 2001. 130(6): p. 1028-34. 
4. 
Smallridge, R.C., et al., American Thyroid Association guidelines for management of patients 
with anaplastic thyroid cancer. Thyroid, 2012. 22(11): p. 1104-39. 
5. 
NCCN clinical practice guidelines in Oncology, D. 
http://www.nccn.org/professionals/physician_gls/pdf/thyroid.pdf. 
6. 
Mooney, C.J., et al., A phase II trial of fosbretabulin in advanced anaplastic thyroid carcinoma 
and correlation of baseline serum-soluble intracellular adhesion molecule-1 with outcome. 
Thyroid, 2009. 19(3): p. 233-40. 
7. 
Sosa, J.A., et al., Thyroidectomy followed by fosbretabulin (CA4P) combination regimen appears 
to suggest improvement in patient survival in anaplastic thyroid cancer. Surgery, 2012. 152(6): p. 
1078-87. 
8. 
Savvides, P., et al., Phase II trial of sorafenib in patients with advanced anaplastic carcinoma of 
the thyroid. Thyroid, 2013. 23(5): p. 600-4. 
9. 
Vesely, M.D., et al., Natural innate and adaptive immunity to cancer. Annu Rev Immunol, 2011. 
29: p. 235-71. 
10. 
Disis, M.L., Immune regulation of cancer. J Clin Oncol, 2010. 28(29): p. 4531-8. 
11. 
Keir, M.E., et al., PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol, 2008. 26: 
p. 677-704. 
12. 
Freeman, G.J., et al., Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family 
member leads to negative regulation of lymphocyte activation. J Exp Med, 2000. 192(7): p. 
1027-34. 
13. 
Garon, E.B., et al., Pembrolizumab for the Treatment of Non-Small-Cell Lung Cancer. N Engl J 
Med, 2015. 
14. 
Ellis, R.J., et al., Programmed Death-Ligand 1 as a prognostic marker in papillary thyroid cancer. 
Journal of the American College of Surgeons. 217(3): p. S30. 
15. 
Wu, H., et al., Anaplastic Thyroid Cancer: Outcome and the Mutation/Expression Profiles of 
Potential Targets. Pathol Oncol Res, 2015. 
16. 
Murugan, A.K. and M. Xing, Anaplastic thyroid cancers harbor novel oncogenic mutations of the 
ALK gene. Cancer Res, 2011. 71(13): p. 4403-11. 
17. 
Godbert, Y., et al., Remarkable Response to Crizotinib in Woman With Anaplastic Lymphoma 
Kinase-Rearranged Anaplastic Thyroid Carcinoma. J Clin Oncol, 2014. 
18. 
Takano, T., et al., BRAF V600E mutation in anaplastic thyroid carcinomas and their 
accompanying differentiated carcinomas. Br J Cancer, 2007. 96(10): p. 1549-53. 
19. 
Rosove, M.H., P.F. Peddi, and J.A. Glaspy, BRAF V600E inhibition in anaplastic thyroid cancer. 
N Engl J Med, 2013. 368(7): p. 684-5. 
20. 
Guerra, A., et al., Genetic mutations in the treatment of anaplastic thyroid cancer: a systematic 
review. BMC Surg, 2013. 13 Suppl 2: p. S44. 
21. 
Robert, C., et al., Pembrolizumab versus Ipilimumab in Advanced Melanoma. N Engl J Med, 
2015. 
22. 
Nanda, R., et al., Abstract S1-09: A phase Ib study of pembrolizumab (MK-3475) in patients with 
advanced triple-negative breast cancer. Cancer Research, 2015. 75(9 Supplement): p. S1-09-
S1-09. 
23. 
Moskowitz, C.H., et al., PD-1 blockade with the monoclonal antibody pembrolizumab (MK-3475) 
in patients with classical Hodgkin lymphoma after brentuximab vedotin failure: preliminary results 
from a phase 1b study (KEYNOTE-013). Blood, 2014. 124(21): p. 290-290. 
24. 
Plimack, E., et al., LBA23A PHASE 1B STUDY OF PEMBROLIZUMAB (PEMBRO; MK-3475) IN 
PATIENTS (PTS) WITH ADVANCED UROTHELIAL TRACT CANCER. Annals of Oncology, 
2014. 25(suppl 4): p. mdu438. 24. 


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25. 
Chow, L., et al., LBA31A PHASE IB STUDY OF PEMBROLIZUMAB (PEMBRO; MK-3475) IN 
PATIENTS (PTS) WITH HUMAN PAPIILLOMA VIRUS (HPV)-POSITIVE AND NEGATIVE 
HEAD AND NECK CANCER (HNC). Annals of Oncology, 2014. 25(suppl 4): p. mdu438. 32. 
 
 


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12.0 
APPENDICES 
 
12.1 ECOG Performance Status 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all pre-disease performance 
without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous activity, but 
ambulatory and able to carry out work of a light or sedentary nature (e.g., 
light housework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, but unable 
to carry out any work activities. Up and about more than 50% of waking 
hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined to bed 
or chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. 
Totally confined to bed or chair. 
5 
Dead. 
* As published in Am. J. Clin. Oncol.:  Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, 
T.E., McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern 
Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative 
Oncology Group, Robert Comis M.D., Group Chair. 
 
12.2 Common Terminology Criteria for Adverse Events V4.0 (CTCAE) 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse 
Events 
(CTCAE) 
version 
4.0 
will 
be 
utilized 
for 
adverse 
event 
reporting. 
(http://ctep.cancer.gov/reporting/ctc.html)