Pembrolizumab for HPV-associated Recurrent Respiratory Papilloma Patients With Laryngeal, Tracheal and/or Pulmonary Involvement
Phase: PHASE2
Conditions: Recurrent Respiratory Papillomatosis
Sponsor: Massachusetts General Hospital

Clinical Trial Protocol and Statistical Plan 
Title: Study of anti-PD1 Therapy for HPV-associated Recurrent Respiratory Papilloma 
Patients with Laryngeal, Tracheal and/or Pulmonary Involvement 
DF/HCC Protocol ID# 15-469 
NCT02632344 
v.09282020

 
DF/HCC Protocol #:  
15-469 
 
Protocol Date: 
 
September 28, 2020  
 
Title:  Study of Anti-PD-1 Therapy for HPV-associated Recurrent Respiratory Papilloma 
Patients with Laryngeal, Tracheal and/or Pulmonary Involvement 
 
Coordinating Center: 
Program for Coordination and Oversight of Research Protocols (PCORP) 
Massachusetts General Hospital  
Cancer Center Protocol Office  
 
 
 
 
125 Nashua St. 
 
 
 
 
Boston, MA 02114 
 
Fax: 617-724-2787 
 
Principal Investigator: 
Sara Pai, MD, PhD 
 
 
 
 
Massachusetts General Hospital 
 
55 Fruit St. 
 
Boston, MA 02114 
 
 
 
 
sara.pai@mgh.harvard.edu 
 
 
Other Investigators:  
Joseph Raviv, MD 
NorthShore University HealthSystem 
2650 Ridge Ave, Burch 100 
Evanston, IL 60201 
jraviv@northshore.org 
 
 
IND #:   
 
128874 
 
IND Sponsor:  
Sara Pai, MD, PhD 
 
Agents:  
 
Pembrolizumab, Merck Sharpe & Dohme, Inc. 
 
 
 
 

 
 
 DF/HCC Protocol #: 15-469 
 
 
Protocol version date: September 28, 2020 
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TABLE OF CONTENTS 
 
 
1.0 
TRIAL SUMMARY.................................................................................................... 5 
2.0 
TRIAL DESIGN ......................................................................................................... 6 
2.1 
Trial design ........................................................................................................... 6 
2.2 
Trial Diagram ........................................................................................................ 7 
3.0 
OBJECTIVES & HYPOTHESES ............................................................................. 8 
3.1 
Primary Objectives & Hypotheses .................................................................... 8 
3.2 
Secondary Objectives & Hypotheses ................................................................ 8 
3.3 
Exploratory Objective & Hypothesis ................................................................ 8 
4.0 
BACKGROUND & RATIONALE ............................................................................ 9 
4.1 
Background ....................................................................................................... 9 
4.1.1 Pharmaceutical and Therapeutic Background ....................................................... 9 
4.1.2 Preclinical and Clinical Trial Data ...................................................................... 10 
4.2 
Rationale ......................................................................................................... 10 
4.2.1 Rationale for the Trial and Selected Subject Population .................................... 10 
4.2.2 Rationale for Dose Selection/Regimen/Modification ......................................... 11 
4.2.3 Rationale for Endpoints ...................................................................................... 13 
5.0 
METHODOLOGY ................................................................................................... 15 
5.1 
Entry Criteria .................................................................................................. 15 
5.1.1 Diagnosis/Condition for Entry into the Trial ...................................................... 15 
5.1.2 Subject Inclusion Criteria ................................................................................... 15 
5.1.3 Subject Exclusion Criteria .................................................................................. 16 
6.0 
REGISTRATION PROCEDURES ......................................................................... 18 
6.1 
General Guidelines for DF/HCC Institutions ........................................................ 18 
Registration Process for DF/HCC Institutions .................................................................... 18 
General Guidelines for Other Investigative Sites ............................................................... 18 
Registration Process for Other Investigative Sites ............................................................. 19 
7.0 
TREATMENT PLAN ............................................................................................... 19 
7.1 
Treatment Regimen ......................................................................................... 19 
7.1.1 Dose Selection/Modification .............................................................................. 20 
7.1.2 Timing of Dose Administration .......................................................................... 21 
7.1.3 Trial Blinding/Masking ....................................................................................... 22 
7.1.4 Stopping Rules .................................................................................................... 22 
7.2 
Randomization or Treatment Allocation ........................................................ 22 
7.3 
Stratification .................................................................................................... 22 
7.4 
Concomitant Medications/Vaccinations (allowed & prohibited) ................... 22 
7.4.1 Acceptable Concomitant Medications ................................................................ 22 
7.4.2 Prohibited Concomitant Medications ................................................................. 23 
7.5 
Rescue Medications & Supportive Care ......................................................... 23 
7.5.1 Supportive Care Guidelines ................................................................................ 23 
7.6 
Diet/Activity/Other Considerations ................................................................ 27 
7.6.1 Diet ...................................................................................................................... 27 
7.6.2 Contraception ...................................................................................................... 27 
7.6.3 Use in Pregnancy ................................................................................................ 27 
7.6.4 Use in Nursing Women ....................................................................................... 28 

 
 
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7.7 
Criteria for Removal from Protocol Treatment .............................................. 28 
7.8 
Discontinuation of Study Therapy after CR ................................................... 29 
7.9 
Subject Replacement Strategy ........................................................................ 29 
7.10 
Criteria for Removal from the Study .............................................................. 29 
7.11 
Clinical Criteria for Early Trial Termination .................................................. 30 
8.0 
BIOMARKER, CORRELATIVE AND SPECIAL STUDIES ............................. 30 
8.1 
Sample Instructions ......................................................................................... 31 
8.1.1 Specimens Required ............................................................................................ 31 
8.1.2 Processing Information ....................................................................................... 32 
8.2 
Shipping Instructions ...................................................................................... 32 
8.2.1 Labeling Instructions .......................................................................................... 32 
8.2.2 Storage and Shipping Instructions ...................................................................... 32 
9.0 
TRIAL FLOW CHART ........................................................................................... 33 
9.1 
Study Flow Chart ............................................................................................ 33 
9.2 
Second Course Phase (Retreatment ONLY) ................................................... 39 
10.0 
TRIAL PROCEDURES ........................................................................................... 42 
10.1 
Trial Procedures .............................................................................................. 42 
10.1.1 Administrative Procedures .................................................................................. 42 
10.1.2 Clinical Procedures/Assessments ........................................................................ 44 
10.1.3 Laboratory Procedures/Assessments .................................................................. 49 
10.1.4 Other Procedures ................................................................................................. 52 
10.1.5 Visit Requirements .............................................................................................. 52 
11.0 
ADVERSE EVENT REPORTING REQUIREMENT .......................................... 55 
11.1 
General ................................................................................................................ 55 
11.2 
Adverse Event Definition ................................................................................... 56 
11.3 
Serious Adverse Events ...................................................................................... 57 
11.4 
Evaluating Adverse Events ................................................................................. 57 
11.5 
Expedited Adverse Event Reporting ................................................................... 61 
11.5.1 Reporting Requirements ..................................................................................... 61 
11.5.2 Reporting to the Sponsor .................................................................................... 61 
11.5.3 Reporting to Merck ............................................................................................. 62 
11.5.4 Events of Clinical Interest ................................................................................... 62 
11.5.5 Definition of an Overdose for This Protocol and Reporting of Overdose to the   
Sponsor and to Merck ......................................................................................... 63 
11.5.6 Reporting of Pregnancy and Lactation to the Sponsor and to Merck ................. 64 
11.5.7 Sponsor Responsibility for Reporting Adverse Events ...................................... 64 
11.5.8 Institutional Review Board (IRB) Notification by Investigator ......................... 64 
11.5.9 Food and Drug Administration (FDA) Notification by Sponsor-Investigator .... 64 
11.5.10 
NIH Office of Biotechnology Activities (OBA) Notification by Investigator65 
11.5.11 
Institutional Biosafety Committee (IBC) Notification by Investigator ....... 65 
11.5.12 
Hospital Risk Management Notification by Investigator ............................ 65 
11.6 
Routine Adverse Event Reporting .................................................................. 65 
12.0 
DATA and SAFETY Monitoring ............................................................................ 65 
12.1 
Data Reporting ................................................................................................ 65 
12.1.1 Method ................................................................................................................ 65 
12.1.2 Data Submission ................................................................................................. 66 

 
 
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12.2 
Data Safety Monitoring ................................................................................... 66 
12.3 
Multi-center Guidelines .................................................................................. 66 
12.4 
Monitoring ...................................................................................................... 67 
13.0 
Regulatory considerations ........................................................................................ 67 
13.1 
Protocol Review and Amendments ................................................................. 67 
13.2 
Informed Consent ............................................................................................ 67 
13.3 
Ethics and Federal Regulations ....................................................................... 68 
13.4 
Study Documentation ...................................................................................... 68 
13.5 
Records Retention ........................................................................................... 69 
13.6 
Cooperative Research and Development Agreement (CRADA)/Clinical 
Trials Agreement (CTA) ................................................................................. 69 
14.0 
STATISTICAL ANALYSIS PLAN ........................................................................ 69 
14.1 
Statistical Analysis Plan Summary ................................................................. 69 
15.0 
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ................................................................................................................. 70 
15.1 
Investigational Product ................................................................................... 70 
15.2 
Ordering Investigational Product .................................................................... 71 
15.3 
Packaging and Labeling Information .............................................................. 71 
15.4 
Clinical Supplies Disclosure ........................................................................... 71 
15.5 
Storage and Handling Requirements .............................................................. 71 
15.6 
Returns and Reconciliation ............................................................................. 71 
16.0 
ADMINISTRATIVE AND REGULATORY DETAILS ....................................... 72 
16.1 
Compliance with Trial Registration and Results Posting Requirements ........ 72 
16.1 
Quality Management System .......................................................................... 72 
17.0 
REFERENCES .......................................................................................................... 73 
18.0 
APPENDICES ........................................................................................................... 74 
A. 
Surgical Scoring 
B. 
ECOG Performance Status 
C. 
Common Terminology Criteria for Adverse Events V4.0 (CTCAE)  
D. 
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for 
Evaluating Response in Solid Tumors 
E. 
Events of Clinical Interest Guidance Document 
F. 
Quality of Life Questionnaires 
G. 
Case Report Forms 
H. 
Merck Drug Request Form 
I. 
MK-3475 Pharmacy Manual 
J. 
Data and Safety Monitoring Plan 
 
 
 
 
 

 
 
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1.0 
TRIAL SUMMARY 
Abbreviated Title 
Phase II Study of pembrolizumab in Subjects with Human 
Papillomavirus-associated Recurrent Respiratory Papillomatosis 
Trial Phase 
II 
Clinical Indication 
The treatment of subjects with recurrent respiratory papillomatosis with 
extensive laryngeal, tracheal and/or pulmonary involvement 
Trial Type 
Interventional 
Type of control 
No treatment control 
Route of administration 
Intravenous 
Trial Blinding 
Unblinded Open-label 
Treatment Groups  
Pembrolizumab 200 mg every 3 weeks 
Number of trial subjects 
Approximately 22 subjects will be enrolled 
Estimated enrollment period 
Approximately 18-24 months 
Estimated duration of trial 
It is estimated that the trial will require approximately 60 months from 
the time the first subject signs the informed consent until the last 
subject’s last visit. 
Duration of Participation 
Each subject will participate in the trial from the time the subject signs 
the Informed Consent Form (ICF) through the final protocol-specified 
contact.  After a screening phase of 28 days, eligible subjects will 
register then to receive treatment on Day 1 of each 3-week dosing cycle.  
Treatment with pembrolizumab will continue until documented 
confirmed 
disease 
progression, 
unacceptable 
adverse 
event(s), 
intercurrent illness that prevents further administration of treatment, 
investigator’s decision to withdraw the subject, subject withdraws 
consent, pregnancy of the subject, noncompliance with trial treatment or 
procedure requirements, completion of 24 months of treatment with 
pembrolizumab, or administrative reasons.  Subjects who attain a 
complete response may consider stopping trial treatment if they meet 
criteria for holding therapy.  These subjects will be eligible for re-
treatment after experiencing disease progression at the discretion of the 
investigator if they meet the criteria for re-treatment and the trial is 
ongoing.  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). Subjects who 
discontinue protocol treatment for reasons other than disease progression 
will have post-treatment follow-up for disease status until first disease 
progression, initiating a non-study cancer treatment, withdrawing 
consent, becoming lost to follow-up, death, or 36 months from study 
registration whichever occurs first.  Following first disease progression, 
subjects will be followed by telephone for overall survival until death, 
withdrawal of consent, or 36 months from study registration whichever 
occurs first. 
 
 
 
 

 
 
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2.0 
TRIAL DESIGN 
2.1 
Trial design 
This is a non-randomized phase II trial in male and female subjects diagnosed with recurrent 
respiratory papillomatosis (RRP) with extensive laryngeal, tracheal and/or pulmonary 
involvement. Approximately 22 subjects will be enrolled in this trial to examine the safety and 
efficacy in this subject population who would be administered up to 200 mg of pembrolizumab 
every 3 weeks. Subjects will be evaluated every 3 weeks (21 days +/- 3 days) in the clinic with a 
video-recorded transnasal flexible laryngoscopy and tracheoscopy examination to assess clinical 
response on treatment (Appendix A) as well as evaluated every 24 weeks (169 days + 14 days) 
with CT scans to assess response per volumetric analysis.  For those patients with pulmonary 
lesions measurable by RECIST 1.1, CT scans of the chest will be obtained every 12 weeks (84 
days +/- 7 days) to assess response per RECIST 1.1 criteria. In addition, patients will complete 
quality of life questionnaires to assess preference of pembrolizumab as compared to standard of 
care treatment, which is surgery, for this patient population (Appendix F).   
As part of the natural course of this disease, patients undergo operative procedures for repeated 
debridement of papillomata within their upper aerodigestive tract in order to improve their 
breathing and/or voice quality. Prior to starting pembrolizumab, subjects will undergo a 
comprehensive laryngoscopy and tracheobronchoscopy to map and score their disease burden in 
the upper aerodigestive tract and a pre-treatment biopsy would be obtained at that time.  
Subsequently, at a minimum of every 12 weeks (84 days + 14 days), subjects will be taken to the 
operating room for a comprehensive laryngoscopy and tracheobronchoscopy and debridement of 
any papillomatous lesions which obstructs the caliber of their airway by more than 50% and/or 
other lesions at the discretion of the surgeon. Some patients will require more frequent visits to 
the operating room depending on their disease burden and associated clinical symptoms. 
Biopsies will be obtained during all operative visits.  
Adverse events will be monitored throughout the trial and graded in severity according to the 
guidelines outlined in the NCI Common Terminology Criteria for Adverse Events (CTCAE) 
version 4.0. Treatment with pembrolizumab will continue until documented disease progression, 
unacceptable adverse event(s), intercurrent illness that prevents further administration of 
treatment, investigator’s decision to withdraw the subject, subject withdraws consent, pregnancy 
of the subject, noncompliance with trial treatment or procedure requirements, completion of 24 
months of treatment with pembrolizumab, or administrative reasons.  Subjects who attain an 
investigator-determined confirmed complete response (CR) may consider stopping trial 
treatment after receiving at least 24 weeks of treatment. Subjects who discontinue after at least 
24 months of therapy for reasons other than disease progression or intolerability or who 
discontinue after attaining a CR may be eligible for up to one year of re-treatment after they have 
experienced clinical and/or radiographic disease progression. The decision to retreat will be at 
the discretion of the investigator if no additional systemic immunotherapeutic treatment was 
administered since the last dose of pembrolizumab, the subject still meets the safety parameters 
listed in the Inclusion/Exclusion criteria and the trial remains open.  

 
 
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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). 
Subjects who discontinue treatment for reasons other than first disease progression will have 
post-treatment follow-up for disease status until disease progression, initiating a non-study 
systemic chemotherapeutic treatment, withdrawing consent, becoming lost to follow-up, death, 
or 36 months post study registration whichever occurs first. Following first disease progression, 
subjects will be followed by telephone contact for overall survival until death, withdrawal of 
consent or 36 months post study registration, whichever comes first. The study will be stopped if 
greater than 30% of patients discontinue pembrolizumab due to an adverse event or for any 
patient death related to toxicity. 
The goal of this study is to evaluate the efficacy of pembrolizumab in this patient population to 
support treatment with systemic immunotherapy which could minimize and/or eliminate the need 
for multiple surgical procedures over the patient’s lifetime.  The primary objectives of the trial 
are to determine the anti-tumor activity, safety, and tolerability of pembrolizumab treatment in 
male and female subjects diagnosed with RRP. Secondary objectives include evaluating the 
relationship between candidate efficacy/resistance biomarkers and anti-tumor activity and 
response duration of pembrolizumab.  An exploratory objective is to assess the quality of life of 
RRP patients with pembrolizumab. Established quality of life is lacking in this patient population 
and, in a separate study, we are establishing baseline quality of life parameters of RRP patients 
being treated with standard of care, which is repeated surgeries.  
The study will be conducted in conformance with Good Clinical Practices. 
Specific procedures to be performed during the trial, as well as their prescribed times and 
associated visit windows, are outlined in the Trial Flow Chart – Section 9.0. Details of each 
procedure are provided in Section 10.0 – Trial Procedures. 
2.2 
Trial Diagram 
The trial design is depicted in Figure 1. 
Figure 1. Trial Design 
 

 
 
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3.0 
OBJECTIVES & HYPOTHESES 
3.1 
Primary Objectives & Hypotheses 
(1) Objective: To determine the best overall clinical response rate (ORR: CR+PR) in 
subjects with RRP with extensive laryngeal, tracheal and/or pulmonary involvement 
based on clinical examination and/or RECIST 1.1. 
Hypothesis:  Intravenous administration of pembrolizumab to subjects with RRP will 
result in a clinically meaningful overall response rate based on clinical examination 
and/or RECIST 1.1.  
(2) Objective: To determine the safety and tolerability of pembrolizumab in subjects with 
RRP. 
Hypothesis:  Intravenous administration of single agent pembrolizumab is sufficiently 
well-tolerated to permit continued clinical investigation. 
3.2 
Secondary Objectives & Hypotheses 
(1) Objective:  To evaluate changes in the expression of various immune biomarkers and 
investigate the relationship between candidate efficacy/resistance immune biomarkers 
and anti-tumor activity of pembrolizumab utilizing pre- and on-treatment tissue biopsies 
and blood sampling.   
Hypothesis:  Intravenous administration of single agent pembrolizumab will result in a 
clinically meaningful change in the tumor microenvironment. 
(2) Objective:  To evaluate the response duration in subjects receiving pembrolizumab.   
Hypothesis:  Intravenous administration of single agent pembrolizumab will result in a 
clinical meaningful response which will lengthen the time interval between required 
surgical debridements. 
3.3 
Exploratory Objective & Hypothesis 
(1) Objective: To assess the quality of life (QOL) with immunotherapy treatment as 
compared to standard of care treatment in RRP patients. 
Hypothesis:  Treatment with intravenous administration of pembrolizumab improves the 
quality of life of RRP patients as compared to standard of care treatment, which is 
repeated surgical debridement over their lifetime.  
 

 
 
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4.0 
BACKGROUND & RATIONALE 
4.1 
Background 
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background information 
on pembrolizumab. 
4.1.1 Pharmaceutical and Therapeutic Background 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades.  Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in 
various malignancies.  In particular, the presence of CD8+ T-cells and the ratio of CD8+ 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 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 

 
 
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has been suggested to regulate tumor-specific T-cell expansion in subjects with melanoma 
(MEL).  This suggests that the PD-1/PD-L1 pathway plays a critical role in tumor immune 
evasion and should be considered as an attractive target for therapeutic intervention. 
Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of the 
IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-
L1 and PD-L2.  KeytrudaTM (pembrolizumab) has recently been approved in the United Stated 
for the treatment of patients with unresectable or metastatic melanoma and disease progression 
following ipilumumab and, if BRAF V600 mutation positive, a BRAF inhibitor. 
4.1.2 Preclinical and Clinical Trial Data 
Refer to the Investigator’s Brochure for Preclinical and Clinical data. 
4.2 
Rationale 
4.2.1 Rationale for the Trial and Selected Subject Population 
This is a nonrandomized, phase II trial in male and female subjects diagnosed with RRP with 
extensive laryngeal, tracheal and/or pulmonary involvement.  
Various mechanisms have been proposed for the resistance of human solid tumors to immune 
recognition and obliteration, including the recruitment of regulatory T cells (Tregs), myeloid 
derived suppressor cells (MDSC), and local secretion of inhibitory cytokines. Recent evidence 
that tumors co-opt physiologic mechanisms of tissue protection from inflammatory destruction 
through the upregulation of immune inhibitory ligands has provided a new perspective for 
understanding tumor immune resistance. Antigen-induced activation and proliferation of T cells 
are regulated by the temporal expression of both co-stimulatory and co-inhibitory receptors and 
their cognate ligands. Coordinated signaling through these receptors modulates the initiation, 
amplification, and subsequent resolution of adaptive immune responses. In the absence of co-
inhibitory signaling, persistent T cell activation can lead to excessive tissue damage in the setting 
of infection as well as autoimmunity. However, in the context of cancer, in which immune 
responses are directed against antigens specifically or selectively expressed by tumor cells, 
immune checkpoints can represent major obstacles to the generation of clinically meaningful 
anti-tumor immunity. Therefore, efforts have been made in the clinical arena to investigate 
blockade of immune checkpoints as novel therapeutic approaches to cancer.  
Our group recently found that the PD-1:PD-L1 immune checkpoint pathway facilitates persistent 
human papillomavirus (HPV) infection and subsequent development of HPV-associated head 
and neck squamous cell carcinomas (HPV-HNSCC) [1]. Our findings supported a model in 
which the PD-1:PD-L1 immune checkpoint pathway becomes induced as an adaptive resistance 
mechanism of tumor against host. Our study provided the rationale for therapeutic blockade of 
this pathway in patients with HPV-HNSCC. 
Given the similar viral etiology, activation of the PD-1:PD-L1 pathway has also been evaluated 
in Recurrent Respiratory Papillomatosis (RRP) patients. A recent report documented that PD-1 
was expressed on a very high percentage of CD4+ T cells and that respiratory papillomas contain 

 
 
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high levels of PD-L1 mRNA [2].  Independently, our group also has demonstrated positive 
staining for CD4, CD8, PD-1, and PD-L1 in RRP tissue as well as has been able to perform 
multi-color flow cytometry on RRP tissue to demonstrate enriched co-expression of PD-1 and 
other co-inhibitory T cell markers on tumor infiltrating lymphocytes (TILs).  
RRP is caused by infection with the low-risk HPV types 6 and 11 and is the most common 
benign tumor of the airway that affects children and adults [3]. The virus induces the 
proliferation of benign squamous epithelium, most commonly in the larynx, which can have 
profound functional consequences for breathing and speech and result in a chronic, debilitating 
disease in the pediatric and adult populations [4]. The virus can also spread to the trachea and 
lungs and, subsequently, block the breathing passages in the lungs causing pulmonary collapse. 
Furthermore, given their chronic viral infection, the lesions are at increased risk for malignant 
transformation. Currently, there is no medical cure for RRP.  Treatment generally involves 
repeated surgical debulking of the virally-infected cells, with an aim of increasing the airway 
caliber to help individuals breathe better and/or improve their voice. Some patients undergo 
hundreds of operative interventions over their lifetime to maintain their airway patency, and the 
risk of permanent hoarseness and vocal cord scarring increases with each operative intervention 
[5]. If left untreated, this disease can be a life-threatening situation leading to complications 
associated with lung collapse, suffocation, malignant transformation, and death [6].  Yet, with 
intervention, studies demonstrate that the impact on voice quality has the biggest impact on long-
term quality of life for patients with RRP [7] and permanent vocal cord scarring can lead to life-
long communication disorders and social stigmas.  Thus, there is a strong unmet clinical need to 
develop novel therapies for RRP. 
 
The clinical entity of RRP is defined by the multiple local recurrences of disease resulting from a 
tolerized host immune response to the virus; as there is no good systemic treatment option 
currently available for this "benign" disease, repeated surgical debridement remains the mainstay 
of therapy.  Radiation and chemotherapy do not play a role in the management of this disease so 
these patients are naïve to these modalities. Infected subjects develop immunologic responses 
against the virus yet the T cells are anergized through activation of the PD-1:PD-L1 pathway. 
Therefore, there is a strong rationale to evaluate systemic immunomodulatory agents, such as 
anti-PD-1 therapy, in RRP patients and, given that the disease localizes to the mucosal lining of 
the upper aerodigestive tract, there is a window of opportunity which allows for directly 
visualizing clinical response during treatment.   
4.2.2 Rationale for Dose Selection/Regimen/Modification  
An open-label Phase I trial (Protocol 001) is being conducted to evaluate the safety and clinical 
activity of single agent pembrolizumab.  The dose escalation portion of this trial evaluated three 
dose levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 weeks (Q2W) in subjects 
with advanced solid tumors.  All three dose levels were well tolerated and no dose-limiting 
toxicities were observed.  This first in human study of pembrolizumab showed evidence of target 
engagement and objective evidence of 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.  Recent data from other clinical 
studies within the pembrolizumab program has shown that a lower dose of pembrolizumab and a 
less frequent schedule may be sufficient for target engagement and clinical activity. 

 
 
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PK data analysis of pembrolizumab 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 pembrolizumab 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.  Pembrolizumab 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 pembrolizumab in the melanoma indication. The exposure 
margins are based on the notion of similar efficacy and safety in melanoma at 10 mg/kg Q3W vs. 
the proposed dose regimen of 2 mg/kg Q3W (i.e. 5-fold higher dose and exposure). The 
population PK evaluation revealed that there was no significant impact of tumor burden on 
exposure. In addition, exposure was similar between the NSCLC and melanoma indications. 
Therefore, there are no anticipated changes in exposure between different indication settings. 
 
The rationale for further exploration of 2 mg/kg and comparable doses of pembrolizumab in 
solid tumors is based on: 1) similar efficacy and safety of pembrolizumab when dosed at either 2 
mg/kg or 10 mg/kg Q3W in melanoma patients, 2) the flat exposure-response relationships of 
pembrolizumab for both efficacy and safety in the dose ranges of 2 mg/kg Q3W to 10 mg/kg 
Q3W, 3) the lack of effect of tumor burden or indication on distribution behavior of 
pembrolizumab (as assessed by the population PK model) and 4) the assumption that the 
dynamics of pembrolizumab target engagement will not vary meaningfully with tumor type. 
The choice of the 200 mg Q3W as an appropriate dose for the switch to fixed dosing is based on 
simulations performed using the population PK model of pembrolizumab showing that the fixed 
dose of 200 mg every 3 weeks will provide exposures that 1) are optimally consistent with those 
obtained with the 2 mg/kg dose every 3 weeks, 2) will maintain individual patient exposures in 
the exposure range established in melanoma as associated with maximal efficacy response and 3) 
will maintain individual patients exposure in the exposure range established in melanoma that 
are well tolerated and safe.  
A fixed dose regimen will simplify the dosing regimen to be more convenient for physicians and 
to reduce potential for dosing errors.  A fixed dosing scheme will also reduce complexity in the 
logistical chain at treatment facilities and reduce wastage.  However, for the pediatric population, 
a dose based on weight (2 mg/kg up to a maximum of 200 mg) will be implemented. 

 
 
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4.2.3 Rationale for Endpoints 
4.2.3.1 Efficacy Endpoints 
The primary efficacy objective of this study is to evaluate the anti-tumor activity of 
pembrolizumab in male and female subjects diagnosed with RRP with extensive laryngeal, 
tracheal and/or pulmonary involvement. Response rate per clinical assessment and/or RECIST 
1.1 will be evaluated in those subjects with disease measurable by RECIST. 
Clinical response rates will be the primary measure for assessment of tumor response and as a 
basis for all protocol guidelines related to disease status (e.g. discontinuation of study therapy). 
Clinical response will be assessed by direct visualization and scoring of disease burden within 
the upper aerodigestive tract (Appendix A: Surgical Scoring and Appendix G: CRFs).   
 
The burden of disease will be assessed at each direct laryngoscopy and tracheoscopy 
examination performed in the clinic and in the operating room, and the extent of papilloma 
growth will be measured using an instrument previously described [8, 9]. Briefly, evaluations 
will be made of five major anatomic sites in the larynx (epiglottis, false cords, ventricle, true 
cords, and subglottis), which are subdivided into 23 subsites.  Four major anatomic sites in the 
tracheo-bronchial tree (trachea, tracheostomy site, if present, carina and mainstem bronchus) are 
divided into 6 subsites.  The rating incorporates three components.  Number of sites (AS) is the 
actual number of affected sites.  For laryngeal disease, this value can range from 0 to 23.  
Surface area (SA) involvement at each major site is rated on the following scale: 0 (none), 1 
(under 1/3 of area is affected), 2 (under 2/3 of area), or 3 (more than 2/3 of area).  For the total of 
five major sites this value can range from 0 to 15.  Extent of lumen obstruction (LO) reflects the 
degree of airway obstruction at each site, on a similar scale of 0-3.  For the total of five major 
sites this value can range from 0 to 15.  The three components (AS, SA and LO) are summed to 
yield a single overall rating, but the scores are entered separately into the computer to permit 
analysis of separate components of the score if desired.  The potential range of this scoring 
system is 0 to 53 for laryngeal disease; the range observed in previous studies was 0 to 43 
(www.clinicaltrials.gov; NCT00571701).  Scores for tracheobronchial disease are calculated 
similarly.  The maximum possible AS score is 6.  The maximum SA and LO scores are each 12.  
Therefore, the maximum summed score for tracheo-bronchial involvement is 30.  Copies of the 
scoring sheet pages are included in the appendix, as part of the case report forms. 
Overall response rates according to clinical assessment will be derived from time-point response 
assessments as follows: 
 
! Complete Response (CR): Complete disappearance of all tumor lesions (and no new 
lesions). CR must be confirmed by repeated, consecutive assessments made no less than 4 
weeks from the date first documented.  
! Partial Response (PR): Decrease in the summed score for laryngeal and tracheo-bronchial 
involvement by 25% or greater by a consecutive assessment at least 4 weeks after first 
documentation.  
! Stable Disease (SD): Failure to meet criteria for CR or PR, in absence of PD.  

 
 
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! Progressive Disease (PD): At least 25% increase in the summed score for laryngeal and 
tracheo-bronchial involvement, confirmation by a repeat, consecutive assessment no less than 
4 weeks from the date first documented.  
 
Immunotherapeutic agents such as pembrolizumab may produce antitumor effects by 
potentiating endogenous tumor-specific immune responses which may be functionally anergic.  
The response patterns seen with such an approach may extend beyond the typical time course of 
responses seen with cytotoxic agents, and can manifest a clinical response after an initial 
increase in tumor burden or even the appearance of new lesions.   
For those patients with pulmonary lesions measurable by RECIST 1.1, CT scans of the chest will 
be obtained every 12 weeks (84 days +/- 7 days) to assess response per RECIST 1.1 criteria.  
Standard RECIST criteria may not provide a complete response assessment of 
immunotherapeutic agents such as pembrolizumab. Therefore, RECIST 1.1 will be used with the 
following adaptation: 
If radiologic imaging shows PD, tumor assessment should be repeated a minimum of 4 weeks 
later in order to confirm PD with the option of continuing treatment per below while awaiting 
radiologic confirmation of progression.  If repeat imaging shows a reduction in the tumor burden 
compared to the initial scan demonstrating PD, treatment may be continued as per treatment 
calendar. If repeat imaging confirms progressive disease, subjects will be discontinued from 
study therapy. In determining whether or not the tumor burden has increased or decreased, all 
target lesions as well as non-target lesions should be considered. 
In subjects who have initial evidence of radiological PD, it is at the discretion of the treating 
physician whether to continue a subject on study treatment until repeat imaging is obtained a 
minimum of 4 weeks later. This decision should be based on the clinical judgment of the 
subject’s overall clinical condition, including performance status, clinical symptoms, and 
laboratory data.  Subjects may receive treatment while waiting for confirmation of PD if they are 
clinically stable as defined by the following criteria: 
 
*absence of signs and symptoms indicating disease progression 
 
*no decline in ECOG performance status 
 
*absence of rapid progression of disease 
When feasible, subjects should not be discontinued from protocol treatment until progression is 
confirmed. This allowance to continue treatment despite initial radiologic progression takes into 
account the observation that some subjects can have a transient tumor flare in the first few 
months after the start of immunotherapy, but with subsequent disease response. Subjects that are 
deemed clinically unstable are not required to have repeat imaging for confirmation of 
progressive disease.  
 

 
 
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5.0 
METHODOLOGY 
5.1 
Entry Criteria 
5.1.1 Diagnosis/Condition for Entry into the Trial 
Male and female subjects with RRP with tracheal and/or pulmonary involvement. 
5.1.2 Subject Inclusion Criteria 
In order to be eligible for participation in this trial, the subject must: 
1. The subject or their legal guardian be willing and able to provide written informed 
consent for the trial. 
2. Be ≥ 18 years of age on day of signing informed consent and > 12 years of age on day of 
signing assent.  
3. Have histologically confirmed diagnosis of RRP that involves the trachea, lungs, and/or 
larynx. If a subject is enrolled with laryngeal disease only, the subject must have 
undergone at least 3 or more surgeries/procedures in any one year to remove the lesions 
from their larynx. Subjects must have evaluable disease either based on RECIST 1.1 
and/or endoscopic parameters, as discussed above.  
4. Be required to provide tissue from a newly obtained biopsy of a tumor lesion.  Newly-
obtained is defined as a specimen obtained up to 6 weeks (42 days) prior to study 
registration.  Subjects for whom newly-obtained samples cannot be provided (e.g. 
inaccessible or subject safety concern) may submit an archived specimen only upon 
agreement from PI. 
5. Have confirmed human papillomavirus-associated lesions based on in-situ hybridization 
testing and/or polymerase chain reaction which may be performed on a newly obtained 
biopsy or archived sample. 
6. Have a performance status of 0 or 1 on the ECOG Performance Scale. 
7. Demonstrate adequate organ function as defined in  Table 1, all screening labs should be 
performed within 28 days of study registration.   
  Table 1:  Adequate Organ Function Laboratory Values 
SYSTEM 
LABORATORY VALUE 
Hematological 
 
Absolute neutrophil count (ANC) 
≥1,500 /mcL 
Platelets 
≥100,000 / mcL 
Hemoglobin 
≥9 g/dL or ≥5.6 mmol/L without transfusion or EPO dependency 
(within 7 days of assessment) 
Renal 
 
Serum creatinine OR 
Measured or calculateda creatinine 
≤1.5 X institutional upper limit of normal (ULN) OR 
 

 
 
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SYSTEM 
LABORATORY VALUE 
clearance 
(GFR can also be used in place of 
creatinine or CrCl) 
≥60 mL/min for subject with creatinine levels > 1.5 X 
institutional ULN 
Hepatic 
 
Serum total bilirubin 
≤ 1.5 X institutional ULN OR 
 
Direct bilirubin ≤ institutional ULN for subjects with total 
bilirubin levels > 1.5 institutional ULN 
AST (SGOT) and ALT (SGPT) 
≤ 2.5 X institutional ULN  OR 
≤ 5 X institutional 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 institutional 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 institutional 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. 
 
8. Female subject of childbearing potential should have a negative urine or serum pregnancy 
test within 28 days of study registration*.  If the urine test is positive or cannot be 
confirmed as negative, a serum pregnancy test will be required.  *Please refer to the study 
calendar for requirements regarding a pregnancy test 72 hours prior to receiving any dose 
of study medication upon subject enrollment into the study. 
9. 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 7.6.2).  
Subjects of childbearing potential are those who have not been surgically sterilized or 
have not been free from menses for > 1 year. The methods of surgical sterilization 
include having had a hysterectomy (removal of the uterus), bilateral oophorectomy 
(removal of both ovaries), tubal ligation (having your tubes tied), and transvaginal 
occlusion (blocking the tubes with a coil). 
10. 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. 
5.1.3 Subject Exclusion Criteria 
The subject must be excluded from participating in the trial if the subject: 
1. Is currently participating and receiving study therapy or 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. Has a known diagnosis of immunodeficiency or is receiving systemic steroid therapy or 
any other form of immunosuppressive therapy within 7 days prior to study registration. 
 
3. Has a known history of active TB (Bacillus Tuberculosis) 

 
 
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4. Has a known hypersensitivity to pembrolizumab or any of its excipients. 
5. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study 
registration or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events 
due to agents administered more than 4 weeks earlier. 
6. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 
2 weeks prior to study registration or who has not recovered (i.e., ≤ Grade 1 or at 
baseline) from adverse events due to a previously administered agent. 
NOTE:  Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may 
qualify for the study. 
7. Recovery from effects of any major surgery or significant traumatic injury at least 28 
days before the first dose of study treatment.  Endoscopic debridement of RRP lesions 
is NOT considered a major surgery 
8. Has a known diagnosis of invasive squamous cell carcinoma within the past 2 years. 
9. Patients with invasive squamous cell carcinoma derived from their RRP who are not 
considered appropriate for surgery, radiation therapy, or chemotherapy by their treating 
oncology team may be considered eligible for the study.  
10. Has active autoimmune disease that has required systemic treatment in the past 2 years 
(i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). 
Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement 
therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic 
treatment.  
11. Has a history of (non-infectious) pneumonitis that required steroids or current 
pneumonitis. 
12. Evidence of interstitial lung disease. 
13. Has an active infection requiring systemic therapy. 
14. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the trial, interfere with the subject’s participation for 
the full duration of the trial, or is not in the best interest of the subject to participate, in 
the opinion of the treating investigator.   
15. Has known psychiatric or substance abuse disorders that would interfere with cooperation 
with the requirements of the trial. 
16. 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. 

 
 
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17. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent. 
18. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 
19. Has known active Hepatitis B (e.g., HBsAg reactive) or known active Hepatitis C (e.g., 
HCV RNA [qualitative] is detected). 
20. 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. 
6.0 
REGISTRATION PROCEDURES 
6.1 
GENERAL GUIDELINES FOR DF/HCC INSTITUTIONS 
Institutions will register eligible participants in the Clinical Trials Management System (CTMS) 
OnCore. Registrations must occur prior to the initiation of protocol therapy. Any participant not 
registered to the protocol before protocol therapy begins will be considered ineligible and 
registration will be denied. 
An investigator will confirm eligibility criteria and a member of the study team will complete the 
protocol-specific eligibility checklist. 
Following registration, participants may begin protocol therapy. Issues that would cause 
treatment delays should be discussed with the Overall Principal Investigator (PI). If a participant 
does not receive protocol therapy following registration, the participant’s registration on the 
study must be canceled. Registration cancellations must be made in OnCore as soon as possible.  
Registration Process for DF/HCC Institutions 
 
DF/HCC Standard Operating Procedure for Human Subject Research Titled Subject Protocol 
Registration (SOP #: REGIST-101) must be followed.   
General Guidelines for Other Investigative Sites 
 
Eligible participants will be entered on study centrally by the Coordinating Center.  All sites 
should call the Coordinating Center to verify slot availabilities.   
Following registration, participants should begin protocol treatment within 14 days of 
registration. Issues that would cause treatment delays should be discussed with the Principal 
Investigator/Sponsor. If a participant does not receive protocol therapy following registration, the 
participant’s registration on the study must be canceled.  The Coordinating Center should be 
notified of cancellations as soon as possible  

 
 
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Registration Process for Other Investigative Sites 
To register a subject, the following documents should be completed by the participating 
institution and forwarded to the Coordinating Center: 
• Copy of source documentation for inclusion/exclusion criteria and screening procedures, 
including but not limited to 
o Pathology report 
o Medical history and physical exam 
o Laboratory reports 
o Concomitant medication list 
• Demographics information. 
• Signed study consent form. 
• Study Entry Note 
• HIPAA authorization form, if applicable 
• Eligibility checklist 
The Coordinating Center will review the above documentation to confirm eligibility and consent. 
To complete the registration process, the Coordinating Center will follow DF/HCC Standard 
Operating Procedure for Human Subject Research Titled Subject Protocol Registration (SOP #: 
REGIST-101) and register the participant on the protocol.  Once registered a confirmation email 
with the participant study number, and if applicable the dose treatment level, will be sent to the 
participating site.   
NOTE:  Registrations can only be conducted by the Coordinating Center during the business 
hours of 8:30 AM and 5:00 PM Eastern Standard Time (or Eastern Daylight Time when 
applicable), Monday through Friday.  A complete registration packet, including all documents 
listed above, must be received at least 1 business day prior to the anticipated registration to 
ensure adequate review.  Same day treatment registrations will only be accepted with prior notice 
and discussion with the DF/HCC Lead Institution.  
Treatment may not begin without confirmation from the Coordinating Center that the 
participant has been registered.  
 
7.0 
TREATMENT PLAN 
7.1 
Treatment Regimen 
The treatment to be used in this trial is outlined below in Table 2. 

 
 
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Table 2:  Trial Treatment 
 
Drug 
 
Dose/ 
Potency 
Dose 
Frequency 
Route of 
Administration 
Regimen/Treatment 
Period 
Use 
Pembrolizumab 200mg* 
Q3W 
IV infusion 
Day 1 of each  
3 week cycle 
Experimental 
* For the pediatric population, the dose is 2 mg/kg up to a maximum of 200 mg 
 
7.1.1 Dose Selection/Modification 
7.1.1.1 Dose Selection 
The rationale for selection of doses to be used in this trial is provided in Section 4.0 – 
Background and Rationale.   
Details on preparation and administration of pembrolizumab are provided in the Pharmacy 
Manual.   
7.1.1.2 Dose Modification  
Adverse events (both non-serious and serious) associated with pembrolizumab exposure may 
represent an immunologic etiology.  These adverse events may occur shortly after the first dose 
or several months after the last dose of treatment. Pembrolizumab must be withheld for drug-
related toxicities and severe or life-threatening AEs as per Table 3 below. See Section 7.5.1 and 
Events of Clinical Interest (ECI) Guidance Document (Appendix E) for supportive care 
guidelines, including use of corticosteroids. 
Table 3: Dose Modification Guidelines for Drug-Related Adverse Events 
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 

 
 
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Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting Treatment 
Discontinue Subject 
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. 
7.1.2 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 9.0).  Trial treatment may be 
administered up to 3 days before or after the scheduled Day 1 of each cycle due to administrative 
or other reasons. 
All trial treatments will typically be administered on an outpatient basis. 
Pembrolizumab up to 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).  Pembrolizumab 
will be administered after the operative endoscopy.  If the patient is found to have progressive 
disease by endoscopic evaluation, the patient will continue to receive pembrolizumab until the 
next in–office clinical examination in 3 weeks which confirms progressive disease of the target 
lesion. 

 
 
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The Pharmacy Manual contains specific instructions for the preparation of the pembrolizumab 
infusion fluid and administration of infusion solution. 
7.1.3 Trial Blinding/Masking 
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the 
treatment administered. 
7.1.4 Stopping Rules 
The study will be stopped if greater than 30% of patients discontinue pembrolizumab due to an 
adverse event or for any patient death related to toxicity. 
7.2 
Randomization or Treatment Allocation 
Subjects participating in this trial will be allocated to trial treatment by non-random assignment. 
7.3 
Stratification 
No stratification based on age, sex, or other characteristics will be used in this trial. 
7.4 
Concomitant Medications/Vaccinations (allowed & prohibited) 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for one of these or other medications or 
vaccinations specifically prohibited during the trial, discontinuation from trial therapy or 
vaccination may be required.  The 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.  
7.4.1 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 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 prior to study registration 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 11.0: Adverse Event Reporting Requirement. 

 
 
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7.4.2 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. 
• Intralesional or systemic antiviral treatment within 30 days prior to the first dose of trial 
treatment and while participating in the trial. 
 
Subjects who, in the assessment by the treating investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from protocol treatment.  
Subjects may receive other medications that the treating investigator deems to be medically 
necessary. 
The Exclusion Criteria describes other medications which are prohibited in this trial. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
7.5 
Rescue Medications & Supportive Care 
7.5.1 Supportive Care Guidelines 
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Suggested supportive care measures for the management of adverse events 
with potential immunologic etiology are outlined below 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 

 
 
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24 
 
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 7.1.1 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 greater than 3 days, treat with 
intravenous steroids followed by high dose oral steroids.   
o When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 
 
• Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) or ≥ 
Grade 3 Hyperglycemia, if associated with ketosis (ketonuria) or metabolic acidosis 
(DKA) 
o For T1DM or Grade 3-4 Hyperglycemia 
! Insulin replacement therapy is recommended for Type I diabetes mellitus 
and for Grade 3-4 hyperglycemia associated with metabolic acidosis or 
ketonuria.  
! Evaluate patients with serum glucose and a metabolic panel, urine ketones, 
glycosylated hemoglobin, and C-peptide.  

 
 
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• 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 3-4 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 at least 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 intravenous corticosteroids. 
o When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks.  
 

 
 
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• 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 
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). 
 
Subsequent rate of infusions should 
be no more than 50% of rate at 
which reaction occurred. 
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. 
 
 

 
 
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27 
 
7.6 
Diet/Activity/Other Considerations 
7.6.1 Diet 
Subjects should maintain a normal diet unless modifications are required to manage an AE such 
as diarrhea, nausea or vomiting. 
7.6.2 Contraception 
Pembrolizumab may have adverse effects on a fetus in utero.  Furthermore, it is not known if 
pembrolizumab has transient adverse effects on the composition of sperm.  Non-pregnant, non-
breast-feeding women may be enrolled if they are willing to use 2 methods of birth control or are 
considered highly unlikely to conceive.  Highly unlikely to conceive is defined as 1) surgically 
sterilized, or 2) postmenopausal (a woman who is ≥45 years of age and has not had menses for 
greater than 1 year will be considered postmenopausal), or 3) not heterosexually active for the 
duration of the study.  The two birth control methods can be either two barrier methods or a 
barrier method plus a hormonal method to prevent pregnancy. Subjects should start using birth 
control from study Visit 1 throughout the study period up to 120 days after the last dose of study 
therapy.  
The following are considered adequate barrier methods of contraception: diaphragm, condom (by 
the partner), copper intrauterine device, sponge, or spermicide.  Appropriate hormonal 
contraceptives will include any registered and marketed contraceptive agent that contains an 
estrogen and/or a progestational agent (including oral, subcutaneous, intrauterine, or 
intramuscular agents). 
Subjects should be informed that taking the study medication may involve unknown risks to the 
fetus (unborn baby) if pregnancy were to occur during the study.  In order to participate in the 
study they must adhere to the contraception requirement (described above) for the duration of the 
study and during the follow-up period defined in Section 11.5.6: 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. 
7.6.3 Use in Pregnancy 
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab, the subject 
will immediately be removed from the study treatment.  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 Coordinating Center and to Merck without 
delay;  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 outcome must 
be reported within 24 hours to the Coordinating Center and within 2 working days to Merck.   
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 

 
 
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28 
 
the pregnancy reported to the Coordinating Center and to Merck and followed as described 
above and in Section 11.5.6. 
7.6.4 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. 
7.7 
Criteria for Removal from Protocol Treatment  
Subjects may withdraw consent for protocol treatment and/or study itself at any time for any 
reason or be removed from the protocol treatment and/or study itself at the discretion of the 
investigator should any untoward effect occur.  In addition, a subject may be withdrawn by the 
treating 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 10.1.4: Other Procedures. 
Treatment may continue until one of the following criteria applies: 
 
• The subject withdraws consent to treatment. 
• Confirmed 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 
• Unacceptable adverse experiences as described in Section 7.1.1 
• Intercurrent illness that prevents further administration of treatment 
• Investigator’s decision to withdraw the subject 
• The subject has a confirmed positive serum pregnancy test 
• Noncompliance with trial treatment or procedure requirements 
• The subject is lost to follow-up 
• Completed 24 months of uninterrupted treatment with pembrolizumab or 35 
administrations of study medication, whichever is later. 
NOTE: 24 months of study medication is calculated from the date of first dose. 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 10.1.5.5 
• Treatment was held for 9 weeks for reasons other than complete response 
• Administrative reasons 

 
 
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Participants will be removed from the protocol therapy when any of these criteria apply.  
Participants removed from protocol therapy for unacceptable adverse event(s) will be followed 
until resolution or stabilization of the adverse event.  Alternative care options will be discussed 
with the participant. 
The reason for removal from protocol therapy, and the date the participant was removed, must be 
documented in the case report form (CRF). The research team also updates the relevant Off 
Treatment/Off Study information in OnCore; the Coordinating Center updates the relevant 
information for participating sites.  
The End of Treatment and Follow-up visit procedures are listed in Section 9 (Protocol Flow 
Chart) and Section 10.1.5 (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).  Subjects who discontinue for reasons other than first 
progressive disease will have post-treatment follow-up for disease status until disease 
progression, initiating a non-study cancer treatment, withdrawing consent, becoming lost to 
follow-up, death, or 36 months post-study registration.  After documented first disease 
progression each subject will be followed by telephone for overall survival until death, 
withdrawal of consent, or 36 months post-study registration, whichever occurs first. 
7.8 
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.   
7.9 
Subject Replacement Strategy 
Additional subjects may be enrolled to ensure that the required number of evaluable subjects in 
each cohort is achieved.  A subject that discontinues protocol treatment for first progressive 
disease or a drug-related AE will not be replaced and will be counted in the evaluable population 
of subjects for the respective cohort.   
7.10 
Criteria for Removal from the Study  
Participants will be removed from study when any of the following criteria apply: 
• The subject or legal representative (such as a parent or legal guardian) withdraws 
consent. 
• Death 
• Investigator’s decision to withdraw the subject 

 
 
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• Noncompliance with trial treatment or procedure requirements 
• The subject is lost to follow-up 
• Other administrative reasons 
The reason for taking a participant off study, and the date the participant was removed, must be 
documented in the case report form (CRF). 
The research team updates the relevant Off Treatment/Off Study information in OnCore; the 
Coordinating Center updates the relevant information for participating sites.  
7.11 
Clinical Criteria for Early Trial Termination 
Early trial termination will be the result of the criteria specified below: 
• Quality or quantity of data recording is inaccurate or incomplete 
• Poor adherence to protocol and regulatory requirements 
• Incidence or severity of adverse drug reaction in this or other studies indicates a potential 
health hazard to subjects 
• Plans to modify or discontinue the development of the study drug 
In the event of a Merck decision to no longer supply study drug, ample notification will be 
provided so that appropriate adjustments to subject treatment can be made. 
8.0 
BIOMARKER, CORRELATIVE AND SPECIAL STUDIES 
Additional biomarker research to identify factors important for pembrolizumab therapy may also 
be pursued. For example, pre-, on- and post-dose tumor and blood samples from this study may 
undergo proteomic, genomic and transcriptional analyses. Additional research may evaluate 
factors important for predicting responsiveness or resistance to pembrolizumab therapy and other 
immunologic targets. 
Assays may include but are not limited to:  
 
Multi-parametric IHC  
Spatial association of PD-1+ tumor infiltrating lymphocytes (TILs) and PD-L1+ cells (tumor and 
myeloid cells) suggests “induction” of PD-L1. Interferon-gamma (IFN-g) production by antigen-
specific PD-1+ CD8+ T cells is hypothesized to drive local intratumoral upregulation of PD-L1 
on adjacent tumor and myeloid cells, leading to a “stalled cytotoxic T cell (CTL)” response 
which may be predictive of response to pembrolizumab therapy. By assessing both the required 
elements and identifying the cell types which are expressing these proteins, a multi-color IHC 
assay may be a better predictor of response than PD-L1 positivity alone.  
 
Transcriptional Analyses  
Next-generation sequencing (RNAseq) will be used to profile global RNA expression in tissue 
specimens, to define a gene set critical for clinical response to pembrolizumab. The hypothesis to 
be tested is that pembrolizumab responders will exhibit a “stalled CTL” response within the 

 
 
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31 
 
tumor reflected in the physical proximity between PD-1 and PD-L1 expression and the presence 
of an aborted interferon-gamma transcriptional program will be detectable by profiling analyses. 
Expression of individual genes related to the immune system may also be evaluated, such as 
immune signatures and critical cytokines (e.g., IL-10).  
 
Gene Sequencing  
New data are emerging that suggest we can define certain tumor types as being ‘hypermutated’ 
or expressing neoantigens. There is a potential that this hypermutated state may correlate with 
response to pembrolizumab therapy, and/or that the converse, ‘hypomutated’ state may correlate 
with non-response. 
T cell receptor (TCR) repertoire 
Tumor infiltrating lymphocytes will be extracted from the tissue and TCR diversity assessed 
with the treatment of Pembrolizumab. 
8.1 
Sample Instructions 
8.1.1 Specimens Required 
Correlative Blood Samples 
 
Study Screening  and D1 of each cycle corresponding to an operating room visit 
• Ten 10ml green top or CPT tubes*  
• One 10 ml red top  
 
*For the pediatric population, five 10 ml green top or CPT tubes would be needed for study 
screening.  
 
 
Blood sample tubes should be completely filled to ensure adequate sample for testing. 
Tissue Samples 
A fresh tissue biopsy will be collected and processed as a formalin fixed paraffin embedded 
tumor block and a separate piece stored in RNALater at 4oC, when sufficient tissue is present, at 
the baseline endoscopy and at each operating room visit.  
Specimens must be collected on Mondays, Tuesdays, Wednesdays or Thursdays for same-day 
shipment.   
Archival formalin fixed paraffin embedded tumor blocks and/or unstained slides will also be 
requested for the correlative assays stated in Section 8.0. 

 
 
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32 
 
8.1.2 Processing Information 
8.2 
Shipping Instructions 
The correlative blood samples and/or tissue should be shipped for overnight delivery to: 
Sara Pai, MD, PhD 
Massachusetts General Hospital 
255 Charles St GRJ-910 
Boston MA, 02114 
Archival tissue can be batched shipped ambient to:  
Sara Pai, MD, PhD 
Massachusetts General Hospital 
255 Charles St GRJ-910 
Boston MA, 02114 
Prior to shipping any samples, please email Dr. Pai (sara.pai@mgh.harvard.edu) and the 
Coordinating Center with confirmation of the shipment including an inventory of the samples 
included and a tracking number.  Ship Monday, Tuesday, Wednesday, or Thursdays as 
shipments cannot be received on weekends and/or on holidays.  The inventory sheet must 
accompany each shipment and include a complete list of samples shipped (patient number, time 
point, study #) and a contact name, address and phone number of the person who is responsible 
for the shipment.  Please sign and date the inventory sheet and retain a copy for site record 
maintenance.  .  
8.2.1 Labeling Instructions 
Each tube should be labeled as follows: 
DFCI #: 15-469 
Study of anti-PD1 Therapy for 
HPV-associated RRP Patients 
Subject ID: 
Subject Initials: 
Visit#:                     Date: 
 
8.2.2 Storage and Shipping Instructions 
The research related blood and tissue must be stored in a secure, limited-access location until 
shipment. The samples should be shipped Monday through Thursday for overnight delivery.  
Participating sites are responsible for packaging and shipping expenses. 

 
 
DF/HCC Protocol #: 15-469 
 
 
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33 
 
 
9.0 
TRIAL FLOW CHART 
9.1 
Study Flow Chart 
 Trial Period: 
Screening Phase 
Treatment Cycles 
End of 
Treatment 
(early or 
at 24 
months) 
Post-Treatment 
Treatment Cycle/Title: 
 
Main 
Study 
Screening 
(Visit 1) 
1 
2  
3 
4 
To be repeated beyond 8 
cycles 
Discon 
Safety 
Follow-up 
Follow Up 
Visits24 
Survival 
Follow-
Up 
5 
6 
7 
8 
Scheduling Window (Days)1: 
 
-28 to -1 
 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
At time of 
Discon 
30 days 
post 
discon 
+ 2 weeks 
Every 8 
weeks post 
discon 
+ 2 weeks 
Every 
24 
weeks 
+ 2 
weeks  
Administrative Procedures 
Informed Consent2 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and Medical History 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Prior and Concomitant Medication Review3 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X3 
 
 
Trial Treatment Administration 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Post-study anticancer therapy status 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X20 
Survival Status 
 
 
 
 
 
 
 
 
 
 
 
 
 
X20 
Clinical Procedures/Assessments 
Review Adverse Events4 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X5 
X5 
 
Full Physical Examination6 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 

 
 
DF/HCC Protocol #: 15-469 
 
 
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34 
 
 Trial Period: 
Screening Phase 
Treatment Cycles 
End of 
Treatment 
(early or 
at 24 
months) 
Post-Treatment 
Treatment Cycle/Title: 
 
Main 
Study 
Screening 
(Visit 1) 
1 
2  
3 
4 
To be repeated beyond 8 
cycles 
Discon 
Safety 
Follow-up 
Follow Up 
Visits24 
Survival 
Follow-
Up 
5 
6 
7 
8 
Scheduling Window (Days)1: 
 
-28 to -1 
 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
At time of 
Discon 
30 days 
post 
discon 
+ 2 weeks 
Every 8 
weeks post 
discon 
+ 2 weeks 
Every 
24 
weeks 
+ 2 
weeks  
Directed Physical Examination6 
 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
 
 
Vital Signs and Weight7 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
ECOG Performance Status 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Laboratory Procedures/Assessments: analysis performed by LOCAL laboratory 
Pregnancy Test –Serum β-HCG8 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
PT/INR and aPTT9 
 
X10 
 
 
 
 
 
 
 
 
 
 
 
 
CBC with Differential11 
 
X10 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X17 
 
 
Comprehensive Serum Chemistry Panel11 
 
X10 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X17 
 
 
Urinalysis11 
 
X10 
 
 
 
X12 
 
 
 
 
X 
X17 
 
 
T3, FT4 and TSH11 
 
X10 
 
 
 
X12 
 
 
 
 
 
X17 
 
 
Efficacy Measurements 
Radiographic Tumor Imaging13 
 
X 
 
 
 
 
 
 
 
X14 
X15 
 
X16 
X20 
Clinical Imaging: Video-recording of 
flexible fiberoptic laryngoscopy, 
tracheoscopy, and/or bronchoscopy 
examination22 
 
X21 
X 
X 
X 
X 
 
 
X 
X 
 
 
X 
X 
X15 
X 
 
 
X 
 
 
X20 
Tumor Biopsies/Archival Tissue Collection/Correlative Studies Blood 

 
 
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 Trial Period: 
Screening Phase 
Treatment Cycles 
End of 
Treatment 
(early or 
at 24 
months) 
Post-Treatment 
Treatment Cycle/Title: 
 
Main 
Study 
Screening 
(Visit 1) 
1 
2  
3 
4 
To be repeated beyond 8 
cycles 
Discon 
Safety 
Follow-up 
Follow Up 
Visits24 
Survival 
Follow-
Up 
5 
6 
7 
8 
Scheduling Window (Days)1: 
 
-28 to -1 
 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
At time of 
Discon 
30 days 
post 
discon 
+ 2 weeks 
Every 8 
weeks post 
discon 
+ 2 weeks 
Every 
24 
weeks 
+ 2 
weeks  
Archival or Newly Obtained Tissue 
Collection 
 
X 
 
 
 
X18 
 
 
 
X18 
X19 
 
 
 
HPV testing 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Correlative Studies Blood Collection 
 
X 
 
 
 
X 
 
 
 
X 
X19 
 
 
 
Quality of Life Questionnaires23 
 
X 
 
 
 
X 
 
 
 
X 
X19 
 
 
 

 
 
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 Trial Period: 
Screening Phase 
Treatment Cycles 
End of 
Treatment 
(early or 
at 24 
months) 
Post-Treatment 
Treatment Cycle/Title: 
 
Main 
Study 
Screening 
(Visit 1) 
1 
2  
3 
4 
To be repeated beyond 8 
cycles 
Discon 
Safety 
Follow-up 
Follow Up 
Visits24 
Survival 
Follow-
Up 
5 
6 
7 
8 
Scheduling Window (Days)1: 
 
-28 to -1 
 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
At time of 
Discon 
30 days 
post 
discon 
+ 2 weeks 
Every 8 
weeks post 
discon 
+ 2 weeks 
Every 
24 
weeks 
+ 2 
weeks  
1In general, the window for each visit is +/- 3 days unless otherwise noted. For patients who have to travel >50 miles for treatment, there will be a window of +/- 7 
days for each visit.  
2Written consent must be obtained prior to performing any protocol specific procedure. Results of a test performed prior to the subject signing consent as part of 
clinical management are acceptable in lieu of a screening test if performed within the specific time frame (e.g. within 28 days prior to study registration). 
Assign baseline number when the study informed consent is signed. A remote consent can be obtained if the patient lives >50 miles from the treatment site. 
The informed consent document can be sent by facsimile and/or through a secure email account. The consent interview can be performed by telephone and 
a signed consent form can be returned to the clinical investigator by facsimile and/or through a secure email account to protect the confidentiality of the 
subject. The patient must be re-consented in person prior to starting treatment. 
3Prior medications – Record all medications taken within 28 days of study registration. Concomitant medications – Enter new medications started during the trial 
through the Safety Follow-up visit.  Record all medications taken for SAEs as defined in Section 11.0. 
4AEs and laboratory safety measurements will be graded per NCI CTCAE version 4.0.  All AEs, whether gradable by CTCAE or not, will also be evaluated for 
seriousness. 
5Record all AEs occurring within 30 days after the last dose of trial treatment.  Report all SAEs (related and unrelated to trial treatment) and ECIs occurring up 
until 90 days after the last dose of trial treatment or the start of new anti-cancer treatment, whichever comes first.  Afterwards, report only SAEs and ECIs 
that are related to trial treatment. 
6Full physical examination should be performed every 4 cycles after cycle 5. Otherwise, perform a directed physical examination the day of the study treatment 
visit. 
7Vital signs to include temperature, pulse, respiratory rate, weight and blood pressure.  Height will be measured at visit 2 only. 
8For women of reproductive potential, a serum pregnancy test should be performed within 72 hours prior to any dose of trial treatment. 
9Coagulation factors (PT/INR and aPTT) should be tested as part of the screening procedures for all subjects. Any subject receiving anticoagulant therapy 

 
 
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37 
 
 Trial Period: 
Screening Phase 
Treatment Cycles 
End of 
Treatment 
(early or 
at 24 
months) 
Post-Treatment 
Treatment Cycle/Title: 
 
Main 
Study 
Screening 
(Visit 1) 
1 
2  
3 
4 
To be repeated beyond 8 
cycles 
Discon 
Safety 
Follow-up 
Follow Up 
Visits24 
Survival 
Follow-
Up 
5 
6 
7 
8 
Scheduling Window (Days)1: 
 
-28 to -1 
 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
At time of 
Discon 
30 days 
post 
discon 
+ 2 weeks 
Every 8 
weeks post 
discon 
+ 2 weeks 
Every 
24 
weeks 
+ 2 
weeks  
should have coagulation factors monitored closely throughout the trial. 
10Laboratory tests for screening are to be performed within 28 days prior to study registration. See Section 10.1.3 for details regarding laboratory tests. 
11After Cycle 1, lab samples can be collected up to 72 hours prior to the scheduled time point.  See Section 10.1.3 for details regarding laboratory tests. 
12To be repeated every 4 cycles. 
13The initial tumor imaging will be performed within 28 days prior to study registration. Scans performed as part of routine clinical management are acceptable for 
use as the screening scan if they are of diagnostic quality and performed within 28 days prior to study registration.  The initial tumor imaging study will be 
performed with intravenous contrast (unless the patient has an allergy to contrast) and subsequent scans will be performed without intravenous contrast. 
14On-study radiographic imaging will be performed every 8 cycles (+/- 14 days) after the first dose of trial treatment. For those patients with  pulmonary lesions 
measurable by RECIST 1.1, lymphadenopathy, or extra-tracheal disease (exception being the larynx), radiographic imaging will be obtained every 4 cycles 
(+/- 7 days). Per the 3-dimensional tracheal reconstruction volumetric measurement and/or modified RECIST 1.1 used in this protocol, if imaging shows 
progressive disease, repeat imaging assessment should be performed at a minimum of 4 weeks later in order to confirm progressive disease. Image timing 
should follow calendar days and should not be adjusted for delays in cycle starts.  For patients who have to travel >50 miles for treatment, there will be a 
window of +/- 7 days for imaging. 
15In subjects who discontinue study therapy without confirmed disease progression, a radiological and/or clinical imaging should be performed at the time of 
treatment discontinuation (i.e. date of discontinuation +/- 4 week window). If a previous scan was obtained within 4 weeks prior to the date of discontinuation, 
then a scan at treatment discontinuation is not mandatory. 
16In subjects who discontinue study therapy (early or at 24 months) without documented disease progression, every effort will be made to continue monitoring 
their disease status by radiologic imaging every 6 months (+/- 2 weeks) until: 1) documented disease progression; 2) death; or 3) 36 months post study 
registration, whichever occurs first. 
17Unresolved labs that are drug related AEs should be followed until resolution. Labs do not need to be repeated after the end of treatment if labs are within 

 
 
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38 
 
 Trial Period: 
Screening Phase 
Treatment Cycles 
End of 
Treatment 
(early or 
at 24 
months) 
Post-Treatment 
Treatment Cycle/Title: 
 
Main 
Study 
Screening 
(Visit 1) 
1 
2  
3 
4 
To be repeated beyond 8 
cycles 
Discon 
Safety 
Follow-up 
Follow Up 
Visits24 
Survival 
Follow-
Up 
5 
6 
7 
8 
Scheduling Window (Days)1: 
 
-28 to -1 
 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
At time of 
Discon 
30 days 
post 
discon 
+ 2 weeks 
Every 8 
weeks post 
discon 
+ 2 weeks 
Every 
24 
weeks 
+ 2 
weeks  
normal range. 
18Tumor biopsy will be obtained only if there are lesions present. 
19Tumor biopsy, blood for correlative studies for clinically stable subjects, and quality of life questionnaires should be obtained at treatment discontinuation. 
20Survival status should be obtained at each clinic visit and/or each tumor assessment. Following first disease progression, subjects will be followed by telephone 
for overall survival until death, withdrawal of consent, or 36 months from study registration, whichever occurs first. 
21Endoscopic evaluations at baseline should be done within 6 weeks prior to enrollment into the study.  
22Clinical imaging assessed by laryngoscopy and tracheoscopy will be performed every 3 weeks (21 days+/- 3 days).  In addition, a comprehensive 
laryngoscopy, tracheoscopy, and bronchoscopy will be performed every 4 cycles in the operating room.   
23VHI-10 questionnaire is required only for subjects enrolled after IRB approval and/or activation of Protocol AM 10 
24After 1 year, the clinical assessment will be reduced to 24 weeks for 12 months only. 
 
 
 

 
 
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9.2 
Second Course Phase (Retreatment ONLY)  
Trial Period: 
Treatment Cycles1 
End of 
Treatment 
Post-Treatment 
Treatment Cycle/Title: 
1 
2  
3 
4 
To be repeated beyond 8 
cycles 
Discon 
Safety 
Follow-up 
Follow Up 
Visits2 
Survival 
Follow-
Up 
5 
6 
7 
8 
Scheduling Window (Days) 3: 
 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
At time of 
Discon 
30 days 
post 
discon 
+ 2 weeks 
Every 8 
weeks post 
discon 
+ 2 weeks 
Every 
24 
weeks 
 + 2 
weeks 
Administrative Procedures 
Eligibility Criteria4 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Medication Review5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X5 
 
 
Trial Treatment Administration6 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Post-study anticancer therapy status 
 
 
 
 
 
 
 
 
 
 
X 
X19 
Survival Status 
 
 
 
 
 
 
 
 
 
 
 
X19 
Clinical Procedures/Assessments 
Review Adverse Events7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X8 
X8 
 
Full Physical Examination 
X 
 
 
 
X9 
 
 
 
 
 
 
 
Directed Physical Examination 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
 
 
Vital Signs and Weight11 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
ECOG Performance Status 
X 
X 
X 
X 
X 
X 
X 
X12 
X 
 
 
 
Laboratory Procedures/Assessments: 
Pregnancy Test –Serum β-HCG13 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
PT/INR and aPTT14 
X15 
 
 
 
 
 
 
 
 
 
 
 
CBC with Differential16 
X15 
X 
X 
X 
X 
X 
X 
X 
X 
X17 
 
 
Comprehensive Serum Chemistry Panel16 
X15 
X 
X 
X 
X 
X 
X 
X 
X 
X17 
 
 
T3, FT4 and TSH16 
X15 
 
 
X10 
 
 
 
 
 
X17 
 
 

 
 
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Efficacy Measurements 
Radiographic Tumor Imaging18 
X 
 
 
 
 
 
 
X 
X19 
 
X2 
X 
Clinical Imaging: Video-recording of 
flexible fiberoptic laryngoscopy, 
tracheoscopy, and/or bronchoscopy 
examination 
X 
X 
X 
X 
 
 
X 
X 
 
 
X 
X 
X 
X 
 
 
X 
 
 
X 
Tumor Biopsy20 
 
 
 
X 
 
 
 
X 
X21 
 
 
 
Correlative Studies Blood Collection 
X 
 
 
X 
 
 
 
X 
X21 
 
 
 
Quality of Life Questionnaires22 
X 
 
 
X 
 
 
 
X 
X21 
 
 
 
1In general, assessments/procedures are to be performed on Day 1 and prior to the first dose of treatment for each cycle unless otherwise 
specificed.  Treatment cycles are 3 weeks.  
2In subjects who discontinue study therapy without documented disease progression, every effort should be made to continue monitoring 
their disease status by radiologic imaging until: 1) the start of new anti-cancer treatment, 2) documented disease progression, 3) 
death, or 4) the end of the study, whichever occurs first. 
3In general, the window for each visit is + 3 days unless otherwise noted. For patients who have to travel >50 miles for treatment, there will 
be a window of +/- 7 days 
4Subjects who either: a) attain a CR and discontinue treatment or b) discontinue treatment after 24 months on pembrolizumab for reasons 
other than disease progression or intolerability may restart trial treatment if they meet the criteria specific in Section 10.1.5.5. 
5Concomitant medications – Enter new medications started during the trial through the Safety Follow-up visit. Record all medications taken 
for SAEs as defined in Section 11.0. 
6Subjects who restart treatment should resume at the same dose and cycle interval which they were receiving prior to discontinuation. 
Record all medications taken for SAEs as defined in Section 11.0. 
7AEs and laboratory safety measurements will be graded per NCI CTCAE version 4.0.  All AEs, whether gradable by CTCAE or not, will 
also be evaluated for seriousness. 
8Record all AEs occurring within 30 days after the last dose of trial treatment.  Report all SAEs (related and unrelated to trial treatment) 
and ECIs occurring up until 90 days after the last dose of trial treatment or the start of new anti-cancer treatment, whichever comes 
first.  Afterwards, report only SAEs and ECIs that are related to trial treatment. 
9Following Cycle 8, the directed physical exam is only required at Cycle 11, 15, 18 and every 4 cycles thereafter. 
10To be repeated every 4 cycles. 
11Vital signs to include temperature, pulse, respiratory rate, weight, and blood pressure. 
12Following Cycle 8, the ECOG performance status should be determined only in conjunction with a protocol-specified full or directed 
physical exam (Cycles 8, 11, 13, 15, 17, 19, and every 3 cycles thereafter.) 
13For women of reproductive potential, a serum pregnancy test should be performed within 72 hours prior to any dose of trial treatment. 

 
 
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14Coagulation factors (PT/INR and aPTT) should be monitored closely throughout the trial for any subject receiving anticoagulant therapy. 
15Laboratory tests for determining eligibility for retreatment are to be performed within 28 days prior to the first retreatment dose of 
pembrolizumab. See Section 10.1.3 for details regarding laboratory tests.16After the first dose, lab samples can be collected up to 72 
hours prior to the scheduled time point.  See Section 10.1.3 for details regarding laboratory tests. 
17Unresolved labs that are drug related AEs should be followed until resolution. Labs do not need to be repeated after the end of treatment 
if labs are within normal range. 
18A scan must be performed within 28 days prior to restarting treatment with pembrolizumab. The initial tumor imaging study will be 
performed with intravenous contrast (unless the patient has an allergy to contrast) and subsequent scans will be performed without 
intravenous contrast. On-study radiographic imaging will be performed every 8 cycles (+/- 14 days) after the first dose of retreatment. 
For those patients with pulmonary lesions measurable by RECIST 1.1, lymphadenopathy, or extra-tracheal disease (exception being 
the larynx), radiographic imaging will be obtained every 4 cycles (+/- 7 days). Per the 3-dimensional tracheal reconstruction volumetric 
measurement and/or modified RECIST 1.1 used in this protocol, if imaging shows progressive disease, repeat imaging assessment 
should be performed at a minimum of 4 weeks later in order to confirm progressive disease. Image timing should follow calendar days 
and should not be adjusted for delays in cycle starts.   For patients who have to travel >50 miles for treatment, there will be a window 
of +/- 7 days. 
19In subjects who discontinue study therapy without confirmed disease progression, a radiological evaluation should be performed at the 
time of treatment discontinuation (i.e. date of discontinuation +/- 4 week window). If a previous scan was obtained within 4 weeks prior 
to the date of discontinuation, then a scan at treatment discontinuation is not mandatory. In subjects who discontinue study therapy 
(early or at 24 months) without documented disease progression, every effort will be made to continue monitoring their disease status 
by radiologic imaging every 6 months (+/- 2 weeks) until: 1) documented disease progression; 2) death; or 3) 36 months post study 
registration, whichever occurs first. 
20Tumor biopsy will be obtained only if there are lesions present. 
21Tumor biopsy, blood for correlative studies in clinically stable subjects, and quality of life questionnaires will be obtained at treatment 
discontinuation. 
22VHI-10 questionnaire is required only for subjects enrolled after IRB approval and/or activation of Protocol AM 10 

 
 
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10.0 
TRIAL PROCEDURES  
10.1 
Trial Procedures 
The Trial Flow Chart - Section 9.0 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. 
10.1.1 Administrative Procedures 
10.1.1.1 Informed Consent 
The Investigator must obtain documented consent from each potential subject prior to 
participating in a clinical trial. 
10.1.1.1.1 General Informed Consent 
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature of 
the person conducting the consent discussion. A remote consent can be obtained if the subject 
lives >50 miles from the treatment site. The informed consent document can be sent by facsimile 
and/or through a secure email account. The consent interview can be performed by telephone and 
a signed consent form can be returned to the clinical investigator by facsimile and/or through a 
secure email account to protect the confidentiality of the subject. The patient must be re-
consented in person prior to starting treatment. 
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.   

 
 
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The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations and 
Sponsor requirements. 
10.1.1.2 Inclusion/Exclusion Criteria 
All inclusion and exclusion criteria will be reviewed by the treating investigator or qualified 
designee to ensure that the subject qualifies for the trial.  
10.1.1.3 Medical History 
A medical history will be obtained by the treating 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.   
10.1.1.4 Prior Medications Review 
The treating investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the subject within 
28 days before starting the trial.  Treatment for the disease for which the subject has enrolled in 
this study will be recorded separately and not listed as a prior medication.  
10.1.1.5 Concomitant Medications Reviews 
The treating investigator or qualified designee will record medication, if any, taken by the 
subject during the trial.  All medications related to reportable SAEs and ECIs should be recorded 
as defined in Section 11.0. 
10.1.1.6 Disease Details 
The treating investigator or qualified designee will obtain prior and current details regarding 
disease status.  
10.1.1.7 Prior Treatment Details 
The treating investigator or qualified designee will review all prior treatments including systemic 
and intralesional treatments, radiation and surgeries. 
10.1.1.8 Subsequent Therapy Status 
The treating investigator or qualified designee will review all new surgical, systemic and 
intralesional therapy initiated after the last dose of trial treatment.  If a subject initiates a new 
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 therapy has been initiated the 
subject will move into survival follow-up.  

 
 
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10.1.1.9 Assignment of Screening Number 
All consented subjects will be given a unique screening number that will be used to identify the 
subject for all procedures that occur prior to randomization or treatment allocation. Each subject 
will be assigned only one screening number. Screening numbers must not be re-used for different 
subjects. Any subject who is screened multiple times will retain the original screening number 
assigned at the initial screening visit. 
10.1.1.10 
Assignment of Randomization Number 
All eligible subjects will be allocated, by non-random assignment, to trial treatment and will 
receive a unique number. This unique number is termed a randomization number throughout the 
protocol for operational purposes. The randomization number identifies the subject for all 
procedures occurring after treatment allocation. Once a randomization number is assigned to a 
subject, it can never be re-assigned to another subject. 
A single subject cannot be assigned more than 1 unique number. 
10.1.1.11 
Trial Compliance (Medication/Diet/Activity/Other) 
Any interruptions from the protocol specified treatment plan due to toxicity will result in the 
patient withdrawing from treatment. 
Administration of trial medication will be witnessed by the investigator and/or trial staff. The 
total volume of trial treatment infused will be compared to the total volume prepared to 
determine compliance with each dose administered. 
10.1.2 Clinical Procedures/Assessments 
10.1.2.1 Adverse Event (AE) Monitoring and Rapid Review Overview 
The treating 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.  Toxicities will be characterized in 
terms regarding 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 separate ECI guidance document in Appendix 4 regarding the 
identification, evaluation and management of potential irAEs.   
Please refer to Section 11.0 for detailed information regarding the assessment and recording of 
AEs.   

 
 
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10.1.2.2 Full Physical Exam 
The treating investigator or qualified designee will perform a complete physical exam during the 
screening period.  Clinically significant abnormal findings should be recorded as medical history.  
A full physical exam should be performed during screening.  
10.1.2.3 Directed Physical Exam 
For cycles that do not require a full physical exam per the Trial Flow Chart, the treating 
investigator or qualified designee will perform a directed physical exam as clinically indicated 
prior to trial treatment administration.  Patients will undergo a video-recorded transnasal flexible 
fiberoptic laryngoscopy and tracheoscopy examination within +/- 24 hours that they receive each 
dose of pembrolizumab. The treating surgeon will complete the Severity Scoring Sheets (found 
in Section 18.0A Surgical Scoring sheets) at each session and document procedure findings. 
10.1.2.4 Vital Signs 
The treating investigator or qualified designee will take vital signs at screening, prior to the 
administration of each dose of trial treatment and at treatment discontinuation as specified in the 
Trial Flow Chart (Section 9.0).  Vital signs should include temperature, pulse, respiratory rate, 
weight and blood pressure.  Height will be measured at screening only. 
10.1.2.5 Eastern Cooperative Oncology Group (ECOG) Performance Scale 
The treating investigator or qualified designee will assess ECOG status at screening, prior to the 
administration of each dose of trial treatment and discontinuation of trial treatment as specified 
in the Trial Flow Chart.   
10.1.2.6 Tumor Imaging and Assessment of Disease 
Clinical response rates will be the primary measure for assessment of tumor response and as a 
basis for all protocol guidelines related to disease status (e.g. discontinuation of study therapy). 
Clinical response will be assessed by direct visualization and scoring of disease burden within 
the upper aerodigestive tract (Appendix A: Surgical Scoring and Appendix G: CRFs).   
 
The burden of disease will be assessed at each direct laryngoscopy/tracheoscopy examination 
performed in clinic and in the operating room, and the extent of papilloma growth will be 
measured using an instrument previously described [8, 9]. Briefly, evaluations will be made of 
five major anatomic sites in the larynx (epiglottis, false cords, ventricle, true cords, and 
subglottis), which are subdivided into 23 subsites.  Four major anatomic sites in the tracheo-
bronchial tree (trachea, tracheostomy site, if present, carina and mainstem bronchus) are divided 
into 6 subsites.  The rating incorporates three components.  Number of sites (AS) is the actual 
number of affected sites.  For laryngeal disease, this value can range from 0 to 23.  Surface area 
(SA) involvement at each major site is rated on the following scale: 0 (none), 1 (under 1/3 of 
area is affected), 2 (under 2/3 of area), or 3 (more than 2/3 of area).  For the total of five major 
sites this value can range from 0 to 15.  Extent of lumen obstruction (LO) reflects the degree of 
airway obstruction at each site, on a similar scale of 0-3.  For the total of five major sites this 

 
 
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value can range from 0 to 15.  The three components (AS, SA and LO) are summed to yield a 
single overall rating, but the scores are entered separately into the computer to permit analysis of 
separate components of the score if desired.  The potential range of this scoring system is 0 to 53 
for laryngeal disease; the range observed in previous studies was 0 to 43 (www.clinicaltrials.gov; 
NCT00571701).  Scores for tracheobronchial disease are calculated similarly.  The maximum 
possible AS score is 6.  The maximum SA and LO scores are each 12.  Therefore, the maximum 
summed score for tracheo-bronchial involvement is 30.  Copies of the scoring sheet pages are 
included in the appendix, as part of the case report forms (Appendix A: Surgical Scoring and 
Appendix G: CRFs). 
To ensure protocol compliance and consistency among participating sites, a Rapid Review will 
be conducted. The videos from the screening clinic and operating room visit for each 
institution’s first three cases will be reviewed by Dr. Sara Pai and the Site Investigator via a 
WebEx and Teleconference. Rapid Reviews will be conducted within 14 days of the surgery. 
Additional reviews may be requested by the Principal Investigator until protocol compliance is 
adequately demonstrated. Review will be arranged by the Coordinating Center as per procedures 
listed below: 
Process for Endoscopic Video and Score Sheet Rapid Review: 
1. At the time of registration, the Coordinating Center will identify if the patient is subject 
to Rapid Review.  
2. Coordinating Center is notified of the date and time of the surgery to be reviewed for 
each case by the external sites. Video and score sheets will be sent per instructions below 
to the Coordinating Center.  
3. Once the video and score sheet are reviewed, the PI and Site Investigator will review the 
video via a WebEx and teleconference arranged by the Coordinating Center. 
4. Any issues identified during the review will be communicated, documented, and resolved 
at the time of review.  
5. The Coordinating Center notifies the study team at the participating site that the review is 
complete and provides email confirmation to the study team.  
De-identified videos of the endoscopic (laryngoscopy, tracheoscopy, and/or bronchoscopy) 
examination will be sent to the Coordinating Center every 4 cycles (at the time of surgical 
biopsy). Videos maybe downloaded onto a secure server and/or sent via a USB drive or CD 
labeled with two patient identifiers to the following address: 
MGH CCPO Multi-Center Program  
c/o Lisa Raeke-Program Manager 
125 Nashua Street, #9424 
Boston, MA 02114 
 

 
 
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Severity Scoring sheets should be submitted to the Coordinating Center in real time. PDFs of all 
sheets should be emailed to Dr. Sara Pai at sara.pai@mgh.harvard.edu and the MC Coordinator 
over a secure network. In subject header include study number (15-469) and patient’s ID number 
and initials.    
10.1.2.6.1 Assessment of Response 
 
Overall response rates according to clinical assessment will be derived from time-point response 
assessments as follows: 
 
! Complete Response (CR): Complete disappearance of all tumor lesions (and no new 
lesions). CR must be confirmed by repeated, consecutive assessments made no less than 4 
weeks from the date first documented.  
! Partial Response (PR): Decrease in the summed score for laryngeal and tracheo-bronchial 
involvement by 25% or greater by a consecutive assessment at least 4 weeks after first 
documentation.  
! Stable Disease (SD): Failure to meet criteria for CR or PR, in absence of PD.  
! Progressive Disease (PD): At least 25% increase in the summed score for laryngeal and 
tracheo-bronchial involvement, confirmation by a repeat, consecutive assessment no less than 
4 weeks from the date first documented.  
 
3-Dimension tracheal reconstruction with volumetric analysis and RECIST 1.1 will be applied as 
another measure for assessing tumor response in those patients with tracheal and/or pulmonary 
involvement, respectively, and will contribute to the basis for all protocol guidelines related to 
disease status (e.g. discontinuation of study therapy).  
 
For those patients with pulmonary lesions measurable by RECIST 1.1, CT scans of the chest will 
be obtained every 12 weeks (84 days +/- 7 days) to assess response per RECIST 1.1 criteria.  
Imaging assessments will be adapted as follows to account for the unique tumor response seen in 
this class of therapeutics. 
 
At the baseline imaging study, if there is no evidence of pulmonary disease measurable by 
RECIST 1.1, the patient will be followed with serial laryngoscopy/tracheoscopy examinations 
every 3 weeks and serial CT scans will be obtained every 6 months until the end of the study.  If 
there is evidence of pulmonary disease, lymphadenopathy, and/or extra-tracheal disease (except 
those involving the larynx) measurable by RECIST 1.1, the patient will undergo repeat imaging 
every 12 weeks (+ 7 days).  If two consecutive imaging assessments demonstrate SD or CR, the 
patient will undergo repeat imaging every 6 months until the end of the study.  If imaging shows 
PD, tumor assessment should be repeated no less than 4 weeks from the date first documented in 
order to confirm PD with the option of continuing treatment for clinically stable subjects as 
discussed below in the Table.   
 
Clinically stable is defined by the following criteria: 
 

 
 
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*Absence of signs and symptoms indicating disease progression 
* No decline in ECOG performance status 
*Absence of rapid progression of disease 
 
 
 
Clinical Stable 
Clinically Unstable 
 
Imaging 
Treatment 
Imaging 
Treatment 
1st radiologic 
evidence of PD 
Repeat imaging 
at > 4 weeks to 
confirm PD 
May continue 
study treatment 
at the 
Investigator’s 
discretion while 
awaiting 
confirmatory 
scan 
Repeat imaging at 
>4 weeks to 
confirm PD if 
possible 
Discontinue 
treatment 
Repeat scan 
confirms PD 
No additional 
imaging 
required 
Discontinue 
treatment 
No additional 
imaging required 
N/A 
Repeat scan 
shows SD, PR 
or CR 
Continue 
imaging 
assessments  
Continue study 
treatment at the 
Investigator’s 
discretion 
Continue imaging 
assessments if 
possible 
May restart 
study 
treatment if 
condition has 
improved 
and/or 
clinically 
stable per 
Investigator’s 
discretion 
 
In determining whether or not the tumor burden has increased or decreased, all target lesions as 
well as non-target lesions should be considered. Subjects that are deemed clinically unstable are 
not required to have repeat imaging for confirmation. If radiologic progression is confirmed, then 
the subject will be discontinued from trial treatment. If radiologic progression is not confirmed, 
then the subject should resume/continue trial treatment and have their next scan in 12 weeks (84 
± 7 days).   
 
After the first documentation of progression, it is at the discretion of the investigator to keep a 
clinically stable subject on trial treatment or to stop trial treatment until repeat imaging 
performed at least 28 days later confirms progression. When feasible, subjects should not be 
discontinued until progression is confirmed. Subjects that are deemed clinically unstable are not 
required to have repeat imaging for confirmation. If progression is confirmed, then the subject 
will be discontinued from trial treatment. If progression is not confirmed, then the subject should 
resume/continue trial treatment.  
 

 
 
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NOTE: If a subject with confirmed radiographic progression (i.e. 2 scans at least 28 days apart 
demonstrating progressive disease) is clinically stable or clinically improved, and there is no 
further increase in the tumor dimensions at the confirmatory scan, an exception may be 
considered to continue treatment upon consultation with the Sponsor. Clinically stable subjects 
should also have at the confirmatory scan no further increase in the target lesions, no 
unequivocal increase in non-target lesions, and no additional new lesions develop (non-
worsening PD) to continue study treatment.  
 
Imaging during the follow-up period is to be repeated every 6 months for subjects who 
discontinue trial treatment for reasons other than disease progression until the subject 
experiences confirmed disease progression or starts a new antineoplastic therapy.  
 
Any new pulmonary findings on imaging which are not found to be clinically relevant or 
associated with RRP will be managed with standard guidelines and risk stratification of solitary 
pulmonary nodules. 
 
10.1.2.7 Tumor Tissue Collection and Correlative Studies Blood Sampling 
The natural clinical course of these subjects is the need for repeated operative procedures to 
debride recurrent growths of papillomatous lesions which may block the airway. A baseline 
tissue sample prior to starting systemic treatment will be collected.  Subsequently, a tumor 
biopsy of one progressing and/or one regressing lesion, whenever possible and at the discretion 
of the surgeon, should be obtained at each operative visit which will occur at a minimum of 
every 12 weeks (84 days +/- 7 days) while on the study.  If there are no lesions in the upper 
aerodigestive tract at the time of the operative examination, a biopsy will not be obtained. Some 
patients may require more frequent debridements based on the clinical symptoms and at the 
discretion of the surgeon and biopsies will be obtained at each operative visit. The tumor samples 
will be evaluated for changes in expression of various immune biomarkers which will include, 
but are not limited to: PD-1, PD-L1, PD-L2, CD4, CD8, FoxP3, CTLA-4, Lag-3, Tim-3, IFN-g, 
and HPV-specific CD8+ T cells. 
Blood for correlative biomarker studies will be collected at baseline, at each cycle which 
corresponds with an operating room visit, and upon disease progression. The blood will be 
evaluated for changes in circulating HPV-specific CD8+ T cells and cytokines. For those patients  
eligible for a Second Course Phase (Retreatment), blood will also be collected on day 1 of the 
first cycle of re-treatment. 
10.1.2.8 Quality of Life Questionnaires 
Quality of life questionnaires will be completed prior to treatment and every fourth cycle 
thereafter until the end protocol treatment. (See Appendix F). 
10.1.3 Laboratory Procedures/Assessments 
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below  

 
 
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Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) 
Laboratory tests for hematology, chemistry, urinalysis, and others are specified in Table 5.   

 
 
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Table 5:  Laboratory Tests 
Hematology 
Chemistry 
Urinalysis 
Other 
Hematocrit 
Albumin 
Blood 
Serum β-human chorionic gonadotropin† 
Hemoglobin 
Alkaline phosphatase 
Glucose 
  (β-hCG)† 
Platelet count 
Alanine aminotransferase (ALT) 
Protein 
PT (INR) 
WBC (total and differential) 
Aspartate aminotransferase (AST) 
Specific gravity  
aPTT 
Red Blood Cell Count 
Lactate dehydrogenase (LDH) 
Microscopic exam (If abnormal)  
Total thriiodothyronine (T3) 
Absolute Neutrophil Count 
Carbon Dioxide ‡ 
results are noted 
Free thyroxine (T4) 
Absolute Lymphocyte Count 
  (CO2 or biocarbonate) 
 
Thyroid stimulating hormone (TSH) 
 
Uric Acid 
 
 
 
Calcium 
 
 
 
Chloride 
 
Blood for correlative studies 
 
Glucose 
 
  
 
Phosphorus 
 
  
 
Potassium   
 
  
 
Sodium 
 
  
 
Magnesium 
 
  
 
Total Bilirubin 
 
  
 
Direct Bilirubin (If total bilirubin is 
elevated above the upper limit of 
normal) 
 
 
 
Total protein 
 
 
 
Blood Urea Nitrogen 
 
 
† Perform on women of childbearing potential only. ‡ If considered standard of care in your region. 
 
 
 

 
 
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Laboratory tests for screening or entry into the Second Course Phase should be performed within 
28 days prior to the first dose of treatment.  After Cycle 1, pre-dose laboratory procedures can be 
conducted up to 72 hours prior to dosing.  Results must be reviewed by the investigator or 
qualified designee and found to be acceptable prior to each dose of trial treatment.  
10.1.4 Other Procedures 
10.1.4.1 Withdrawal/Discontinuation 
When a subject discontinues/withdraws from protocol treatment and/or the study itself, all 
applicable activities scheduled for the final trial visit should be performed at the time of 
discontinuation.  Any adverse events which are present at the time of discontinuation/withdrawal 
should be followed in accordance with the safety requirements outlined in Section 11.0 - 
Assessing and Recording Adverse Events.  Subjects who a) attain a CR or b) complete 24 
months of treatment with pembrolizumab may discontinue treatment with the option of restarting 
treatment if they meet the criteria specified in Section 10.1.5.5.  After discontinuing treatment 
following assessment of CR, these subjects should return to the site for a Safety Follow-up Visit 
(described in Section 10.1.5.3.1) and then proceed to the Follow-Up Period of the study 
(described in Section 10.1.5.4). 
10.1.4.2 Blinding/Unblinding 
This is an open label trial; there is no blinding for this trial. 
10.1.5 Visit Requirements 
Visit requirements are outlined in Section 9.0 - Trial Flow Chart.   Specific procedure-related 
details are provided above in Section 10.1 - Trial Procedures. 
10.1.5.1 Screening 
10.1.5.1.1 Screening Period 
Approximately 28 days prior to study registration, potential subjects will be evaluated to 
determine that they fulfill the entry requirements as set forth in Section 5.1. Visit requirements 
are outlined in Section 9.0 – Trial Flow Chart.  
 
Written consent for the main study must be obtained prior to performing any protocol specific 
procedure. Results of a test performed prior to the subject signing consent as part of routine 
clinical management are acceptable in lieu of a screening test if performed within the specified 
time frame. Screening procedures are to be completed within 28 days prior to study registration 
except for the following:  
 
•  For women of reproductive potential, a urine pregnancy test will be performed within 28 
days prior to study registration. If urine pregnancy results cannot be confirmed as negative, a 
serum pregnancy test will be required (performed by the local study site laboratory)  

 
 
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Subjects may be rescreened after initially failing to meet the inclusion/exclusion criteria. Results 
from assessments performed during the initial screening period are acceptable in lieu of a repeat 
screening test if performed within the specified time frame and the inclusion/exclusion criteria is 
met. 
10.1.5.2 Treatment Period  
On-study visits will occur on day 1 of each cycle of Pembrolizumab and will include the 
following at every visit: 
1. 
Directed physical examination with flexible fiberoptic laryngoscopy and tracheoscopy 
2. 
Review of concomitant medications 
3. 
Vital signs to include temperature, pulse, respiratory rate, weight, and blood pressure. 
4. 
Performance status evaluation 
5. 
Determination adverse events 
6. 
Serum pregnancy test for women of reproductive potential 
7. 
Quality of Life Questionnaires will be done every fourth cycle 
8. 
Laboratory studies:  CBC with differential, serum chemistries, liver function tests starting 
on day 1 of Cycle 2 
9. 
Urinalysis and TSH and Free T4 will be done every fourth cycle  
10. 
CT scans of chest and abdomen will be done during cycle 8 
11. 
Correlative blood collection on Day 1 of each Cycle that corresponds to an operating 
room visit. 
After clinically evident progression the patient will be seen for a study visit, at which the 
following will be addressed: 
1. 
Directed physical examination with flexible fiberoptic laryngoscopy and tracheoscopy  
2. 
Review of concomitant medications 
3. 
Performance status evaluation 
4. 
Determination adverse events 
5. 
Laboratory studies:  CBC with differential, serum chemistries, liver function tests, 
unrinalysis, T3, FT4, and TSH 
Fresh tumor specimens will be obtained if feasible during therapy if the patient undergoes 
examination under general anesthesia and/or debridement for a standard-of-care clinical purposes 
per the study flow chart. 

 
 
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10.1.5.3 Post-Treatment Visits 
10.1.5.3.1 Safety Follow-Up Visit 
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the last 
dose of 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, recorded and reported.  Subjects who are eligible for retreatment with pembrolizumab 
(as described in Section 10.1.5.5) may have up to two safety follow-up visits, one after the 
Treatment Period and one after the Second Course Phase. 
10.1.5.4 Follow-up Visits  
Subjects who discontinue trial treatment for a reason other than disease progression will move 
into the Follow-Up Phase and should be assessed every 8 weeks (56 days + 7 days) by clinical 
examination and 6 months (+ 2 weeks) by radiologic imaging to monitor disease status.  After 1 
year, the clinical assessment will be reduced to 24 weeks for up to 12 months and CT imaging 
will not be required. Every effort should be made to collect information regarding disease status 
until the start of new anti-neoplastic therapy, disease progression, death, 36 months post study 
registration, or if the subject begins retreatment with pembrolizumab as detailed in Section 
10.1.5.5.  Information regarding post-study anti-neoplastic and/or anti-viral treatment will be 
collected if new treatment is initiated. 
Subjects who are eligible to receive retreatment with pembrolizumab will move from the follow-
up phase to the Second Course Phase when they experience disease progression.  Details are 
provided in Section 9.2 – Trial Flow Chart for Re-treatment.    
10.1.5.4.1 Survival Follow-up 
Once a subject experiences confirmed disease progression, the subject moves into the survival 
follow-up phase and should be contacted by telephone every 24 weeks to assess for survival 
status until death, withdrawal of consent, or 36 months post study registration, whichever occurs 
first.  
10.1.5.5 Second Course Phase (Retreatment Period) 
Subjects who stop pembrolizumab with SD or better may be eligible for up to one year of 
additional pembrolizumab therapy if they progress after stopping study treatment.  This 
retreatment is termed the Second Course Phase of this study and is only available if the study 
remains open and the subject meets the following conditions: 
EITHER: 
o Stopped initial treatment with pembrolizumab after attaining an investigator-
determined confirmed CR according to RECIST 1.1, and 

 
 
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! 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 clinical and/or 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 28 days. (Please refer to the study calendar for requirements regarding a 
pregnancy test 72 hours prior to receiving any dose of study medication upon subject 
enrollment into the study.)   
• 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. 
11.0 
ADVERSE EVENT REPORTING REQUIREMENT 
11.1 
General 
Adverse event collection and reporting is a routine part of every clinical trial. This study will use 
the descriptions and grading scales found in the NCI Common Terminology Criteria for Adverse 
Events version 4.0 (CTCAE v4.0) that is available at http://ctep.cancer.gov/reporting//ctc.html. 
Information on all adverse events, whether reported by the participant, directly observed, or 
detected by physical examination, laboratory test or other means, will be collected, recorded, 
followed and reported as described in the following sections. 

 
 
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Adverse events experienced by participants will be collected and reported from signing of 
consent, throughout the study, and within 30 days of the last dose of study medication. 
Participants who experience an ongoing adverse event or related to study procedures and/or 
study medication beyond 30 days will continue to be contacted by a member of the study team 
until the event is resolved, stabilized, or determined to be irreversible by the participating 
investigator. 
Participants should be instructed to report any serious post-study event(s) that might reasonably 
be related to participation in this study. The investigator should notify the IRB and any other 
applicable regulatory agency of any unanticipated death or adverse event occurring after a 
participant has discontinued or terminated study participation that may reasonably be related to 
the study. 
11.2 
Adverse Event Definition  
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. 

 
 
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All adverse events will be recorded from the time the consent form is signed through 30 days 
following cessation of treatment and at each examination on the Adverse Event case report 
forms/worksheets. The reporting timeframe for adverse events meeting any serious criteria is 
described in Section 11.0. 
11.3 
Serious Adverse Events 
A serious adverse event is any untoward medical occurence at any dose or 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 an important medical event  
Refer to Table 6 for additional details regarding each of the above criteria. 
Events not considered to be serious adverse events are hospitalizations for: 
• routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition, or for elective procedures 
• treatment planned before signing informed consent for a pre-existing condition that 
did not worsen  
• emergency outpatient treatment for an event not fulfilling the serious criteria outlined 
above and not resulting in inpatient admission 
• respite care 
• Abnormal lab values that do not require medical intervention to return to baseline 
value 
Progression of the cancer under study is not considered an adverse event unless it results in 
hospitalization or death. 
All subjects with serious adverse events must be followed up for outcome. 
11.4 
Evaluating Adverse Events 
An investigator who is a treating investigator or qualified designee 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.   
The causality of SAEs (their relationship to all study treatment/procedures) and the expectedness 

 
 
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will be assessed by the treating investigator(s) and communicated to the Sponsor-Investigator.  
The causal relationship can be one of the following: 
• Related:  There is a reasonable causal relationship between study drug administration and 
the AE. 
• Not Related:  There is not a reasonable causal relationship between study drug 
administration and the AE. 
 

 
 
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Table 6:  Evaluating Adverse Events 
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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11.5 
Expedited Adverse Event Reporting 
Investigators must report to the Coordinating Center and Overall PI any serious adverse event 
(SAE) that occurs after the initial dose of study treatment, during treatment, or within 90 days of 
the last dose of treatment.    
11.5.1 Reporting Requirements 
For multi-institution studies where a DF/HCC investigator is serving as the Overall Principal 
Investigator, each participating institution must abide by the reporting requirements set by the 
DF/HCC. In addition to SAEs that meet criteria set forth in Section 11.3, the Sponsor requires 
reporting of any medical event equivalent to an unexpected grade 2 or 3 with a possible, 
probable or definite attribution, unexpected grade 4 toxicities, and grade 5 (death) regardless of 
study phase or attribution. 
Each investigative site will be responsible to report SAEs that occur at that institution to their 
respective IRB. It is the responsibility of each participating investigator to report serious adverse 
events to the study sponsor and/or others as described below. 
 
11.5.2 Reporting to the Sponsor 
Investigative sites within DF/HCC will report AEs directly to the DFCI Office for Human 
Research Studies (OHRS) per the DFCI IRB reporting policy.  
Other investigative sites will report AEs to their respective IRB according to the local IRB’s 
policies and procedures in reporting adverse events. A copy of the submitted institutional AE 
form should be forwarded to the Coordinating Center within the timeframes detailed in the table 
below.   
 
 
 
Attribution 
DF/HCC Reportable AEs 
Gr. 2 & 3 AE 
Expected 
Gr. 2 & 3 AE 
Unexpected 
Gr. 4 AE Expected 
Gr. 4 AE 
Unexpected 
Gr. 5 AE Expected 
or Unexpected 
Unrelated 
Unlikely 
Not required 
Not required 
5 calendar days# 
5 calendar days 
24 hours* 
Possible 
Probable 
Definite 
 
Not required 
 
5 calendar days 
 
5 calendar days# 
 
5 calendar days 
 
24 hours* 
# If listed in protocol as expected and not requiring expedited reporting, event does not need to be reported. 
* For participants enrolled and actively participating in the study or for AEs occurring within 30 days of the last intervention, 
the AE should be reported within 1 business day of learning of the event. 
 
Participating investigators must report each serious adverse event to the Coordinating Center in 
accordance with the table above. In the event that the participating investigator does not become 
aware of the serious adverse event immediately (e.g., participant sought treatment elsewhere) or 
within the reporting timeframes listed in the table above, the participating investigator is to 

 
 
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report the event within 1 business day after learning of it and document the time of his or her 
first awareness of the adverse event. Report serious adverse events by email or facsimile to:  
 
Coordinating Center 
Fax: 617-724-2787 
 
The Coordinating Center will submit AE reports from outside institutions to the DFCI OHRS 
according to DFCI IRB policies and procedures in reporting adverse events.  
11.5.3 Reporting to Merck 
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 Coordinating Center 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.  
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 Coordinating Center and to Merck. 
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 at the time of submission to FDA. 
The Coordinating Center will submit all SAE reports, 15 day reports, FDA reports and any other 
relevant safety information to Merck & Co., Inc on behalf of the Sponsor at: 
Merck Global Safety 
Attn: Worldwide Product Safety  
Fax number:  +1-215-661-6229 
 
11.5.4 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 Coordinating Center and within 2 working days to Merck Global 
Safety. The Coordinating Center will submit all safety reports to Merck on behalf of the Sponsor.  

 
 
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Events of clinical interest for this trial include: 
1.  An overdose of Merck product, as defined in Section 11.5.5 - 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 institutional 
limit of normal and an elevated total bilirubin lab value that is greater than or equal to 2X the 
upper institutional limit of normal and, at the same time, an alkaline phosphatase lab value 
that is less than 2X the upper institutional limit of normal, as determined by way of protocol-
specified laboratory testing or unscheduled laboratory testing.* 
*NOTE:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require an 
additional evaluation for an underlying etiology.  The trial site guidance for assessment and 
follow up of these criteria can be found in the Investigator Trial File Binder (or equivalent). 
3. 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 Coordinating Center and within 2 working days to Merck Global Safety 
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. 
 
11.5.5 
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 Coordinating Center and within 2 working days hours to Merck Global Safety.  The 
Coordinating Center will submit all safety reports to Merck on behalf of the Sponsor. 
11.5.6  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 
traeting 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 Coordinating Center and within 2 working 
days to Merck Global Safety.  The Coordinating Center will submit all safety reports to Merck 
on behalf of the Sponsor. 
11.5.7    Sponsor Responsibility for Reporting Adverse Events 
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations.  
11.5.8   Institutional Review Board (IRB) Notification by Investigator 
The participating investigator will report all adverse events and serious adverse events to the 
Coordinating Center and to the IRB according to the local IRB’s policies and procedures in 
reporting adverse events.  
 
11.5.9   Food and Drug Administration (FDA) Notification by Sponsor-Investigator 
The Overall PI, as study sponsor, will be responsible for all communications with the FDA. The 
Coordinating Center, on behalf of the Sponsor, will report to the FDA any adverse event that is 
serious, unexpected and reasonably related (i.e., possible, probable, definite) to the study 
treatment. 

 
 
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Unexpected fatal or life-threatening experiences associated with the use of the study treatment 
will be reported to the FDA as soon as possible but in no event later than 7 calendar days after 
initial receipt of the information. 
 
All other serious unexpected experiences associated with the use of the study treatment will be 
reported to the FDA as soon as possible but in no event later than 15 calendar days after initial 
receipt of the information. 
 
Events will be reported to the FDA by telephone (1-800-FDA-1088) or by fax (1-800-FDA-
0178) using Form FDA 3500A (Mandatory Reporting Form for investigational agents) or 
FDA Form 3500 (Voluntary Reporting Form for commercial agents). Forms are available at 
http://www.fda.gov/medwatch/getforms.htm. 
 
11.5.10  NIH Office of Biotechnology Activities (OBA) Notification by Investigator 
Not applicable 
11.5.11  Institutional Biosafety Committee (IBC) Notification by Investigator 
Not applicable 
11.5.12  Hospital Risk Management Notification by Investigator 
The participating investigator will report to the Coordinating Center and to local Risk 
Management any subject safety reports or sentinel events that require reporting according to 
institutional policy. 
 
11.6 
Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions to the Overall PI on the 
toxicity case report forms.  AEs reported through expedited processes (e.g., reported to the 
IRB, FDA, etc.) must also be reported in routine study data submissions. 
12.0 
DATA AND SAFETY MONITORING 
12.1 
Data Reporting  
12.1.1 Method  
The DF/HCC Office of Data Quality (ODQ) will collect, manage, and audit data for this 
study.  
 

 
 
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12.1.2 Data Submission  
The schedule for completion and submission of case report forms (paper or electronic) to the 
ODQ is as follows: 
 
Form 
Submission Timeline 
Eligibility Checklist 
Complete prior to registration   
On Study Form 
Within 14 days of registration 
Baseline Assessment Form 
Within 14 days of registration 
Treatment Form 
Within 10 days of the last day of the cycle 
Adverse Event Report Form 
Within 10 days of the last day of the cycle 
Response Assessment Form 
Within 10 days of the completion of the 
cycle required for response evaluation 
Off Treatment/Off Study 
Form 
Within 14 days of completing treatment or 
being taken off study for any reason 
Follow up/Survival Form 
Within 14 days of the protocol defined 
follow up visit date or call 
 
12.2 
Data Safety Monitoring 
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity 
and accrual data from this trial. The committee is composed of clinical specialists with 
experience in oncology and who have no direct relationship with the study. Information that 
raises any questions about participant safety will be addressed with the Principal Investigator and 
study team. 
 
The DSMC will meet approximately quarterly and/or more often if required to review toxicity 
and accrual data. Information to be provided to the committee may include:  up-to-date 
participant accrual; current dose level information; all grade 2 or higher unexpected adverse 
events that have been reported; summary of all deaths occurring within 30 days for Phase I or II 
protocols; summary of all deaths while being treated and during active follow-up; any response 
information; audit results, and a summary provided by the study team. Other information (e.g. 
scans, laboratory values) will be provided upon request.  
 
12.3 
Multi-center Guidelines 
This protocol will adhere to the policies and requirements of the DF/HCC Multi-Center Data and 
Safety Monitoring Plan.  The specific responsibilities of the Overall PI, Coordinating Center, and 
Participating Institutions and the procedures for auditing are presented in Appendix I. 
• The Overall PI/Coordinating Center is responsible for distributing all IND Action Letters 
or Safety Reports to all participating institutions for submission to their individual IRBs 
for action as required. 
• Mechanisms will be in place to ensure quality assurance, protocol compliance, and 
adverse event reporting at each site. 

 
 
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• Except in very unusual circumstances, each participating institution will order the study 
agent(s) directly from supplier.  A participating site may order the agent(s) only after the 
initial IRB approval for the site has been forwarded to the Coordinating Center. 
 
12.4 
Monitoring 
Involvement in this study as a participating investigator implies acceptance of potential audits 
or inspections, including source data verification, by representatives designated by the 
Principal Investigator (or Protocol Chair) or DF/HCC. The purpose of these audits or 
inspections is to examine study-related activities and documents to determine whether these 
activities were conducted and data were recorded, analyzed, and accurately reported in 
accordance with the protocol, institutional policy, Good Clinical Practice (GCP), and any 
applicable regulatory requirements.  
 
All data will be monitored for timeliness of submission, completeness, and adherence to 
protocol requirements. Monitoring will begin at the time of participant registration and will 
continue during protocol performance and completion.  
 
13.0 
REGULATORY CONSIDERATIONS 
 
13.1 
Protocol Review and Amendments 
This protocol, the proposed informed consent and all forms of participant information 
related to the study (e.g., advertisements used to recruit participants) and any other 
necessary documents must be submitted, reviewed and approved by a properly constituted 
IRB governing each study location. 
 
Any changes made to the protocol must be submitted as amendments and must be approved 
by the IRB prior to implementation. Any changes in study conduct must be reported to the 
IRB. The Principal Investigator (or Protocol Chair) will disseminate protocol amendment 
information to all participating investigators. 
 
All decisions of the IRB concerning the conduct of the study must be made in writing. 
 
13.2 
Informed Consent 
All participants must be provided a consent form describing this study and providing sufficient 
information for participants to make an informed decision about their participation in this study. 
The formal consent of a participant, using the IRB approved consent form, must be obtained 
before the participant is involved in any study-related procedure. The consent form must be 
signed and dated by the participant or the participant’s legally authorized representative, and by 
the person obtaining the consent. A remote consent can be obtained if the subject lives >50 miles 
from the treatment site. The informed consent document can be sent by facsimile and/or through 
a secure email account. The consent interview can be performed by telephone and a signed 
consent form can be returned to the clinical investigator by facsimile and/or through a secure 
email account to protect the confidentiality of the subject. The patient must be re-consented in 

 
 
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person prior to starting treatment. The participant must be given a copy of the signed and dated 
consent document before participation in the trial. The original signed copy of the consent 
document must be retained in the medical record or research file.  
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. 
 
13.3 
Ethics and Federal Regulations 
This study is to be conducted according to the following considerations, which represent 
good and sound research practice: 
 
• US Code of Federal Regulations (CFR) governing clinical study conduct and ethical 
principles that have their origin in the Declaration of Helsinki 
o Title 21 Part 50 – Protection of Human Subjects 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr50_02.html  
o Title 21 Part 54 – Financial Disclosure by Clinical Investigators 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr54_02.html  
o Title 21 Part 56 – Institutional Review Boards 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr56_02.html  
o Title 21 Part 312 – Investigational New Drug Application 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr312_02.html  
• State laws 
• Institutional research policies and procedures:  
www.dfhcc.harvard.edu/clinical-research-support/clinical-research-operations-
cro/policies-and-procedures 
 
It is understood that deviations from the protocol should be avoided, except when necessary 
to eliminate an immediate hazard to a research participant. In such case, the deviation must 
be reported to the IRB according to the local reporting policy. 
 
13.4 
Study Documentation 
The investigator must prepare and maintain adequate and accurate case histories designed to 
record all observations and other data pertinent to the study for each research participant. This 
information enables the study to be fully documented and the study data to be subsequently 
verified. 
 

 
 
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Original source documents supporting entries in the case report forms include but are not 
limited to hospital records, clinical charts, laboratory and pharmacy records, recorded data 
from automated instruments, microfiches, photographic negatives, microfilm or magnetic 
media, and/or x rays. 
 
13.5 
Records Retention 
All study-related documents must be retained for the maximum period required by 
applicable federal regulations and guidelines or institutional policies.  
13.6 
Cooperative Research and Development Agreement (CRADA)/Clinical Trials 
Agreement (CTA) 
Not applicable 
 
14.0 
STATISTICAL ANALYSIS PLAN 
14.1 
Statistical Analysis Plan Summary 
The primary endpoint of this trial is to evaluate the overall response rate (ORR:CR+PR) via 
clinical assessment and/or RECIST criteria for adult patients with measurable disease on CT 
scan. A Simon two-stage design will be used to minimize the number of adult patients exposed 
to this regimen and the specific sample size and operating characteristics were chosen to be able 
to rule out a 15% response rate. The rate chosen for the null hypothesis is based on several 
considerations:  
1) There is no effective therapy for the patient population in this protocol. 
2) This protocol represents the first time that this patient population will receive a systemic 
treatment option. 
3) The response rate observed using the regimen under study in this protocol in patients with 
HPV positive head and neck cancer [10] was 20% with corresponding exact 95% CI 
(5.7% to 43.7%) and although it is anticipated that the patients in this protocol with 
benign tumors could experience a higher RR since their tumors are chemotherapy and/or 
RT naïve, this is still unknown.  
In the first stage, accrual will continue until 11 evaluable adult patients are entered. If there are 
≤1 adult patients whose disease shows best overall response of CR/PR, accrual to this trial will 
be closed with the expectation that there is little evidence that the RR would reach 38%. The 
probability that the trial will close early is 49% if the true RR is 15%. If there are ≥2 adult 
patients whose disease shows best overall response of CR/PR, accrual will continue until a total 
of 21 adult evaluable patients who started protocol treatment are entered. If there are ≥6 adult 
patients among 21 evaluable whose disease shows best overall response of CR/PR, further 
testing of this regimen will be considered. If the true response rate is 38%, the probability of 
concluding the regimen is effective is 86%, if the true response rate is 15%, the probability of 
concluding the regimen is effective is 8%. Allowing 1 adult patient to not begin protocol 

 
 
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treatment or be classified as ineligible, a total of 22 adult patients will be entered. In addition, 
approximately 2-3 pediatric patients will be entered as an exploratory cohort. 
The primary efficacy population includes all eligible adult patients who begin protocol treatment. 
ORR will be summarized as a proportion with corresponding exact 95% confidence interval (CI) 
(if the trial closes to accrual after the first stage), or a corresponding 95% two-stage CI if the trial 
closes to accrual after the second stage. Best overall response for the pediatric patients will also 
be summarized. 
Another endpoint is to assess adverse events. Adverse events will be classified and graded 
according to the CTCAE v.4.0. Frequencies of adverse events will be summarized overall and 
within adult and pediatric subgroups. Another endpoint is to assess quality of life (QOL).  QOL 
will be assessed via self-report questionnaires at the timepoints outlined in the Study Flow Chart. 
Descriptive statistics from the questionnaires will be summarized across timepoints of 
assessment overall and within adult and pediatric subgroups. Rates of drop-out/non-response to 
QOL assessments and corresponding reason will also be summarized across timepoints of 
assessment. Secondary objectives include assessment of biomarkers in blood and tissue. 
Descriptive statistics from the assays will be summarized across timepoints of sample collection 
overall and within adult and pediatric subgroups. Rates of refusal and/or reason sample not 
obtained will be summarized across timepoints of assessment. 
Various correlative studies will also be performed. Tissue and blood will be collected at baseline 
and at post-baseline timepoints as outlined in Section 9 and 10.1.2.7. Markers from tissue and 
blood will be summarized descriptively and graphically overall and within adult and pediatric 
subgroups. Within subject changes in markers will also be analyzed. Twenty-two adult patients 
with baseline and a post-baseline values provides 80% power to detect .65 SD mean difference 
(Wilcoxon sign rank test two-sided 0.05 alpha level). Baseline as well as changes from baseline 
to a post-baseline timepoint will also be compared between patients whose disease responded 
(CR,PR) and those whose disease did not respond using the Wilcoxon rank-sum test . Twenty 
two adult patients provides 82% power (using a two-sided 0.05 alphas level test) to detect a 1.4 
SD difference in means assuming that 38% of the patients have disease which responds.  
With an estimated monthly accrual of 1, the first stage is estimated to complete accrual in 
approximately 12 months. As is customary with this type of design, accrual will be suspended 
after the first stage (n=11 evaluable adult patients) in order to assess outcome, however, this 
suspension is also dependent on the actual observed accrual rate and the number of patients with 
best response confirmed for their disease while the first stage of the trial is accruing. 
15.0 
 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES 
15.1 
Investigational Product 
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and regulations. 

 
 
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Clinical Supplies will be provided by Merck as summarized in Table 7. 
Table 7:  Product Descriptions 
Product Name & Potency 
Dosage Form 
Pembrolizumab 50 mg 
Lyophilized Powder for Injection 
Pembrolizumab 100 mg/ 4mL 
Solution for Injection 
 
15.2 
Ordering Investigational Product 
Participating institutions should order their own investigational product using the Merck Drug 
Order Request found in the Appendix H.   
15.3 
Packaging and Labeling Information 
Clinical supplies will be affixed with a clinical label in accordance with regulatory requirements. 
15.4 
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. 
15.5 
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. 
15.6 
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. 

 
 
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16.0 ADMINISTRATIVE AND REGULATORY DETAILS 
16.1 
Compliance with Trial Registration and Results Posting Requirements 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the Sponsor of the trial is solely 
responsible for determining whether the trial and its results are subject to the requirements for 
submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov.  Information posted 
will allow subjects to identify potentially appropriate trials for their disease conditions and 
pursue participation by calling a central contact number for further information on appropriate 
trial locations and trial site contact information.     
16.1 
Quality Management System 
A quality management system with written development procedures and functional area standard 
operating procedures (SOPs) will be implemented and maintained to ensure that trials are 
conducted and data are generated, documented, and reported in compliance with the protocol and 
all applicable federal, state, and local laws, rules and regulations relating to the conduct of the 
clinical trial.

 
 
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17.0 REFERENCES 
1. 
Lyford-Pike S, Peng S, Young GD, Taube JM, Westra WH, Akpeng B, Bruno TC, 
Richmon JD, Wang H, Bishop JA, Chen L, Drake CG, Topalian SL, Pardoll DM, 
Pai SI. Evidence for a role of the PD-1:PD-L1 pathway in immune resistance of 
HPV-associated head and neck squamous cell carcinoma. Cancer Res 2013 Mar 
15;73(6):1733-41. PMID: 23288508. 
2. 
Hatam, LJ, Devoti JA, Rosenthal DW, Lam F, Abramson AL, Steinberg BM, 
Bonagura VR. Immune suppression in premalignant respiratory papillomas: 
enriched functional CD4+Foxp3+ regulatory T cells and PD-1/PD-L1/L2 
expression. Clin Cancer Res, 2012. 18(7): p. 1925-35. PMID: 22322668. 
3. 
Derkay, CS. Task force on recurrent respiratory papillomas. A preliminary report. 
Arch Otolaryngol Head Neck Surg, 1995. 121(12): p. 1386-91. PMID: 7488368. 
4. 
Gallagher, TQ and Derkay,CS. Recurrent respiratory papillomatosis: update 2008. 
Curr Opin Otolaryngol Head Neck Surg, 2008. 16(6): p. 536-42. PMID: 19005325. 
5. 
Holler, T, Allegro J, Chadha NK, Hawkes M, Harrison RV, Forte V, Campisi P. 
Voice outcomes following repeated surgical Presection of laryngeal papillomata in 
children. Otolaryngol Head Neck Surg, 2009. 141(4): p. 522-6. PMID: 19786223. 
6. 
Sakopoulos A, Kesler KA, Weisberger EC, Turrentine MW, Conces DJ Jr. Surgical 
management of pulmonary carcinoma secondary to recurrent respiratory 
papillomatosis. Ann Thorac Surg 1995;60(6):1806-1807. PMID: 8787491. 
7. 
Chadha, NK, Allegro J, Barton M, Hawkes M, Harlock H, Campisi P, The quality 
of life and health utility burden of recurrent respiratory papillomatosis in children. 
Otolaryngol Head Neck Surg, 2010. 143(5): p. 685-90. PMID: 20974340. 
8. 
Momper JD, Mulugeta Y, Green DJ, Karesh A, Krudys KM, Sachs HC, Yao LP, 
Burckart GJ. Adolescent dosing and labeling since the Food and Drug 
Administration Amendments Act of 2007. JAMA Pediatrics 2013; 167(10):926-
932, PMID:23921678. 
9. 
Abramson AL, Shikowitz MJ, Mullooly VM, Steinberg, BM, Amella CA and 
Rothstein, HR.  Clinical effects of photodynamic therapy on recurrent laryngeal 
papillomas.  Arch Otolaryngol Head Neck Surg 118:25-29, 1992. PMID: 1309420. 
10. 
Shikowitz MJ, Abramson AL, Freeman K, Steinberg BM, Nouri M. Efficacy of 
DHE photodynamic therapy for respiratory papillomatosis: immediate and long-
term results.  Laryngoscope 108:962-7 1998. PMID: 9665239. 
11. 
Seiwert TY, Burtness B, Weiss J, et al. A phase Ib study of MK-3475 in patients 
with human papillomavirus (HPV)-associated and non-HPV–associated head and 
neck (H/N) cancer. J Clin Oncol 2014;32:(suppl; abstr 6011). 
 
 

 
 
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18.0 APPENDICES 
A. 
Surgical Scoring 
 

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

 
 
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C. 
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) 
D. 
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for 
Evaluating Response in Solid Tumors 
RECIST version 1.1* will be used in this study for assessment of tumor response. While either 
CT or MRI may be utilized, as per RECIST 1.1, CT is the preferred imaging technique in this 
study. 
* As published in the European Journal of Cancer: 
E.A. Eisenhauer, P. Therasse, J. Bogaerts, L.H. Schwartz, D. Sargent, R. Ford, J. Dancey, S. 
Arbuck, S. Gwyther, M. Mooney, L. Rubinstein, L. Shankar, L. Dodd, R. Kaplan, D. Lacombe, 
J. Verweij. New response evaluation criteria in solid tumors: Revised RECIST guideline (version 
1.1). Eur J Cancer. 2009 Jan;45(2):228-47. 
In addition, volumetric analysis will be explored by central review for response assessment. 
 
 

 
 
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E. 
Events of Clinical Interest Guidance Document 
F. 
Quality of Life Questionnaires 
G. 
Case Report Forms 
H. 
Merck Drug Request Form 
I. 
MK-3475 Pharmacy Manual 
 
 

 
 
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DFCI IRB Protocol #: 15-469 
 
A Study of Anti-PD-1 therapy for HPV-associated Recurrent Respiratory 
Papilloma Patients with Laryngeal, Tracheal, and/or Pulmonary Involvement 
 
 
APPENDIX J. 
 
Dana-Farber/Harvard Cancer Center 
Multi-Center Data and Safety Monitoring Plan 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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TABLE OF CONTENTS 
1.0 
INTRODUCTION ...................................................................................................... 85 
1.1 
Purpose ............................................................................................................ 85 
1.2 
Multi-Center Data and Safety Monitoring Plan Definitions ........................... 85 
 
2.0 
GENERAL ROLES AND RESPONSIBILITIES ...................................................... 86 
2.1 
DF/HCC Sponsor ............................................................................................ 86 
2.2 
Coordinating Center ........................................................................................ 87 
2.3 
Participating Institution ................................................................................... 87 
 
3.0 
DF/HCC REQUIREMENTS FOR MULTI-CENTER PROTOCOLS ...................... 88 
3.1 
Protocol Distribution ....................................................................................... 88 
3.2 
Protocol Revisions and Closures .................................................................... 88 
3.3 
Informed Consent Requirements .................................................................... 89 
3.4 
IRB Documentation ........................................................................................ 89 
3.5 
IRB Re-Approval ............................................................................................ 89 
3.6 
Participant Confidentiality and Authorization Statement ............................... 90 
3.7 
DF/HCC Multi-Center Protocol Registration Policy ...................................... 90 
3.8 
DF/HCC Protocol Case Number ..................................................................... 91 
3.9 
Safety Assessments and Toxicity Monitoring ................................................ 92 
3.10 
Data Management ........................................................................................... 93 
 
4.0 
REQUISITIONING INVESTIGATIONAL DRUG ................................................... 93 
 
5.0 
MONITORING: QUALITY CONTROL ................................................................... 94 
5.1 
Ongoing Monitoring of Protocol Compliance ................................................ 94 
5.2 
Monitoring Reports ......................................................................................... 95 
5.3 
Accrual Monitoring ......................................................................................... 95 
 
6.0 
AUDITING: QUALITY ASSURANCE .................................................................... 96 
6.1 
Audit Plan: NCI Sponsored Trials .................................................................. 96 
6.2 
Audit Plan: DF/HCC Sponsored Trials .......................................................... 96 
6.3 
Audit Notification ........................................................................................... 96 
6.4 
Audit Reports .................................................................................................. 96 
Participating Institution Performance ................................................................................. 96 
 
 
 

 
 
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1.0 INTRODUCTION 
The Dana-Farber/Harvard Cancer Center Multi-Center Data and Safety Monitoring Plan 
(DF/HCC DSMP) outlines the procedures for conducting a DF/HCC Multi-Center research 
protocol. The DF/HCC DSMP should serve as a reference for any sites external to DF/HCC 
that will be participating in the research protocol. 
 
1.1 Purpose 
To establish standards that will ensure that a Dana-Farber/Harvard Cancer Center Multi-
Center protocol will comply with Federal Regulations, Health Insurance Portability and 
Accountability Act (HIPAA) requirements and applicable DF/HCC Standard Operating 
Procedures.        
 
1.2 Multi-Center Data and Safety Monitoring Plan Definitions  
DF/HCC Multi-Center Protocol:  A research protocol in which one  or more outside 
institutions are collaborating with Dana-Farber/Harvard Cancer Center where  a DF/HCC 
investigator is the sponsor. DF/HCC includes Dana-Farber/Partners Cancer Care (DF/PCC) 
Network Clinical Trial Affiliates.  
 
Lead Institution:  One of the Dana-Farber/Harvard Cancer Center consortium members 
(Dana-Farber Cancer Institute (DFCI), Massachusetts General Hospital (MGH), Beth Israel 
Deaconess Medical Center (BIDMC), Boston Children’s Hospital (BCH), Brigham and 
Women’s Hospital (BWH)) responsible for the coordination, development, submission, and 
approval of a protocol as well as its subsequent amendments per the DFCI IRB and 
applicable regulatory guidelines (CTEP, Food and Drug Administration (FDA), Office of 
Biotechnology Activities (OBA) etc.).  The Lead Institution is typically the home of the 
DF/HCC Sponsor. The Lead Institution also typically serves as the Coordinating Center for 
the DF/HCC Multi-Center Protocol.   
 
DF/HCC Sponsor:  The person sponsoring the submitted Multi-Center protocol.  Within 
DF/HCC, this person is the Overall Principal Investigator who takes responsibility for 
initiation, management and conduct of the protocol at all research locations. In applicable 
protocols, the DF/HCC Sponsor will serve as the single liaison with any regulatory 
agencies. The DF/HCC Sponsor has ultimate authority over the protocol and is responsible 
for the conduct of the study at DF/HCC and all Participating Institutions. In most cases the 
DF/HCC Sponsor is the same person as the DF/HCC Overall Principal Investigator; 
however, both roles can be filled by two different people.  
 
Participating Institution:  An institution that is outside the DF/HCC and DF/PCC 
consortium that is collaborating with DF/HCC on a protocol where the sponsor is a 
DF/HCC Investigator.  The Participating Institution acknowledges the DF/HCC Sponsor 
as having the ultimate authority and responsibility for the overall conduct of the study.    
 

 
 
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Coordinating Center: The entity that provides administrative support to the DF/HCC 
Sponsor in order that he/she may fulfill the responsibilities outlined in the protocol 
document and DSMP, and as specified in applicable regulatory guidelines. In general, the 
Lead Institution is the Coordinating Center for the DF/HCC Multi-Center Protocol.   
 
DF/HCC Office of Data Quality: A group within DF/HCC responsible for ensuring 
high-quality standards are used for data collection and the ongoing management of clinical 
trials, auditing, and data and safety monitoring.  
 
2.0 
GENERAL ROLES AND RESPONSIBILITIES 
 
For DF/HCC Multi-Center Protocols, the DF/HCC Sponsor, the Coordinating Center, and 
the Participating Institutions are expected to adhere to the following general 
responsibilities:  
 
2.1   DF/HCC Sponsor 
 
The DF/HCC Sponsor, Sara Pai MD, PhD will accept responsibility for all aspects of 
conducting a DF/HCC Multi-Center protocol which includes but is not limited to:  
• Oversee the coordination, development, submission, and approval of the protocol 
as well as subsequent amendments.  
• Ensure that the investigators, study team members, and Participating Institutions 
are qualified and appropriately resourced to conduct the protocol.   
• Include the Multi-Center Data and Safety Monitoring Plan as an appendix to the 
protocol. 
• Ensure all Participating Institutions are using the correct version of the protocol. 
• Ensure that each participating investigator and study team member receives 
adequate protocol training and/or a Site Initiation Visit prior to enrolling 
participants and throughout trial’s conduct as needed. 
• Ensure the protocol will be provided to each participating site in a language 
understandable to all applicable site personnel when English is not the primary 
language.  
• Monitor progress and overall conduct of the study at all Participating Institutions.  
• Ensure all DFCI Institutional Review Board (IRB), DF/HCC and other applicable 
(FDA) reporting requirements are met.  
• Review data and maintain timely submission of data for study analysis.  
• Act as the single liaison with FDA (investigator-held IND trials). 
• Ensure compliance with all requirements as set forth in the Code of Federal 
Regulations, applicable DF/HCC requirements, HIPAA requirements, and the 
approved protocol. 
• Commit to the provision that the protocol will not be rewritten or modified by 
anyone other than the DF/HCC Sponsor. 
• Identify and qualify Participating Institutions and obtain accrual commitments 
prior to extending the protocol to that site. 

 
 
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• Monitor accrual and address Participating Institutions that are not meeting their 
accrual requirements.  
 
2.2   Coordinating Center  
 
The general responsibilities of the Coordinating Center may include but are not limited to: 
• Assist in protocol development.  
• Maintain FDA correspondence, as applicable. 
• Review registration materials for eligibility and register participants from 
Participating Institutions. 
• Distribute protocol and informed consent document updates to Participating 
Institutions as needed. 
• Review and approve Participating Site informed consent forms 
• Conduct and document initial and ongoing protocol training 
• Oversee the data collection process from Participating Institutions. 
• Maintain documentation and cumulative reports of Serious Adverse Event (SAE) 
reports and Deviations/Violations across all sites and provide to the DF/HCC 
Sponsor for timely review.   
• Distribute serious adverse events reported to the DF/HCC Sponsor that fall under 
the DFCI IRB Adverse Event Reporting Policy to all Participating Institutions. 
• Provide 
Participating 
Institutions 
with 
information 
regarding 
DF/HCC 
requirements that they will be expected to comply with. 
 
• Carry out approved protocol monitoring plan either by on-site or remote 
monitoring.  
• Maintain essential regulatory documents of all Participating Institutions which 
includes but is not limited to the following: local IRB approvals/notifications from 
all Participating Institutions, confirmation of Federalwide Assurances (FWAs) for 
all sites,  all SAE submissions, Screening Logs for all sites, IRB approved consents 
for all sites, and protocol training documentation 
• Conduct regular communications with all Participating Institutions (conference 
calls, emails, etc) and maintain documentation all relevant communications. 
 
2.3   Participating Institution 
 
Each Participating Institution is expected to comply with all applicable federal regulations 
and DF/HCC requirements, the protocol and HIPAA requirements.  
 
The general responsibilities for each Participating Institution may include but are not 
limited to: 
• Document the delegation of research specific activities to study personnel. 
• Commit to the accrual of participants to the protocol. 
• Submit protocol and/or amendments to their local IRB. 
• Maintain regulatory files as per sponsor requirements. 
• Provide the Coordinating Center with regulatory documents or source documents 
as requested. 

 
 
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• Participate in protocol training prior to enrolling participants and throughout the 
trial as required (i.e. teleconferences). 
• Update Coordinating Center with research staff changes on a timely basis. 
• Register participants through the Coordinating Center prior to beginning research 
related activities.  
• Submit Adverse Event (SAE) reports to local IRB per local requirements and to 
the Coordinating Center, in accordance with DF/HCC or other sponsor 
requirements.  
• Submit protocol deviations and violations to local IRB per local requirements and 
to the DF/HCC Sponsor in accordance with DF/HCC requirements. 
• Order, store and dispense investigational agents and/or other protocol mandated 
drugs per federal guidelines and protocol requirements. 
• Have office space, office equipment, and internet access that meet HIPAA 
standards. 
• Participate in any quality assurance activities and meet with monitors or auditors at 
the conclusion of a visit to review findings. 
• Promptly provide follow-up and/or corrective action plans for any monitoring 
queries or audit findings. 
 
3.0 DF/HCC REQUIREMENTS FOR MULTI-CENTER PROTOCOLS 
 
The following section will clarify DF/HCC Requirements and further detail the expectations 
for participating in a DF/HCC Multi-Center protocol.  
 
3.1   Protocol Distribution 
 
The Coordinating Center will distribute the final DFCI IRB approved protocol and any 
subsequent amended protocols to all Participating Institutions.    
 
3.2   Protocol Revisions and Closures 
 
The Participating Institutions will receive notification of protocol revisions and closures 
from the Coordinating Center.  It is the individual Participating Institution’s responsibility 
to notify its IRB of these revisions. 
 
• Non life-threatening revisions: Participating Institutions will receive written 
notification of protocol revisions regarding non life-threatening events from the 
Coordinating Center. Non-life-threatening protocol revisions must be IRB 
approved and implemented within 90 days from receipt of the notification. 
 
• Revisions for life-threatening causes: Participating Institutions will receive 
immediate notification from the Coordinating Center concerning protocol revisions 
required to protect lives with follow-up by fax, mail, e-mail, etc.  Life-threatening 
protocol revisions will be implemented immediately followed by IRB request for 
approval. 

 
 
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• Protocol closures and temporary holds: Participating Institutions will receive 
notification of protocol closures and temporary holds from the Coordinating 
Center. Closures and holds will be effective immediately.  In addition, the 
Coordinating Center, will update the Participating Institutions on an ongoing basis 
about protocol accrual data so that they will be aware of imminent protocol 
closures. 
 
3.3   Informed Consent Requirements 
 
The DF/HCC approved informed consent document will serve as a template for the 
informed consent for Participating Institutions. The Participating Institution consent form 
must follow the consent template as closely as possible and should adhere to specifications 
outlined in the DF/HCC Guidance Document on Model Consent Language for PI-Initiated 
Investigator Sponsored Multi-Center Trials.  This document will be provided separately to 
each Participating Institution. 
 
Participating Institutions are to send their version of the informed consent document and 
HIPAA authorization, if a separate document, to the Coordinating Center for review and 
approval prior to submission to their local IRB. The approved consent form must also be 
submitted to the Coordinating Center after approval by the local IRB for all consent 
versions. 
 
The Principal Investigator (PI) at each Participating Institution will identify the physician 
members of the study team who will be obtaining consent and signing the consent form 
for therapeutic protocols. Participating institutions must follow the DF/HCC requirement 
that for all interventional drug, biologic, or device research only attending physicians may 
obtain initial informed consent and any re-consent that required a full revised consent 
form).   
 
3.4   IRB Documentation 
 
The following must be on file with the Coordinating Center: 
• Initial approval letter of the Participating Institution's IRB.  
• Copy of the Informed Consent Form(s) approved by the Participating Institution’s 
IRB.  
• Participating Institution’s IRB approval for all amendments. 
• Annual approval letters by the Participating Institution's IRB. 
 
3.5   IRB Re-Approval 
 
Verification of IRB re-approval from the Participating Institutions is required in order to 
continue research activities.  There is no grace period for continuing approvals. 
 

 
 
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The Coordinating Center will not register participants if a re-approval letter is not received 
from the Participating Institution on or before the anniversary of the previous approval 
date.   
 
 
3.6   Participant Confidentiality and Authorization Statement 
 
In 1996, congress passed the first federal law covering the privacy of health information 
known as the Health Insurance Portability and Accountability Act (HIPPA). Any 
information, related to the physical or mental health of an individual is called Protected 
Health Information (PHI). HIPAA outlines how and under what circumstances PHI can be 
used or disclosed.  
 
In order for covered entities to use or disclose protected health information during the 
course of a study, the study participant must sign an authorization statement.  This 
authorization statement may or may not be separate from the informed consent document.  
The Coordinating Center, with the approval from the DFCI IRB, will provide a consent 
template, with information regarding authorization for the disclosure of protected health 
information.  
 
The DF/HCC Sponsor will use all efforts to limit its use of protected health information in 
its trials. However, because of the nature of these trials, certain protected health 
information must be collected. DF/HCC has chosen to use authorizations, signed by the 
participant in the trial, rather than limited data sets with data use agreements. 
 
3.6.1    DF/HCC Multi-Center Protocol Confidentiality 
 
All documents, investigative reports, or information relating to the participant are 
strictly confidential. Whenever reasonably feasible, any participant specific reports 
(i.e. Pathology Reports, MRI Reports, Operative Reports, etc.) submitted to the 
Coordinating Center should be de-identified. It is recommended that the assigned 
DF/HCC QACT case number (as described below) be used for all participant 
specific documents. Participant initials may be included or retained for cross 
verification of identification.  
 
3.7    DF/HCC Multi-Center Protocol Registration Policy 
All participants must be registered with DF/HCC prior to conducting any research-related 
procedures 
 
3.7.1 Participant Registration  
 
Please refer to protocol Section 6.0: Registration Procedures 
 
3.7.2 Initiation of Therapy 
 

 
 
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Participants must be registered with the DF/HCC ODQ before receiving treatment.  
Treatment may not be initiated until the Participating Institution receives 
confirmation of the participant’s registration from the Coordinating Center. The 
DF/HCC Sponsor and DFCI IRB must be notified of any violations to this policy. 
 
3.7.3   Eligibility Exceptions 
 
The DF/HCC ODQ will make no exceptions to the eligibility requirements for a 
protocol without DFCI IRB approval. The DF/HCC ODQ requires each institution to 
fully comply with this requirement. 
 
3.8   DF/HCC Protocol Case Number 
 
At the time of registration, the following identifiers are required for all subjects: initials, 
date of birth, gender, race and ethnicity. Once eligibility has been established and the 
participant successfully registered, the participant is assigned a unique protocol case 
number.  Participating Institutions should submit all de-identified subsequent 
communication and documents to the Coordinating Center, using this case number to 
identify the subject.   
 
3.8.1 Protocol Deviations, Exceptions and Violations 
 
Federal Regulations require an IRB to review proposed changes in a research 
activity to ensure that researchers do not initiate changes in approved research 
without IRB review and approval, except when necessary to eliminate apparent 
immediate hazards to the participant. DF/HCC requires all departures from the 
defined procedures set forth in the IRB approved protocol to be reported to the 
DF/HCC Sponsor, who in turn is responsible for reporting to the DFCI IRB. 
 
 
For reporting purposes, DF/HCC uses the terms “violation”, “deviation” and 
“exception” to describe departures from a protocol. All Participating Institutions 
must adhere to these requirements for reporting to the DF/HCC Sponsor and will 
follow their institutional policy for reporting to their local IRB. 
 
3.8.2 Definitions 
 
Protocol Deviation: Any departure from the defined procedures set forth in the IRB-
approved protocol which is prospectively approved prior to its implementation. 
 
Protocol Exception:  Any protocol deviation that relates to the eligibility criteria, e.g. 
enrollment of a participant who does not meet all inclusion/exclusion criteria. 
 
 
 
Protocol Violation: Any protocol deviation that was not prospectively approved by 
the IRB prior to its initiation or implementation.  
 
 

 
 
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3.8.3 Reporting Procedures 
 
DF/HCC Sponsor: is responsible for ensuring that clear documentation is available 
in the medical record and/or regulatory documents to describe all protocol 
exceptions, deviations and violations. The DF/HCC Sponsor will also be responsible 
for ensuring that all protocol violations/deviations are promptly reported per DFCI 
IRB guidelines.  
 
Participating Institutions: Protocol deviations require prospective approval from the 
DFCI IRB. The Participating Institution must submit the deviation request to the 
Coordinating Center who will then submit the deviation request to the DFCI IRB. 
Upon DFCI IRB approval the deviation is submitted to the Participating Institution 
IRB, per institutional policy. A copy of the Participating Institution’s IRB report and 
determination will be forwarded to the Coordinating Center within 10 business days 
after the original submission.  
 
All protocol violations must be sent to the Coordinating Center in a timely manner.  
 
Coordinating Center:  Upon receipt of the violation/deviation report from the 
Participating Institution, the Coordinating Center will submit the report to the 
DF/HCC Sponsor for review. Subsequently, the Participating Institution’s IRB 
violation/deviation report will be submitted to the DFCI IRB for review per DFCI 
IRB reporting guidelines. DF/HCC will forward all violation reports to CTEP via an 
internal DF/HCC process, as applicable. 
 
3.9 Safety Assessments and Toxicity Monitoring 
 
The study teams at all participating institutions are responsible for protecting the safety, 
rights and well-being of study participants. Recording and reporting of adverse events that 
occur during the course of a study help ensure the continuing safety of study participants.  
 
All participants receiving investigational agents and/or other protocol mandated treatment 
will be evaluated for safety. The safety parameters include all laboratory tests and 
hematological abnormalities, physical examination findings, and spontaneous reports of 
adverse events reported by participants.  All toxicities encountered during the study will 
be evaluated according to the NCI criteria specified in the protocol. Life-threatening 
toxicities must be reported immediately to the DF/HCC Sponsor via the Coordinating 
Center.  
 
Additional safety assessments and toxicity monitoring will be outlined in the protocol. 
 
3.9.1 Guidelines for Reporting Serious Adverse Events  
 
Guidelines for reporting Adverse Events (AEs) and Serious Adverse Events (SAEs) 
are detailed in protocol section 11.0: Adverse Event Reporting Requirement.  
 
 
 
 

 
 
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Participating Institutions must report the SAEs to the DF/HCC Sponsor and the 
Coordinating Center following the DFCI IRB Adverse Event Reporting Policy.  
 
The Coordinating Center will maintain documentation of all Participating Institution 
Adverse Event reports and be responsible for communicating to all participating 
investigators, any observations reportable under the DFCI IRB Reporting 
Requirements.  Participating Institutions will review and submit to their IRB 
according to their institutional policies and procedures 
 
3.9.2 Guidelines for Processing IND Safety Reports  
 
The DF/HCC Sponsor will review all IND Safety Reports and ensure that all IND 
Safety Reports are distributed to the Participating Institutions. Participating 
Institutions will review and submit to their IRB according to their institutional 
policies and procedures. 
 
3.10 
Data Management 
 
The DF/HCC ODQ develops case report forms (CRF/eCRFs), for use with the protocol.  
These forms are designed to collect data for each study. The DF/HCC ODQ provides a 
web based training for eCRF users. 
   
3.10.1 Data Forms Review 
 
Data submissions are monitored for timeliness and completeness of submission. 
Participating Institutions are notified of their data submission delinquencies in 
accordance with the following: 
 
Incomplete or Questionable Data 
If study forms are received with missing or questionable data, the submitting 
institution will receive a written or electronic query from the DF/HCC ODQ Data 
Analyst, Coordinating Center or designee.  Responses to all queries should be 
completed and submitted within 14 calendar days.  Responses may be returned on 
the written query or on an amended paper case report form, or in the case of 
electronic queries, within the electronic data capture (eDC) system. In the case of a 
written query for data submitted on a paper case report form, the query must be 
attached to the specific data being re-submitted in response.   
 
Missing Forms 
If study forms are not submitted on schedule, the Participating Institution will 
receive a Missing Form Report from the Coordinating Center noting the missing 
forms.  These reports are compiled by the DF/HCC ODQ and distributed on a 
monthly basis.  
 
4.0 REQUISITIONING INVESTIGATIONAL DRUG 
 

 
 
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The ordering of investigational agent is specified in the protocol section 15.2: Ordering 
Investigational Product. 
 
Participating Institutions should order their own agent regardless of the supplier. 
 
If the agent is commercially available, check with the local Director of Pharmacy and/or 
the Research Pharmacy to ensure that the agent is in stock. If the agent is not stocked, 
ensure that the agent can be ordered once the protocol is approved by the local IRB.  
 
If the agent is investigational, ensure that the pharmacy will be able to receive and store the 
agent according to state and federal requirements. The local IRB should be kept informed 
of who will supply the agent (i.e., NCI or a pharmaceutical company) so that any 
regulatory responsibilities can be met in a timely fashion.  
 
5.0 MONITORING: QUALITY CONTROL 
 
The quality control process for a clinical trial requires verification of protocol compliance 
and data accuracy. The Coordinating Center, with the aid of the ODQ provides quality 
control oversight for the protocol. 
 
5.1 
Ongoing Monitoring of Protocol Compliance 
  
All Participating Institution will be monitored and are subject to on-site as well as remote 
monitoring conducted by the Coordinating Center. Participating Institutions will be 
required to submit relevant participant source documents to the Coordinating Center for 
monitoring.  
 
The Coordinating Center will implement ongoing monitoring activities to ensure that 
Participating Institutions are complying with regulatory and protocol requirements, data 
quality, and participant safety. Monitoring will occur before the clinical phase of the 
protocol begins, continue during protocol performance and through study completion. 
Monitoring practices include but are not limited to; source verification, review and 
analysis of the following: eligibility requirements of all participants, informed consent 
procedures, 
adverse 
events 
and 
all 
associated 
documentation, 
study 
drug 
administration/treatment, regulatory files, protocol departures, pharmacy records, response 
assessments, and data management.  
 
All DF/HCC sites and Participating Institutions will undergo on-site monitoring by the 
Coordinating Center within 3 months of enrollment of the first patient at each site. 
Combination on-site and remote monitoring will occur every 4-6 months thereafter with at 
least 1 on-site visit every 12 months while the site is actively accruing and treating 
patients.   
 
Once all site participants are off treatment and have completed the post-treatment Safety 
Follow-Up Visit, the follow-up monitoring schedule will be revised to a combination of 
remote and on-site monitoring conducted every 6 months, with at least one on-site visit 

 
 
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every 18 months for confirmation of long term follow-up data.  Once all subjects have 
completed follow-up at a given site, monitoring will be limited to annual, remote review 
of overall survival data, confirm off-study data entry and to verify regulatory review.   
 
Additional monitoring may be conducted for cause or at the discretion of the Principal 
Investigator.  
 
For remote monitoring visits, Participating Institutions will be asked to provide remote 
electronic medical record access to the monitor or will be required to forward de-identified 
copies of participants’ medical record and source documents to the Coordinating Center to 
aid in source data verification.  The participants and CRFs to be reviewed at the visit will 
be communicated at least 2 weeks in advance of the scheduled monitoring visit.  Source 
documentation can be provided to the Coordinating Center via an encrypted memory stick 
or via a secure file transfer system.  During remote monitoring visits, the Site Specific File 
will be reviewed in lieu of the site regulatory binder. 
 
On-Site Monitoring will be scheduled several weeks in advance and will be conducted 
over a 2-3 day period.  During an on-site monitoring visit 2-4 participants will be 
monitored. Source documentation verification (SDV) will be conducted by having access 
to participants’ complete medical record and source documents.  Participating Institutions 
will be expected to coordinate the necessary resources for the monitor, including a desk, 
access to all participant medical and research records (electronic and hard copy), the 
regulatory binders and access to a photocopier.  The Participating Institution will also be 
asked to assist in scheduling a pharmacy visit and a brief exit interview on the final day of 
the visit with the Study Coordinator and the Site investigator. 
 
All Participating Institutions will be required to participate in monthly Coordinating 
Center initiated teleconferences.  Once all participants have completed treatment, 
teleconferences will be scheduled as needed. 
 
5.2 Monitoring Reports 
 
The DF/HCC Sponsor will review all monitoring reports for on-site and remote 
monitoring of Participating Institutions to ensure protocol compliance. The DF/HCC 
Sponsor may increase the monitoring activities at Participating Institutions that are unable 
to comply with the protocol, DF/HCC Sponsor requirements or federal and local 
regulations. Participating Institutions may also be subject to an audit as determined by the 
DF/HCC Sponsor. 
 
5.3 Accrual Monitoring 
 
Prior to extending a protocol to an external site, the DF/HCC Sponsor will establish 
accrual requirements for each participating institution. For Phase II studies, sites are 
expected to accrue at least 3 participants annually, with the exception of rare disease 
groups.  Accrual will be monitored for each participating institution by the DF/HCC 

 
 
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Sponsor or designee. Sites that are not meeting their accrual expectations may be subject 
to termination. 
 
 
 
6.0 AUDITING: QUALITY ASSURANCE 
 
Auditing is a method of Quality Assurance. Its main focus is to measure whether standards 
and procedures were followed. Auditing is the systematic and independent examination of 
all trial related activities and documents.  Audits determine if evaluated activities were 
appropriately conducted and whether data was generated, recorded and analyzed, and 
accurately reported per the protocol, Standard Operating Procedures (SOPs), and the Code 
of Federal Regulations (CFR). 
 
6.1 Audit Plan: NCI Sponsored Trials  
 
Not applicable 
 
6.2 
Audit Plan: DF/HCC Sponsored Trials  
 
One on-site audit will be scheduled by the ODQ, assuming at least three participants have 
been treated on protocol at the site. Approximately 3-4 participants would be audited at 
the site over a 2 day period.  If violations which impact participant safety or the integrity 
of the study are found, more participant records may be audited.  
 
6.3 
Audit Notification 
 
It is the Participating Institution’s responsibility to notify the Coordinating Center of all 
scheduled audit dates (internal or NCI) and re-audit dates (if applicable), which involve 
this protocol. All institutions will forward a copy of final audit and/or re-audit reports and 
corrective action plans (if applicable) to the Coordinating Center, within 12 weeks after 
the audit date.  
 
6.4 
Audit Reports  
 
The DF/HCC Sponsor will review all final audit reports and corrective action plans if 
applicable. The Coordinating Center, must forward these reports to the DF/HCC ODQ per 
DF/HCC policy for review by the DF/HCC Audit Committee. Based upon the audit 
assessments the DF/HCC Audit Committee could accept or conditionally accept the audit 
rating and final report. Conditional approval could require the DF/HCC Sponsor to 
implement recommendations or require further follow-up.  For unacceptable audits, the 
DF/HCC Audit Committee would forward the final audit report and corrective action plan 
to the DFCI IRB as applicable. 
 
6.5 
Participating Institution Performance 
 

 
 
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The DF/HCC Sponsor and the DFCI IRB is charged with considering the totality of an 
institution’s performance in considering institutional participation in the protocol. 
 
6.5.1 Corrective Actions 
 
Participating Institutions that fail to meet the performance goals of accrual, 
submission of timely and accurate data, adherence to protocol requirements, and 
compliance with state and federal regulations, may be recommended for a six-month 
probation period. Such institutions must respond with a corrective action plan and 
must demonstrate during the probation period that deficiencies have been corrected, 
as evidenced by the improved performance measures. Participating Institutions that 
fail to demonstrate significant improvement will be considered by the DF/HCC 
Sponsor for revocation of participation. A DF/HCC Sponsor and/or the DFCI IRB 
may terminate a site’s participation if it is determined that a site is not fulfilling its 
responsibilities as described above.