Conditions: Malignant Melanoma
Keywords: Clinical stage III or resectable stage IV melanoma (MEL)
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 33
Healthy volunteers: no

Brief summary:
The main purpose of this trial is to evaluate the safety, tolerability and adverse event profile of pembrolizumab in subjects who have high risk melanoma before and after their standard of care surgical resection, and to collect tumor tissue from subjects before and after receipt of pembrolizumab to look at how the experimental drug interacts with tumor tissue. Subjects will receive 1 dose of neoadjuvant pembrolizumab, followed by complete resection and then a year of adjuvant pembrolizumab

Detailed description:
detailed description listed above

Arms:
arm 1: All subjects will receive 1 cycle neo-adjuvant pembrolizumab 200mg IV followed by complete surgical resection followed by pembrolizumab Q3weeks for 1 year

Interventions: intervention 1: pembrolizumab
Intervention descriptions: intervention 1: 200 mg Subjects will receive 1 dose of neoadjuvant pembrolizumab, followed by complete resection and then a year of adjuvant pembrolizumab

Protocol document:
Prot_SAP_000.pdf: 
UPCC# 01615: Tissue Collection Study of Pembrolizumab in Advanced Melanoma  
 
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CLINICAL RESEARCH PROTOCOL 
 
 
A Phase Ib Tissue Collection Study of Pembrolizumab (MK-3475) in Subjects with 
Resectable Advanced Melanoma 
Regulatory Sponsor 
Principal Investigator: 
Tara Mitchell, MD 
Abramson Cancer Center 
3400 Spruce Street 
Philadelphia, Pennsylvania 19104 
 
Funding Sponsor: 
 
 
 
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co.  
One Merck Drive 
P.O. Box 100 
Whitehouse Station, NJ 08889-0100 
 
Statistician: 
Rosemarie Mick, MS 
 
Study Product: 
Pembrolizumab (MK-3475) 
 
Protocol Number: 
UPCC 01615 
 
Sub-Investigators:    
Giorgos Karakousis, MD 
 
Lynn M. Schuchter, MD 
 
Ravi K. Amaravadi, MD 
 
Naomi Haas, MD 
 
Robert Vonderheide, MD, DPhil 
 
Gerald P. Linette, MD, PHD 
Basic Science Collaborators: 
John Wherry, PhD 
 
Erica Carpenter, PhD 
 
Alexander Huang, MD 
 
Medical Monitor:    
Arati Desai, MD 
Initial Version: 
03/25/2014 
Amendment 1: 
07/22/2015 
Amendment 2:  
01/23/2017 
Amendment 3: 
06/18/2018 


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1.0 TRIAL SUMMARY 
Abbreviated Title 
Phase Ib Tissue Collection Study of Pembrolizumab (MK-
3475) in Subjects with Resectable Advanced Melanoma 
Trial Phase 
Ib 
Clinical Indication 
Clinical stage III (nodal and/or intransit disease) or 
resectable stage IV melanoma (MEL), with or without prior 
treatment 
Trial Type 
Clinical study 
Type of control 
None 
Route of administration 
IV 
Trial Blinding 
None 
Treatment Groups  
1 
Number of trial subjects 
30 evaluable subjects 
Estimated duration of 
trial 
7 years 
Duration of Participation 
5 years 
 
2.0 TRIAL DESIGN 
2.1 
Trial Design 
Subjects will undergo a tumor tissue collection biopsy prior to treatment, followed by one 
dose of pembrolizumab 200 mg, then undergo a curative intent resection of all remaining 
disease 3 weeks after the initial dose of pembrolizumab. Post-operatively, subjects will 
receive up to 1 year of pembrolizumab 200 mg every 3 weeks. 
 
 


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3.0 OBJECTIVE(S) & HYPOTHESIS(ES) 
3.1 
Primary Objectives & Hypothesis 
1.  To collect tumor tissue pre- and post- treatment with MK-3475 for studies of mechanism 
of action of PD-1 blockade with pembrolizumab. 
Hypothesis: Collection of paired tumor tissue samples will be feasible. Pembrolizumab will 
result in a measurable change in tumor immune biomarkers.  This is a hypothesis generating 
trial which will evaluate change in numerous tumor immune biomarkers. 
2.  To evaluate safety, tolerability and adverse experience profile of pembrolizumab in the 
peri-operative setting. 
Hypothesis: Safety profile of pembrolizumab administered in the peri- and post-operative 
setting is similar to the overall safety profile with an infrequent occurrence of grade 3/4 
adverse events related to the surgical procedure. 
3.2 
Secondary Objectives 
1.  To define the effect of PD-1 blockade with pembrolizumab on other immune regulatory 
pathways, including T cell activation, in paired tumor tissue samples from subjects with 
melanoma before and after treatment with a single dose of pembrolizumab. 
2.  To define the effect of PD-1 blockade with pembrolizumab on immune biomarkers in 
PBMC and serum from subjects before and at serial time points after treatment with a 
single dose of pembrolizumab. 
3.  To evaluate the disease-free-survival (DFS) in subjects with high risk MEL receiving 
pembrolizumab peri-operatively. 
4.  To evaluate overall survival (OS) in subjects with high risk MEL receiving pembrolizumab 
peri-operatively. 
5.  To describe the rate of recurrence and time to disease recurrence for subjects on the 
study. 
4.0 BACKGROUND & RATIONALE 
4.1 
Background 
Advanced melanoma remains a very high risk malignancy with high mortality despite recent 
advances and new drug approvals. Even after curative intent surgery, up to 70% of patients 
with high risk stage III melanoma develop recurrent metastatic disease and die. 


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Immune directed therapy has been effective in treating advanced unresectable melanoma 
with recent promising results with PD-1 blocking agents, which may affect an anti-tumor 
response by blocking the PD-1 mediated negative regulation on T lymphocytes, which are 
prime mediators of tumor immunosurveillance. Programmed Death-1 (PD-1) signaling 
involves binding to several discrete ligands, including PD-L1 and PD-L2. PD-L1 is often 
expressed within the tumor microenvironment including cancer cells and macrophages 
whereas PD-L2 is expressed primarily on professional antigen presenting cells. PD-1 
negatively regulates the effector phase of the T cell response after ligation of PD-L1 to the 
receptor. Antibodies that block the PD-L1/PD-1 interaction prevent the down-regulation of 
the anti-tumor immune response, hence releasing the cytotoxic function of tumor-specific T 
cells. 
Additional studies in human tumor tissue are needed to define the mechanism of action of 
PD-1 inhibition. Defining the mechanism is the first step in developing predictors of 
response to treatment with PD-1 inhibition, which would allow for more strategic 
development of combination immune therapy strategies, ultimately with the goal of 
increasing objective response rates to immune therapy in melanoma and other tumor 
types. This proposed study will generate mechanism of action data, as well as, neoadjuvant 
and adjuvant administration feasibility data. 
Currently, standard options for patients with resected high risk melanoma include close 
observation, high dose interferon, or clinical trials, as high dose interferon has not 
demonstrated a definite overall survival benefit in this patient population. Effective 
therapies that reduce the risk of recurrence and improve survival are needed. 
4.1.1 Pharmaceutical and Therapeutic Background 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades [1].  Accumulating evidence shows a 
correlation between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable 
prognosis in various malignancies [2; 3; 4; 5; 6].  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) [7; 
8].  The structure of murine PD-1 has been resolved [9].  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 


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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 [7; 10; 11; 12].  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 [13; 14].  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 [15; 16].  Expression has also been shown during thymic development on 
CD4-CD8- (double negative) T-cells as well as subsets of macrophages and dendritic cells 
[17].  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 
[18; 19; 20; 13].  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 [13].  Although healthy organs express little (if any) PD-L1, a variety of 
cancers were demonstrated to express abundant levels of this T-cell inhibitor.  PD-1 has 
been suggested to regulate tumor-specific T-cell expansion in subjects with melanoma 
(MEL) [21].  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 (previously known as SCH 900475 and MK-3475) is a potent and highly 
selective humanized monoclonal antibody (mAb) of the IgG4/kappa isotype designed to 
directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2. 
4.1.2 Preclinical and Clinical Trial Data 
Refer to the Investigator’s Brochure for Preclinical and Clinical data. 
4.2 
Rationale 
Pembrolizumab is a highly selective, humanized monoclonal antibody (IgG4/kappa isotype) 
that directly blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, with 
safety and efficacy demonstrated in melanoma and other advanced solid tumors. 
Unfortunately, little is known about the mechanism of action of pembrolizumab in tumor 
tissue and its interaction with other immune regulatory pathways. 
 


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Currently, standard options for patients with resected high risk melanoma include close 
observation, high dose interferon, or clinical trials, as high dose interferon has not 
demonstrated a definite overall survival benefit in this patient population. Effective 
therapies that reduce the risk of recurrence and improve survival are needed. 
Anti-cancer activities by anti- PD-1mAb seen in MEL patients thus far provide a strong 
rationale for evaluation of pembrolizumab in MEL patients with high risk resectable disease. 
Pembrolizumab has been well tolerated with dose levels up to 200 mg and has shown a 
promising response rate of 41% in patients with advanced melanoma, which is much higher 
than the 10-15% response rate observed in ipilimumab registration trials. The existing data 
from the ongoing pembrolizumab study PN001 support the evaluation of the safety and 
efficacy of pembrolizumab in patients with resectable high risk MEL, for whom additional 
treatment options are needed. 
Additional studies in human tumor tissue are needed to define the mechanism of action of 
PD-1 inhibition. Defining the mechanism is the first step in determining factors that predict 
response to treatment with PD-1 inhibition, which would allow for more strategic 
development of combination immune therapy strategies, ultimately with the goal of 
increasing objective response rates to immune therapy in melanoma and other tumor 
types. We do not expect any increased toxicity with pembrolizumab in the peri-operative 
period. This proposed study will generate mechanism of action data, as well as, neoadjuvant 
and adjuvant administration feasibility data. 
4.2.1 Rationale for the Trial and Selected Subject Population 
A total of 30 evaluable subjects will be enrolled in this study. Patients with a diagnosis of 
clinical stage III or resectable stage IV melanoma may be considered for enrollment. This 
patient population is selected as their risk of recurrence is very high, but there are no 
effective systemic therapy options that prolong survival in this population. Subjects will be 
recruited from the Clinical Practices of the University of Pennsylvania. We plan to consent 
sufficient subjects such that 30 evaluable subjects are enrolled. Subjects will be considered 
evaluable if they undergo both tumor tissue collection procedures and receive at least 1 
dose of pembrolizumab. 
4.2.2 Rationale for Dose Selection/Regimen/Modification 
The dose of pembrolizumab, 200mg intravenous every 3 weeks is selected as it has been 
observed to be safe and effective in prior clinical studies of pembrolizumab. Subjects will 
receive one dose of neoadjuvant therapy followed by one year of adjuvant pembrolizumab 
200 mg intravenous every 3 weeks. One year of adjuvant therapy is selected based on the 
rationale that subjects with advanced disease who are treated with pembrolizumab for at 
least 6 months and have a complete response are able to stop therapy with an ongoing 
durable clinical response. Durable complete responses have not been observed with 
stopping pembrolizumab at an earlier time point. Furthermore, 1 year is the standard 


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duration of treatment for adjuvant high dose interferon, which is the only approved 
adjuvant therapy for melanoma. 
Biosamples (blood and tumor) obtained from subjects before and at serial time points 
during treatment will be analyzed. High priority assays will be performed as indicated 
below. Second priority assays will be performed as the budget allows. 
High priority assays: 
1.  Peripheral blood mononuclear cells (PBMC) will be obtained at various time 
points at baseline and during this protocol, including before and after treatment and 
before and after surgery. PBMCs will be analyzed by flow cytometry to measure 
important T cell subsets. This assay will include intracellular staining for multiple T 
cell cytokines and transcription factors in order to determine multifunctionality. 
Expression of inhibitory receptors including PD-1 and others will be examined in 
PBMC populations to test whether changes in such pathways on T occurs following 
treatment. 
 
2.  Tumor-infiltrating lymphocytes (TIL) will be harvested from tumor biopsies before 
and after treatment to analyze treatment-induced effects on TILs using a similar 
multiparameter flow cytometry assay described above for PBMC. 
 
Second priority assays: 
1.  Inflammatory cytokines/chemokines. Serum obtained at various times at baseline 
and during the protocol will be analyzed using Luminex bead array and Invitrogen 
30-plex kits, which can simultaneously quantify/determine concentrations of 30 
important factors, including IL-1, TNF-alpha, IL-6 and others. 
 
2.  T-cells within TIL can also be further expanded in vitro when possible using 
artificial APC systems routinely used in the laboratory to facilitate further study T-
cell specificity and function. 
 
3.  Deep sequencing of the TCR (along with tumor and germline DNA) will also be 
performed when feasible from blood and tumor as a novel way to measure tumor-
specific T-cell responses induced by treatment. This method does not require a priori 
understanding of a particular tumor antigen or MHC. Of particular interest will be 
evidence of TCR clones increasing in the circulation after therapy that are also found 
in the subject’s tumor, per novel analytic methodologies noted in the preliminary 
data section. Such observations would be consistent with a vaccine effect of 
therapy. 


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4.  Antigen-specific T-cell responses will be measured when possible using 
established assays in which PBMC pre and post therapy will be tested in vitro in T-
cell responder assays. For patients who are HLA-A2+, functional responses and 
peptide-MHC quantification will be measured for a panel of melanoma associated 
antigens, as well as, viral antigens as a control. Functional measurements can 
include cytokine production, CD107a mobilization, and lysis against peptide-pulsed 
targets or tumor cells lines expressing the melanoma antigen. In addition, for 
functional assessments of T cells without regard to the patients MHC, we will use 
autologous CD40-activated B cells electroporated with viral or tumor antigen mRNA 
as in vitro stimulators. 
 
5.  New antibodies with reactivity to defined antigens will be measured in serum 
collected before and during treatment. When possible, we will use the ProtoArray 
protein array, which uses chip-based technology to profile 9,000 proteins. Analysis 
will be by Prospector software. The induction of high titer antibodies to defined 
tumor antigens not only reflects a humoral immune response to treatment but also 
a cellular response. 
 
6.  Circulating tumor cells (CTCs) and circulating tumor DNA will be measured in the 
blood pre- and post-treatment using promising cell surface markers in collaboration 
with Dr. Erica Carpenter. Levels of circulating tumor material will be correlated to 
tumor burden and can potentially afford important information with regards to 
response to therapy and prognosis. 
 
Assays noted above may be performed by the specific collaborators currently 
indicated or other academic/industry collaborators as relationships are developed in 
the future. 
 
 
 
 


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5.0 METHODOLOGY 
5.1 
Entry Criteria 
5.1.1 Diagnosis/Condition for Entry into the Trial 
5.1.2 Subject Inclusion Criteria 
In order to be eligible for participation in this trial: 
1.  The subject must have clinical stage III or resectable stage IV MEL. Subject’s may 
not have a diagnosis of uveal or mucosal melanoma. 
2.  The subject must be expected to have an adequate amount of tumor burden to 
yield 2-4 pre-operative research core biopsy (14-gauge needle) specimens or the 
equivalent amount of tissue (4-6 mm punch biopsy), in addition, to the tissue 
required for diagnostic purposes. 
3.  The subject must be expected to have an adequate amount of residual tumor 
after their pre-operative research tumor tissue collection, such that their operative 
research tumor collection will also yield at least 4-6 research core biopsy specimens 
or the equivalent amount of tissue. 
4.  The subject must be willing to undergo the two paired tumor tissue biopsy 
procedures to obtain samples for biomarker analysis. Tissue obtained must not be 
previously irradiated. 
5.  Either the subject or the subject’s legal representative must be willing and able to 
provide written informed consent for the trial. 
6.  The subject must be ≥ 18 years of age on day of signing informed consent. 
7.  The subject must have a performance status of 0 or 1 on the ECOG Performance 
Scale. 
8.  The subject must demonstrate adequate organ function as defined in Table 1, all 
screening labs must be performed within 10 days of treatment initiation. 
Table 1  Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
Hematological 
 
Absolute neutrophil count 
(ANC) 
≥1500/mcL 


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Platelets 
≥100,000/ mcL 
Hemoglobin 
≥9 g/dL or ≥5.6 mmol/L  
Renal 
 
Serum creatinine OR 
Measured or calculateda 
creatinine clearance 
(GFR can also be used in place 
of creatinine or CrCl) 
≤1.5 X upper limit of normal (ULN) OR 
 
≥50 mL/min for subject with creatinine levels > 
1.5 X institutional ULN 
Hepatic 
 
Serum total bilirubin 
≤ 1.5 X ULN OR 
 
Direct bilirubin ≤ ULN for subjects with total 
bilirubin levels > 1.5 ULN 
AST (SGOT) and ALT (SGPT) 
≤ 2.5 X ULN OR 
≤ 5 X ULN for subjects with liver metastases 
Coagulation 
International Normalized Ratio 
(INR) or Prothrombin Time (PT) 
 
Activated Partial 
Thromboplastin Time (aPTT) 
≤1.5 X ULN unless subject is receiving 
anticoagulant therapy as long as PT or PTT is 
within therapeutic range of intended use of 
anticoagulants 
≤1.5 X ULN unless subject is receiving 
anticoagulant therapy 
as long as PT or PTT is within therapeutic range 
of intended use of anticoagulants 
aCreatinine clearance should be calculated per institutional standard. 
 
9.  Female subjects of childbearing potential must have a negative serum pregnancy 
test within 72 hours prior to receiving the first dose of study medication. 
10.  The subject must be willing to use protocol defined method(s) of contraception: 
Female subjects of childbearing potential must be willing to use 2 methods of 
contraception, or abstain from heterosexual sexual intercourse for two weeks 
before the time of the first dose of study medication, while on study, through 120 
days after the last dose of study medication. 


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Female subjects of childbearing potential are defined as those women who have not 
been surgically sterilized or have not been free from menses for > 1 year. 
Male subjects must agree to use an adequate method of contraception starting with 
the first dose of study medication, while on study, through 120 days after the last 
dose of study medication. 
Acceptable forms of birth control include condoms, diaphragms, cervical cap, an 
intra-uterine device (IUD), surgical sterility (tubal ligation or a partner that has 
undergone a vasectomy), or oral contraceptives, OR the subject must agree to 
completely abstain from heterosexual intercourse.  Abstinence at certain times of 
the cycle only, such as during the days of ovulation, after ovulation and withdrawal 
are not acceptable methods of birth control. 
5.1.3 Subject Exclusion Criteria 
The subject will be excluded from participating in the trial if: 
1.  Subject has unresectable disease; i.e. in the opinion of the surgical oncologist, all 
of the subject’s melanoma cannot be completely removed with a clear margin. 
2.  Subject is currently participating in or has participated in a study of an 
investigational agent or using an investigational device within 4 weeks of the first 
dose of study treatment. 
3.  Subject has a known hypersensitivity to pembrolizumab or any of its ingredients. 
4.  Subject has a diagnosis of immunodeficiency or is receiving systemic steroid 
therapy or any other form of immunosuppressive therapy within 7 days prior to 
enrollment. 
5.  Subject has had a prior monoclonal antibody within 4 weeks prior to study Day 1 
or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to 
agents administered more than 4 weeks earlier. 
6.  Subject has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-
CD137, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) agents 
(including ipilimumab), interferon, high dose IL-1 or any other antibody or drug 
specifically targeting T-cell co-stimulation or checkpoint pathways. 
7.  Subject has had prior chemotherapy, targeted small molecule therapy, 2 weeks 
prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from 
adverse events due to a previously administered agent 
Note:  Subjects with ≤ Grade 2 neuropathy are an exception to this criterion 


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8.  For subjects who have received major surgery, the subject must have recovered 
adequately from the toxicity and/or complications from the intervention prior to 
starting study therapy. 
9.  Subject has had radiation therapy to the tumor selected for research collection, 
or has had radiation therapy to any site within 4 weeks prior to study Day 1. 
10.  Subject has received transfusion of blood products (including platelets or red 
blood cells) or administration of colony stimulating factors (including G-CSF, GM-CSF 
or recombinant erythropoietin) within 4 weeks prior to study Day 1. 
11.  Subject has a known additional malignancy that is progressing or requires active 
treatment. 
12.  Subject has known active central nervous system (CNS) metastases and/or 
carcinomatous meningitis. 
Note: Subjects with previously treated brain metastases will be eligible to 
participate provided they are stable (without evidence of progression by 
imaging for at least four weeks prior to the first dose of trial treatment and 
any neurologic symptoms have returned to baseline), have no evidence of 
new or enlarging brain metastases, and are not using steroids for at least 7 
days prior to trial treatment. 
13.  Subject has an active autoimmune disease requiring systemic treatment within 
the past 3 months or a documented history of clinically severe autoimmune disease, 
or a syndrome that requires systemic steroids or immunosuppressive agents. 
Note: Subjects with vitiligo or resolved childhood asthma/atopy are an 
exception to this rule.  Subjects that require intermittent use of 
bronchodilators or local steroid injections will not be excluded from the 
study.  Subjects with hypothyroidism stable on hormone replacement or 
Sjorgen’s syndrome will not be excluded from the study. 
14.  Subject has evidence of interstitial lung disease, active, non-infectious 
pneumonitis or has a history of non-infectious pneumonitis which required steroids. 
15.  Subject has an active infection requiring systemic therapy, including active 
tuberculosis 
16.  Subject 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. 


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17.  Subject has known psychiatric or substance abuse disorders that would interfere 
with cooperation with the requirements of the trial. 
18.  Subject is pregnant or breastfeeding, or expecting to conceive or father a child 
within the projected duration of the trial participation (from 2 weeks prior to the 
first dose of study treatment, while participating on the study and through 120 days 
after the last dose of trial treatment). 
19.  Subject has severe cardiovascular disease, i.e. arrhythmias, requiring chronic 
treatment, congestive heart failure (NYHA Class III or IV) or symptomatic ischemic 
heart disease. 
20.  Subject has hepatic decompensation (Child-Pugh score >6 [class B and C]). 
21.  Subject has uncontrolled thyroid dysfunction 
22.  Subject has uncontrolled diabetes mellitus 
23.  Subject has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 
antibodies) as determined by medical record review. 
24.  Subject has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., 
HCV RNA [qualitative] is detected) as determined by medical record review. 
25.  Subject has received a live vaccine within 30 days prior to the first dose of trial 
treatment. 
5.2 
Trial Treatments 
The treatment to be used in this trial is outlined below in Table 2 
Table 2  Trial Treatment 
Drug 
Dose/Potency 
Dose 
Frequency 
Route of 
Administration 
Regimen/
Treatment 
Period 
Use 
Pembrolizumab 
200 mg 
Q 3 wks 
IV infusion 
1 year  
Experimental 
The pembrolizumab dosing interval may be increased due to toxicity as described in Section 
5.2.1.2. 
 


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5.2.1 Dose Selection/Modification 
5.2.1.1 Dose Selection 
The rationale for selection of doses to be used in this trial is provided in Section 4.0 – 
Background and Rationale. 
5.2.1.2 Dose Modification 
Dose Limiting Toxicity (DLT): Surgical outcomes will be evaluated as the effect of 
Pembrolizumab after surgery, and the effect of pembrolizumab on surgical complications is 
unknown. Dose Limiting toxicity will be defined as Grade 3 non-hematologic, and Grade 4 
hematologic toxicity that is not expected for surgery alone or pembrolizumab alone. DLTs 
will be monitored for up to 6 weeks post-surgery. 
Pembrolizumab will be withheld for drug-related Grade 4 hematologic toxicities, non-
hematological toxicity ≥ Grade 3 including laboratory abnormalities, and severe or life-
threatening AEs as per Table 3 below. 
Table 3: Dose modification guidelines for drug-related adverse events. 
Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting Treatment 
Treatment Discontinuation 
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)a 
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 
2-4 
Toxicity resolves to Grade 0-1. Therapy 
with pembrolizumab can be continued 
while endocrine replacement therapy is 
instituted 
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 
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 
 
Therapy with pembrolizumab can be 
continued while thyroid replacement 
therapy is instituted 
Therapy with pembrolizumab can be continued while thyroid 
replacement therapy is instituted 
 
Infusion Reaction 
2b 
Toxicity resolves to Grade 0-1  
Permanently discontinue if toxicity develops despite adequate 
premedication  
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 
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Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting Treatment 
Treatment Discontinuation 
3-4 or 
Recurrent 
Grade 2 
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 Toxicityc 
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 (Grade 2 for pneumonitis) drug-related AE that recurs or any life-threatening event. 
a 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. 
b 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; Refer to Table 4– Infusion 
Treatment Guidelines for further management details. 
c 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. 
 
With investigator and medical monitor agreement, subjects with a laboratory adverse event 
still at Grade 2 after 12 weeks may continue treatment in the trial only if asymptomatic.  For 
information on the management of adverse events, see Section 5.4.1. 
Subjects who experience a recurrence of the same severe or life-threatening event at the 
same grade or greater with re-challenge of pembrolizumab should be permanently 
discontinued from trial treatment. 
5.2.2 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 
6.0).  Trial treatment may be administered up to 5 days before or after the scheduled Day 1 
of each cycle due to administrative reasons. 
All trial treatments will be administered on an outpatient basis. 
Pembrolizumab will be administered as a 30 minute IV infusion every 3 weeks.  Every effort 
should be made to target infusion timing to be as close to 30 minutes as possible. 
The treatment cycle interval may be increased by 1 week when restarting pembrolizumab 
that was held due to: 
• Grade 2 toxicities that did not resolve to Grade 0-1 within 4 weeks 
• Grade 3 or 4 toxicities 
Trial Blinding/Masking 
This is an open-label trial; therefore, the Sponsor-investigator, sub-investigators and subject 
will know the treatment administered. 


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5.3 
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 must discuss any questions regarding this 
with the Sponsor-Investigator and medical monitor. The final decision on any supportive 
therapy or vaccination rests with the investigator and/or the subject's primary physician. 
However, the decision to continue the subject on trial therapy or vaccination schedule 
requires the mutual agreement of the Sponsor-Investigator, the treating investigator, 
medical monitor and the subject. 
5.3.1 Acceptable Concomitant Medications 
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards 
of medical care. 
All concomitant medications 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 will also be included on the CRF. 
All concomitant medications received within 28 days before the first dose of trial treatment 
and 30 days after the last dose of trial treatment must be recorded.  Concomitant 
medications administered after 30 days after the last dose of trial treatment should be 
recorded for SAEs and ECIs as defined in Section 7.2. 
5.3.2 Prohibited Concomitant Medications 
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase (including retreatment for post-complete response relapse) of this trial: 
1.  Anti-cancer systemic chemotherapy, immune or biological therapy 
2.  Investigational agents other than pembrolizumab 
3.  Radiation therapy 
Note:  Radiation therapy to a symptomatic solitary lesion or to the brain may 
be allowed after consultation with Sponsor-Investigator and medical 
monitor. 
4.  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, chicken pox, yellow fever, rabies, BCG, and 
typhoid (oral) vaccine. Seasonal influenza vaccines for injection are generally killed 


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virus vaccines and are allowed; however intranasal influenza vaccines (e.g. Flu-
Mist®) are live attenuated vaccines, and are not allowed. 
5.  Oral 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-
Investigator and medical monitor.  Inhaled and topical steroids are permitted. 
Subjects who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial.  
Subjects may receive other medications that the investigator or qualified designee 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. 
5.4 
Rescue Medications & Supportive Care 
5.4.1 Supportive Care Guidelines 
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator or qualified designee.   Suggested supportive care measures for the 
management of adverse events with potential immunologic etiology are outlined below. 
Where appropriate, these guidelines include the use of oral or intravenous treatment with 
corticosteroids as well as additional anti-inflammatory agents if symptoms do not improve 
with administration of corticosteroids.   Note that several courses of steroid tapering may 
be necessary as symptoms may worsen when the steroid dose is decreased. For each 
disorder, attempts should be made to rule out other causes such as metastatic disease or 
bacterial or viral infection, which might require additional supportive care. The treatment 
guidelines are intended to be applied when the investigator determines the events to be 
related to pembrolizumab. 
Note: if after the evaluation the event is determined not to be related, the investigator does 
not need to follow the treatment guidance (as outlined below). Refer to Section 5.2.1 for 
dose modification.  
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, 
or skin photography as part of evaluation of the event. 
• Pneumonitis: 
o For Grade 2 events, treat with systemic corticosteroids. When symptoms 
improve to Grade 1 or less, steroid taper should be started and continued 
over no less than 4 weeks. 


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o For Grade 3-4 events, immediately treat with intravenous steroids.  
Administer additional anti-inflammatory measures, as needed. 
o Add prophylactic antibiotics for opportunistic infections in the case of 
prolonged steroid administration. 
Diarrhea/Colitis: 
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such as 
diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of bowel 
perforation (such as peritoneal signs and ileus). 
o All subjects who experience diarrhea/colitis should be advised to drink liberal 
quantities of clear fluids.  If sufficient oral fluid intake is not feasible, fluid 
and electrolytes should be substituted via IV infusion.  For Grade 2 or higher 
diarrhea, consider GI consultation and endoscopy to confirm or rule out 
colitis. 
o For Grade 2 diarrhea/colitis, administer oral corticosteroids.  
o For Grade 3 or 4 diarrhea/colitis, treat with intravenous steroids followed by 
high dose oral steroids. 
o When symptoms improve to Grade 1 or less, steroid taper should be started 
and continued over no less than 4 weeks. 
• Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) or ≥ 
Grade 3 Hyperglycemia, if associated with ketosis (ketonuria) or metabolic acidosis 
(DKA) 
o For T1DM or Grade 3-4 Hyperglycemia 
 Insulin replacement therapy is recommended for Type I diabetes 
mellitus and for Grade 3-4 hyperglycemia associated with metabolic 
acidosis or ketonuria. 
 Evaluate patients with serum glucose and a metabolic panel, urine 
ketones, glycosylated hemoglobin, and C-peptide. 
• Hypophysitis: 
o For Grade 2 events, treat with corticosteroids. When symptoms improve to 
Grade 1 or less, steroid taper should be started and continued over no less 
than 4 weeks. Replacement of appropriate hormones may be required as the 
steroid dose is tapered. 
o For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed 
by oral corticosteroids. When symptoms improve to Grade 1 or less, steroid 


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taper should be started and continued over no less than 4 weeks. Replacement 
of appropriate hormones may be required as the steroid dose is tapered. 
• Hyperthyroidism or Hypothyroidism: 
Thyroid disorders can occur at any time during treatment. Monitor patients for 
changes in thyroid function (at the start of treatment, periodically during treatment, 
and as indicated based on clinical evaluation) and for clinical signs and symptoms of 
thyroid disorders. 
o Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism): 
 In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are 
suggested as initial therapy. 
 In hypothyroidism, thyroid hormone replacement therapy, with 
levothyroxine or liothyroinine, is indicated per standard of care. 
o Grade 3-4 hyperthyroidism  
 Treat with an initial dose of IV corticosteroid followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid 
taper should be started and continued over no less than 4 weeks. 
Replacement of appropriate hormones may be required as the steroid 
dose is tapered. 
• Hepatic: 
o For Grade 2 events, monitor liver function tests more frequently until returned 
to baseline values (consider weekly). 
 Treat with IV or oral corticosteroids 
o For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 hours.  
o When symptoms improve to Grade 1 or less, a steroid taper should be started 
and continued over no less than 4 weeks. 
• Renal Failure or Nephritis: 
o For Grade 2 events, treat with corticosteroids. 
o For Grade 3-4 events, treat with systemic corticosteroids. 
o When symptoms improve to Grade 1 or less, steroid taper should be started 
and continued over no less than 4 weeks.  
• Management of Infusion Reactions: Signs and symptoms usually develop during or 
shortly after drug infusion and generally resolve completely within 24 hours of 
completion of infusion. 
 
Table 4 below shows treatment guidelines for subjects who experience an infusion reaction 
associated with administration of pembrolizumab. 


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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, 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 
 
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 
1.5 h (± 30 minutes) prior to 
infusion of pembrolizumab 
(MK-3475) with:  
 
Diphenhydramine 50 mg po (or 
equivalent dose of 
antihistamine). 
 
Acetaminophen 500-1000 mg 
po (or equivalent dose of 
antipyretic). 
Grades 3 or 4 
 
Grade 3: 
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial improvement; 
hospitalization indicated for other 
clinical sequelae (e.g., renal 
impairment, pulmonary 
infiltrates) 
 
Grade 4: 
Life-threatening; pressor or 
ventilatory support indicated 
 
Stop Infusion and Monitor Symptoms. 
Additional appropriate medical therapy 
may include but is not limited to: 
     IV fluids 
     Antihistamines 
     NSAIDS 
     Acetaminophen 
 
     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 


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NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
Appropriate resuscitation equipment will be available in the room and a physician readily available during the 
period of drug administration. 
 
 
5.5 
Diet/Activity/Other Considerations 
5.5.1 Diet 
Subjects should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea or vomiting. 
5.5.2 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. Male subjects of reproductive potential 
must agree to avoid impregnating a partner while receiving study drug and for 120 days 
after the last dose of study drug either by practicing total abstinence from heterosexual 
activity or with a female partner using 2 methods of birth control.  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, copper intrauterine device, sponge, or spermicide. Appropriate hormonal 
contraceptives will include any registered and marketed contraceptive agent that contains 
an estrogen and/or a progestational agent (including oral, subcutaneous, intrauterine, or 
intramuscular agents). 
Subjects should be informed that taking the study medication may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the study. In order to participate 
in the study, they must adhere to the contraception requirement (described above) for the 
duration of the study and during the follow-up period defined in section 7.6.2-Reporting of 
Pregnancy and Lactation to the Sponsor-Investigator 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. 


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5.5.3 Use in Pregnancy 
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab, the 
subject will immediately be removed from the study. The site will contact the subject at 
least monthly and document the subject’s status until the pregnancy has been completed or 
terminated. The outcome of the pregnancy will be reported to the Sponsor-Investigator and 
to Merck without delay and within 24 hours if the outcome is a serious adverse experience 
(e.g., death, abortion, congenital anomaly, or other disabling or life-threatening 
complication to the mother or newborn). The study investigator will make every effort to 
obtain permission to follow the outcome of the pregnancy and report the condition of the 
fetus or newborn to the Sponsor.  If a male subject impregnates his female partner the 
study personnel at the site must be informed immediately and the pregnancy reported to 
the Sponsor-Investigator and to Merck and followed as described above and in Section 
7.6.2. 
5.5.4 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. 
5.6 
Subject Withdrawal/Discontinuation Criteria 
Subjects may withdraw consent at any time for any reason or be dropped from the trial at 
the discretion of the investigator should any untoward effect occur. In addition, a subject 
may be withdrawn by the investigator or the Sponsor if enrollment into the trial is 
inappropriate, the trial plan is violated, or for administrative and/or other safety reasons.  
Specific details regarding discontinuation or withdrawal are provided in Section 7.1.2 – 
Other Procedures. 
A subject must be discontinued from the trial for any of the following reasons: 
1.  The subject or legal representative withdraws consent. 
2.  Confirmed radiographic disease progression 
3.  Unacceptable adverse experiences as described in Section 5.2.1.2 
4.  Intercurrent illness that prevents further administration of treatment 
5.  Investigator’s decision to withdraw the subject 
6.  The subject has a confirmed positive serum pregnancy test 
7.  Noncompliance with trial treatment or procedure requirements 


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8.  The subject is lost to follow-up 
9.  Administrative reasons 
After the end of treatment (C4 of pembrolizumab per trial flow chart, section 6.0), each 
subject will be followed for 30 days for adverse event monitoring (serious adverse events 
will be collected for 90 days after the end of treatment as described in Section 7.2).  
Subjects will have post-treatment follow-up for disease status until disease recurrence, 
withdrawing consent or becoming lost to follow-up. After documented disease progression 
each subject will be followed by telephone for overall survival until death, withdrawal of 
consent, or the end of the study, whichever occurs first. 
5.7 
Clinical Criteria for Early Trial Termination 
The study will be terminated early if there is evidence that the rate of DLTs is greater than 
33%. A DLT is defined as any grade 3 or higher hematologic or non-hematologic toxicity that 
is at least possibly related to Pembrolizumab and is not an expected adverse event for 
Pembrolizumab or surgery and which occurs anytime from the initiation of study therapy to 
6 weeks post-surgery. 
Early termination rules will be used to monitor DLTs during the enrollment and treatment of 
patients. Toxicity data will likely be reviewed after groups of 5 patients have been treated 
and followed for 6 weeks post-surgery. Enrollment will be terminated if the data indicate 
that the rate of DLTs, as defined above, is >33%. There are published data on the safety of 
Pembrolizumab in other populations of melanoma patients. Thus, we will assume a 
modestly informative beta (.5,1.5) prior which is equivalent to information on 2 treated 
patients. Given the prior and the observed data, the Bayesian posterior probability that the 
toxicity rate exceeds 33%, is calculated. If the number of patients with a DLT equals or 
exceeds the number in the table below, then it is likely that the toxicity rate is 
unacceptable, as noted by Bayesian posterior probabilities. 
Bayesian Early Termination Rules for Toxicity 
Patients treated  
5 
10 
15 
20 
25 
30 
Patients with toxicity 
3 
5 
7 
9 
11 
13 
Posterior Prob[tox rate  >33%] 
0.81 
0.81 
0.82 
0.83 
0.84 
0.85 
Action 
Terminate accrual, re-evaluate trial  
 
Early trial termination will be the result of the criteria specified below: 
1.  Quality or quantity of data recording is inaccurate or incomplete 
2.  Poor adherence to protocol and regulatory requirements 
3.  Incidence or severity of adverse drug reaction in this or other studies indicates a 
potential health hazard to subjects 


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4.  Plans to modify or discontinue the development of the study drug 
In the event of Merck decision to no longer supply study drug, ample notification will be 
provided so that appropriate adjustments to subject treatment can be made. 
 
 


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6.0 TRIAL FLOW CHART 
6.1 
Study Flow Chart 
Study Therapy 
 
 
 
 
 
Screening 1 
(Within 28 
days of 
cycle 1) 
Week/Cycle (21 Days ± 5 Days) 
 
Post-
Treatment 
Visit 
(notes 13-16) 
Week  
 
0 3 
6 
9 
12 
15 
18 
21 
24 
27 
30 
33 
36 
Until 
Wk52 
N 
Cycle  
 
1 22 
3 
4 
 5 
6   
7  
8 
9 
10  11  12  13  N 
  
Study Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics/Medical History/ 
Prior Medications 4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs/Weight 5 
X 
X X 
X 
X 
X 
X 
 X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Examination 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG Performance Status 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Study Therapy 
 
 
 
 
 
Screening 1 
(Within 28 
days of 
cycle 1) 
Week/Cycle (21 Days ± 5 Days) 
 
Post-
Treatment 
Visit 
(notes 13-16) 
Week  
 
0 3 
6 
9 
12 
15 
18 
21 
24 
27 
30 
33 
36 
Until 
Wk52 
N 
Cycle  
 
1 22 
3 
4 
 5 
6   
7  
8 
9 
10  11  12  13  N 
  
Review Adverse Events 6 
 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Review Concomitant Medications 
 
X  X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Tissue collection 7 
X7 
 
X7 
 
 
 
 
 
 
 
 
 
 
 
 
X 
(recurrence)7 
Research Blood Collection 
(up to 120mL per draw) 
X17 
X X 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
(every 
3rd 
cycle) 
X 
(recurrence)17 
CBC with Differential 8 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Comprehensive Serum Chemistry 
Panel 9 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy Test -Serum β-HCG 10 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Study Therapy 
 
 
 
 
 
Screening 1 
(Within 28 
days of 
cycle 1) 
Week/Cycle (21 Days ± 5 Days) 
 
Post-
Treatment 
Visit 
(notes 13-16) 
Week  
 
0 3 
6 
9 
12 
15 
18 
21 
24 
27 
30 
33 
36 
Until 
Wk52 
N 
Cycle  
 
1 22 
3 
4 
 5 
6   
7  
8 
9 
10  11  12  13  N 
  
HLA type11 
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
T3, FT4 and TSH12 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Survival status13 
 
 
 
 
 
 
 
  
 
  
 
 
 
  
 
X15 
Tumor Imaging14 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
Pembrolizumab 
 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Blood collection (up to 10 mL) for 
DNA7 
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
1 
Routine laboratory tests (serum chemistry; hematology) for screening should be performed within 10 days of Cycle 1 Day 1. 
2 
Cycle 2 pembrolizumab may occur up to 9 weeks after cycle 1 to allow for full surgical recovery. All subsequent cycles will be 
every 21 days (+/-5 days) up to week 52. 


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3 
Written consent must be obtained prior to performing any protocol specific procedure. Results of a test performed as part of 
routine clinical management are acceptable in lieu of a screening test if performed within the specified time frame (e.g. within 
28 days prior to Cycle 1, Day 1). 
4 
Includes history of treatment for the primary diagnosis, including prior systemic, radiation treatment and surgical treatment, 
and best response to prior systemic treatments. Date of last prior cancer treatment must be documented.  Radiographic 
studies performed prior to study entry may be collected for review by the investigator. Report complete medication history 
for 30 days prior to the screening visit (Visit 1). 
5 
Vital signs to include temperature, pulse, respiratory rate and blood pressure. 
6 
Adverse experiences and laboratory safety measurements will be graded per NCI CTCAE version 4.0. All adverse experiences, 
whether gradable by CTCAE or not, will also be evaluated for seriousness. 
7 
Tumor tissue collection sample #1 to be collected during screening. C1 (Week 0) treatment to occur within 7 days of sample 
#1 collection. Collection of sample #2 (complete surgical resection of all remaining tumor) is to be performed approximately 3 
weeks after administration of pembrolizumab C1 (Week 0). There will be a 7 day window of flexibility to receive the first dose 
of pembrolizumab (up to 14 days after the initial screening biopsy). A tissue sample of at least one tumor lesion is mandatory 
at baseline (prior to Cycle 1) and at the time of complete resection. Additional biopsy samples at disease progression are 
highly desirable when it is feasible. The tissue samples should have proper size to enable all planned biomarker analyses. Fine 
needle aspiration will not be acceptable. The biopsy techniques allowed in the study include core biopsies or surgical biopsies. 
The same biopsy techniques should be used as routinely used for a given tumor lesion/location and specimens will be 
processed and stored according to the standard process. For patients who give consent to the optional Future Biological 
Research, the remaining tissue samples after the study biomarker analyses will be retained for future biological analyses. DNA 
sample for analysis should be obtained pre-dose, on Day 1 (or with any subsequent scheduled blood draw). 
8 
PT/INR and aPTT should be collected at Screening. Coagulation parameters should be determined throughout the study when 
clinically indicated. After Cycle 1, pre-dose laboratory procedures can be conducted up to 72 hours prior to dosing. 
9 
Comprehensive serum chemistry panel must include sodium, potassium, BUN, Creatinine, AST, ALT, alkaline phosphatase, 
total bilirubin and lactate dehydrogenase.  After Cycle 1, pre-dose laboratory procedures can be conducted up to 72 hours 
prior to dosing.   
10 
For women of reproductive potential, a serum pregnancy test will be performed within 72 hours of the first dose. Women 
with amenorrhea for <1 years and who have not had a hysterectomy and oophorectomy will only be considered not to be of 
reproductive potential if they have a documented FSH value in the postmenopausal range. 


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11 
HLA can be drawn once, at the time of any scheduled blood draw, or may be omitted, per PI decision.  
12 
Analysis of T3, FT4 and TSH will be performed by the local study site laboratory.  TSH is recommended with each cycle; T3 and 
T4 as indicated. 
13 
Once a subject completes 12 months of pembrolizumab therapy, experiences disease recurrence or starts a new 
antineoplastic therapy, the subject will complete the below noted safety follow up and move into the survival follow-up phase 
and should be contacted by telephone every 12 weeks to assess for survival status. 
14 
Tumor imaging will be performed at timepoints in accordance with standard of care anticipated to be within 30 days prior to 
enrollment and every 3-6 months on and post-treatment. 
15 
The mandatory Safety Follow-Up visit will be conducted within 4 weeks after the last dose of study drug or before the 
initiation of a new antineoplastic treatment, whichever comes first. Patients with an AE of Grade >1 will be further followed 
until the resolution of the AE to Grade 0-1 or until beginning of a new antineoplastic therapy, whichever occurs first. 
16 
AEs occurring within 30 days after the last dose of study drug should be recorded. After this time, record only AEs that are 
considered related to study drug.  SAEs that occur within 90 days of the end of treatment or before initiation of a new anti-
cancer treatment should also be followed and recorded. 
17 
Whole blood samples will be drawn on biopsy and resection days, every cycle for the first 5 cycles, then every 3 cycles while 
on pembrolizumab, with final sample as recurrence sample for PBMC analysis if available.  


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7.0 TRIAL PROCEDURES 
7.1 
Trial Procedures 
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to 
perform these procedures at unscheduled time points if deemed clinically necessary by the 
investigator. 
Furthermore, additional evaluations/testing may be deemed necessary by the Sponsor-
Investigator and/or Merck for reasons related to subject safety. In these cases, such 
evaluations/testing will be performed in accordance with those regulations. 
7.1.1 Administrative Procedures 
7.1.1.1 Informed Consent 
The Investigator or qualified designee must obtain documented consent from each 
potential subject prior to participating in a clinical trial. 
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated 
signature of the person conducting the consent discussion. 
A copy of the signed and dated consent form should be given to the subject before 
participation in the trial. 
The initial informed consent form, any subsequent revised written informed consent form 
and any written information provided to the subject must receive the IRBs 
approval/favorable opinion in advance of use.  The subject or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available 
that may be relevant to the subject’s willingness to continue participation in the trial.  The 
communication of this information will be provided and documented via a revised consent 
form or addendum to the original consent form that captures the subject’s dated signature 
or by the subject’s legally acceptable representative’s dated signature. 
Specifics about a trial and the trial population will be added to the consent form template at 
the protocol level. 
The informed consent process will adhere to IRB requirements, applicable laws and 
regulations and Sponsor-Investigator requirements. 


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7.1.1.2 Inclusion/Exclusion Criteria 
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the trial. Waivers to the eligibility criteria will not be 
granted. 
7.1.1.3 Medical History 
A medical history will be obtained by the investigator or qualified designee.  Medical history 
will include all active conditions, and any condition diagnosed within the prior 10 years that 
are considered to be clinically significant by the Investigator. Details regarding the disease 
for which the subject has enrolled in this study will be recorded separately and not listed as 
medical history. 
7.1.1.4 Prior and Concomitant Medications Review 
7.1.1.4.1 Prior Medications 
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the subject 
within 28 days before starting the trial.  Treatment for the disease for which the subject has 
enrolled in this study will be recorded separately and not listed as a prior medication. 
7.1.1.4.2 Concomitant Medications 
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial. All medications related to reportable SAEs and ECIs should be recorded as 
defined in Section 7.2. 
7.1.1.5 Disease Details and Treatments 
7.1.1.5.1 Disease Details 
The investigator or qualified designee will obtain prior and current details regarding disease 
status. 
7.1.1.5.2 Prior Treatment Details 
The investigator or qualified designee will review all prior cancer treatments including 
systemic treatments, radiation and surgeries. 
7.1.1.5.3 Subsequent Anti-Cancer Therapy Status 
The investigator or qualified designee will review all new anti-neoplastic therapy initiated 
after the last dose of trial treatment.  If a subject initiates a new anti-cancer therapy prior to 
4 weeks after the last dose, Safety Follow-up visit must occur before the first dose of the 


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new therapy. Once new anti-cancer therapy has been initiated the subject will move into 
survival follow-up. 
7.1.1.6 Adverse Event (AE) Monitoring 
The investigator or qualified designee will assess each subject to evaluate for potential new 
or worsening AEs as specified in the Trial Flow Chart and more frequently if clinically 
indicated. Adverse experiences will be graded and recorded throughout the study and 
during the follow-up period according to NCI CTCAE Version 4.0.  Toxicities will be 
characterized in terms regarding seriousness, causality, toxicity grading, and action taken 
with regard to trial treatment. 
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 (irAE). 
Please refer to section 7.2 for detailed information regarding the assessment and recording 
of AEs. 
7.1.1.7 Full Physical Exam 
The investigator or qualified designee will perform a complete physical exam during the 
screening period.  Clinically significant abnormal findings should be recorded as medical 
history. A full physical exam should be performed during screening. 
7.1.1.8 Vital Signs 
The investigator or qualified designee will take vital signs at screening, prior to the 
administration of each dose of trial treatment and at treatment discontinuation as specified 
in the Trial Flow Chart (Section 6.0). Vital signs should include temperature, pulse, 
respiratory rate, and blood pressure. Height will be measured at screening only. 
7.1.1.9 Eastern Cooperative Oncology Group (ECOG) Performance Scale 
The investigator or qualified designee will assess ECOG status (see Section 11.1) at 
screening, prior to the administration of each dose of trial treatment and discontinuation of 
trial treatment as specified in the Trial Flow Chart. 
7.1.1.10 Tumor Imaging and Assessment of Disease 
Investigators may use CT, PET or MRI imaging for baseline screening imaging and to assess 
for disease recurrence in accordance with standard of care. 


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7.1.1.11 Tumor Tissue Collection and Correlative Studies Blood Sampling 
Biosamples (blood and tumor tissue) obtained from subjects before and at serial time points 
during treatment will be analyzed. Tissue will be collected according to the Trial Flow Chart - 
Section 6.0. 
7.1.1.12 Laboratory Procedures/Assessment 
Laboratory tests for screening or entry must be performed within 10 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. 
The total amount of blood/tissue to be drawn/collected over the course of the trial (from 
pre-trial to post-trial visits), including approximate blood/tissue volumes drawn/collected 
by visit and by sample type per subject may vary depending upon clinical course of the 
subject and length of time on trial. 
In melanoma patients, presence of tumor infiltrating lymphocytes correlates with improved 
prognosis with CD8 T cells being the primary mediators of tumor lysis, while CD4+FoxP3+ 
Tregs result in immune suppression. As a result, a high CD8:Treg ratio correlates with a 
balance in favor of anti-tumor immunity. Indeed, CD8:Treg ratio has been shown to 
correlate with survival in ovarian cancer (Sato PNAS 2005), and therefore is an ideal primary 
endpoint that is reasonable biologically and may be meaningful clinically. 
 
We will analyze a population of terminally exhausted T cells defined as Eomeshi PD1hi by 
flow cytometry. Previous work from the Wherry lab has shown differential exhaustion 
profiles including a terminally exhausted Eomeshi PD1hi population of cells which do not 
respond to anti-PDL1 therapy in vitro in contrast to a TbethiiPD1int (less exhausted 
phenotype) population of T cells that do respond well to PD-L1 blockade in vitro. (Paley, 
Wherry Science 2012) Quantification of the terminally exhausted T cell population (Eomeshi 
PD1hi population) may be of prognostic significance as we hypothesize that a higher 
percentage of Eomeshi PD1hi T cells pre and post PD-1 therapy would be expected to 
correlate with treatment resistance. We will also do functional assessment of these T cell 
subsets pre and post anti PD-1 therapy via flow cytometry with Ki67 and Granzyme B to see 
if pembrolizumab is able to restore T cell function in the terminally exhausted (Eomeshi 
PD1hi population) T cell populations, as indicated by increased Ki67 and Granzyme B in these 
T cells after PD-1 blockade. 
 
Analysis of multiple other inhibitory T cell markers including CTLA4, LAG3, TIM3, 2B4, and 
CD160 will be done with quantification of MFI. Tumor specific T cells from melanoma TILs 
show significant exhaustion with upregulation of multiple inhibitory markers. (Baitsch J Clin 
Invest 2011)  PD-1 blockade may have differential effects on these markers (may increase or 
decrease their expression).  For example, disruption of the PD1-PDL1 axis by anti -PDL-1 


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therapy results in decreased expression of LAG-3 and upregulation of PD-1 in a T cell 
exhaustion model (chronic viral infection model). In this T cell exhaustion model, 
combination therapy with anti- LAG3 and anti –PDL1 increased antigen specific T cells, T cell 
function, as well as viral control. (Blackburn, Wherry Nat Immunol 2009).  As a result, 
assessing the effect of PD-1 blockade on other inhibitory molecules will be valuable in 
determining immune target candidates for combination immunotherapies with PD-1 
blockade. 
 
7.1.2 Other Procedures 
7.1.2.1 Withdrawal/Discontinuation 
When a subject discontinues/withdraws prior to trial completion, all applicable activities 
scheduled for the final trial visit should be performed at the time of discontinuation. Any 
adverse events which are present at the time of discontinuation/withdrawal should be 
followed in accordance with the safety requirements outlined in Section 7.2 - Assessing and 
Recording Adverse Events. 
7.1.3 Visit Requirements 
Visit requirements are outlined in Section 6.0 - Trial Flow Chart. Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures. 
7.1.3.1 Screening 
Screening requirements are outlined in Section 6.0 - Trial Flow Chart. The first tumor biopsy 
is collected during the screening period after informed consent. If the subject is able to 
undergo collection of the screening period tumor specimen and meets all other eligibility 
requirements, the subject can be enrolled in the study. 
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 repeating a screening test if performed within the specified time frame and the 
results meet the inclusion/exclusion criteria. 
7.1.3.2 Treatment Period 
Subjects who have signed informed consent, are eligible for the study and who have 
undergone the screening tumor biopsy can be enrolled on the study and must receive the 
week 0 (cycle 1) treatment with pembrolizumab within 1 week of enrollment. 
There will be a 7 day window of flexibility to receive the first dose of pembrolizumab (up to 
14 days after the initial screening biopsy). If therapy cannot be started within this time 
frame, the patient will be removed from the study and replaced. 
 


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Subjects must then undergo a complete resection of their remaining tumor within 3 weeks 
(up to 1 week later, or up to 3 days earlier) after C1 of pembrolizumab treatment date. 
In the event that there is a complete response after the first dose of study drug, and there is 
no surgical tissue available, the patient will have the option to continue with the study drug 
for up to one year, but will be considered non-evaluable and replaced for the study. 
If the resection surgery is delayed by more than one week after the 3 week window (more 
than 28 days after the first dose of pembrolizumab), the patient may continue with surgery 
and pembrolizumab afterwards. Patients are expected to initiate adjuvant pembrolizumab 
within 9 weeks of cycle 1 to allow for post-surgical recovery. Patients will be evaluated by 
both the surgeon and the oncologist or qualified designee to determine adequate surgical 
recovery before initiation of study drug. In the event of delays, there is no timeframe 
restriction in terms of when adjuvant pembrolizumab is initiated. 
Up to 12 months of pembrolizumab are given every 3 weeks after C1 per the Trial Flow 
Chart, Section 6.0. 
7.1.3.3 Post-Treatment Visits 
Subjects are evaluated within 4 weeks of their last dose of pembrolizumab and then 
according to the Trial Flow Chart, Section 6.0. 
7.1.3.3.1 Safety Follow-Up Visit 
The mandatory Safety Follow-Up Visit should be conducted within 4 weeks after the last 
dose of trial treatment or before the initiation of a new anti-cancer treatment, whichever 
comes first. All AEs that occur prior to the Safety Follow-Up Visit should be recorded.  
Subjects with an AE of Grade > 1 will be followed until the resolution of the AE to Grade 0-1 
or until the beginning of a new anti-neoplastic therapy, whichever occurs first. SAEs that 
occur within 90 days of the end of treatment or before initiation of a new anti-cancer 
treatment should also be followed and recorded. 
7.1.3.4 Follow-up Visits 
Subjects will move into the Follow-Up Phase after completing pembrolizumab and should 
be assessed every 3-6 months by radiologic imaging to monitor disease status (Section 6.0 - 
Trial Flow Chart). Every effort should be made to collect information regarding disease 
status until the start of new anti-neoplastic therapy, disease progression, death, or end of 
the study. 
7.1.3.4.1 Survival Follow-up 
Once a subject experiences confirmed disease progression or starts a new anti-cancer 
therapy, the subject moves into the survival follow-up phase and should be contacted by 


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telephone every 12 weeks to assess for survival status until death, withdrawal of consent, 
or the end of the study, whichever occurs first. 
7.1.3.4.2 Definition of Evaluable Patients 
A patient who has both adequate tissue collected prior to surgery and adequate tissue 
collected at surgery, will be deemed evaluable. Patients who do not have adequate tissue 
collected at either time point or who do not undergo surgery, are deemed unevaluable and 
will be replaced. If such patients received Pembrolizumab, then they will be evaluated in all 
safety analyses. 
7.1.3.4.3 Definition of Time-to-event Outcomes 
Disease-free survival (DFS) is defined as the time from date of surgery to date of first 
documented disease progression, death due to any cause or last date that patient was 
documented to be disease-free (i.e., scan date). DFS is the preferred outcome because 
patients are rendered NED from surgery. Overall survival (OS) is defined as the time from 
date of surgery to date of death due to any cause or last patient contact alive. Both DFS and 
OS outcomes will be measured from date of surgery, and not date of pre-surgery single 
dose Pembrolizumab, in order to compare DFS and OS estimates to published outcomes 
from other trials in this population. Both DFS and OS will be estimated by the Kaplan-Meier 
method. 
7.2 
Assessing and Recording Adverse Events 
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not 
necessarily have to have a causal relationship with this treatment. An adverse event can 
therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding, for example), symptom, or disease temporally associated with the use of a 
medicinal product or protocol-specified procedure, whether or not considered related to 
the medicinal product or protocol-specified procedure.  Any worsening (i.e., any clinically 
significant adverse change in frequency and/or intensity) of a preexisting condition that is 
temporally associated with the use of the pembrolizumab, is also an adverse event. 
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. 
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 


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report forms/worksheets. The reporting timeframe for adverse events meeting any serious 
criteria is described in section 7.2. 1. 
Adverse events will not be collected for subjects during the pre-screening period (for 
determination of archival tissue status) as long as that subject has not undergone any 
protocol-specified procedure or intervention.  If the subject requires a blood draw, fresh 
tumor biopsy etc., the subject is first required to provide consent to the main study and AEs 
will be captured according to guidelines for standard AE reporting. 
7.2.1  Applicable reporting to Abramson Cancer Center Data and Safety Monitoring 
Committee (DSMC) will occur as follows: 
On-Site subjects (this includes any subjects enrolled at other sites on an in-house study) 
Every effort should be made to report an event as a diagnosis, not as a list of symptoms. 
Symptoms that led to the diagnosis should be included in the event description, but should 
not be the actual event. 
 
     1. Unless covered by exclusions below Grade 3 or higher events must be reported within 
10 days of knowledge. 
     2. All unexpected deaths within one business day of knowledge. 
     3. All others deaths within 30 days of knowledge. Deaths of subjects off-study for greater 
than 30 days from the last study treatment/intervention are not reportable unless a 
longer time frame is specified in the protocol. 
 
EXCEPTIONS to AE/SAE Reporting: 
 
a. Grade 3 or 4 events that are judged by a study investigator to be clearly 
unrelated to protocol therapy.   The reason for determining that the event is 
unrelated must be clearly documented in the EMR. 
b. Grade 3 or 4 events that are probably or definitely related to progression of 
disease as judged by a study investigator. The fact that this event is related to 
disease progression must be clearly documented in the EMR.  
c. Grade 3 or 4 events that are probably or definitely related to an FDA 
approved agent. The fact that this event is related to the FDA approved agent 
must be clearly documented in the EMR. 
 
 
7.3 
7.3  Exceptions 
 


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A one time, intentional action (planned prospectively) or process that departs from the IRB 
and CTSRMC approved study protocol, intended for one occurrence.  Advance documented 
IRB and DSMC approval is required. 
For in-house studies with a Medical Monitor or Safety Monitoring Committee (not DSMB), 
approval must be obtained from the Medical Monitor or Safety Monitoring Committee prior 
to submitting the exception request to the DSMC.  The following information must be 
contained in your exception request: 
• When it is needed and why it is needed in that timeframe 
• Has the Medical Monitor or Sponsor approved and provide the documentation of 
approval 
• Is this an exception from eligibility, treatment, disease progression, study calendar 
windows, etc.  
• Why the exception is needed (cite the section(s) of the protocol) along with the full 
clinical details of the subject. This must be determined by the sub-Investigator or PI.  
• The reason why the protocol currently doesn't allow the situation for which an 
exception is being requested. This must be determined by the sub-Investigator or PI. 
• If there are plans to amend the protocol and if not, why not. 
• If additional follow-up or interventions will be required in order to protect the 
subject as a result of this exception. 
 
Study Exceptions the DSMC may Reject: 
 
Exceptions to eligibility, treatment/dosing, contraindicated treatment/therapies/ 
interventions or safety tests for the following types of studies may be rejected by the 
DSMC:1. Any investigator-initiated treatment study. 
2. Any treatment study involving on-campus manufacturing of any component, regardless 
of sponsor. 
  
To seek approval, you must provide the DSMC with strong and compelling scientific and 
clinical information to support your request. You should also include a statement explaining 
whether or not the protocol will be amended. If the protocol will not be amended your 
reasoning must be provided. If this situation is likely to happen again, the DSMC will require 
a protocol amendment. 
 
 
7.4 
7.4  Deviation 
 
Any unintentional action or process that departs from the IRB and DSMC approval and is 
identified retrospectively.  The deviation is reportable to the DSMC and the IRB within 10 


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days from the time the event becomes known to the study team only when: one or more 
participants were placed at increased risk of harm, or, the event has the potential to occur 
again, or the event has the potential to qualify as serious or continuing noncompliance. 
 
 
If the PI determines that a deviation has any potential to impact participant safety (harm 
and/or risk), or the integrity of data produced from the participant, or some other overall 
impact on the study, the PI must report the deviation to the IRB and DSMC as described 
above. The IRB will make the final assessment of the impact. The DSMC will assess for 
additional safety and scientific integrity concerns. 
 
The following information must be contained in your deviation report: 
• When it happened? When the study team (any member) became aware 
• The full description of the deviation including important dates, test results, actions 
taken towards the subject, etc. Also, why it happened and how it was identified. 
• Was the Medical Monitor or Sponsor notified. If so, their response? 
• The PIs assessment of the impact on risk, safety and/or outcome. If no impact, why. 
If impact, what and what will happen next. 
• The corrective actions that have been implemented to date and the impact of those 
corrective action plans. 
• Future corrective action plans (if applicable) and the impact of those plans. 
• If there are plans to amend the protocol (if applicable to prevent future deviations) 
and if not, why not. 
 
If the PI determines that the event had no potential to impact participant safety (harm 
and/or risk) or the integrity of data produced from the participant, the PI must fully 
document his/her rationale for each category (risk, harm, and participant data).  
 
. 
 
7.5 
7.5  Events Requiring Prompt Reporting to the IRB including Unanticipated Problem 
Involving Risks to Subjects or Others Reporting Requirements 
Federal Regulation 21CFR §56.108(b)(1) and 45 CFR 46.103(b)(5) require the IRB to "follow 
written procedures for ensuring prompt reporting to the IRB…any unanticipated problems 
involving risk to human subjects or others."   
In alignment with 21 CFR 312, investigators are required to promptly report to the IRB: 
 (1) Unanticipated problems including suspected adverse reactions and adverse reactions. 


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• An event is considered a “suspected adverse reaction” when there is reasonable 
possibility that the drug/investigational product caused the adverse event.  For these 
reporting purposes, reasonable possibility means there is evidence to suggest a 
causal relationship between the drug/investigational product and the event. 
• For University of Pennsylvania IRB reporting, this means an event should be 
considered probably or definitely related to the research procedures. 
• An event is “unexpected” if it is not listed in the investigator’s brochure/package 
insert, or, is not listed at the specificity or severity that has previously been observed 
with the specific drug/investigational product; if an investigator’s brochure/package 
insert is not available, is not consistent with the risk information described in the 
general investigational plan.) 
• “Unexpected” also refers to events that are mentioned in the investigator’s 
brochure/package insert as occurring with a class of drugs or as anticipated, but, are 
not mentioned as to have been occurring (have been seen) with the particular 
drug/investigational product under study.  
 (2) Unanticipated adverse device reaction. Any serious adverse effect on health or safety or 
any life-threatening problem or death caused by, or associated with, a device, if that effect, 
problem, or death was not previously identified in nature, severity, or degree of incidence 
in the investigational plan or application (including a supplementary plan or application, or 
any other unanticipated serious problem associated with a device that relates to the rights, 
safety, or welfare of subjects. 
• For drug/investigational product and device events, “serious” is defined as any 
death, life-threatening adverse event, inpatient hospitalization or prolongation of 
existing hospitalization, a persistent or significant incapacity or substantial 
disruption of the ability to conduct normal life functions, or a congenital 
anomaly/birth defect.  Other events that may be considered “serious” but not meet 
the prior criteria include: those events that may jeopardize the patient or subject 
and may require medical or surgical intervention to prevent one of the outcomes 
noted above. 
 (3) In addition to unanticipated problems, the IRB also requires prompt reporting of the 
following events: 
• Complaint of a participant when the complaint indicates unexpected risks or the 
complaint cannot be resolved by the research team. 
• Violation or deviation (meaning an accidental or unintentional change to the IRB 
approved protocol) only when: one or more participants were placed at increased 
risk of harm, or, the event has the potential to occur again, the event represents 
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 (4)  Breach of confidentiality. 
 (5) Incarceration of a participant when the research was not previously approved under 
Subpart C and the investigator believes it is in the best interest of the subject to remain on 
the study. 
7.6 
7.6 Reporting to the Sponsor and to Merck 
7.6.1 7.6.1  Definition of an Overdose for This Protocol and Reporting of Overdose 
to the Sponsor and to Merck 
For purposes of this trial, an overdose is any dose higher than 20% over the prescribed dose 
for pembrolizumab. No specific information is available on the treatment of overdose of 
pembrolizumab.   Pembrolizumab should be discontinued and the subject should be 
observed closely for signs of toxicity.  Appropriate supportive treatment should be provided 
if clinically indicated. 
If an adverse event(s) is associated with (“results from”) the overdose of a Merck product, 
the adverse event(s) is reported as a serious adverse event, even if no other seriousness 
criteria are met. 
If a dose of Merck’s product meeting the protocol definition of overdose is taken without 
any associated clinical symptoms or abnormal laboratory results, the overdose is reported 
as a non-serious Event of Clinical Interest (ECI), using the terminology “accidental or 
intentional overdose without adverse effect.” 
All reports of overdose with and without an adverse event must be reported within 24 
hours to the Sponsor-Investigator and within 2 working days hours to Merck Global Safety. 
(Attn: Worldwide Product Safety; FAX 215 993-1220) 
7.6.2 7.6.2 Reporting of Pregnancy and Lactation to the Sponsor-Investigator and 
to Merck 
Although pregnancy and lactation are not considered adverse events, it is the responsibility 
of investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them), including the pregnancy of a male subject's female 
partner that occurs during the trial or within 120 days of completing the trial 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. 


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Such events must be reported within 24 hours to the Sponsor-Investigator and within 2 
working days to Merck Global Safety. (Attn: Worldwide Product Safety; (FAX 215 993-1220) 
7.6.3 7.6.3 Immediate Reporting of Adverse Events to the Sponsor and to Merck 
7.6.3.1 7.6.3.1 Serious Adverse Events 
A serious adverse event is any adverse event occurring at any dose or during any use of 
Merck’s product that: 
-Results in death; 
-Is life threatening; 
-Results in persistent or significant disability/incapacity; 
-Results in or prolongs an existing inpatient hospitalization; 
-Is a congenital anomaly/birth defect; 
-Is a new cancer (that is not a condition of the study); 
-Is associated with an overdose; 
-Is another important medical event 
SAE reports and any other relevant safety information are to be forwarded to the Merck 
Global Safety facsimile number:  +1-215-993-1220 within two (2) business days of learning 
of the information. 
Refer to Table 10 for additional details regarding each of the above criteria. 
Progression of the cancer under study is not considered an adverse event unless it results in 
hospitalization or death. 
Additionally, any serious adverse event, considered by an investigator who is a physician or 
qualified designee to be related to Merck product that is brought to the attention of the 
investigator at any time outside of the time period specified in the previous paragraph also 
must be reported immediately to the Sponsor-Investigator and to Merck. 
All subjects with serious adverse events must be followed up for outcome. 
7.6.3.2 Events of Clinical Interest 
Selected non-serious and serious adverse events are also known as Events of Clinical 
Interest (ECI) and must be recorded as such on the Adverse Event case report 
forms/worksheets and reported within 24 hours to the Sponsor and within 2 working days 
to Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220) 


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Events of clinical interest for this trial include: 
1.  An overdose of Merck product, as defined in Section 7.2.1 - Definition of an Overdose for 
This Protocol and Reporting of Overdose to the Sponsor, that is not associated with clinical 
symptoms or abnormal laboratory results. 
2.  An elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the upper 
limit of normal and, at the same time, an alkaline phosphatase lab value that is less than 2X 
the upper limit of normal, as determined by way of protocol-specified laboratory testing or 
unscheduled laboratory testing.* 
*Note:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may 
require an additional evaluation for an underlying etiology. 
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. 
ECIs that occur in any subject from the date of first dose through 90 days following 
cessation of treatment, or the initiation of a new anticancer therapy, whichever is earlier, 
whether or not related to the Merck’s product, must be reported within 24 hours to the 
Sponsor-Investigator and to Merck Global Safety within 2 working days. 
7.6.4 Evaluating Adverse Events 
An investigator who is a physician 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. 


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Table 10  Evaluating Adverse Events 
An investigator who is a physician or qualified designee, will evaluate all adverse events as to: 
V4.0 CTCAE 
Grading 
Grade 1 
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention not 
indicated. 
 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate 
instrumental ADL. 
 
Grade 3 
Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation or hospitalization indicated; disabling; limiting self-care ADL. 
 
Grade 4 
Life threatening consequences; urgent intervention indicated. 
 
Grade 5 
Death related to AE 
Seriousness 
A serious adverse event is any adverse event occurring at any dose or during any use of Merck product that: 
 
†Results in death; or 
 
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the 
event as it occurred (Note: This does not include an adverse event that, had it occurred in a more severe form, 
might have caused death.); or 
 
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct 
normal life functions); or 


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Table 10  Evaluating Adverse Events 
 
†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? 


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Table 10  Evaluating Adverse Events 
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 physician or qualified designee. 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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Table 10  Evaluating Adverse Events 
  
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? 


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Table 10  Evaluating Adverse Events 
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a physician or 
qualified designee according to his/her best clinical judgment, including consideration of the above elements. 
Record one of the 
following 
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of 
a Merck product relationship). 
Yes, there is a reasonable 
possibility of Merck 
product relationship. 
There is evidence of exposure to the Merck product.  The temporal sequence of the AE onset 
relative to the administration of the Merck product is reasonable.  The AE is more likely explained 
by the Merck product than by another cause. 
No, there is not a 
reasonable possibility 
Merck product 
relationship 
Subject did not receive the Merck product OR temporal sequence of the AE onset relative to 
administration of the Merck product is not reasonable OR there is another obvious cause of the AE.  
(Also entered for a subject with overdose without an associated AE.) 


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7.6.5 Sponsor Responsibility for Reporting Adverse Events 
All Adverse Events will be reported to regulatory authorities, IRB and investigators in 
accordance with all applicable global laws and regulations. 
8.0 8.0    STATISTICAL CONSIDERATIONS 
 
8.1       Design 
This a single arm Phase 1b trial in patients with resectable advanced melanoma that will: 
1) establish the safety and feasibility of Pembrolizumab as adjuvant therapy and 2) 
investigate the immunologic effects of Pembrolizumab in tumor and peripheral blood. 
Patients will have tumor tissue collected at study entry, and then they receive one dose 
of Pembrolizumab prior surgical tumor resection. After surgery, patients receive 
adjuvant Pembrolizumab for up to one year, during which time serial blood samples will 
be taken. 
 
8.2      Objectives 
The primary objectives are to: 
1. Collect tumor tissue before and after a single dose of Pembrolizumab for exploratory 
analyses of the immunologic effects of Pembrolizumab and to generate testable and 
reasonable hypotheses. These analyses will examine immunologic components of tumor 
infiltrating lymphocytes (TILs). 
2.  Evaluate safety, tolerability and adverse events of Pembrolizumab when given peri-
operatively and as adjuvant therapy. 
The secondary objectives are to: 
1. To examine the effects of Pembrolizumab on other immune regulatory pathways, from 
paired tumor tissue samples after treatment with a single dose of Pembrolizumab. 
 
2. To examine the effects of Pembrolizumab on immune biomarkers in PBMC and serum at 
serial time points during and after treatment with Pembrolizumab. 
 
3. To evaluate the disease-free-survival (DFS) and overall survival (OS) in patients receiving 
Pembrolizumab as adjuvant therapy. 
 
4. To describe the rate of recurrence and time to disease recurrence in patients receiving 
Pembrolizumab as adjuvant therapy. 
 


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8.3       Endpoints 
Evaluability. A patient will be deemed evaluable for immune biomarker analysis if the 
patient received one pre-operative dose of Pembrolizumab and had adequate tissue 
collected at both baseline and tumor resection. Non-evaluable patients will be replaced. 
 
Toxicity. CTCAE version 4.0 grades will be employed. Any patient who receives any 
amount of Pembrolizumab will be included in the toxicity analysis. 
 
Immune biomarkers. Priority assays will include: characterization of Tregs, CD8 T cells, 
exhausted T cells defined as EomeshiPD1hi and Ki67 and Granzyme B in TILs. A full 
description of all immunologic outcomes and hypotheses is included in Section 7.1.1.12. 
 
Disease-free and overall survival. Disease-free survival (DFS) is defined as the time from 
date of surgery to date of first documented disease progression, death due to any cause 
or last date that patient was documented to be disease-free (i.e., a scan date). Overall 
survival (OS) is defined as the time from date of surgery to date of death due to any 
cause or last patient contact alive. Both DFS and OS outcomes will be measured from 
date of surgery to allow us to compare DFS and OS estimates with those of other 
adjuvant trials. 
8.4     Monitoring Toxicity 
The study will be terminated early if there is evidence that the rate of serious adverse 
events is greater than 33%. A serious adverse event is defined as any grade 3 or higher 
hematologic or non-hematologic toxicity that is at least possibly related to 
Pembrolizumab and is not an expected adverse event for either Pembrolizumab or 
surgery and which occurs anytime from the initiation of study therapy to 6 weeks post-
surgery. Early termination rules are defined in Section 5.7. 
8.5     Plans for Data Analysis 
Patient Evaluability. Only evaluable patients will contribute to the primary analysis that 
characterizes the immunologic effects of Pembrolizumab in tumor tissue and secondary 
analyses on other immune regulatory pathways. All patients, regardless of time on study 
and procurement of tissue, will contribute to the primary analysis of safety and to the 
secondary analyses of immunologic effects of Pembrolizumab in peripheral blood and of 
disease-free and overall survival. 
 
Toxicity: All observed adverse events which occur anytime from the initiation of study 
therapy to 30 days after the final dose of Pembrolizumab will be graded and tabled. All 
grade 3 or higher hematologic or non-hematologic toxicities that are at least possibly 
related to Pembrolizumab and not an expected adverse event for either Pembrolizumab 
or surgery and which occur anytime from the initiation of study therapy to 6 weeks post-
surgery will be described separately. 
 


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Immune biomarkers: Immunologic outcomes will be described using scatter and box 
plots and descriptive statistics (e.g., mean, median, SD, range). Pre-treatment to post-
treatment paired comparisons will employ paired Student’s t-test or Wilcoxon signed 
ranks test, as appropriate. With several post-treatment blood samples intended, trends 
over time will be described using scatter and box plots, descriptive statistics (e.g., fold 
changes from baseline). Comparisons of post-treatment values to the baseline value will 
be performed by repeated measures ANOVA. Longitudinal modeling using linear mixed 
effects models will also be attempted, in order to extend this investigation to 
characterized trends over time and could include modeling jointly the inter-dependency 
among several longitudinally measured immunologic outcomes. 
 
Disease-free and overall survival:  will be estimated by the method of Kaplan and Meier. 
Median and 1-year DFS and OS rates and 95% CIs will be estimated. 
 
8.6       Sample Size 
This study will enroll 30 evaluable patients. Assuming that at most 5% of enrolled 
patients will not be evaluable, we expect that no more than 32 patients will be enrolled. 
 
Primary objective: Treatment of 30-32 patients will firmly establish the safety of the 
treatment. If the true underlying serious adverse rate is as low as 10%, then the failure 
to observe at least one adverse event in 32 treated patients, is <5% (binomial 
probability is 0.042). If the observed serious adverse event rate is 16.7% (5 of 30 
patients), then the true event rate is likely to be no higher than 30%, since the upper 
bound of the 2-sided 95% confidence interval is 30%. 
 
Primary objective: For exploratory analyses of immunological effects of Pembrolizumab 
in tumor tissue, we anticipate conducting many paired comparisons. Due to multiple 
parameters tested, we will control the false positive rate by calculating adjusted p 
values using the Bonferroni-Holm method. 
 
We have estimated the detectable effect sizes for two of our immunologic endpoints, 
CD8/Treg ratio and Granzyme B level using data on peripheral blood. In 17 melanoma 
patients treated with Pembrolizumab, the mean pre- and maximum post-treatment 
Granzyme B levels in peripheral blood were 27.49 and 41.72, respectively. The standard 
deviation of paired differences (sd) was 15.90, yielding an effect size of 0.89sd. The 
mean pre- and maximum post-treatment CD8/Treg ratio in peripheral blood were 5.61 
and 11.82, respectively. The standard deviation of paired differences (sd) was 8.61, 
yielding an effect size of 0.72sd. With 30 evaluable patients, there is 99% power to 
detect an effect size of 0.89sd and 96% power to detect an effect size of 0.72sd using a 
paired Student’s t-test at 2-sided 5% error. 
 
These two endpoints were selected because they had the most dramatic post-treatment 
increases in peripheral blood. More heterogeneity and smaller effect sizes are possible 
in tissue. But we still have sufficient power to detect smaller effect sizes. For example, 


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an effect size of 0.55sd can be detected with 82% power by a paired t-test at 2-sided 5% 
significance level. 
 
8.7       Study Duration 
With an estimated accrual of 5 patients per month, it is anticipated that accrual will 
continue for 6 months. We plan to follow patients for an additional 2 years after 
enrollment has been completed, in order to better estimate DFS and OS. 
9.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL SUPPLIES 
9.1 
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. 
Clinical Supplies will be provided by Merck as summarized in Table 11. 
Table 11 Product Descriptions 
Product Name & Potency 
Dosage Form 
Pembrolizumab 100 mg/ 4mL 
Solution for Injection 
 
9.2 
Packaging and Labeling Information 
Clinical supplies will be affixed with a clinical label in accordance with regulatory requirements. 
9.3 
Clinical Supplies Disclosure 
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor-Investigator, sub-
investigators 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. 
9.4 
Storage and Handling Requirements 
Clinical supplies must be stored in a secure, limited-access location under the storage conditions 
specified on the label.  They will be stored in the PCAM Investigational Drug Pharmacy as part of the 
Abramson Cancer Center. 
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. 


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9.5 
Returns and Reconciliation 
The investigator is responsible for keeping accurate records of the clinical supplies received from Merck 
or designee, the amount dispensed to and returned by the subjects and the amount remaining at the 
conclusion of the trial. 
Upon completion or termination of the study, all unused and/or partially used investigational product 
will be destroyed at the site per institutional policy. It is the Investigator’s responsibility to arrange 
for disposal of all empty containers, provided that procedures for proper disposal have been 
established according to applicable federal, state, local and institutional guidelines and procedures, and 
provided that appropriate records of disposal are kept. 
10.0  ADMINISTRATIVE AND REGULATORY DETAILS 
10.1 Confidentiality 
Information about study subjects will be kept confidential and managed according to the requirements 
of the Health Insurance Portability and Accountability Act (HIPAA). Those regulations require a signed 
subject authorization informing the subject of the following: 
- What protected health information (PHI) will be collected from subjects in this study 
- Who will have access to that information and why 
- Who will use or disclose that information 
- The rights of a research subject to revoke their authorization for use of their PHI. 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by regulation, 
retains the ability to use all information collected prior to the revocation of subject authorization. For 
subjects that have revoked authorization to collect or use PHI, attempts should be made to obtain 
permission to collect at least vital status (i.e. that the subject is alive) at the end of their scheduled study 
period. 
10.2 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. 
10.3 Quality Management System 
The Data Safety and Monitoring Committee (DSMC) of the University of Pennsylvania’s Abramson 
Cancer Center will monitor the data quality and adherence to safety rules. Additionally, the DSMC will 
review all safety/toxicity data for the trial and recommend trial suspension or termination as needed. 


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Specific details of monitoring and audit frequency will be included in the Monitoring Plan, but will be at 
least every 6 months. 
Medical monitor 
This study will be monitored in accordance with the DSMC monitoring plan.  Dr. Arati Desai, an 
independent clinician in the Department of Medicine, Division of Hematology Oncology, will serve as 
medical monitor and will consult on decisions made as a part of this trial as noted above.  The medical 
monitor will perform a regular review and assessment of the number and type of serious adverse events 
(at minimum yearly, but may occur more frequently as needed). 
It is the responsibility of the Principal Investigator to oversee the safety of the study. This safety 
monitoring will include careful assessment and appropriate reporting of adverse events, as noted above, 
as well as the construction and implementation of a site data and safety monitoring plan.  
Monitoring Plan: 
Please see the DSMC Monitoring Plan. 
10.4 Data Management 
Data collection and management will be carried out by the staff of the Clinical Research Unit at 
Penn’s Abramson Cancer Center. The study case report form (CRF) is the primary data 
collection instrument for the study. All data requested on the CRF must be recorded. All entries 
will be entered into an electronic data capture system (EDC) via VELOS. 
10.5 Compliance with Auditing and Inspecting 
The investigator will permit the Cancer Center’s Administrative Director of Compliance and 
Auditing or her designee, and the Abramson Cancer Center Data Safety and Monitoring 
Committee (DCOM), to review records, data and facilities at mutually agreeable times in 
accordance with the DSMC monitoring plan. 
The investigator also agrees to allow IRB review and regulatory authority (FDA) inspection of 
trial-related documents and procedures and provide for direct access to all trial-related source 
data and documents. 
The investigator shall prepare and maintain complete and accurate trial documentation in 
compliance with Good Clinical Practice standards and applicable federal, state and local laws, 
rules and regulations; and, for each subject participating in the trial, provide all data, and, upon 
completion or termination of the clinical trial, submit any other reports to the Sponsor-
Investigator and Merck as required by this protocol. 
10.6 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 


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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. 
10.7    Ethical Considerations 
This study is to be conducted according to US and international standards of Good Clinical 
Practice (FDA Title 21 part 312 and International Conference on Harmonization guidelines), 
applicable government regulations and Institutional research policies and procedures. This 
protocol and any amendments will be submitted to the University of Pennsylvania IRB and 
CTSRMC for formal approval of the study conduct. The decision of the IRB concerning the 
conduct of the study will be made in writing to the investigator and a copy of this decision will 
be provided before commencement of this study. 
All subjects for this study will be provided a consent form describing this study and providing 
sufficient information for subjects to make an informed decision about their participation in 
this study. This consent form will be submitted with the protocol for review and approval by the 
IRB and CTSRMC for the study. The formal consent of a subject, using the IRB-approved consent 
form, must be obtained before that subject is submitted to any study procedure. This consent 
form must be signed by the patient or legally acceptable surrogate, and the physician-
investigator obtaining the consent. 
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Ölcher M, Braun M, Friedrichs N, Rudlowski C, Bercht E, Fimmers R, et al. Foxp3+ cell 
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12.0 APPENDICES 
12.1 ECOG Performance Status 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction. 


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Grade 
Description 
1 
Symptoms, but ambulatory. Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, 
but unable to carry out any work activities. Up and about more than 
50% of waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-
care. Totally confined to bed or chair. 
5 
Dead. 
* 
As published in Am. J. Clin. Oncol.:  Oken, M.M., Creech, R.H., Tormey, D.C., 
Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of 
The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982. The 
Eastern Cooperative Oncology Group, Robert Comis M.D., Group Chair. 
 
12.2 Common Terminology Criteria for Adverse Events V4.0 (CTCAE) 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0 will be utilized for adverse event reporting. 
(https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm) 
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.