A Phase II Trial of Pembrolizumab (MK-3475) in Metastatic Cutaneous Squamous Cell Carcinoma
Phase: PHASE2
Conditions: Recurrent Skin Carcinoma, Skin Squamous Cell Carcinoma
Sponsor: Emory University

1 
 
 
SPONSOR: Ragini Kudchadkar, MD 
 
 
TITLE:  Winship 3185-16 A Phase II trial of pembrolizumab (MK-3475) in metastatic 
cutaneous squamous cell carcinoma  
 
IND NUMBER: 129700 
 
 
Protocol version: 5.0 (12-13-2016) 
 
 
Principal Investigator: Ragini Kudchadkar, MD 
 
Sub- Investigators: 
 
David Lawson, M.D. 
Melinda Yushak, M.D. 
Mandy Ford, Ph.D 
Brian Pollack, M.D., Ph.D. 
Keith Delman, M.D. 
 
Statistician:  
Zhengia Chen, Ph.D 
 
Study Support:  Merck, Inc. 
 
 
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Table of Content 
 
 
 
 
 
 
 
 
       Page 
 
Trial Summary 
 
 
 
 
 
 
 
 
 
3 
 
Trial Design   
 
 
 
 
 
 
 
 
 
3 
 
Objectives and Hypothesis 
 
 
 
 
 
 
 
 
3 
 
Background and Rationale 
 
 
 
 
 
 
 
 
4 
 
Methodology  
 
 
 
 
 
 
 
 
 
8 
 
Trial Flow Chart 
 
 
 
 
 
 
 
 
 
22 
 
Trial Procedures 
 
 
 
 
 
 
 
 
 
24 
 
Statistical Analysis Plan 
 
 
 
 
 
 
 
 
40 
 
Labeling, Packaging, Storage and Return of Clinical Supply 
 
 
 
41 
 
Administrative and Regulatory Details 
 
 
 
 
 
 
42 
 
References 
 
 
 
 
 
 
 
 
 
 
44 
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1.0 TRIAL SUMMARY 
Abbreviated Title 
Pembrolizumab in cSCC 
Trial Phase 
II 
Clinical Indication 
cSCC, metastatic and unresectable 
Trial Type 
Interventional therapeutic 
Type of control 
None 
Route of administration 
IV 
Trial Blinding 
None 
Treatment Groups  
 
Number of trial subjects 
29 
Estimated 
enrollment 
period 
12 months 
Estimated duration of trial  
Duration of Participation 
 
 
 
2.0 TRIAL DESIGN 
2.1 
Trial Design 
This is a phase II trial of pembrolizumab in metastatic and unresectable cSCC. We hypothesize 
that pembrolizumab will increase active anti-tumor effect in patients with metastatic cSCC with 
an estimated RECIST response rate from 20% to 40%. The Type I error rate is set at 10% and 
power of this study will be at least 80%. The study will be conducted with Simon’s optimal two 
stage design.  In the first stage, 12 patients will be enrolled. If 2 or less of the 12 patients 
achieve response, the study will close to further accrual and pembrolizumab is deemed to be 
ineffective. If RECIST response is seen in 3 or more of the 12 patients, then the trial continues 
with the second stage in which additional 13 patients will be enrolled for a total of 25 patients. At 
the end of complete enrollment, we require 8 or more out of the total of 25 subjects to achieve 
response for the pembrolizumab to be deemed to have sufficiently improved clinical activity and 
justify further clinical development. Otherwise if 7 or less out of the 25 patients achieve 
response, the trial will conclude that pembrolizumab cannot increase active anti-tumor effect in 
patients with metastatic cSCC with an estimated RECIST response rate to 40%. 
 
3.0 OBJECTIVE(S) & HYPOTHESIS(ES) 
3.1 
Primary Objective(s) & Hypothesis(es) 
Objective: To establish the response rate of pembrolizumab in metastatic cutaneous 
squamous cell carcinoma. 
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Hypothesis:  We hypothesize that pembrolizumab will have active anti-tumor effect in 
patients with metastatic, unresectable cSCC with an estimated RECIST response rate of 
40% 
3.2 
Secondary Objective(s) & Hypothesis(es) 
Objective: To determine the 6-month progression-free survival and 1 year overall survival of 
metastatic cSCC treated with pembrolizumab 
Hypothesis:  We hypothesize that treatment with pembrolizumab will improve 6-month PFS 
and 1-year OS over historic controls.  
 
3.3 
Exploratory Objective 
Objective: To evaluate biomarkers of response in both tumor specimens and PBMCs in 
patients treated with cSCC. The biomarkers will determine PD-L1 staining on tumor 
specimens and its correlation with response.  The expression of co-stimulator and co-
inhibitory molecules on and functionality of T cell populations in peripheral blood, tumor, 
normal skin of patients with advanced cSCC before and after treatment with systemic 
pembrolizumab.  
Hypothesis:  We hypothesize that PD-L1 positive tumors will have a higher response rate 
than PDL1 negative tumors. 
 
4.0  BACKGROUND & RATIONALE 
4.1   Background 
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background information 
on MK-3475. 
4.1.1 Pharmaceutical and Therapeutic Background 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades.  Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in 
various malignancies.  In particular, the presence of CD8+ T-cells and the ratio of CD8+ effector 
T-cells / FoxP3+ regulatory T-cells seems to correlate with improved prognosis and long-term 
survival in many solid tumors. 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control.  The normal function of PD-1, expressed on the cell surface of activated T-cells 
under healthy conditions, is to down-modulate unwanted or excessive immune responses, 
including autoimmune reactions.  PD-1 (encoded by the gene Pdcd1) is an Ig superfamily 
member related to CD28 and CTLA-4 which has been shown to negatively regulate antigen 
receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2).  The structure of 
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murine PD-1 has been resolved.  PD-1 and family members are type I transmembrane 
glycoproteins containing an Ig Variable-type (V-type) domain responsible for ligand binding and 
a cytoplasmic tail which is responsible for the binding of signaling molecules.  The cytoplasmic 
tail of PD-1 contains 2 tyrosine-based signaling motifs, an immunoreceptor tyrosine-based 
inhibition motif (ITIM) and an immunoreceptor tyrosine-based switch motif (ITSM).  Following T-
cell stimulation, PD-1 recruits the tyrosine phosphatases SHP-1 and SHP-2 to the ITSM motif 
within its cytoplasmic tail, leading to the dephosphorylation of effector molecules such as CD3ζ, 
PKCθ and ZAP70 which are involved in the CD3 T-cell signaling cascade.  The mechanism by 
which PD-1 down modulates T-cell responses is similar to, but distinct from that of CTLA-4 as 
both molecules regulate an overlapping set of signaling proteins.  PD-1 was shown to be 
expressed on activated lymphocytes including peripheral CD4+ and CD8+ T-cells, B-cells, T 
regs and Natural Killer cells.  Expression has also been shown during thymic development on 
CD4-CD8- (double negative) T-cells as well as subsets of macrophages and dendritic cells.  
The ligands for PD-1 (PD-L1 and PD-L2) are constitutively expressed or can be induced in a 
variety of cell types, including non-hematopoietic tissues as well as in various tumors .  Both 
ligands are type I transmembrane receptors containing both IgV- and IgC-like domains in the 
extracellular region and contain short cytoplasmic regions with no known signaling motifs.  
Binding of either PD-1 ligand to PD-1 inhibits T-cell activation triggered through the T-cell 
receptor.  PD-L1 is expressed at low levels on various non-hematopoietic tissues, most notably 
on vascular endothelium, whereas PD-L2 protein is only detectably expressed on antigen-
presenting cells found in lymphoid tissue or chronic inflammatory environments.  PD-L2 is 
thought to control immune T-cell activation in lymphoid organs, whereas PD-L1 serves to 
dampen unwarranted T-cell function in peripheral tissues.  Although healthy organs express 
little (if any) PD-L1, a variety of cancers were demonstrated to express abundant levels of this 
T-cell inhibitor.  PD-1 has been suggested to regulate tumor-specific T-cell expansion in 
subjects with melanoma (MEL).  This suggests that the PD-1/PD-L1 pathway plays a critical role 
in tumor immune evasion and should be considered as an attractive target for therapeutic 
intervention. 
Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of the 
IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-
L1 and PD-L2.  KeytrudaTM (pembrolizumab) has recently been approved in the United Stated 
for the treatment of patients with unresectable or metastatic melanoma and disease progression 
following ipilumumab and, if BRAF V600 mutation positive, a BRAF inhibitor. 
4.1.2 Preclinical and Clinical Trial Data 
Refer to the Investigator’s Brochure for Preclinical and Clinical data. 
4.2 
Rationale 
4.2.1 Rationale for the Trial and Selected Subject Population 
Cutaneous squamous cell of the skin (cSCC) is the second most common skin cancer in the US 
with over 700,000 new cases each year.  Approximately 2000 individuals die from non-
melanoma skin cancers in the US each year. This is likely an underestimation given that most 
are not reported because of their high incidence and typically excellent prognosis.  Most are 
curable with surgery and/or radiation. However, especially in the elderly and immunosuppressed 
populations, squamous cell carcinomas can become aggressive. Approximately 5% of tumors 
will become metastatic, with a higher rate of metastases in tumors from the head and neck. 
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Tumors that are 2 cm or larger, greater than 4 mm in depth, or poorly differentiated have a poor 
prognosis.  There are no known systemic treatments to improve overall survival in patients with 
metastatic disease that cannot be treated with surgery or radiation. Platinum based 
chemotherapy and EGFR inhibitors have been used, all with a poor overall response rate of 
between 10-20% and none have shown to improve clinical outcomes such as survival or 
progression free survival. Most data in this population is generated by case series and show 
median progression-free survival to be less than 6 months and median overall survival to be 
approximately 10 months (Jarkowski et al A, K Clin Oncol 2014). 
Squamous cell carcinoma of the skin is a tumor related to immunosuppression. Chronic 
immunosuppression of T cells in solid organ transplant patients as well as bone marrow 
transplant patients is linked to an increased incidence of aggressive squamous cell carcinomas. 
In addition HIV and CLL patients also have an increased risk of cSCC development. Studies 
have shown that PD-1 and PD-L1 signals are in part responsible for the development and 
progression of squamous cell carcinomas 
Belai et al (Carcinogenesis 2014) demonstrated that systemic inhibition of PD-1 resulted in a 
decreased number and delayed incidence rate of cSCCs in a murine model of SCC.  This study 
also demonstrated that PD-1-PD-L1 interaction contributes to SCC development as seen in 
increasing numbers of SCC in mice. Increased CD8+ and CD4+ T cells were seen in tumor 
tissue after anti-PD1 treatment and were associated with decrease tumor incidence in the 
murine model. 
cSCC in the advanced setting currently have no therapeutic options that improve outcome or 
are associated with long-term survival. Pre-clinical data demonstrates the importance of the PD-
1 pathway in cSCC development and this is highlighted by the patient population that is mostly 
affected by this disease (patients with T cell suppression).  Because of this, PD-1 blockade 
holds promise to improve outcomes in this clinical setting. Therefore, this trial is to evaluate the 
response rate of metastatic cSCC to pembrolizumab along with correlative studies to establish 
the role of the PD-1 pathway in this disease.   
4.2.2 Rationale for Dose Selection/Regimen/Modification  
An open-label Phase I trial (Protocol 001) is being conducted to evaluate the safety and clinical 
activity of single agent MK-3475.  The dose escalation portion of this trial evaluated three dose 
levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 weeks (Q2W) in subjects with 
advanced solid tumors.  All three dose levels were well tolerated and no dose-limiting toxicities 
were observed.  This first in human study of MK-3475 showed evidence of target engagement 
and objective evidence of tumor size reduction at all dose levels (1 mg/kg, 3 mg/kg and 10 
mg/kg Q2W).  No MTD has been identified to date.  10.0 mg/kg Q2W, the highest dose tested in 
PN001, will be the dose and schedule utilized in Cohorts A, B, C and D of this protocol to test 
for initial tumor activity.  Recent data from other clinical studies within the MK-3475 program has 
shown that a lower dose of MK-3475 and a less frequent schedule may be sufficient for target 
engagement and clinical activity. 
 
PK data analysis of MK-3475 administered Q2W and Q3W showed slow systemic clearance, 
limited volume of distribution, and a long half-life (refer to IB).  Pharmacodynamic data (IL-2 
release assay) suggested that peripheral target engagement is durable (>21 days).  This early 
PK and pharmacodynamic data provides scientific rationale for testing a Q2W and Q3W dosing 
schedule.   
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A population pharmacokinetic analysis has been performed using serum concentration time 
data from 476 patients. Within the resulting population PK model, clearance and volume 
parameters of MK-3475 were found to be dependent on body weight. The relationship between 
clearance and body weight, with an allometric exponent of 0.59, is within the range observed for 
other antibodies and would support both body weight normalized dosing or a fixed dose across 
all body weights.  MK-3475 has been found to have a wide therapeutic range based on the 
melanoma indication.  The differences in exposure for a 200 mg fixed dose regimen relative to a 
2 mg/kg Q3W body weight based regimen are anticipated to remain well within the established 
exposure margins of 0.5 – 5.0 for MK-3475 in the melanoma indication. The exposure margins 
are based on the notion of similar efficacy and safety in melanoma at 10 mg/kg Q3W vs. the 
proposed dose regimen of 2 mg/kg Q3W (i.e. 5-fold higher dose and exposure). The population 
PK evaluation revealed that there was no significant impact of tumor burden on exposure. In 
addition, exposure was similar between the NSCLC and melanoma indications. Therefore, there 
are no anticipated changes in exposure between different indication settings. 
 
The rationale for further exploration of 2 mg/kg and comparable doses of pembrolizumab in 
solid tumors is based on: 1) similar efficacy and safety of pembrolizumab when dosed at either 
2 mg/kg or 10 mg/kg Q3W in melanoma patients, 2) the flat exposure-response relationships of 
pembrolizumab for both efficacy and safety in the dose ranges of 2 mg/kg Q3W to 10 mg/kg 
Q3W, 3) the lack of effect of tumor burden or indication on distribution behavior of 
pembrolizumab (as assessed by the population PK model) and 4) the assumption that the 
dynamics of pembrolizumab target engagement will not vary meaningfully with tumor type. 
The choice of the 200 mg Q3W as an appropriate dose for the switch to fixed dosing is based 
on simulations performed using the population PK model of pembrolizumab showing that the 
fixed dose of 200 mg every 3 weeks will provide exposures that 1) are optimally consistent with 
those obtained with the 2 mg/kg dose every 3 weeks, 2) will maintain individual patient 
exposures in the exposure range established in melanoma as associated with maximal efficacy 
response and 3) will maintain individual patients exposure in the exposure range established in 
melanoma that are well tolerated and safe.  
A fixed dose regimen will simplify the dosing regimen to be more convenient for physicians and 
to reduce potential for dosing errors.  A fixed dosing scheme will also reduce complexity in the 
logistical chain at treatment facilities and reduce wastage. 
 
4.2.3 Rationale for Endpoints 
4.2.3.1 Efficacy Endpoints 
The efficacy endpoints were established to evaluate the effectiveness of pembrolizumab in 
cutaneous squamous cell carcinoma. This will be the first in class use of PD-1 antibodies in this 
disease site and therefore no previous response rate has been established.  
4.2.3.2 Biomarker Research 
Biomarker of PDL-1 has been evaluated in both lung and melanoma and has been a marker 
associated with higher response rates. Therefore our biomarker studies outlined above will 
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further elucidate this marker is cSCC and establish whether it should be used to guide treatment 
options. 
 
5.0 METHODOLOGY 
5.1 
Entry Criteria 
5.1.1 Diagnosis/Condition for Entry into the Trial 
All subjects must have cutaneous squamous cell carcinoma that is not curable by surgery or 
radiation. Both locally advanced and metastatic squamous cell carcinoma will be included.  
5.1.2 Subject Inclusion Criteria 
In order to be eligible for participation in this trial, the subject must: 
1. Be willing and able to provide written informed consent/assent for the trial. 
2. Be ≥ 18 years of age on day of signing informed consent. 
3. Have measurable disease based on RECIST 1.1.   
4. Be willing to provide tissue from a newly obtained core or excisional biopsy of a tumor 
lesion.  Newly-obtained is defined as a specimen obtained up to 6 weeks (42 days) prior 
to initiation of treatment on Day 1.  Subjects for whom newly-obtained samples cannot 
be provided (e.g. inaccessible or subject safety concern) may submit an archived 
specimen only upon agreement from the Sponsor. 
5. Be willing to undergo normal skin biopsy prior to initiation of treatment and after 
treatment. 
6. Have a performance status of 0 or 1 on the ECOG Performance Scale. 
7. Demonstrate adequate organ function as defined in Table 1, all screening labs should be 
performed within 10 days of treatment initiation.   
Table 1  Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
Hematological 
 
Absolute 
neutrophil 
count 
(ANC) 
≥1,500 /mcL 
Platelets 
≥100,000 / mcL 
Hemoglobin 
≥9 g/dL or ≥5.6 mmol/L without transfusion or 
EPO dependency (within 7 days of assessment) 
Renal 
 
Serum creatinine OR 
Measured or calculated 
≤1.5 X upper limit of normal (ULN) OR 
 
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creatinine clearance 
(GFR can also be used in place 
of creatinine or CrCl) 
≥60 mL/min for subject with creatinine levels > 
1.5 X institutional ULN 
Hepatic 
 
Serum total bilirubin 
≤ 1.5 X ULN OR 
 
Direct bilirubin ≤ ULN for subjects with total 
bilirubin levels > 1.5 ULN 
AST (SGOT) and ALT (SGPT) 
≤ 2.5 X ULN  OR 
≤ 5 X ULN for subjects with liver metastases 
Albumin 
>2.5 mg/dL 
Coagulation 
International Normalized Ratio 
(INR) or Prothrombin Time (PT) 
 
Activated Partial 
Thromboplastin Time (aPTT) 
≤1.5 X ULN unless subject is receiving 
anticoagulant therapy 
as long as PT or PTT is within therapeutic 
range of intended use of anticoagulants 
≤1.5 X ULN unless subject is receiving 
anticoagulant therapy 
as long as PT or PTT is within therapeutic 
range of intended use of anticoagulants 
aCreatinine clearance should be calculated per institutional standard. 
 
8. Female subject of childbearing potential should have a negative urine or serum 
pregnancy within 72 hours prior to receiving the first dose of study medication.  If the 
urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be 
required.   
9. Female subjects of childbearing potential should be willing to use 2 methods of birth 
control or be surgically sterile, or abstain from heterosexual activity for the course of the 
study through 120 days after the last dose of study medication (Reference Section 
5.7.2).  Subjects of childbearing potential are those who have not been surgically 
sterilized or have not been free from menses for > 1 year.  
10. Male subjects should agree to use an adequate method of contraception starting with 
the first dose of study therapy through 120 days after the last dose of study therapy. 
5.1.3 Subject Exclusion Criteria 
The subject must be excluded from participating in the trial if the subject: 
1. Is currently participating and receiving study therapy or has participated in a study of an 
investigational agent and received study therapy or used an investigational device within 
4 weeks of the first dose of treatment. 
2. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any 
other form of immunosuppressive therapy within 7 days prior to the first dose of trial 
treatment.  Patients with HIV adequately controlled on antiretrovirals (undetectable viral 
load) and patients with CLL not requiring systemic treatment will be included.  In 
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addition, steroids for physiologic replacement will be allowed (must be equal to or less 
than 10mg of Prednisone/day). 
3. Has a known history of active TB   (Bacillus Tuberculosis) 
 
4. Hypersensitivity to pembrolizumab or any of its excipients. 
5. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study 
Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due 
to agents administered more than 4 weeks earlier. 
6. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy 
within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at 
baseline) from adverse events due to a previously administered agent. 
- 
Note:  Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and 
may qualify for the study. 
- 
Note:  If subject received major surgery, they must have recovered adequately 
from the toxicity and/or complications from the intervention prior to starting 
therapy.   
7. Has a known additional malignancy that is progressing or requires active treatment.  
Exceptions include basal cell carcinoma of the skin that has undergone potentially 
curative therapy or in situ cervical cancer.  Asysmptomatic CLL, not requiring 
intervention will be included as long as patients meet routine laboratory parameters of 
the study as outlined above.  In addition, patients who have undergone curative bone 
marrow transplant and currently not requiring immunosuppression, will be allowed on 
study. 
8. Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis.  Subjects with previously treated brain metastases may participate provided 
they are stable (without evidence of progression by imaging for at least four weeks prior 
to the first dose of trial treatment and any neurologic symptoms have returned to 
baseline), have no evidence of new or enlarging brain metastases, and are not using 
steroids for at least 7 days prior to trial treatment.  This exception does not include 
carcinomatous meningitis which is excluded regardless of clinical stability.   
9. Has active autoimmune disease that has required systemic treatment in the past 2 years 
(i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). 
Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement 
therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic 
treatment.  
10. Has a history of (non-infectious) pneumonitis that required steroids or current 
pneumonitis 
11. Has an active infection requiring systemic therapy. Exception HIV on antiretrovirals with 
negative viral load. 
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12. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the trial, interfere with the subject’s participation for the 
full duration of the trial, or is not in the best interest of the subject to participate, in the 
opinion of the treating investigator.   
13. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 
14. Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the trial, starting with the pre-screening or screening visit through 
120 days after the last dose of trial treatment. 
15. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent. 
16. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected). 
17. Has received a live vaccine within 30 days of planned start of study therapy. 
18. cSCC that is curable via radiation or surgery.  Palliative radiation is allowed as long as 
measurable disease outside radiation field is present for study.  
Note:  Seasonal influenza vaccines for injection are generally inactivated flu vaccines 
and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live 
attenuated vaccines, and are not allowed. 
5.2 
Trial Treatments 
The treatment to be used in this trial is outlined below in Table 2 
Table 2  Trial Treatment 
Drug 
Dose/Pot
ency 
Dose 
Frequen
cy 
Route of 
Administratio
n 
Regimen/Treatm
ent Period 
Use 
Pembrolizumab 
200 mg  
Q3W 
IV infusion 
Day 1 of each 3 
week cycle 
Experimental 
 
Trial treatment should begin on the day of randomization or as close as possible to the date on 
which treatment is allocated/assigned. 
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.   
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Details on preparation and administration of pembrolizumab (MK-3475) are provided in the 
Pharmacy Manual.   
5.2.1.2 Dose Modification  
Adverse events (both non-serious and serious) associated with pembrolizumab exposure may 
represent an immunologic etiology.  These adverse events may occur shortly after the first dose 
or several months after the last dose of treatment. Pembrolizumab must be withheld for drug-
related toxicities and severe or life-threatening AEs as per Table 3 below. See Section 5.6.1for 
supportive care guidelines, including use of corticosteroids. 
Table 3 
Dose Modification Guidelines for Drug-Related Adverse Events 
 
Toxicity 
Hold 
Treatme
nt For 
Grade 
Timing for Restarting 
Treatment 
Discontinue Subject 
Diarrhea/Coli
tis 
2-3 
 
Toxicity resolves to Grade 0-
1. 
Toxicity does not resolve within 12 weeks of 
last dose or inability to reduce corticosteroid to 
10 mg or less of prednisone or equivalent per 
day within 12 weeks. 
4 
Permanently discontinue 
Permanently discontinue 
AST, ALT, or 
Increased 
Bilirubin 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of 
last dose. 
3-4 
Permanently discontinue 
(see exception below)1 
Permanently discontinue 
Type 1 
diabetes 
mellitus (if 
new onset) 
or 
Hyperglycem
ia 
T1DM or  
3-4 
Hold pembrolizumab for new 
onset 
Type 
1 
diabetes 
mellitus 
or 
Grade 
3-4 
hyperglycemia 
associated 
with evidence of beta cell 
failure.  
 
Resume pembrolizumab when patients are 
clinically and metabolically stable. 
Hypophysitis 
2-3 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of 
last dose or inability to reduce corticosteroid to 
10 mg or less of prednisone or equivalent per 
day within 12 weeks. 
4 
Permanently discontinue 
Permanently discontinue 
Hyperthyroidi
sm  
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 
Hypothyroidi
sm 
2-4 
Therapy with pembrolizumab 
can be continued while 
Therapy with pembrolizumab can be continued 
while treatment for the thyroid disorder is 
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Toxicity 
Hold 
Treatme
nt For 
Grade 
Timing for Restarting 
Treatment 
Discontinue Subject 
treatment for the thyroid 
disorder is instituted 
instituted. 
Infusion 
Reaction 
3-4 
Permanently discontinue 
Permanently discontinue 
Pneumonitis 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of 
last dose or inability to reduce corticosteroid to 
10 mg or less of prednisone or equivalent per 
day within 12 weeks. 
3-4 
Permanently discontinue 
Permanently discontinue 
Renal Failure 
or Nephritis 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of 
last dose or inability to reduce corticosteroid to 
10 mg or less of prednisone or equivalent per 
day within 12 weeks. 
3-4 
Permanently discontinue 
Permanently discontinue 
All Other 
Drug-Related 
Toxicity2 
3 or 
Severe 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of 
last dose or inability to reduce corticosteroid to 
10 mg or less of prednisone or equivalent per 
day within 12 weeks. 
4 
Permanently discontinue 
Permanently discontinue 
Note: Permanently discontinue for any severe or Grade 3 drug-related AE that recurs or any life-
threatening event. 
1 For patients with liver metastasis who begin treatment with Grade 2 AST or ALT, if AST or ALT increases 
by greater than or equal to 50% relative to baseline and lasts for at least 1 week then patients should be 
discontinued. 
2 Patients with intolerable or persistent Grade 2 drug-related AE may hold study medication at physician 
discretion.  Permanently discontinue study drug for persistent Grade 2 adverse reactions for which 
treatment with study drug has been held, that do not recover to Grade 0-1 within 12 weeks of the last 
dose.   
 
Dosing interruptions are permitted in the case of medical / surgical events or logistical reasons 
not related to study therapy (e.g., elective surgery, unrelated medical events, patient vacation, 
and/or holidays). Subjects should be placed back on study therapy within 3 weeks of the 
scheduled interruption, unless otherwise discussed with the Sponsor. The reason for 
interruption should be documented in the patient's study record. 
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 3 business 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. 
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Pembrolizumab 200 mg will be administered as a 30 minute IV infusion every 3 weeks.  Sites 
should make every effort to target infusion timing to be as close to 30 minutes as possible.  
However, given the variability of infusion pumps from site to site, a window of -5 minutes and 
+10 minutes is permitted (i.e., infusion time is 30 minutes: -5 min/+10 min). 
The Pharmacy Manual contains specific instructions for the preparation of the pembrolizumab 
infusion fluid and administration of infusion solution. 
5.2.3 Trial Blinding/Masking 
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the 
treatment administered. 
5.3 
Randomization or Treatment Allocation 
This is a nonrandomized trial. 
5.4 
Stratification 
Patients will be stratified by locally advanced versus metastatic disease.  
5.5 
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 sponsor-investigator should discuss any questions regarding 
this with the Merck Clinical team.  The final decision on any supportive therapy or vaccination 
rests with the investigator and/or the subject's primary physician.  
5.5.1 Acceptable Concomitant Medications 
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care.  All concomitant medication will be recorded on the case report form (CRF) 
including all prescription, over-the-counter (OTC), herbal supplements, and IV medications and 
fluids.  If changes occur during the trial period, documentation of drug dosage, frequency, route, 
and date may also be included on the CRF. 
All concomitant medications received within 28 days before the first dose of trial treatment and 
30 days after the last dose of trial treatment should be recorded.  Concomitant medications 
administered after 30 days after the last dose of trial treatment should be recorded for SAEs and 
ECIs as defined in Section 7.2. 
5.5.2 Prohibited Concomitant Medications 
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase (including retreatment for post-complete response relapse) of this trial: 
• 
Antineoplastic systemic chemotherapy or biological therapy  
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• 
Immunotherapy not specified in this protocol 
• 
Chemotherapy not specified in this protocol 
• 
Investigational agents other than pembrolizumab 
• 
Radiation therapy  
o Note:  Radiation therapy to a symptomatic solitary lesion or to the brain may be 
allowed at the investigator’s discretion if approved by the principal investigator. 
• 
Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial.  Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and 
typhoid vaccine.  
• 
Systemic glucocorticoids for any purpose other than to modulate symptoms from an 
event of clinical interest of suspected immunologic etiology.  The use of physiologic 
doses of corticosteroids may be approved after consultation with the Sponsor. 
Subjects who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial.  Subjects 
may receive other medications that the investigator deems to be medically necessary. 
The Exclusion Criteria describes other medications which are prohibited in this trial. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
5.6 
Rescue Medications & Supportive Care 
5.6.1 Supportive Care Guidelines 
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Suggested supportive care measures for the management of adverse 
events with potential immunologic etiology are outlined below and in greater detail in the ECI 
guidance document. Where appropriate, these guidelines include the use of oral or intravenous 
treatment with corticosteroids as well as additional anti-inflammatory agents if symptoms do not 
improve with administration of corticosteroids.   Note that several courses of steroid tapering 
may be necessary as symptoms may worsen when the steroid dose is decreased. For each 
disorder, attempts should be made to rule out other causes such as metastatic disease or 
bacterial or viral infection, which might require additional supportive care. The treatment 
guidelines are intended to be applied when the investigator determines the events to be related 
to pembrolizumab.  
Note: if after the evaluation the event is determined not to be related, the investigator is 
instructed to follow the ECI reporting guidance but does not need to follow the treatment 
guidance (as outlined in the ECI guidance document). Refer to Section 5.2.1 for dose 
modification.  
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event. Suggested conditional procedures, as 
appropriate, can be found in the ECI guidance document. 
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• 
Pneumonitis:  
o For Grade 2 events, treat with systemic corticosteroids. When symptoms 
improve to Grade 1 or less, steroid taper should be started and continued over 
no less than 4 weeks. 
o For Grade 3-4 events, immediately treat with intravenous steroids.  Administer 
additional anti-inflammatory measures, as needed. 
o Add prophylactic antibiotics for opportunistic infections in the case of prolonged 
steroid administration. 
 
 
• 
Diarrhea/Colitis:  
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such as 
diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of bowel 
perforation (such as peritoneal signs and ileus).   
 
o All subjects who experience diarrhea/colitis should be advised to drink liberal 
quantities of clear fluids.  If sufficient oral fluid intake is not feasible, fluid and 
electrolytes should be substituted via IV infusion.  For Grade 2 or higher diarrhea, 
consider GI consultation and endoscopy to confirm or rule out colitis. 
o For Grade 2 diarrhea/colitis that persists greater than 3 days, administer oral 
corticosteroids.  
o For Grade 3 or 4 diarrhea/colitis that persists > 1 week, treat with intravenous 
steroids followed by high dose oral steroids.   
o When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 
 
 
• 
Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) or ≥ 
Grade 3 Hyperglycemia, if associated with ketosis (ketonuria) or metabolic 
acidosis (DKA) 
 
o For T1DM or Grade 3-4 Hyperglycemia 
 
Insulin replacement therapy is recommended for Type I diabetes mellitus 
and for Grade 3-4 hyperglycemia associated with metabolic acidosis or 
ketonuria.  
 
Evaluate patients with serum glucose and a metabolic panel, urine 
ketones, glycosylated hemoglobin, and C-peptide.  
 
• 
Hypophysitis: 
 
o For Grade 2 events, treat with corticosteroids. When symptoms improve to 
Grade 1 or less, steroid taper should be started and continued over no less than 
4 weeks. Replacement of appropriate hormones may be required as the steroid 
dose is tapered. 
o For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed by 
oral corticosteroids. When symptoms improve to Grade 1 or less, steroid taper 
should be started and continued over no less than 4 weeks. Replacement of 
appropriate hormones may be required as the steroid dose is tapered. 
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• 
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 liothyronine, is indicated per standard of care. 
o Grade 3-4 hyperthyroidism  
 
Treat with an initial dose of IV corticosteroid followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid taper 
should be started and continued over no less than 4 weeks. Replacement 
of appropriate hormones may be required as the steroid dose is tapered. 
 
 
• 
Hepatic: 
o For Grade 2 events, monitor liver function tests more frequently until returned to 
baseline values (consider weekly). 
 
Treat with IV or oral corticosteroids 
o For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 hours.  
o When symptoms improve to Grade 1 or less, a steroid taper should be started 
and continued over no less than 4 weeks. 
 
• 
Renal Failure or Nephritis: 
o For Grade 2 events, treat with corticosteroids. 
o For Grade 3-4 events, treat with systemic corticosteroids. 
o When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks.  
 
• 
Management of Infusion Reactions: Signs and symptoms usually develop during or 
shortly after drug infusion and generally resolve completely within 24 hours of 
completion of infusion.  
 
Table 4 below shows treatment guidelines for subjects who experience an infusion reaction 
associated with administration of pembrolizumab (MK-3475). 
Table 4 Infusion Reaction Treatment Guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
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NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
Grade 1 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated 
Increase monitoring of vital signs 
as medically indicated until the 
subject is deemed medically 
stable in the opinion of the 
investigator. 
None 
Grade 2 
Requires infusion 
interruption but responds 
promptly to symptomatic 
treatment (e.g., 
antihistamines, NSAIDS, 
narcotics, IV fluids); 
prophylactic medications 
indicated for < =24 hrs 
Stop Infusion and monitor 
symptoms. 
Additional appropriate medical 
therapy may include but is not 
limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs 
as medically indicated until the 
subject is deemed medically 
stable in the opinion of the 
investigator. 
If symptoms resolve within one 
hour of stopping drug infusion, 
the infusion may be restarted at 
50% of the original infusion rate 
(e.g., from 100 mL/hr to 50 
mL/hr).  Otherwise dosing will be 
held until symptoms resolve and 
the subject should be 
premedicated for the next 
scheduled dose. 
Subjects who develop Grade 2 
toxicity despite adequate 
premedication should be 
permanently discontinued 
from further trial treatment 
administration. 
Subject may be 
premedicated 1.5h (± 
30 minutes) prior to 
infusion of 
pembrolizumab (MK-
3475) with: 
 
Diphenhydramine 50 
mg po (or equivalent 
dose of antihistamine). 
 
Acetaminophen 500-
1000 mg po (or 
equivalent dose of 
antipyretic). 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not 
rapidly responsive to 
symptomatic medication 
and/or brief interruption 
of infusion); recurrence of 
symptoms following initial 
improvement; 
hospitalization indicated 
Stop Infusion. 
Additional appropriate medical 
therapy may include but is not 
limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
No subsequent dosing 
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NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
for other clinical sequelae 
(e.g., renal impairment, 
pulmonary infiltrates) 
Grade 4: 
Life-threatening; pressor 
or ventilatory support 
indicated 
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. 
Appropriate resuscitation equipment should be available in the room and a physician 
readily available during the period of drug administration. 
 
 
 
5.7 
Diet/Activity/Other Considerations 
5.7.1 Diet 
Subjects should maintain a normal diet unless modifications are required to manage an AE such 
as diarrhea, nausea or vomiting. 
5.7.2 Contraception 
Pembrolizumab may have adverse effects on a fetus in utero.  Furthermore, it is not known if 
pembrolizumab has transient adverse effects on the composition of sperm.  Non-pregnant, non-
breast-feeding women may be enrolled if they are willing to use 2 methods of birth control or are 
considered highly unlikely to conceive.  Highly unlikely to conceive is defined as 1) surgically 
sterilized, or 2) postmenopausal (a woman who is ≥45 years of age and has not had menses for 
greater than 1 year will be considered postmenopausal), or 3) not heterosexually active for the 
duration of the study.  The two birth control methods can be either two barrier methods or a 
barrier method plus a hormonal method to prevent pregnancy. Subjects should start using birth 
control from study Visit 1 throughout the study period up to 120 days after the last dose of study 
therapy.  
The following are considered adequate barrier methods of contraception: diaphragm, condom 
(by the partner), copper intrauterine device, sponge, or spermicide.  Appropriate hormonal 
contraceptives will include any registered and marketed contraceptive agent that contains an 
estrogen and/or a progestational agent (including oral, subcutaneous, intrauterine, or 
intramuscular agents). 
Subjects should be informed that taking the study medication may involve unknown risks to the 
fetus (unborn baby) if pregnancy were to occur during the study.  In order to participate in the 
study they must adhere to the contraception requirement (described above) for the duration of 
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the study and during the follow-up period defined in section 7.2.2-Reporting of Pregnancy and 
Lactation to the Sponsor and to Merck.  If there is any question that a subject will not reliably 
comply with the requirements for contraception, that subject should not be entered into the 
study. 
5.7.3 Use in Pregnancy 
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab, the subject 
will immediately be removed from the study.  The site will contact the subject at least monthly 
and document the subject’s status until the pregnancy has been completed or terminated.  The 
outcome of the pregnancy will be reported to the Sponsor and to Merck without delay and within 
24 hours to the Sponsor and within 2 working days to Merck if the outcome is a serious adverse 
experience (e.g., death, abortion, congenital anomaly, or other disabling or life-threatening 
complication to the mother or newborn).   
The study investigator will make every effort to obtain permission to follow the outcome of the 
pregnancy and report the condition of the fetus or newborn to the Sponsor.   If a male subject 
impregnates his female partner the study personnel at the site must be informed immediately 
and the pregnancy reported to the Sponsor and to Merck and followed as described above and 
in Section 7.2.2. 
5.7.4 Use in Nursing Women 
It is unknown whether pembrolizumab is excreted in human milk.  Since many drugs are 
excreted in human milk, and because of the potential for serious adverse reactions in the 
nursing infant, subjects who are breast-feeding are not eligible for enrollment. 
5.8 
Subject Withdrawal/Discontinuation Criteria 
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur.  In addition, a subject may be 
withdrawn by the investigator or the Sponsor if enrollment into the trial is inappropriate, the trial 
plan is violated, or for administrative and/or other safety reasons.  Specific details regarding 
discontinuation or withdrawal are provided in Section 7.1.4 – Other Procedures. 
A subject must be discontinued from the trial for any of the following reasons: 
• 
The subject or legal representative (such as a parent or legal guardian) withdraws 
consent. 
• 
Confirmed radiographic disease progression 
Note: For unconfirmed radiographic disease progression, please see Section 5.2.2 
Note: A subject may be granted an exception to continue on treatment with 
confirmed radiographic progression if clinically stable or clinically improved. 
• 
Unacceptable adverse experiences as described in Section 5.2.1.2 
• 
Intercurrent illness that prevents further administration of treatment 
• 
Investigator’s decision to withdraw the subject 
• 
The subject has a confirmed positive serum pregnancy test 
• 
Noncompliance with trial treatment or procedure requirements 
• 
The subject is lost to follow-up 
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• 
Completed 24 months of uninterrupted treatment with pembrolizumab or 35 
administrations of study medication, whichever is later. 
Note: 24 months of study medication is calculated from the date of first dose. Subjects 
who stop pembrolizumab after 24 months may be eligible for up to one year of additional 
study treatment if they progress after stopping study treatment provided they meet the 
requirements. 
• 
Administrative reasons 
 
The End of Treatment and Follow-up visit procedures are listed in Section 6 (Protocol Flow 
Chart) and Section 7.1.5 (Visit Requirements).  After the end of treatment, each subject will be 
followed for 30 days for adverse event monitoring (serious adverse events will be collected for 
90 days after the end of treatment as described in Section 7.2.3.1).  Subjects who discontinue 
for reasons other than progressive disease will have post-treatment follow-up for disease status 
until disease progression, initiating a non-study cancer treatment, withdrawing consent or 
becoming lost to follow-up.  After documented disease progression each subject will be followed 
by telephone for overall survival until death, withdrawal of consent, or the end of the study, 
whichever occurs first. 
5.8.1 Discontinuation of Study Therapy after CR  
Discontinuation of treatment may be considered for subjects who have attained a confirmed CR 
that have been treated for at least 24 weeks with pembrolizumab and had at least two 
treatments with pembrolizumab beyond the date when the initial CR was declared.  Subjects 
who then experience radiographic disease progression may be eligible for up to one year of 
additional treatment with pembrolizumab via the Second Course Phase at the discretion of the 
investigator if no cancer treatment was administered since the last dose of pembrolizumab, the 
subject meets the safety parameters listed in the Inclusion/Exclusion criteria, and the trial is 
open.  Subjects will resume therapy at the same dose and schedule at the time of initial 
discontinuation.  Additional details are provided in Section 7.1.5.5. 
5.9 
Subject Replacement Strategy 
Subjects that do not complete one cycle of treatment will be replaced.   
5.10 Clinical Criteria for Early Trial Termination 
Early trial termination will be the result of the criteria specified below: 
1. Quality or quantity of data recording is inaccurate or incomplete 
2. Poor adherence to protocol and regulatory requirements 
3. Incidence or severity of adverse drug reaction in this or other studies indicates a potential 
health hazard to subjects 
4. Plans to modify or discontinue the development of the study drug 
 
In the event of Merck decision to no longer supply study drug, ample notification will be provided 
so that appropriate adjustments to subject treatment can be made. 
 
 
 
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6.0 TRIAL FLOW CHART 
6.1 
Study Flow Chart 
Trial Period 
Screening Phase 
Treatment Cycles 
End of 
Treatment 
Post-Treatment 
Treatment 
Cycle(q3week)/Title: 
Pre-
screening  
(Visit 1) 
Main 
Study 
Screening 
(Visit 2) 
1 
2  
3 
4 
To be repeated 
beyond 8 cycles 
D/C 
Safety 
Follow-up 
Survival 
Follow-
Up 
5 
6 
7 
8 
Scheduling Window (Business 
Days): 
 
-28 to -1 
 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
At time of 
D/C 
30 days 
post D/C 
Every 12 
weeks  
Administrative Procedures 
Informed Consent 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics & Medical 
History 
 
x 
 
 
 
 
 
 
 
 
 
 
 
Prior & Concomitant 
Medication Review 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
Drug Administration 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
Post Study Anti-Cancer 
Therapy 
 
 
 
 
 
 
 
 
 
 
x 
x 
x 
Survival Status 
 
 
 
 
 
 
 
 
 
 
x 
x 
x 
Clinical Procedures/Assessments 
Review Adverse Events 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Full Physical Examination 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Vital Signs & Weight 
 
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 
 
Laboratory Procedures/Assessments: Analysis Performed by LOCAL Laboratory 
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Trial Period 
Screening Phase 
Treatment Cycles 
End of 
Treatment 
Post-Treatment 
Treatment 
Cycle(q3week)/Title: 
Pre-
screening  
(Visit 1) 
Main 
Study 
Screening 
(Visit 2) 
1 
2  
3 
4 
To be repeated 
beyond 8 cycles 
D/C 
Safety 
Follow-up 
Survival 
Follow-
Up 
5 
6 
7 
8 
Scheduling Window (Business 
Days): 
 
-28 to -1 
 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
At time of 
D/C 
30 days 
post D/C 
Every 12 
weeks  
Pregnancy Test – Urine or 
Serum 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
PT/INR & aPTT 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
CBC with Differential 
 
x 
 
 
 
 
 
 
 
 
 
 
 
Comprehensive Serum 
Chemistry Panel 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Urinalysis 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
T3, FT4, TSH, ACTH, 
Cortisol 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
Efficacy Measurements 
Tumor Imaging* 
 
x 
 
 
 
 
x 
 
 
 
x 
 
 
Tumor Biopsies/Archival Tissue Collection/Correlative Studies Blood 
Archival or Newly Obtained 
Tissue Collection** 
 
x 
 
 
 
 
x 
 
 
 
x 
 
 
Correlative Studies Blood 
Collection*** 
 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
 
Normal Skin biopsy**            
 
x 
 
 
 
 
x 
 
 
 
x 
 
 
*Tumor Imaging and Assessments will be performed after every 4 cycles. Tumor Imagining at D/C will have a +/-5 business day window. 
**Tumor tissue and Normal Skin biopsy will be performed only at screening, after 4th cycle, and at progression. The normal skin biopsy and newly obtained tumor tissue biopsy are 
optional at time of treatment discontinuation. 
***Blood for correlative will be drawn just prior to each cycle until cycle 5, then at progression 
 
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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 and/or 
Merck for reasons related to subject safety. In some cases, such evaluation/testing may be 
potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations may 
require that additional informed consent be obtained from the subject.  In these cases, such 
evaluations/testing will be performed in accordance with those regulations. 
7.1.1 Administrative Procedures 
7.1.1.1 Informed Consent 
The Investigator must obtain documented consent from each potential subject prior to 
participating in a clinical trial. 
7.1.1.1.1 General Informed Consent 
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature of 
the person conducting the consent discussion.  
A copy of the signed and dated consent form should be given to the subject before participation 
in the trial. 
The initial informed consent form, any subsequent revised written informed consent form and 
any written information provided to the subject must receive the IRB/ERC’s approval/favorable 
opinion in advance of use.  The subject or his/her legally acceptable representative should be 
informed in a timely manner if new information becomes available that may be relevant to the 
subject’s willingness to continue participation in the trial.  The communication of this information 
will be provided and documented via a revised consent form or addendum to the original 
consent form that captures the subject’s dated signature or by the subject’s legally acceptable 
representative’s dated signature. 
Specifics about a trial and the trial population will be added to the consent form template at the 
protocol level.   
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations 
and Sponsor 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.  
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 within 30 days 
after the last dose of trial treatment, the 30 day Safety Follow-up visit must occur before the first 
dose of the new therapy.  Once new anti-cancer therapy has been initiated the subject will move 
into survival follow-up.  
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7.1.1.6 Assignment of Screening Number 
Screening numbers will be assigned at time of consent.  Numbers will be in order of consent.  
7.1.2 Clinical Procedures/Assessments 
7.1.2.1 Adverse Event (AE) Monitoring 
The investigator or qualified designee will assess each subject to evaluate for potential new or 
worsening AEs as specified in the Trial Flow Chart and more frequently if clinically indicated.  
Adverse experiences will be graded and recorded throughout the study and during the follow-up 
period according to NCI CTCAE Version 4.0 (see Section 11.2).  Toxicities will be characterized 
in terms regarding seriousness, causality, toxicity grading, and action taken with regard to trial 
treatment.  
For subjects receiving treatment with pembrolizumab all AEs of unknown etiology associated 
with pembrolizumab exposure should be evaluated to determine if it is possibly an event of 
clinical interest (ECI) of a potentially immunologic etiology (termed immune-related adverse 
events, or irAEs). 
Please refer to section 7.2 for detailed information regarding the assessment and recording of 
AEs.   
7.1.2.2 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,  
7.1.2.3 Directed Physical Exam 
For cycles that do not require a full physical exam per the Trial Flow Chart, the investigator or 
qualified designee will perform a directed physical exam as clinically indicated prior to trial 
treatment administration.   
7.1.2.4 Vital Signs 
The investigator or qualified designee will take vital signs at screening, prior to the 
administration of each dose of trial treatment and at treatment discontinuation as specified in the 
Trial Flow Chart (Section 6.0).  Vital signs should include temperature, pulse, respiratory rate, 
weight and blood pressure.  Height will be measured at screening only. 
7.1.2.5 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.   
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7.1.2.6 Tumor Imaging and Assessment of Disease 
Patients must have measurable disease by RECISIT 1.1 criteria.  Photographs may be used to 
follow disease.  CT or MRI will be used to measure and follow response per RECIST v1.1 
criteria.   
7.1.2.7 Tumor Tissue Collection and Correlative Studies Blood Sampling 
Tumor tissue will be collected at time point designated in the trial flow chart. At baseline archival 
specimen or fresh may be obtained to the equivalent of 15 unstained slides. 
Fresh skin biopsy will consistent of 6mm punches to non-cancerous skin site per institution 
protocol.  
Blood specimens will be obtained at the time of routine lab draw and will consistent of 20cc of 
additional blood drawn into 4 Cytotec tubes set sent to the biorepository of cryopreservation for 
future analysis. 
Blood and tissue specimen will be stored in the laboratories of Mandy Ford, PhD and Brian 
Pollack MD, PhD.  They will be stored for five years after end of the study enrollment. 
Specimens will be destroyed if a patient chooses to with draw consent. 
The following studies will be conducted on blood and tissue specimens: 
1) The frequencies of T cell subsets will be analyzed by flow cytometry using stains for CD3, 
CD8, CD4, CD25, HLA-DR, CD57, CCR7, CD45RA and FoxP3. T cell activation/ 
differentiation will be determined based on CD45RA status, and central and effector 
memory cells will be further subdivided into CCR7+ and CCR7- subsets, respectively (14). 
Special attention will be paid to the frequency of CD8+ effector (HLA-DR+ CCR7- CD45RA-) 
and CD4+CD25+FoxP3+ regulatory T cells (15). This overall T cell subset analysis will be 
carried prior, during, and after treatment with pembrolizumab.  
2) Expression of the T cell inhibitory molecules PD-1, TIM-3, 2B4, CD160, Ptger4, Lag-3 and 
CTLA-4 on CD8+ T cells will be evaluated using fluorophore-labeled monoclonal antibodies 
to the inhibitory molecules and detected by flow cytometry. We hypothesize that reduced 
expression of other T cell coinhibitory molecules following pembrolizumab administration 
will be a biomarker positively associated with responsiveness to treatment and other major 
prognostic indicators for survival.    
3) T cell functionality before and after pembrolizumab will be assessed by flow cytometry-
based intracellular cytokine staining using fluorophore-labeled antibodies to IFN-γ, IL-2, IL-
17 and TNF. We hypothesize that increased expression of these T cell cytokines following 
pembrolizumab administration will be a biomarker positively associated with 
responsiveness to treatment and other major prognostic indicators for survival. 
4) To interrogate the impact of pembrolizumab on cutaneous immune homeostasis and 
immune cell trafficking, biopsies from normal skin and locally recurrent and/or metatatic 
cSCCs will be taken and evaluated using standard histopathology and 
immunohistochemistry.  To identify cytotoxic T cells (CTLs), regulatory T cells (Tregs), 
dendritic cells (DCs) and tumor associated macrophages (TAM), biopsy sections will be 
stained with antibodies recognizing CD8 or FoxP3, for CTLs and T regs respectively, CD68 
for TAMs, and CD1a for tumor infiltrating DCs.  We will couple the aforementioned IHC 
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staining with whole slide scanning and automated image analysis as we have done before 
to quantify IHC signals (Pollack, B et al Clinical Cancer Research, 2011). 
 
  
7.1.3 Laboratory Procedures/Assessments 
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) 
Laboratory tests for hematology, chemistry, urinalysis, and others are specified in Table 5.  
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Table 5  Laboratory Tests 
 
Hematology 
Chemistry 
Urinalysis 
Other 
Hematocrit 
Albumin 
Blood 
Serum β-human chorionic 
gonadotropin† 
Hemoglobin 
Alkaline phosphatase 
Glucose 
  (β-hCG)† 
Platelet count 
Alanine aminotransferase 
(ALT) 
Protein 
PT (INR) 
WBC (total and differential) 
Aspartate aminotransferase 
(AST) 
Specific gravity  
aPTT 
Red Blood Cell Count 
Lactate dehydrogenase (LDH) 
Microscopic exam (If 
abnormal)  
Total thriiodothyronine (T3) 
Absolute Neutrophil Count 
Carbon Dioxide ‡ 
results are noted 
Free tyroxine (T4) 
Absolute Lymphocyte Count   (CO2 or biocarbonate) 
Urine pregnancy test † 
Thyroid stimulating hormone (TSH) 
 
Uric Acid 
 
PK 
 
Calcium 
 
 
 
Chloride 
 
Blood for correlative studies 
 
Glucose 
 
  
 
Phosphorus 
 
  
 
Potassium   
 
  
 
Sodium 
 
  
 
Magnesium 
 
  
 
Total Bilirubin 
 
  
 
Direct Bilirubin (If total bilirubin 
is elevated above the upper 
limit of normal) 
 
 
 
Total protein 
 
 
 
Blood Urea Nitrogen 
 
 
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Hematology 
Chemistry 
Urinalysis 
Other 
† Perform on women of childbearing potential only. If urine pregnancy results cannot be confirmed as negative, a serum pregnancy 
test will be required.   
‡ If considered standard of care in your region. 
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Laboratory tests for screening or entry into the Second Course Phase should be performed 
within 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.  
7.1.3.1 Pharmacokinetic/Pharmacodynamic Evaluations 
7.1.3.1.1 Blood Collection for Serum Pembrolizumab 
Sample collection, storage and shipment instructions for serum samples will be provided in 
the Laboratory Manual. 
The timepoints for PK blood sampling are described in Section 6 – Trial Flow Chart.  
7.1.3.1.2 Blood Collection for Anti-Pembrolizumab Antibodies  
Sample collection, storage and shipment instructions for blood samples will be provided in 
the Laboratory Manual. 
7.1.4 Other Procedures 
7.1.4.1 Withdrawal/Discontinuation 
When a subject discontinues/withdraws prior to trial completion, all applicable activities 
scheduled for the final trial visit should be performed at the time of discontinuation.  Any 
adverse events which are present at the time of discontinuation/withdrawal should be 
followed in accordance with the safety requirements outlined in Section 7.2 - Assessing and 
Recording Adverse Events.  Subjects who a) attain a CR or b) complete 24 months of 
treatment with pembrolizumab may discontinue treatment with the option of restarting 
treatment if they meet the criteria specified in Section 7.1.5.5.  After discontinuing treatment 
following assessment of CR, these subjects should return to the site for a Safety Follow-up 
Visit (described in Section 7.1.5.3.1) and then proceed to the Follow-Up Period of the study 
(described in Section 7.1.5.4). 
7.1.5 Visit Requirements 
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.   Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures. 
7.1.5.1 Safety Follow-up Visits 
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the 
last dose of trial treatment or before the initiation of a new anti-cancer treatment, whichever 
comes first.  All AEs that occur prior to the Safety Follow-Up Visit should be recorded.  
Subjects with an AE of Grade > 1 will be followed until the resolution of the AE to Grade 0-1 
or until the beginning of a new anti-neoplastic therapy, whichever occurs first.  SAEs that 
occur within 90 days of the end of treatment or before initiation of a new anti-cancer 
treatment should also be followed and recorded.  Subjects who are eligible for retreatment 
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with pembrolizumab (as described in Section 7.1.5.5) may have up to two safety follow-up 
visits, one after the Treatment Period and one after the Second Course Phase. 
 
7.1.5.2 Follow-up Visits 
Subjects who discontinue trial treatment for a reason other than disease progression will 
move into the Follow-Up Phase and should be assessed every 6 weeks (42 ± 7 days) by 
radiologic imaging to monitor disease status.  After 1 year, the imaging time point will occur 
every 9 weeks (± 7 days). Every effort should be made to collect information regarding 
disease status until the start of new anti-neoplastic therapy, disease progression, death, end 
of the study or if the subject begins retreatment with pembrolizumab as detailed in Section 
7.1.5.5.  Information regarding post-study anti-neoplastic treatment will be collected if new 
treatment is initiated. 
Subjects who are eligible to receive retreatment with pembrolizumab according to the criteria 
in Section 7.1.5.5 will move from the follow-up phase to the Second Course Phase when 
they experience disease progression.  Details are provided in Section 6.2 – Trial Flow Chart 
for Retreatment.    
7.1.5.2.1 Survival Follow-up 
Once a subject experiences confirmed disease progression or starts a new anti-cancer 
therapy, the subject moves into the survival follow-up phase and should be contacted by 
telephone every 12 weeks to assess for survival status until death, withdrawal of consent, or 
the end of the study, whichever occurs first.  
7.1.5.3 Second Course Phase (Retreatment Period) 
Subjects who stop pembrolizumab with SD or better may be eligible for up to one year of 
additional pembrolizumab therapy if they progress after stopping study treatment.  This 
retreatment is termed the Second Course Phase of this study and is only available if the 
study remains open and the subject meets the following conditions: 
• 
Either  
o Stopped initial treatment with pembrolizumab after attaining an investigator-
determined confirmed CR according to RECIST 1.1, and 
 
Was treated for at least 24 weeks with pembrolizumab before discontinuing 
therapy 
 
Received at least two treatments with pembrolizumab beyond the date 
when the initial CR was declared 
 
 
OR 
o Had SD, PR or CR and stopped pembrolizumab treatment after 24 months of 
study therapy for reasons other than disease progression or intolerability 
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AND 
• 
Experienced an investigator-determined confirmed radiographic disease progression 
after stopping their initial treatment with pembrolizumab 
• 
Did not receive any anti-cancer treatment since the last dose of pembrolizumab 
• 
Has a performance status of 0 or 1 on the ECOG Performance Scale 
• 
Demonstrates adequate organ function as detailed in Section 5.1.2 
• 
Female subject of childbearing potential should have a negative serum or urine 
pregnancy test within 72 hours prior to receiving retreatment with study medication.   
• 
Female subject of childbearing potential should be willing to use 2 methods of birth 
control or be surgically sterile, or abstain from heterosexual activity for the course of 
the study through 120 days after the last dose of study medication (Reference 
Section 5.7.2).  Subjects of child bearing potential are those who have not been 
surgically sterilized or have been free from menses for > 1 year.  
• 
Male subject should agree to use an adequate method of contraception starting with 
the first dose of study therapy through 120 days after the last dose of study therapy.   
• 
Does not have a history or current evidence of any condition, therapy, or laboratory 
abnormality that might interfere with the subject’s participation for the full duration of 
the trial or is not in the best interest of the subject to participate, in the opinion of the 
treating investigator. 
Subjects who restart treatment will be retreated at the same dose and dose interval as when 
they last received pembrolizumab.  Treatment will be administered for up to one additional 
year. 
Visit requirements are outlined in Section 6.0 – Trial Flow Chart. 
 
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 investigational product, is also an adverse event. 
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  
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Examples of this may include, but are not limited to, teething, typical crying in infants and 
children and onset of menses or menopause occurring at a physiologically appropriate time. 
Merck product includes any pharmaceutical product, biological product, device, diagnostic 
agent or protocol-specified procedure, whether investigational (including placebo or active 
comparator medication) or marketed, manufactured by, licensed by, provided by or 
distributed by Merck for human use. 
Adverse events may occur during the course of the use of Merck product in clinical trials or 
within the follow-up period specified by the protocol, or prescribed in clinical practice, from 
overdose (whether accidental or intentional), from abuse and from withdrawal. 
Adverse events may also occur in screened subjects during any pre-allocation baseline 
period as a result of a protocol-specified intervention, including washout or discontinuation 
of usual therapy, diet, placebo treatment or a procedure. 
Progression of the cancer under study is not considered an adverse event unless it is 
considered to be drug related by the investigator. 
All adverse events will be recorded from the time the consent form is signed through 30 
days following cessation of treatment and at each examination on the Adverse Event case 
report forms/worksheets. The reporting timeframe for adverse events meeting any serious 
criteria is described in section 7.2.3.1. 
7.2.1 Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor and to Merck 
For purposes of this trial, an overdose of pembrolizumab will be defined as any dose of 
1,000 mg or greater (≥5 times the indicated dose).  No specific information is available on 
the treatment of overdose of pembrolizumab. Appropriate supportive treatment should be 
provided if clinically indicated. In the event of overdose, the subject should be observed 
closely for signs of toxicity.  Appropriate supportive treatment should be provided if clinically 
indicated. 
 
If an adverse event(s) is associated with (“results from”) the overdose of a Merck product, 
the adverse event(s) is reported as a serious adverse event, even if no other seriousness 
criteria are met. 
If a dose of Merck’s product meeting the protocol definition of overdose is taken without any 
associated clinical symptoms or abnormal laboratory results, the overdose is reported as a 
non-serious Event of Clinical Interest (ECI), using the terminology “accidental or intentional 
overdose without adverse effect.” 
All reports of overdose with and without an adverse event must be reported within 24 hours 
to the Sponsor and within 2 working days hours to Merck Global Safety. (Attn: Worldwide 
Product Safety; FAX 215 993-1220) 
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7.2.2 Reporting of Pregnancy and Lactation to the Sponsor and to Merck 
Although pregnancy and lactation are not considered adverse events, it is the responsibility 
of investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them), including the pregnancy of a male subject's female 
partner that occurs during the trial or within 120 days of completing the trial completing the 
trial, or 30 days following cessation of treatment if the subject initiates new anticancer 
therapy, whichever is earlier.  All subjects and female partners of male subjects who 
become pregnant must be followed to the completion/termination of the pregnancy.  
Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, 
blighted ovum, fetal death, intrauterine death, miscarriage and stillbirth must be reported as 
serious events (Important Medical Events).  If the pregnancy continues to term, the outcome 
(health of infant) must also be reported. 
Such events must be reported within 24 hours to the Sponsor and within 2 working days to 
Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220) 
7.2.3 Immediate Reporting of Adverse Events to the Sponsor and to Merck 
7.2.3.1 Serious Adverse Events 
A serious adverse event is any adverse event occurring at any dose or during any use of 
investigational product that: 
• 
Results in death; 
• 
Is life threatening; 
• 
Results in persistent or significant disability/incapacity; 
• 
Results in or prolongs an existing inpatient hospitalization; 
• 
Is a congenital anomaly/birth defect; 
• 
Is a new cancer (that is not a condition of the study); 
• 
Is associated with an overdose; 
• 
Is another important medical event  
Refer to Table 6 for additional details regarding each of the above criteria. 
Any serious adverse event, or follow up to a serious adverse event, including death due to 
any cause other than progression of the cancer under study that occurs to any subject from 
the time the consent is signed through 90 days following cessation of treatment, or the 
initiation of new anti-cancer therapy, whichever is earlier, whether or not related to Merck 
product, must be reported within 24 hours to the Sponsor and within 2 working days to 
Merck Global Safety.  
Non-serious Events of Clinical Interest will be forwarded to Merck Global Safety and will be 
handled in the same manner as SAEs.  
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to Merck product that is brought to the attention of the investigator at 
any time outside of the time period specified in the previous paragraph also must be 
reported immediately to the Sponsor and to Merck. 
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SAE reports and any other relevant safety information are to be forwarded to the Merck 
Global Safety facsimile number:  +1-215-993-1220 
A copy of all 15 Day Reports and Annual Progress Reports is submitted as required by FDA, 
European Union (EU), Pharmaceutical and Medical Devices agency (PMDA) or other local 
regulators. Investigators will cross reference this submission according to local regulations 
to the Merck Investigational Compound Number (IND, CSA, etc.) at the time of submission.  
Additionally investigators will submit a copy of these reports to Merck & Co., Inc. (Attn: 
Worldwide Product Safety; FAX 215 993-1220) at the time of submission to FDA. 
All subjects with serious adverse events must be followed up for outcome. 
7.2.3.2 Events of Clinical Interest 
Selected non-serious and serious adverse events are also known as Events of Clinical 
Interest (ECI) and must be recorded as such on the Adverse Event case report 
forms/worksheets and reported within 24 hours to the Sponsor and within 2 working days to 
Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220)Events of clinical 
interest for this trial include: 
1.  An overdose of Merck product, as defined in Section 7.2.1 - Definition of an Overdose for 
This Protocol and Reporting of Overdose to the Sponsor, that is not associated with clinical 
symptoms or abnormal laboratory results.  
2.  an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the upper 
limit of normal and, at the same time, an alkaline phosphatase lab value that is less than 2X 
the upper limit of normal, as determined by way of protocol-specified laboratory testing or 
unscheduled laboratory testing.* 
*Note:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may 
require an additional evaluation for an underlying etiology.  The trial site guidance for 
assessment and follow up of these criteria can be found in the Investigator Trial File 
Binder (or equivalent). 
 
 
 
7.2.4 Evaluating Adverse Events 
An investigator who is a qualified physician will evaluate all adverse events according to the 
NCI Common Terminology for Adverse Events (CTCAE), version 4.0. Any adverse event 
which changes CTCAE grade over the course of a given episode will have each change of 
grade recorded on the adverse event case report forms/worksheets. 
All adverse events regardless of CTCAE grade must also be evaluated for seriousness. 
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Table 6  Evaluating Adverse Events 
An investigator who is a qualified physician, will evaluate all adverse events as to: 
V4.0 CTCAE 
Grading 
Grade 1 
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention 
not indicated. 
 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate 
instrumental ADL. 
 
Grade 3 
Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation or hospitalization indicated; disabling; limiting self-care ADL. 
 
Grade 4 
Life threatening consequences; urgent intervention indicated. 
 
Grade 5 
Death related to AE 
Seriousness A serious adverse event is any adverse event occurring at any dose or during any use of investigational  product 
that: 
 
†Results in death; or 
 
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the 
event as it occurred (Note: This does not include an adverse event that, had it occurred in a more severe form, 
might have caused death.); or 
 
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct 
normal life functions); or 
 
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient 
admission, regardless of length of stay, even if the hospitalization is a precautionary measure for continued 
observation. (Note: Hospitalization [including hospitalization for an elective procedure] for a preexisting condition 
which has not worsened does not constitute a serious adverse event.); or 
 
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to 
diagnosis);or 
 
Is a new cancer; (that is not a condition of the study) or 
 
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered 
a serious adverse event. An overdose that is not associated with an adverse event is considered a non-serious 
event of clinical interest and must be reported within 24 hours. 
 
Other important medical events that may not result in death, not be life threatening, or not require 
hospitalization may be considered a serious adverse event when, based upon appropriate medical judgment, the 
event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes 
listed previously (designated above by a †). 
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38 
 
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 investigational product to be discontinued? 
Relationship 
to test drug  
Did the investigational product cause the adverse event? The determination of the likelihood that the Merck 
product caused the adverse event will be provided by an investigator who is a qualified physician. The 
investigator’s signed/dated initials on the source document or worksheet that supports the causality noted on the 
AE form, ensures that a medically qualified assessment of causality was done. This initialed document must be 
retained for the required regulatory time frame. The criteria below are intended as reference guidelines to assist 
the investigator in assessing the likelihood of a relationship between the test drug and the adverse event based 
upon the available information.  
The following components are to be used to assess the relationship between the Merck product and the 
AE; the greater the correlation with the components and their respective elements (in number and/or intensity), the 
more likely the Merck product caused the adverse event (AE): 
 
Exposure 
Is there evidence that the subject was actually exposed to the Merck product such as: reliable 
history, acceptable compliance assessment (pill count, diary, etc.), expected pharmacologic effect, 
or measurement of drug/metabolite in bodily specimen? 
 
Time 
Course 
Did the AE follow in a reasonable temporal sequence from administration of the Merck product?  
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with 
investigational medicinal product)? 
 
Likely 
Cause 
Is the AE not reasonably explained by another etiology such as underlying disease, other 
drug(s)/vaccine(s), or other host or environmental factors 
 
 
 
 
Relationship The following components are to be used to assess the relationship between the test drug and the AE: 
(continued) 
to Merck 
product 
(continued)  
Dechallenge Was the investigational 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.) 
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39 
 
 
Rechallenge Was the subject re-exposed to the Merck product in this study? 
If yes, did the AE recur or worsen? 
If yes, this is a positive rechallenge. If no, this is a negative rechallenge. 
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, 
or (2) the trial is a single-dose drug trial); or (3) Merck product(s) is/are used only one time). 
NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS 
AND WHICH MAY HAVE BEEN CAUSED BY THE MERCK PRODUCT, OR IF REEXPOSURE 
TO THE MERCK PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT RISK TO THE 
SUBJECT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE U.S. 
CLINICAL MONITOR AS PER DOSE MODIFICATION GUIDELINES IN THE PROTOCOL. 
 
Consistency 
with Trial 
Treatment 
Profile 
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the 
Merck product or drug class pharmacology or toxicology? 
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified 
physician according to his/her best clinical judgment, including consideration of the above elements. 
Record one of the 
following 
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a Merck product relationship). 
Yes, there is a reasonable 
possibility of Merck 
product relationship. 
There is evidence of exposure to the Merck product.  The temporal sequence of the AE onset 
relative to the administration of the Merck product is reasonable.  The AE is more likely explained 
by the Merck product than by another cause. 
No, there is not a 
reasonable possibility 
Merck product relationship 
Subject did not receive the Merck product OR temporal sequence of the AE onset relative to 
administration of the Merck product is not reasonable OR there is another obvious cause of the 
AE.  (Also entered for a subject with overdose without an associated AE.) 
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40 
 
7.2.5 Sponsor Responsibility for Reporting Adverse Events 
Written IND safety reports will be submitted to the FDA by the IND sponsor, for serious, 
unexpected suspected adverse reactions within 15 calendar days of learning of its occurrence. If 
the event is fatal or is deemed to be life threatening, the report will be made within 7 calendar 
days.  The IND sponsor will also make an assessment of whether the event constitutes an 
unanticipated problem posing risks to subjects or others (UP). This assessment will be provided 
to the Emory University IRB, which, in turn will make a final determination.  If the Emory IRB 
determines an event is a UP it will notify the appropriate regulatory agencies and institutional 
officials. 
8.0 STATISTICAL ANALYSIS PLAN 
8.1 
Statistical Analysis Plan  
The study will be conducted with optimal two stage design (Simon R Control Clin Trials 1989 
10(1)1-10).   
The Type I error rate is set at 10% and power of this study will be at least 80%. The study will 
be conducted with Simon’s optimal two stage design.  In the first stage, 12 patients will be 
enrolled. If 2 or less of the 12 patients achieve response, the study will close to further accrual 
and pembrolizumab is deemed to be ineffective. If RECIST response is seen in 3 or more of the 
12 patients, then the trial continues with the second stage in which additional 13 patients will be 
enrolled for a total of 25 patients. At the end of complete enrollment, we require 8 or more out of 
the total of 25 subjects to achieve response for the pembrolizumab to be deemed to have 
sufficiently improved clinical activity and justify further clinical development. Otherwise if 7 or 
less out of the 25 patients achieve response, the trial will conclude that pembrolizumab cannot 
increase active anti-tumor effect in patients with metastatic cSCC with an estimated RECIST 
response rate to 40%. 
The response rate of pembrolizumab in metastatic cutaneous squamous cell carcinoma will be 
estimated as percentage and 95% confidence interval (CI) will be constructed assuming a 
binomial distribution. The 6-month progression-free survival and 1 year overall survival of 
metastatic cSCC treated with pembrolizumab will be estimated with Kaplan Meier method and 
compared between different groups using Logrank test. Cox proportional model will be further 
employed to assess the treatment effect on survival with and without adjusting for other factors. 
Similar survival analysis will be conducted for the 6-month progression-free survival and 1 year 
overall survival of metastatic cSCC treated with pembrolizumab.  
8.2 
Exploratory Objective 
OBJECTIVE:  To evaluate biomarkers of response in both tumor specimens and PBMCs in 
patients treated with cSCC. The biomarkers will determine PD-L1 staining on tumor specimens 
and its correlation with response.  The expression of co-stimulator and co-inhibitory molecules 
on and functionality of T cell populations in peripheral blood, tumor, normal skin of patients with 
advanced cSCC before and after treatment with systemic pembrolizumab.  
Hypothesis:  We hypothesize that PD-L1 positive tumors will have a higher response rate than 
PDL1 negative tumors. 
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41 
 
 
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 7. 
Table 7  Product Descriptions 
Product Name & Potency 
Dosage Form 
Pembrolizumab 50 mg 
Lyophilized Powder for Injection 
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 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.   
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. 
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. 
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10.0 ADMINISTRATIVE AND REGULATORY DETAILS 
The Data and Safety Monitoring Committee (DSMC) of the Winship Cancer Institute will provide 
oversight for the conduct of this study.  The DSMC functions independently within Winship 
Cancer Institute to conduct internal monitoring functions to ensure that research being 
conducted by Winship Cancer Institute Investigators produces high-quality scientific data in a 
manner consistent with good clinical practice (GCP) and appropriate regulations that govern 
clinical research.    Depending on the risk level of the protocol, the DSMC review may occur 
every 6 months or annually.  For studies deemed High Risk, initial study monitoring will occur 
within 6 months from the date of the first subject accrued, with 2 of the first 5 subjects being 
reviewed.  For studies deemed Moderate Risk, initial study monitoring will occur within 1 year 
from the date of the first subject accrued, with 2 of the first 5 subjects being reviewed.  
Subsequent monitoring will occur in routine intervals per the Winship Data and Safety 
Monitoring Plan (DSMP).  
The DSMC will review pertinent aspects of the study to assess subject safety, compliance with 
the protocol, data collection, and risk-benefit ratio. Specifically, the Winship Cancer Institute 
Internal Monitors assigned to the DSMC may verify informed consent, eligibility, data entry, 
accuracy and availability of source documents, AEs/SAEs, and essential regulatory documents.  
Following the monitoring review, monitors will provide a preliminary report of monitoring findings 
to the PI and other pertinent individuals involved in the conduct of the study.  The PI is required 
to address and respond to all the deficiencies noted in the preliminary report.  Prior to the 
completion of the final summary report, monitors will discuss the preliminary report responses 
with the PI and other team members (when appropriate).  A final monitoring summary report will 
then be prepared by the monitor.  Final DSMC review will include the final monitoring summary 
report with corresponding PI response, submitted CAPA (when applicable), PI Summary 
statement, and available aggregate toxicity and safety data.   
The DSMC will render a recommendation and rating based on the overall trial conduct.  The PI 
is responsible for ensuring that instances of egregious data insufficiencies are reported to the 
IRB.  Continuing Review submissions will include the DSMC recommendation letter.  Should 
any revisions be made to the protocol-specific monitoring plan after initial DSMC approval, the 
PI will be responsible for notifying the DSMC of such changes.  The Committee reserves the 
right to conduct additional audits if necessary. 
Trial expansion 
The Melanoma Working Group will review the status of every patient enrolled to the study in the 
weekly meetings. The Melanoma working group will make recommendations whether sufficient 
data is available to move forward or stop study after Stage I of the design is completed. The PI 
or designee will obtain approval from the DSMC for enrollment in part II of the study.  The PI will 
provide an update on all relevant safety data of patients entered to a dose level to the DSMC 
when dose escalation is planned. 
 Monitoring plan 
Dr. Kudchadkar and the investigators on the melanoma working group, the clinical research 
coordinator and the regulatory affairs coordinator will meet on a regular basis to review and 
discuss study data to ensure subject safety. The research coordinators will maintain one spread 
sheet which will summarize all the patient data for patients actively being treated on the trial as 
well as a roadmap detailing pending tests/treatments for each individual patient. During the 
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team meeting the group will review the eligibility criteria for each new patient. Adverse events 
(AE/SAE) will be maintained using the standard CTO AE log. Investigators will review the 
toxicities, grade and attribute each toxicity. During the team meeting the group will review all the 
toxicity (AE/SAE) logs, case report form completion and roadmap for each patient on the trial. 
Spot checks will be performed to ensure completion of CRF. All CRF will be maintained 
electronically in OnCore®. Documentation of the discussions during these meetings are 
completed, filed and forwarded to the Winship Cancer Institute (“WCI”) Data Safety Monitoring 
Committee (DSMC) at WCI.  
Prior to study activation, the study team will undergo a training session lead by the study P.I. 
After completion of training, the regulatory staff will obtain signatures for all study team 
members on a training log. The material used for training (i.e. power point slides) and the 
training logs will be maintained by the regulatory staff. In case new team members join the trial 
during the study conduct, individual training will be performed at that time. The P.I. and the 
study investigators will discuss any required modifications to this study at the team meetings. 
No modifications to this study are implemented until they are submitted for review and approved 
by the Emory University IRB. After changes are approved by the IRB, the PI will conduct training 
focused on the new changes. The comments from the WCI DSMC are forwarded to the IRB at 
the time of the annual renewal of this study or sooner if warranted and requested by the WCI 
DSMC.    
The Sponsor-Investigator will ensure that monitoring is competed and all reporting requirements 
are met.  
APPENDICES 
10.1 ECOG Performance Status 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, 
but unable to carry out any work activities. Up and about more than 
50% of waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-
care. Totally confined to bed or chair. 
5 
Dead. 
* As published in Am. J. Clin. Oncol.:  Oken, M.M., Creech, R.H., Tormey, D.C., 
Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: Toxicity And Response 
Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 
1982. The Eastern Cooperative Oncology Group, Robert Comis M.D., Group Chair. 
 
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10.2 Common Terminology Criteria for Adverse Events V4.0 (CTCAE) 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0 will be utilized for adverse event reporting. 
(http://ctep.cancer.gov/reporting/ctc.html) 
10.3 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. 
11.0 REFERENCES 
Jarkowski A 3rd, Hare R, Loud P, Skitzki JJ, Kane JM 3rd, May KS, Zeitouni NC, Nestico J, 
Vona KL, Groman A, Khushalani NI. Systemic Therapy in Advanced Cutaneous Squamous Cell 
Carcinoma (CSCC): The Roswell Park Experience and a Review of the Literature.  Am J Clin 
Oncol. 2014 May 29. 
Belai EB1, de Oliveira CE, Gasparoto TH, Ramos RN, Torres SA, Garlet GP, Cavassani KA, 
Silva JS, Campanelli AP. Carcinogenesis. 2014 Feb;35(2):424-31.  
Pollack BP, Sapkota B, and Cartee TV. Epidermal growth factor receptor inhibition augements 
the expression of MHC class I and II genes.  Clin Cancer Res. 2011 Jul 1: 17(13): 4400-13. 
Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials. 1989 
Mar:10(1):1-10. 
Oken MM, Creech RH, Tormey DC, Hortn J, Davis TE, McFadden ET, and Carbone PP. 
Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 
1982 Dec;5(6):649-55. 
Eisenhauer E$A, Therasee P, Bogaerts J, Schwartz LH, Sarent D, Ford R, Dancey J, Arbuck S, 
Gwyther S, Mooney M, Rubinsein L, Shankar L, Dodd L, Kaplan R, Lacombe D, and Verweij J. 
New response evaluation criteria in solid tumors: revised RECIST guideline (version 1.1). Eur J 
Cancer. 2009 Jan;45(2)228-47. 
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