Neoadjuvant Lenvatinib Plus Pembrolizumab in Resectable Merkel Cell Carcinoma
Phase: PHASE2
Conditions: Merkel Cell Carcinoma, Neuroendocrine Carcinoma of the Skin, Trabecular Carcinoma of the Skin
Sponsor: H. Lee Moffitt Cancer Center and Research Institute

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TITLE:  Neoadjuvant lenvatinib plus pembrolizumab in resectable merkel cell carcinoma 
 
 
 
 
PI: Andrew Brohl, MD 
Sub-Investigator: Nikhil Khushalani, MD 
Sub-Investigator: Zeynep Eroglu, MD 
Sub-Investigator: Ahmad Tarhini, MD 
Sub-Investigator: Vernon Sondak, MD 
Biostatistician: Youngchul Kim, PhD 
Pathologist: Ken Tsai, MD, PhD 
 
 
Protocol Version: 1.5 
 
Protocol Date: 08/12/2020 

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TABLE OF CONTENTS 
Statement of Compliance…………………………………………………………………………………………………………………5 
1.0 Trial Summary…………………………………………………………………………………………………………………………..6 
2.0 Trial Design……………………………………………………………………………………………………………………………….6 
2.1 Trial Design……………………………………………………………………………………………….………………….6 
2.2 Trial Diagram…………………………………………………………………………………………………….…………7 
3.0 Objectives and Hypotheses………………………………………………………………………………………………………..7 
3.1 Primary Objectives and Hypotheses………………………………………………………………………………7 
3.2 Secondary Objective and Hypotheses……………………………………………………………………………7 
3.3 Exploratory Objective………………….……………………………………………………………………………….7 
4.0 Background and Rationale………………………………………………………………………………………………………..8 
4.1 Background………………………………………………………………………………………………………………….8 
4.1.1 
Pharmaceutical and Therapeutic Background……………………………………………8 
4.1.2 
Preclinical and Clinical Trial Data………………………………………………………………10 
4.2 Rationale……………………………………………………………………………………………………………………..10 
4.2.1 
Rationale for the Trial and Selected Population………………………………………..10 
4.2.2 
Justification for Dose…………………………………………………………………………………11 
4.2.3 
Rationale for Endpoints…………………………………………………………………………….13 
4.2.3.1 Efficacy Endpoints………………………………………………………………………..13 
4.2.3.2 Biomarker Research……………………………………………………………………..13 
5.0 Methodology……………………………………………………………………………………….………………………………….13 
5.1 Study Population………………………………………………………………………………………………………..13 
5.1.1 
Participant Inclusion Criterion………………………………………………………………….13 
5.1.2 
Participant Exclusion Criterion…………………………………………………………………15 
5.1.3 
Lifestyle Restrictions……………………………………………………………………………….17 
5.1.3.1 Meals and Dietary Restrictions……………………………………………………17 
5.1.3.2 Contraception…………………………………………………………………………….17 
5.1.4 
Pregnancy………………………………………………………………………………………………18 
5.1.5 
Use in Nursing Women…………………………………………………………………………..18 
5.1.6 
Screen Failures……………………………………………………………………………………….18 
5.2 Trial Treatments………………………………………………………………………………………………………..18 
5.2.1 
Timing of Dose Administration……………………………………………………………….19 
5.2.2 
Study Intervention Compliance………………………………………………………………19 
5.2.3 
Dose Modification and Toxicity management for immune-related AEs 
associated with pembrolizumab…………………………………………………………….19 
5.2.4 
Dose Modifications for Lenvatinib associated toxicities………………………….27 
5.3 Concomitant Medications/Vaccinations…………………………………………………………………..27 
5.3.1 
Acceptable Concomitant Medications……………………………………………………27 
5.3.2 
Prohibited Concomitant Medications……………………………………………………..28 
5.3.3 
Rescue Medications & Supportive Care…………………………………………………..29 
5.4 Participant Withdrawal/Discontinuation Criteria………………………………………………………29 
5.5 Lost to Follow-up………………………………………………………………………………………………………30 
5.6 Clinical Criteria for Early Trial Discontinuation…………………………………………………………..30 
6.0 Trial Flow Chart……………………………………………………………………………………………………………………32 
7.0 Trial Procedures……………………………………………………………………………………………………………………36 
7.1 Trial Procedures……………………………………………………………………………………………………….36 

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7.1.1 
Administrative Procedures………………………………………………………………………36 
7.1.1.1 Informed Consent………………………………………………………………………36 
7.1.1.1.1 
General Informed Consent………………………………………36 
7.1.1.2 Inclusion/Exclusion Criteria…………………………………………………………37 
7.1.1.3 Medical History…………………………………………………………………………..37 
7.1.1.4 Medication Review…………………………………………………………………….37 
7.1.1.4.1 
Prior Medications……………………………………………………37 
7.1.1.4.2 
Concomitant Medications……………………………………….37 
7.1.1.5 Disease Details and Treatments………………………………………………….37 
7.1.1.5.1 
Disease Details………………………………………………………..37 
7.1.1.5.2 
Prior Treatments……………………………………………………..37 
7.1.1.5.3 
Subsequent Anti-Cancer Treatments………………………..37 
7.1.1.6 Registration Procedures………………………………………………………………38 
7.1.2 
Clinical Procedures……………………………………………………………………………………38 
7.1.2.1 Adverse Event Monitoring……………………………………………………………38 
7.1.2.2 Full Physical Exam……………………………………………………………………….38 
7.1.2.3 Directed Physical Exam……………………………………………………………….38 
7.1.2.4 Vital Signs……………………………………………………………………………………38 
7.1.2.5 ECOG performance status……………………………………………………………39 
7.1.2.6 Tumor Imaging…………………………………………………………………………..39 
7.1.2.6.1 
Initial Tumor Imaging………………………………………………39 
7.1.2.6.2 
Tumor Imaging During the Study......……………………….40 
7.1.2.6.3 
Surveillance Imaging……………………………………………….40 
7.1.2.7 Tissue Collection and Correlative Blood Collection………………………40 
7.1.3 
Laboratory Procedures and Assessments………………………………………………..40 
7.1.4 
Other Procedures…………………………………………………………………………………..42 
7.1.4.1 Withdrawal/Discontinuation……………………………………………………..42 
7.1.5 
Visit Requirements…………………………………………………………………………………42 
7.1.5.1 Post-treatment Visits…………………………………………………………………42 
7.1.5.1.1 
Safety follow-up Visit……………………………………………..42 
7.1.5.1.2 
Follow-up Visits………………………………………………………42 
7.1.5.1.3 
Survival Follow-up………………………………………………….43 
7.2 Assessing and Recording Adverse Events ………………………………………………………………….43 
7.2.1 
Defining and Reporting of Overdose……………………………………………………….44 
7.2.2 
Reporting of Pregnancy and Lactation…………………………………………………..45 
7.2.3 
Immediate Reporting of Adverse Events………………………………………………..45 
7.2.3.1 Serious Adverse Events………………………………………………………………45 
7.2.3.2 Events of Clinical Interest…………………………………………………………..46 
7.2.4 
Evaluating Adverse Events……………………………………………………………………...47 
7.2.5 
Sponsor Responsibility for Reporting Adverse Events………………………………51 
8.0 Statistical Analysis Plan………………………………………………………………………………………………………….51 
8.1 Statistical Analysis Plan Summary………………………………………………………………………………51 
8.2 Sample Size Determination and Accrual……………………………………………………………………..51 
8.3 Population for Analysis………………………………………………………………………………………………..51 
8.4 Data Analysis Plan……………………………………………………………………………………………………..52 
9.0 Labeling, Packaging, Storage, and Return of Clinical Supplies………………………………………………….52 
9.1 Investigational Product………………………………………………………………………………………………..52 

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9.2 Packaging and Labeling Information…………………………………………………………………………..52 
9.3 Clinical Supplies Disclosure………………………………………………………………………………………….52 
9.4 Storage and Handling Requirements…………………………………………………………………………….52 
9.5 Returns and Reconciliation…………………………………………………………………………………………….53 
10.0 
Administrative and Regulatory Details…………………………………………………………………………………53 
10.1 Internal Monitoring…………………………………………………………………………………………………….53 
10.2 Quality Assurance and Quality Control…………………………………………………………………………53 
10.3 Data Collection and Management Responsibilities………………………………………………………54 
10.4 Study Records Retention………………………………………………………………………………………………54 
10.5 Protocol Monitoring Committee…………………………………………………………………………………..54 
10.6 External Sites………………………………………………………………………………………………………………..54 
10.6.1 Compliance to the Protocol…………………………………………………………………………54 
10.6.2 Access to Clinical Trial Database………………………………………………………………..54 
10.6.3 Registration Procedures for External Sites…………………………………………………54 
10.6.4 Required Documentation for Extrenal Sites………………………………………………55 
10.6.5 SAE Reporting Special Language for External Sites……………………………………56 
10.6.6 External Site Monitoring and Reporting……………………………………………………56 
11.0 
References……………………………………………………………………………………………………………………………56 
12.0 
Appendices…………………………………………………………………………………………………………………………60 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Statement of Compliance 
 
The trial will be conducted in accordance with the ICH E6, the Code of Federal Regulations on the Protection of 
Human Subjects (45 CFR Part 46), and the Supporting Agency Terms. The Principal Investigator will assure that 
no deviation from, or changes to the protocol will take place without prior agreement from the sponsor and 
documented approval from the Institutional Review Board, except where necessary to eliminate an immediate 
hazard(s) to the trial participants. All personnel involved in the conduct of this study have completed Human 
Subjects Protection Training. 
 
I agree to ensure that all staff members involved in the conduct of this study are informed of their obligation 
to meet the above commitments. 
 
 
Principal Investigator: 
   
 Print/Type Name 
 
 
Signed: 
   
 Date: 
 

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1.0 TRIAL SUMMARY 
Abbreviated Title 
Neoadjuvant lenvatinib plus pembrolizumab in merkel cell carcinoma 
Trial Phase 
II 
Clinical Indication 
Resectable merkel cell carcinoma 
Trial Type 
interventional 
Type of control 
n/a 
Route of administration 
IV/PO 
Trial Blinding 
none 
Treatment Groups  
Single arm 
Number of trial participants 
12 to 26 
Estimated enrollment period 
2 years 
Estimated duration of trial 
5 years 
Duration of Participation 
3 years 
Estimated average length of 
treatment per patient 
1 year 
 
 
 
 
2.0 TRIAL DESIGN 
2.1 Trial Design 
This is a single arm, phase 2 trial with a planned interim analysis for futility.  The first stage will 
enroll 12 patients and expansion to 26 patients total will occur if efficacy criteria are met.  
Patients with Merkel cell carcinoma amenable to complete resection will receive two cycles (6 
weeks) of therapy with the combination of lenvatinib plus pembrolizumab and then proceed to 
planned resection within 2-4 weeks following completion of cycle 2.  Following surgical 
recovery and completion of adjuvant radiation therapy (if indicated), treatment will resume with 
pembrolizumab monotherapy with intent to complete 17 cycles total of pembrolizumab. 
 
 
 
 
 
 

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2.2 Trial Diagram 
 
3.0 OBJECTIVE(S) & HYPOTHESIS(ES) 
3.1 Primary Objective(s) & Hypothesis(es) 
Objective: Assess the pathological complete response rate for resectable Merkel cell 
carcinoma treated with the combination of pembrolizumab and lenvatinib in the neoadjuvant 
setting.   
Hypothesis:  Treatment with pembrolizumab plus lenvatinib will lead to a higher 
pathological complete response rate compared to that expected by anti-PD1 therapy alone. 
3.2 Secondary Objective(s) & Hypothesis(es) 
(1) Objective:  Assess the progression free survival of resectable Merkel cell carcinoma treated 
with neoadjuvant pembrolizumab and lenvatinib 
(2) Objective: Assess the feasibility of neoadjuvant therapy with pembrolizumab and lenvatinib 
for potentially resectable Merkel cell carcinoma 
3.3 Exploratory Objective 
(1) 
Objective: Biobanking for post-hoc exploratory translational immunological endpoints 
Screening/
Baseline 
Two Cycles of 
Pembrolizumab 
+ Lenvatinib 
Surgery +/- 
adjuvant 
radiation 
therapy 
15 Cycles of 
Pembrolizumab  
Follow-up 

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4.0 BACKGROUND & RATIONALE 
4.1 Background 
Merkel cell carcinoma (MCC) is a relatively rare, aggressive cutaneous malignancy.  There are 
approximately 1600 cases of Merkel cell carcinoma in the United States each year [Lemos and 
Nghiem, 2007]. The reported incidence of MCC has almost tripled in the past 20 years, rising 
from 0.15 cases per 100,000 in 1986 to 0.44 cases per 100,000 in 2001[Heath et al.,2008; 
Hodgson et al, 2005]. 
 
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody (mAb) 
with high specificity of binding to the programmed cell death 1 (PD-1) receptor, thus inhibiting 
its interaction with programmed cell death ligand 1 (PD-L1) and programmed cell death ligand 2 
(PD-L2).  Based on preclinical in vitro data, pembrolizumab has high affinity and potent receptor 
blocking activity for PD-1.  Pembrolizumab has an acceptable preclinical safety profile and is in 
clinical development as an intravenous (IV) immunotherapy for advanced malignancies.  
Keytruda® (pembrolizumab) is indicated for the treatment of patients across a number of 
indications because of its mechanism of action to bind the PD-1 receptor on the T cell.  For more 
details on specific indications refer to the Investigator brochure. 
Lenvatinib 
4-[3-Chloro-4-(N’-cyclopropylureido)phenoxyl]- 
7-methoxyquinoline- 
6- 
carboxamide methanesulfonate (lenvatinib mesilate) is an oral, potent multiple receptor tyrosine 
kinase (RTK) inhibitor that selectively inhibits vascular endothelial growth factor (VEGF) 
receptors, VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4), in addition to other pro-
angiogenic and oncogenic pathway-related RTKs including fibroblast growth factor (FGF) 
receptor FGFR1-4, platelet-derived growth factor (PDGF) receptor PDGFRα, KIT, and RET.  
Lenvatinib has an acceptable preclinical safety profile and is in clinical development as an oral 
therapy for advanced malignancies.  Lenvima® (lenvatinib) is indicated for the treatment of 
patients across several indications.  For more details on specific indications refer to the 
Investigator brochure. 
4.1.1 Pharmaceutical and Therapeutic Background 
The importance of intact immune surveillance function in controlling outgrowth of neoplastic 
transformations has been known for decades [Disis, 2010].  Accumulating evidence shows a 
correlation between tumor-infiltrating lymphocytes 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 (T-regs) correlates with improved prognosis and long-term 
survival in solid malignancies, such as ovarian, colorectal, and pancreatic cancer; hepatocellular 
carcinoma; malignant melanoma; and renal cell carcinoma.  Tumor-infiltrating lymphocytes can 
be expanded ex vivo and reinfused, inducing durable objective tumor responses in cancers such 
as melanoma [Dudley et al., 2005; Hunder et al., 2008]. 
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 

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autoimmune reactions. PD-1 (encoded by the gene Pdcd1) is an immunoglobulin (Ig) 
superfamily member related to cluster of differentiation 28 (CD28) and cytotoxic T-lymphocyte-
associated protein 4 (CTLA-4) that has been shown to negatively regulate antigen receptor 
signaling upon engagement of its ligands (PD-L1 and/or PD-L2) [Greenwald et al., 2005; 
Okazaki et al., 2001]. 
The structure of murine PD-1 has been resolved [Zhang et al., 2004].  PD-1 and its family 
members are type I transmembrane glycoproteins containing an Ig-variable–type (IgV-type) 
domain responsible for ligand binding and a cytoplasmic tail 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, and an immunoreceptor tyrosine-based switch 
motif.  Following T-cell stimulation, PD-1 recruits the tyrosine phosphatases, SHP-1 and SHP-2, 
to the immunoreceptor tyrosine-based switch motif within its cytoplasmic tail, leading to the 
dephosphorylation of effector molecules such as CD3 zeta (CD3ζ), protein kinase C-theta 
(PKCθ), and zeta-chain-associated protein kinase (ZAP70), which are involved in the CD3 T-cell 
signaling cascade [Okazaki et al., 2001; Chemnitz et al., 2004; Sheppard et al., 2004; and Riley, 
2009].  The mechanism by which PD-1 down-modulates T-cell responses is similar to, but 
distinct from, that of CTLA-4, because both molecules regulate an overlapping set of signaling 
proteins [Parry et al., 2005; Francisco, 2010].  As a consequence, the PD-1/PD-L1 pathway is an 
attractive target for therapeutic intervention in Merkel cell carcinoma.   
Angiogenesis, the formation of new blood vessels from a pre-existing vascular network, is 
essential for tumor growth and metastasis. The angiogenesis process begins with local 
degradation of the basement membrane surrounding capillaries, followed by invasion of the 
surrounding stroma by underlying endothelial cells in the direction of the angiogenic stimulus.  
Endothelial cell migration is accompanied by the proliferation of endothelial cells and their 
organization into three-dimensional structures that join with other similar structures to form a 
network of new blood vessels. This process involves an alteration in the balance between 
proangiogenic and antiangiogenic molecules.  In Merkel cell carcinoma, increased expression 
of proangiogenic vascular endothelial growth factor receptors (VEGFRs) has been correlated 
with poor prognosis and inhibition of this pathway has been proposed as a rationale target for 
therapy in this disease [Fernandez-Figueras, et al .,2007; Kervarrec, et al., 2019].   
Recent evidence suggests that proangiogenic signaling, especially VEGFR signaling have an 
important immunosuppressive role in the tumor microenvironment (TME), where 
immunosuppressive tumor associated macrophages (TAMs) and regulatory T cells are 
increased, while differentiation/maturation of dendritic cells (antigen-presenting cells) is 
impaired, and CD8+ T cells are depleted.  FGF / FGFR signaling also support migration and 
survival of TAM in the TME.  Accumulation of TAMs in the TME predicts poor prognosis in 
patients with many types of cancers [Joyce and Pollard, 2009; Ding, et al., 2009; Heusinkveld 
and van der Burg, 2011; Takase, et al., 2006)].  TAMs produce a variety of 
cytokines/chemokines such as transforming growth factor β, interleukin- 10, VEGF, and basic 
FGF, and could inhibit the attack of tumor killing CD8+ T cells on cancer cells, as well as 
promoting tumor angiogenesis [Pollard, 2004; Riabov, et al., 2014; Noy and Pollard, 2014].  
Endothelial cells in the TME, under a constitutive proangiogenic signaling could have an 
immunosuppressive function upregulating immune checkpoint molecules, prevent 

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extravasation of CD8+ T cells, and expressing Fas-ligands leading to Fas- mediated apoptosis of 
CD8+ T cells. Therefore, blocking both immune checkpoint signals and proangiogenic 
signaling should be not only a combination of immune therapy and antiangiogenesis therapy, 
but also a new strategy for accelerated anticancer immune therapy [Lantis et al, 2015; Ott, et 
al., 2015; Yang, et al., 2018]. 
Lenvatinib and lenvatinib in combination with immune checkpoint inhibitor, rat anti-murine 
PD-1 mAb showed significant tumor growth inhibition against various murine tumor isografts 
in immunocompetent mice including RCC, lung carcinoma, HCC, and colon carcinoma [Kato 
et al, 2019].  The antitumor activity of the combination was greater than each monotherapy in 
all isograft models tested.  Results of recent in vivo nonclinical pharmacodynamics studies 
suggest that in addition to its antiangiogenesis activity, lenvatinib has an immunomodulatory 
activity probably due to its inhibitory activity against VEGF/VEGFR and involving the 
decrease of immunosuppressive TAMs, increase of activated cytotoxic T cells, and an 
activation of IFN-γ signaling in tumor microenvironment that contributes to its antitumor 
activity.  Since the mode of immunomodulatory activity of lenvatinib is complementary to that 
of an immune checkpoint inhibitor, anti-PD-1 mAb, these nonclinical pharmacodynamics 
results suggest that the combination of lenvatinib and pembrolizumab may provide an effective 
therapeutic option for many cancers. 
 
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 Population 
Merkel cell carcinoma is an aggressive cutaneous malignancy.  The historically reported 5‐year 
relative survival (estimate of MCC‐specific survival) for patients with local, nodal and metastatic 
disease is 64%, 39% and 18% respectively [Lemos et al., 2010].  Therefore even patients with 
potentially surgically resectable disease are at high risk for recurrence and disease-related 
mortality.   
 
For resectable MCC, standard care is directed towards the primary tumor and/or regional 
lymphatics.  This is typically a wide excision of the primary lesion as well as surgical evaluation 
of the regional lymphatics. Since MCC has a high propensity for regional spread via the 
lymphatics, regional lymph nodes are generally evaluated clinically and when indicated, 
pathologically (via sentinel lymph node biopsy and/or lymphadenectomy)[Gupta et al., 2006]. 
For patients with confirmed metastasis in the regional lymph nodes, definitive management is 
usually directed at the regional lymphatics. Such treatment may include either a therapeutic 
lymph node dissection or radiation therapy (RT). Adjuvant RT is commonly used to reduce the 
risk of loco‐regional recurrence, but does not appear to have a significant effect on overall 
survival (OS) [Bhatia et al., 2016]. Adjuvant chemotherapy is offered at some centers to reduce 
the risk of systemic recurrence, but does not appear to have a significant impact on OS [Bhatia et 

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al., 2016] and is not routinely recommended by current guidelines [NCCN version 2.2019]. 
Furthermore, adjuvant chemotherapy can be associated with considerable morbidity in this 
relatively elder population. There is therefore a strong unmet need for effective neoadjuvant 
or adjuvant systemic therapy in MCC patients at high‐risk of recurrence.  
 
Checkpoint inhibitor immunotherapy has recently become standard initial treatment for patients 
with advanced disease based on high response rates as well as response durability in this setting 
[Nghiem et al, 2019; D’Angelo et al, 2018].  Anti-PD-1 therapy therefore makes an attractive 
therapeutic target in the adjuvant or neoadjuvant setting and several of these agents are in 
ongoing single-agent adjuvant clinical trials for high risk disease.  Regarding neoadjuvant 
therapy, in the CheckMate 358 trial of nivolumab in virus-associated cancers, patients with 
resectable Merkel cell carcinoma were treated with two neoadjuvant doses of the anti-PD-1 agent 
nivolumab.  In preliminary reports from this study presented at ASCO 2018, this approach was 
highly feasible and induced a pathological complete response in 47% of tumors that underwent 
central review [Topalian, et al, 2018].  Further study of neoadjuvant immunotherapy in this 
disease was therefore highly encouraged by the authors of this study. 
Single agent anti-PD-1 checkpoint inhibitor therapy, while highly effective in advanced MCC, 
still only benefits approximately half of the population.  Combination therapies adding to an anti-
PD-1 backbone in hopes of increased efficacy is therefore a high priority for study in this 
disease.  Targeting the angiogenic pathway as an addition to anti-PD-1 immunotherapy has a 
strong scientific rationale in MCC and in malignancy more generally (see 4.1.1 for details).  
Specifically, the combination of pembrolizumab and lenvatinib has strong preclinical rationale 
for use and this combination is already in clinical study in several non-MCC cancer histologies.  
In summary, we have compelling rationale for combining pembrolizumab and lenvatinib in 
resectable MCC.  This is a high area of unmet clinical need and the combination proposed is 
supported by strong preclinical rationale across malignancies as well as in MCC specifically.   
4.2.2 Justification for Dose  
The planned dose of pembrolizumab for this study is 200 mg every 3 weeks (Q3W).  Based on 
the totality of data generated in the Keytruda development program, 200 mg Q3W is the 
appropriate dose of pembrolizumab for adults across all indications and regardless of tumor type.  
As outlined below, this dose is justified by: 
• Clinical data from 8 randomized studies demonstrating flat dose- and exposure-efficacy 
relationships from 2 mg/kg Q3W to 10 mg/kg every 2 weeks (Q2W),  
• Clinical data showing meaningful improvement in benefit-risk including overall survival 
at 200 mg Q3W across multiple indications, and 
• Pharmacology data showing full target saturation in both systemic circulation (inferred 
from pharmacokinetic [PK] data) and tumor (inferred from physiologically-based PK 
[PBPK] analysis) at 200 mg Q3W 

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Among the 8 randomized dose-comparison studies, a total of 2262 participants were enrolled 
with melanoma and non-small cell lung cancer (NSCLC), covering different disease settings 
(treatment naïve, previously treated, PD-L1 enriched, and all-comers) and different treatment 
settings (monotherapy and in combination with chemotherapy).  Five studies compared 2 mg/kg 
Q3W versus 10 mg/kg Q2W (KN001 Cohort B2, KN001 Cohort D, KN002, KN010, and 
KN021), and 3 studies compared 10 mg/kg Q3W versus 10 mg/kg Q2W (KN001 Cohort B3, 
KN001 Cohort F2 and KN006).  All of these studies demonstrated flat dose- and exposure-
response relationships across the doses studied representing an approximate 5- to 7.5-fold 
difference in exposure.  The 2 mg/kg (or 200 mg fixed-dose) Q3W provided similar responses to 
the highest doses studied.  Subsequently, flat dose-exposure-response relationships were also 
observed in other tumor types including head and neck cancer, bladder cancer, gastric cancer and 
classical Hodgkin Lymphoma, confirming 200 mg Q3W as the appropriate dose independent of 
the tumor type.  These findings are consistent with the mechanism of action of pembrolizumab, 
which acts by interaction with immune cells, and not via direct binding to cancer cells. 
Additionally, pharmacology data clearly show target saturation at 200 mg Q3W.  First, PK data 
in KN001 evaluating target-mediated drug disposition (TMDD) conclusively demonstrated 
saturation of PD-1 in systemic circulation at doses much lower than 200 mg Q3W.  Second, a 
PBPK analysis was conducted to predict tumor PD-1 saturation over a wide range of tumor 
penetration and PD-1 expression.  This evaluation concluded that pembrolizumab at 200 mg 
Q3W achieves full PD-1 saturation in both blood and tumor. 
Finally, population PK analysis of pembrolizumab, which characterized the influence of body 
weight and other participant covariates on exposure, has shown that the fixed-dosing provides 
similar control of PK variability as weight based dosing, with considerable overlap in the 
distribution of exposures from the 200 mg Q3W fixed dose and 2 mg/kg Q3W dose.  Supported 
by these PK characteristics, and given that fixed-dose has advantages of reduced dosing 
complexity and reduced potential of dosing errors, the 200 mg Q3W fixed-dose was selected for 
evaluation across all pembrolizumab protocols. 
The planned dose of lenvatinib is 20mg orally once daily.  This dose was selected as the 
recommended phase 2 dose when used in combination with pembrolizumab on the basis of 
results from a dose-finding phase 1b study [Taylor et al, 2016].  Of note this same dose 
combination is in use in several ongoing studies of this drug combination across several disease 
histologies.  In advanced endometrial carcinoma, interim analysis of an ongoing study of 
pembroliuzmab plus lenvatinib reported this dose combination to have a manageable toxicity 
profile [Makker et al, 2019].    
4.2.3 Rationale for Endpoints 
4.2.3.1 Efficacy Endpoints 
The study design is a phase II with a primary efficacy endpoint of pathological response.  
Generally, response rate is a well-accepted endpoint for phase II study of oncologic therapies.  
As an example, in a recent review of 87 phase II checkpoint inhibitor trials response rate was 
identified as the most common endpoint [Ritchie, et al., 2018].  Pathological response rate is a 

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potentially more sensitive endpoint to the more typical clinical/radiographic response rate and 
has been well validated in neoadjuvant trials more generally.   Specifically in MCC with 
checkpoint inhibitor treatment, in the preliminary report from the CheckMate 358 trial of 
neoadjuvant nivolumab pathological response rate was higher than radiographic response rate 
[Topalian, et al, 2018].  In advanced MCC, responses to checkpoint inhibitor therapy are often 
durable and correlate strongly with overall survival [Knepper, et al, 2019].  Therefore, we 
propose pathological response rate as an appropriate primary efficacy endpoint for study. 
Additional efficacy endpoints include progression free survival and feasibility of surgery after 
study therapy.   
4.2.3.2 Biomarker Research 
The trial includes a significant biobanking initiative for the purposes of post-hoc biomarker 
research.   
5.0 METHODOLOGY 
5.1 Study Population 
5.1.1 Participant Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
1. Male/female participants who are at least 18 years of age on the day of signing informed 
consent with histologically confirmed diagnosis of Merkel cell carcinoma will be 
enrolled in this study. The clinical stage of the patient must be stage II, III, or IV (AJCC 
8th edition) at the time of enrollment. 
 
Male participants: 
2. A male participant must agree to use contraception as detailed in Appendix 3 of this 
protocol during the treatment period and for at least 6 days after the last dose of study 
treatment and refrain from donating sperm during this period. 
 
Female participants: 
 
3. A female participant is eligible to participate if she is not pregnant (see Appendix 3), not 
breastfeeding, and at least one of the following conditions applies:  
a.) Not a woman of childbearing potential (WOCBP) as defined in Appendix 3  
OR  
b.) A WOCBP who agrees to follow the contraceptive guidance in Appendix 3 during the 
treatment period and for at least 30 days after the last dose of study treatment. 
 

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4. The participant (or legally acceptable representative if applicable) provides written 
informed consent for the trial.   
 
5. Have clinically or radiographically detectable disease that is felt by the treating physician 
to be amenable to complete surgical resection.   
 
6. Have provided archival tumor tissue sample or newly obtained core or excisional biopsy 
of a tumor lesion not previously irradiated.  Formalin-fixed, paraffin embedded (FFPE) 
tissue blocks are preferred to slides.  Newly obtained biopsies are preferred to archived 
tissue. 
Note: If submitting unstained cut slides, newly cut slides should be submitted to the 
testing laboratory within 14 days from the date slides are cut.  
7. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.  
8. Be willing and able to perform home blood pressure monitoring 
9. Have adequate organ function as defined in the following table (Table 1).   
 
Table 1  Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
Hematological 
 
Absolute neutrophil count (ANC) 
≥1500/µL 
Platelets 
≥100 000/µL 
Hemoglobin 
≥9.0 g/dL or ≥5.6 mmol/La 
Renal 
 
Creatinine OR 
Measured or calculatedb creatinine clearance 
(GFR can also be used in place of creatinine or 
CrCl) 
≤1.5 × ULN OR 
≥30 mL/min for participant with creatinine 
levels >1.5 × institutional ULN 
Hepatic 
 
Total bilirubin 
≤1.5 ×ULN OR direct bilirubin ≤ULN for 
participants 
with 
total 
bilirubin 
levels 
>1.5 × ULN 
AST (SGOT) and ALT (SGPT) 
≤2.5 × ULN (≤5 × ULN for participants with 
liver metastases) 

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5.1.2 Participant Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
1. A WOCBP who has a positive urine pregnancy test (see Appendix 3).  If the urine test is 
positive or cannot be confirmed as negative, a serum pregnancy test will be required. 
2. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an 
agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, 
OX-40, CD137). 
 
3. Has receive prior therapy with a systemic anti-VEGFR inhibitor for oncologic purposes 
 
4. Uncontrolled blood pressure (Systolic BP>140 mmHg or diastolic BP >90 mmHg) in 
spite of an optimized regimen of antihypertensive medication.  
 
5. Significant cardiovascular impairment: history of congestive heart failure greater than 
New York Heart Association (NYHA) Class II, unstable angina, myocardial infarction or 
stroke within 6 months of the first dose of study drug, or cardiac arrhythmia requiring 
medical treatment at Screening.  
 
6. Bleeding or thrombotic disorders or subjects at risk for severe hemorrhage. The degree of 
tumor invasion/infiltration of major blood vessels (e.g. carotid artery) should be 
considered because of the potential risk of severe hemorrhage associated with tumor 
shrinkage/necrosis following lenvatinib therapy.   
 
7. Subjects having > 1+ proteinuria on urine dipstick testing unless a 24-hour urine 
collection for quantitative assessment indicates that the urine protein is <1 g/24 hours.   
Coagulation 
 
International normalized ratio (INR) OR 
prothrombin time (PT) 
Activated partial thromboplastin time (aPTT) 
≤1.5 × ULN unless participant is receiving 
anticoagulant therapy as long as PT or aPTT is 
within therapeutic range of intended use of 
anticoagulants 
ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase); AST (SGOT)=aspartate 
aminotransferase (serum glutamic oxaloacetic transaminase); GFR=glomerular filtration rate; ULN=upper 
limit of normal. 
a Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) 
transfusion within last 2 weeks.  
b Creatinine clearance (CrCl) should be calculated per institutional standard. 
Note: This table includes eligibility-defining laboratory value requirements for treatment; laboratory value 
requirements should be adapted according to local regulations and guidelines for the administration of 
specific chemotherapies. 

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8. Has received prior systemic anti-cancer therapy including investigational agents within 
4 weeks [could consider shorter interval for kinase inhibitors or other short half-life 
drugs] prior to [randomization /allocation]. 
Note: Participants must have recovered from all AEs due to previous therapies to 
≤Grade 1 or baseline. Participants with ≤Grade 2 neuropathy may be eligible. 
Note: If participant received major surgery, they must have recovered adequately from 
the toxicity and/or complications from the intervention prior to starting study treatment. 
9. Has received prior radiotherapy within 2 weeks of start of study treatment.  Participants 
must have recovered from all radiation-related toxicities, not require corticosteroids, and 
not have had radiation pneumonitis.  A 1-week washout is permitted for palliative 
radiation (≤2 weeks of radiotherapy) to non-CNS disease. 
 
10. Has received a live vaccine within 30 days prior to the first dose of study drug.  Examples 
of live vaccines include, but are not limited to, the following:  measles, mumps, rubella, 
varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette–Guérin (BCG), 
and typhoid vaccine.  Seasonal influenza vaccines for injection are generally killed virus 
vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live 
attenuated vaccines and are not allowed. 
 
11. Is currently participating in or has participated in a study of an investigational agent or 
has used an investigational device within 4 weeks prior to the first dose of study 
treatment. 
Note:  Participants who have entered the follow-up phase of an investigational study may 
participate as long as it has been 4 weeks after the last dose of the previous 
investigational agent. 
 
12. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in 
dosing exceeding 10 mg daily of prednisone equivalent) or any other form of 
immunosuppressive therapy within 7 days prior to the first dose of study drug. 
 
13. Has a known additional malignancy that is progressing or has required active treatment 
within the past 3 years.  Note:  Participants with basal cell carcinoma of the skin, 
squamous cell carcinoma of the skin, chronic lymphocytic leukemia or other indolent 
malignancy not requiring therapy and not expected to require therapy during the study 
treatment period, carcinoma in situ (e.g. breast carcinoma, cervical cancer in situ) that 
have undergone potentially curative therapy are not excluded. 
14. Has known active CNS metastases and/or carcinomatous meningitis.   

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15. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients. 
 
16. 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.  
17. Has a history of (non-infectious) pneumonitis that required steroids or has current 
pneumonitis. 
18. Has an active infection requiring systemic therapy. 
19. Has a known history of Human Immunodeficiency Virus (HIV).   
20. Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] 
reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is 
detected) infection. Note: no testing for Hepatitis B and Hepatitis C is required unless 
mandated by local health authority.  
21. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the study, interfere with the subject’s participation for 
the full duration of the study, or is not in the best interest of the subject to participate, in 
the opinion of the treating investigator.   
22. Has known psychiatric or substance abuse disorders that would interfere with cooperation 
with the requirements of the trial. 
23. Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the study, starting with the screening visit through 120 days after 
the last dose of trial treatment. 
 
5.1.3 Lifestyle Restrictions 
5.1.3.1 Meals and Dietary Restrictions 
Participants should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea or vomiting. 
5.1.3.2 Contraception 
Pembrolizumab and lenvatinib may have adverse effects on a fetus in utero.  Refer to Appendix 
3 for approved methods of contraception. 

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For this study, male participants will be considered to be of non-reproductive potential if they 
have azoospermia (whether due to having had a vasectomy or due to an underlying medical 
condition).   
5.1.4 Pregnancy 
If a participant inadvertently becomes pregnant while on treatment with pembrolizumab and/or 
lenvatinib, the participant will be immediately discontinued from study treatment.  The site will 
contact the participant at least monthly and document the participant’s status until the pregnancy 
has been completed or terminated.  The outcome of the pregnancy will be reported to Merck 
within 2 working days if the outcome is a serious adverse experience (eg, 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 Merck.  If a male 
participant impregnates his female partner, the study personnel at the site must be informed 
immediately and the pregnancy must be reported to Merck and followed as described in Section 
7.2.2. 
5.1.5 Use in Nursing Women 
It is unknown whether pembrolizumab and/or lenvatinib 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, participants who are breast-feeding are not eligible for enrollment. 
5.1.6   Screen Failures 
 
Screen failures are defined as participants who consent to participate in the clinical trial but are 
not subsequently entered in the study. A minimal set of screen failure information is required to 
ensure transparent reporting of screen failure participants, to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure details, eligibility criteria, 
and any serious adverse event (SAE). 
 
Screen failure individuals who do not meet the criteria for participation in this trial because of a 
modifiable factor may be rescreened. Rescreened participants should be assigned the same 
participant number as for the initial screening. 
 
5.2 Trial Treatments 
The treatment to be used in this trial is outlined below in Table 2 
Table 2  Trial Treatment 
Drug 
Dose/Potency 
Dose 
Frequency 
Route of 
Administration 
Regimen/Treatment 
Period 
Use 

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Drug 
Dose/Potency 
Dose 
Frequency 
Route of 
Administration 
Regimen/Treatment 
Period 
Use 
Pembrolizumab 200 mg 
Q3W 
IV infusion 
Day 1 of each 3 week 
cycle 
Experimental 
Lenvatinib 
20mg 
Daily  
PO 
Day 1-21 of each 3 
week cycle (i.e. 
continuous) for 
cycles #1 and #2 only 
(neoadjuvant) 
Experimental 
 
5.2.1 Timing of Dose Administration 
Trial treatment should be administered on Day 1 of each cycle after all procedures/assessments 
have been completed as detailed on the Trial Flow Chart (Section 6.0).  Trial treatment may be 
administered up to 3 days before or after the scheduled Day 1 of each cycle due to administrative 
reasons. 
All trial treatments will be administered on an outpatient basis. 
Pembrolizumab 200 mg will be administered as a 30 minute IV infusion every 3 weeks.  Sites 
should make every effort to target infusion timing to be as close to 30 minutes as possible.  
However, given the variability of infusion pumps from site to site, a window of -5 minutes and 
+10 minutes is permitted (i.e., infusion time is 30 minutes: -5 min/+10 min). 
Lenvatinib will be self-administered on a once-daily basis.   
The Pharmacy Manual contains specific instructions for the preparation of the pembrolizumab 
infusion fluid and administration of infusion solution. 
5.2.2 Study intervention compliance 
To assess compliance to oral medication, patient daily drug diaries will be utilizing.  This 
participant drug log will be used to calculate study intervention compliance of the self-
administered oral study medication.  
 
To assess compliance of home BP monitoring, a daily blood pressure diary will be utilized.  
 
 
5.2.3 Dose Modification and toxicity management for immune-related AEs associated 
with pembrolizumab 
AEs associated with pembrolizumab exposure may represent an immunologic etiology. These 
immune-related AEs (irAEs) may occur shortly after the first dose or several months after the 
last dose of pembrolizumab treatment and may affect more than on body system simultaneously. 
Therefore, early recognition and initiation of treatment is critical to reduce complications.  Based 
on existing clinical study data, most irAEs were reversible and could be managed with 

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interruptions of pembrolizumab, administration of corticosteroids and/or other supportive care. 
For suspected irAEs, ensure adequate evaluation to confirm etiology or exclude other causes. 
Additional procedures or tests such as bronchoscopy, endoscopy, skin biopsy may be included as 
part of the evaluation. Based on the severity of irAEs, withhold or permanently discontinue 
pembrolizumab and administer corticosteroids. Dose modification and toxicity management 
guidelines for irAEs associated with pembrolizumab are provided in Table 3. 

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Table 3 Dose modification and toxicity management guidelines for immune-related AEs associated with pembrolizumab  
General instructions: 
1. Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks. 
2. For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to Grade 1 or 0 and 
corticosteroid has been tapered. Pembrolizumab should be permanently discontinued if AE does not resolve within 12 weeks of last dose or 
corticosteroids cannot be reduced to ≤10 mg prednisone or equivalent per day within 12 weeks.  
3. For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other immunosuppressive treatment 
should be initiated if irAEs cannot be controlled by corticosteroids. 
 
Immune-related 
AEs 
Toxicity grade or 
conditions 
(CTCAEv5.0) 
Action taken to 
pembrolizumab 
irAE management with 
corticosteroid and/or other 
therapies  
Monitor and follow-up  
Pneumonitis  
Grade 2 
Withhold  
• Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper 
 
• 
Monitor participants for signs and 
symptoms of pneumonitis 
• 
Evaluate participants with suspected 
pneumonitis with radiographic imaging and 
initiate corticosteroid treatment 
• 
Add prophylactic antibiotics for 
opportunistic infections 
Grade 3 or 4, or 
recurrent Grade 2 
Permanently 
discontinue 
Diarrhea / Colitis  Grade 2 or 3 
Withhold 
• Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper 
 
• 
Monitor participants for signs and symptoms 
of enterocolitis (ie, diarrhea, abdominal 
pain, blood or mucus in stool with or 
without fever) and of bowel perforation 
(ie, peritoneal signs and ileus). 
• 
Participants with ≥ Grade 2 diarrhea 

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Grade 4 
Permanently 
discontinue 
suspecting colitis should consider GI 
consultation and performing endoscopy to 
rule out colitis.  
• 
Participants with diarrhea/colitis should be 
advised to drink liberal quantities of clear 
fluids.  If sufficient oral fluid intake is not 
feasible, fluid and electrolytes should be 
substituted via IV infusion. 
AST / ALT 
elevation or 
Increased 
bilirubin 
Grade 2 
Withhold 
• Administer corticosteroids (initial 
dose of 0.5- 1 mg/kg prednisone or 
equivalent) followed by taper 
• 
Monitor with liver function tests (consider 
weekly or more frequently until liver 
enzyme value returned to baseline or is 
stable 
Grade 3 or 4  
Permanently 
discontinue 
• Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper 
Type 1 diabetes 
mellitus (T1DM) 
or 
Hyperglycemia 
 
Newly onset 
T1DM or  
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of β-cell 
failure 
Withhold 
• Initiate insulin replacement 
therapy for participants with 
T1DM  
• Administer anti-hyperglycemic in 
participants with hyperglycemia  
 
• 
Monitor participants for hyperglycemia or 
other signs and symptoms of diabetes. 
Hypophysitis 
Grade 2 
Withhold 
• Administer corticosteroids and 
initiate hormonal replacements as 
clinically indicated.   
 
• 
Monitor for signs and symptoms of 
hypophysitis (including hypopituitarism and 
adrenal insufficiency)  
Grade 3 or 4  
Withhold or 
permanently 
discontinue1  
Hyperthyroidism  
Grade 2 
Continue  
• Treat with non-selective beta-
blockers (eg, propranolol) or 
thionamides as appropriate  
• 
Monitor for signs and symptoms of thyroid 
disorders.  
 
Grade 3 or 4  
Withhold or  
permanently 
discontinue1 
Hypothyroidism 
Grade 2-4 
Continue  
• Initiate thyroid replacement 
hormones (eg, levothyroxine or 
• 
Monitor for signs and symptoms of thyroid 
disorders.  

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23 
 
liothyroinine) per standard of care 
 
Nephritis and 
Renal 
dysfunction 
Grade 2 
Withhold  
• Administer corticosteroids 
(prednisone 1-2 mg/kg or 
equivalent) followed by taper. 
• 
Monitor changes of renal function 
 
Grade 3 or 4  
Permanently 
discontinue 
Myocarditis 
Grade 1 or 2 
Withhold 
• Based on severity of AE 
administer corticosteroids 
• 
Ensure adequate evaluation to confirm 
etiology and/or exclude other causes 
 
Grade 3 or 4 
Permanently 
discontinue 
All other 
immune-related 
AEs 
Intolerable/ 
persistent Grade 2 
Withhold 
• Based on type and severity of AE 
administer corticosteroids  
• 
Ensure adequate evaluation to confirm 
etiology and/or exclude other causes 
 
Grade 3 
Withhold or 
discontinue based 
on the type of 
event.  Events that 
require 
discontinuation 
include and not 
limited to:  
Gullain-Barre 
Syndrome, 
encephalitis 
Grade 4 or 
recurrent Grade 3  
Permanently 
discontinue 
1. Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician.   
NOTE:  
For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, pembrolizumab may be resumed 
when AE resolves to ≤ Grade 2 and is controlled with hormonal replacement therapy or achieved metabolic control (in case of T1DM).   
 
 
 

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Dose modification and toxicity management of infusion-reactions related to pembrolizumab 
Pembrolizumab may cause severe or life threatening infusion-reactions including severe hypersensitivity or anaphylaxis. Signs and 
symptoms usually develop during or shortly after drug infusion and generally resolve completely within 24 hours of completion of 
infusion. Dose modification and toxicity management guidelines on pembrolizumab associated infusion reaction are provided in Table 
4.  
 
Table 4  Pembrolizumab Infusion Reaction Dose modification and Treatment Guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at Subsequent Dosing 
Grade 1 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated 
Increase monitoring of vital signs as medically indicated until the 
participant is deemed medically stable in the opinion of the investigator. 
None 
Grade 2 
Requires therapy or infusion 
interruption but responds 
promptly to symptomatic 
treatment (e.g., antihistamines, 
NSAIDs, narcotics, IV fluids); 
prophylactic medications 
indicated for ≤24 hrs 
Stop Infusion. 
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 
participant is deemed medically stable in the opinion of the investigator. 
If symptoms resolve within 1 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 participant should be premedicated for the next scheduled dose. 
Participants who develop Grade 2 toxicity despite adequate 
premedication should be permanently discontinued from further 
study drug treatment 
Participant may be premedicated 1.5h 
(± 30 minutes) prior to infusion of 
_____ with: 
Diphenhydramine 50 mg po (or 
equivalent dose of antihistamine). 
Acetaminophen 500-1000 mg po (or 
equivalent dose of analgesic). 

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Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial improvement; 
hospitalization indicated for 
other clinical sequelae (e.g., 
renal impairment, pulmonary 
infiltrates) 
Grade 4: 
Life-threatening; pressor or 
ventilatory support indicated 
Stop Infusion. 
Additional appropriate medical therapy may include but is not limited to: 
Epinephrine** 
IV fluids 
Antihistamines 
NSAIDs 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Increase monitoring of vital signs as medically indicated until the 
participant is deemed medically stable in the opinion of the investigator. 
Hospitalization may be indicated. 
**In cases of anaphylaxis, epinephrine should be used immediately. 
Participant is permanently discontinued from further study drug 
treatment. 
No subsequent dosing 
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the period of drug administration. 
For further information, please refer to the Common Terminology Criteria for Adverse Events v5.0 (CTCAE) at http://ctep.cancer.gov 
 

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Other allowed dose interruption for pembrolizumab  
Pembrolizumab may be interrupted for situations other than treatment-related AEs such as 
medical / surgical events or logistical reasons not related to study therapy. Participants 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. 
 
5.2.4 Dose Modifications for lenvatinib associated toxicities 
For intolerable grade 2 toxicities and for all grade 3 toxicities attributable to lenvatinib, 
therapy should be interrupted until resolved to Grade 0-1 or baseline at which point treatment 
can be reinitiated at dose reduction (Table 5).  For hematologic toxicity or proteinuria, 
treatment can restart when resolved to Grade 2 at the discretion of the treating investigator.   
Treatment with lenvatinib should be discontinued in cases of life-threatening reactions 
(Grade 4), with the exception of Grade 4 laboratory abnormalities judged to be non-life 
threatening, in which case they should be managed as severe reactions (e.g. Grade 3).   
Table 5: Lenvatinib dose modifications  
Dose Level 
Daily Dose 
Number of Capsules 
Starting dose 
20 mg orally once daily  
Two 10 mg capsules  
First dose reduction  
14 mg orally once daily 
One 10 mg capsule plus one 
4 mg capsule   
Second dose reduction  
10 mg orally once daily 
One 10 mg capsule  
Third dose reduction  
8 mg orally once daily 
Two 4 mg capsules  
 
5.3 Concomitant Medications/Vaccinations (allowed & prohibited) 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for one of these or other medications 
or vaccinations specifically prohibited during the trial, discontinuation from trial therapy or 
vaccination may be required.  The final decision on any supportive therapy or vaccination 
rests with the investigator and/or the participants's primary physician.  
5.3.1 Acceptable Concomitant Medications 
All treatments that the investigator considers necessary for a participant’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 

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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. 
5.3.2 Prohibited Concomitant Medications 
Parcticipants are prohibited from receiving the following therapies during the Screening and 
Treatment Phase of this trial: 
• Antineoplastic systemic chemotherapy or biological therapy  
• Immunotherapy not specified in this protocol 
• Chemotherapy not specified in this protocol 
• Investigational agents other than pembrolizumab 
• Radiation therapy, with the exception of adjuvant radiation therapy as per the overall 
treatment schema (see section 2.2) 
• Live vaccines within 30 days prior to the first dose of study treatment and while 
participating in the study.  Examples of live vaccines include, but are not limited to, 
the following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, 
and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed 
virus vaccines and are allowed; however, intranasal influenza vaccines (eg, 
FluMist®) are live attenuated vaccines and are not allowed.  
• 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. 
Participants who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the study.  All 
treatments that the Investigator considers necessary for a participant’s welfare may be 
administered at the discretion of the Investigator in keeping with the community standards of 
medical care.   
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing study.  If there is a clinical indication for any medication or vaccination 
specifically prohibited during the study, discontinuation from study therapy or vaccination 
may be required.  The final decision on any supportive therapy or vaccination rests with the 
investigator and/or the participant's primary physician.  However, the decision to continue 
the participant on study treatment requires the mutual agreement of the investigator, the 
Sponsor and the participant. 

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There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
5.3.3 Rescue Medications & Supportive Care 
Participants should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Suggested supportive care measures for the management of AEs with 
potential immunologic etiology are outlined along with the dose modification guidelines in 
Section 5.2.2, [Table 3].  Where appropriate, these guidelines include the use of oral or IV 
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 of the event, it is determined not to be related to pembrolizumab, 
the Investigator does not need to follow the treatment guidance.  Refer to [Table 3] in Section 
5.2.2 for guidelines regarding dose modification and supportive care.  
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event.  
5.4 Participant Withdrawal/Discontinuation Criteria 
Participants may discontinue study treatment at any time for any reason or be dropped from 
the study treatment at the discretion of the investigator should any untoward effect occur.  In 
addition, a participant may be discontinued from study treatment by the investigator or the 
Sponsor if study treatment is inappropriate, the trial plan is violated, or for administrative 
and/or other safety reasons.  Specific details regarding procedures to be performed at study 
treatment discontinuation are provided in Section 7.1.4 – Other Procedures. 
A participant must be discontinued from study treatment but continue to be monitored in the 
study for any of the following reasons: 
• The participant  or participant’s legally acceptable representative requests to 
discontinue study treatment 
• Confirmed disease progression outlined in Section 7.1.2.6 
• Unable to undergo complete surgical resection following the neoadjuvant portion of 
protocol therapy 
• Any progression or recurrence of any malignancy, or any occurrence of another 
malignancy that requires active treatment 
• Unacceptable adverse experiences as described in Section 5.2.2. 

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• The participant has a medical condition or personal circumstance which, in the 
opinion of the investigator and/or sponsor, placed the participant at unnecessary risk 
from continued administration of study treatment. 
• The participant  has a confirmed positive serum pregnancy test 
• Noncompliance with study treatment or procedure requirements 
• Recurrent Grade 2 pneumonitis 
• The participant is lost to follow-up 
• Administrative reasons 
5.5 Lost to Follow-Up 
A participant will be considered lost to follow-up if he or she fails to return for 3 scheduled 
visits and if study site staff are unable to contact the participant.  
 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
• The site will attempt to contact the participant and reschedule the missed visit  within 
a one month time frame and counsel the participant on the importance of maintaining 
the assigned visit schedule and ascertain whether the participant wishes to and/or 
should continue in the study. 
• Before a participant is deemed lost to follow-up, the investigator or designee will 
make every effort to regain contact with the participant (where possible, by making 3 
telephone calls and, if necessary, by sending a certified letter to the participant’s last 
known mailing address or local equivalent methods). These contact attempts should 
be documented in the participant’s medical record or study file.  
• A minimum of 2 years should be spent attempting to locate the patient.  If after that 
period of time the coordinator has sufficiently documented all failed attempts to 
locate the patient, including sending a certified letter with no response, then he or she 
will be considered to have withdrawn from the study for the primary reason of being 
lost to follow-up. 
 
5.6 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 participants 

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

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6.0 TRIAL FLOW CHART 
Trial Period: 
Screening Phase 
Treatment Cyclesa 
End of 
Treatment 
Post-Treatment 
Treatment Cycle/Title: 
Screening Visit  
1 
2  
Pre-
operati
ve 
evaluat
ion 
Post-
operati
ve 
evaluat
ion 
3 
4 
5-17 
(odd) 
6-16 
(even) 
Discontinue 
Safety 
Follow-
up 
Follow 
Up 
Visitsb 
Survival 
Follow-
Upb 
Scheduling Window (Days): 
-28 to -1 
± 3 
± 3 
± 7 
± 7 
± 3 
± 3 
± 3 
± 3 
At time of 
Discontinue 
30±7 
days post 
disconuat
ion 
Every 3 
months±
14 days  
Every 6 
months  
 
Administrative Procedures 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Prior and Concomitant Medication Review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Trial Treatment Administration 
 
X 
X 
 
 
X 
X 
X 
X 
 
 
 
 
Post-study anticancer therapy status 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Survival Status 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
Clinical Procedures/Assessments 
Review Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Full Physical Examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Directed Physical Examination 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Vital Signs and Weightc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECOG Performance Status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Laboratory Procedures/Assessments: analysis performed by LOCAL laboratory 
Pregnancy Test – Urine or Serum β-HCG 
X 
 
 
 
 
X 
 
X 
 
X 
X 
 
 
PT/INR and aPTT 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
CBC with Differential 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Comprehensive Serum Chemistry Panel 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Urinalysis 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 

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Trial Period: 
Screening Phase 
Treatment Cyclesa 
End of 
Treatment 
Post-Treatment 
Treatment Cycle/Title: 
Screening Visit  
1 
2  
Pre-
operati
ve 
evaluat
ion 
Post-
operati
ve 
evaluat
ion 
3 
4 
5-17 
(odd) 
6-16 
(even) 
Discontinue 
Safety 
Follow-
up 
Follow 
Up 
Visitsb 
Survival 
Follow-
Upb 
Scheduling Window (Days): 
-28 to -1 
± 3 
± 3 
± 7 
± 7 
± 3 
± 3 
± 3 
± 3 
At time of 
Discontinue 
30±7 
days post 
disconuat
ion 
Every 3 
months±
14 days  
Every 6 
months  
T3, FT4 and TSH 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Efficacy Measurements 
Tumor Imaging/Surveillance Imagingd 
X 
 
 
X 
 
X 
 
 
 
 
 
X 
 
 
Tumor Biopsies/Archival Tissue Collection/Correlative Studies Blood 
Archival or Newly Obtained Tissue 
Collectione 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Correlative Studies Blood Collectionf 
X 
 
X 
X 
X 
 
X 
 
 
X 
 
 
 

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Trial Period: 
Screening Phase 
Treatment Cyclesa 
End of 
Treatment 
Post-Treatment 
Treatment Cycle/Title: 
Screening Visit  
1 
2  
Pre-
operati
ve 
evaluat
ion 
Post-
operati
ve 
evaluat
ion 
3 
4 
5-17 
(odd) 
6-16 
(even) 
Discontinue 
Safety 
Follow-
up 
Follow 
Up 
Visitsb 
Survival 
Follow-
Upb 
Scheduling Window (Days): 
-28 to -1 
± 3 
± 3 
± 7 
± 7 
± 3 
± 3 
± 3 
± 3 
At time of 
Discontinue 
30±7 
days post 
disconuat
ion 
Every 3 
months±
14 days  
Every 6 
months  
 
a Treatment consists of 21 day cycles.  Cycle #1 and #2 are to be administered with neoadjuvant intent.  A pre-operative evaluation will 
be undertaken at the completion of cycle #2 and surgery will be planned 2-4 weeks following completion of cycle #2 unless delays 
are clinically necessary for toxicity or administrative concerns.  A post-operative study evaluation will take place 2 weeks ± 7 days 
after surgical resection.  Adjuvant radiation therapy may then be administered as per standard of care of the treating institution if 
indicated.  Cycles 3-17 will take place in the adjuvant setting and after completion of radiation therapy (if administered). Cycle #3 
can be scheduled once adequate surgical recovery has been achieved as per treating physician and after radiation therapy is complete 
(if administered) and radiation associated toxicities have resolved to Grade 1 or less (if applicable) but must be started within 12 
weeks of completion of locally directed therapies (surgery ± radiation).   For treatment cycle related laboratories and ECOG 
assessment, these may be completed up to 72 hours prior to dosing.   
bPost-treatment study follow-up visits will be conducted for a 3 year period starting from the date of surgery.  The follow-up visits 
should be scheduled to be concurrent with timing of surveillance imaging (see d) ± 14 days.  Survival Follow-up will continue to 
complete 5 years total starting from the date of surgery. 
cIn addition to vital sign monitoring during study visits, patients will be instructed to conduct daily home monitoring of  blood pressure 
while on active therapy and to contact the study team if BP increases to >140 systolic or >90 diastolic.  Vital signs should include 
temperature, pulse, respiratory rate, weight and blood pressure.  Height should be measured at screening visit only. 
dComputed tomography (CT) scan of any known sites of measureable disease are required at the time of screening and pre-operative 
evaluations, with the exception of clinically measureable cutaneous disease. For clinically measurable cutaneous disease, clinical 
measurements may instead be substituted at these timepoints. For surveillance for metastatic disease, either CT scan including chest, 
abdomen and pelvis or positron emission tomography/computed tomography (PET/CT) scans may be utilized as per standard of care 
of the treating institution.  Surveillance imaging for metastatic disease should be performed at the time of screening, prior to the start 
of adjuvant systemic therapy (cycle #3) and every 3 months (90 days ± 14 days) thereafter, including both during the treatment and 
post-treatment follow-up timeframe.   
eIn addition to tissue collected during the screening phase, tissue from the surgical resection performed will also be collected for 
assessment of pathological response as well as for correlative studies.   New biopsy is not required at the time of screening if 
archival tissue is available. 
fCorrelative blood will include collection of 40mL of blood in green top tubes at all marked timepoints. This will be separated for 
PBMC and plasma and banked for later use.  At screening, Cycle #2, pre-operative, post-operative, Cycle #4 and end of treatment 
timepoints correlative studies will also include anti merkel cell panel (AMERK) testing if the screening sample has detectable level 
of merkel cell oncoprotein.  If the screening AMERK timepoint has no detectable merkel cell oncoprotein, then this test is not 
repeated. 

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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 participant 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 participant.  In these cases, 
such evaluations/testing will be performed in accordance with those regulations. 
7.1.1 Administrative Procedures 
7.1.1.1 Informed Consent 
The Investigator or designated staff must obtain documented consent from each potential 
participant prior to participating in a clinical trial. 
An optional informed consent to allow for biobanking of collected specimens for future 
unspecified studies will also be presented to the patient.  
7.1.1.1.1 General Informed Consent 
Consent must be documented by the participant’s dated signature or by the participant’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 participant before 
participation in the trial. 
The initial informed consent form, any subsequent revised written informed consent form 
and any written information provided to the participant must receive the IRB/ERC’s 
approval/favorable opinion in advance of use.  The participant or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available 
that may be relevant to the participant’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 participant’s dated signature 
or by the participant’s legally acceptable representative’s dated signature. 
Specifics about a trial and the trial population will be added to the consent form template at 
the protocol level.   

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The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations 
and Sponsor requirements. 
 
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 participant 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 participant 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 participant 
within 28 days before starting the trial.  Treatment for the disease for which the participant 
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 participant 
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. 

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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 participant 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 
participant will move into survival follow-up.  
7.1.1.6 Registration Procedure 
All subjects must be registered with the Moffitt Clinical Research Network (MCRN) at 
Moffitt Cancer Center to be able to participate in the trial.  The participating site must fax or 
email the completed study specific eligibility checklist and registration forms, supporting 
documents and signed informed consent to the Coordinating Center.  Once documents are 
received, the MCRN research coordinator will review them to confirm eligibility and to 
complete the registration process.  If eligibility cannot be confirmed, the research coordinator 
will query the site ofr clarification or additional documents as needed.  Subjects failing to 
meet all study eligibility will not be registered and will be unable to participate in the trial.   
7.1.2 Clinical Procedures/Assessments 
7.1.2.1 Adverse Event (AE) Monitoring 
The investigator or qualified designee will assess each participant 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 5.0 (see Appendix 2).  Toxicities 
will be characterized in terms regarding seriousness, causality, toxicity grading, and action 
taken with regard to trial treatment.  
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.   

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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 Appendix 1) at 
screening, prior to the administration of each dose of trial treatment, at discontinuation of 
trial treatment, and at the 30 day safety follow-up visit as specified in the Trial Flow Chart.   
7.1.2.6 Tumor Imaging and Assessment of Disease Progression 
Tumor imaging is strongly preferred to be acquired by computed tomography (CT) with 
iodinated contrast unless the contrast is contraindicated.  The same imaging technique 
regarding modality, ideally the same scanner, and the use of contrast should be used in a 
participant throughout the study to optimize the reproducibility of the assessment of existing 
and new tumor burden and improve the accuracy of the assessment of response or 
progression based on imaging. 
For patients with measurable disease (not required for study entry) tumor response to 
neoadjuvant therapy will be assessed per RECIST 1.1 comparing the screening and pre-
operative imaging.   
Progressive disease will be defined by the detection (clinically or radiographically) of any 
recurrent disease following complete surgical resection or by progression of disease that is 
not amenable to complete surgical resection prior to planned surgery.   Of note, RECIST 1.1 
will NOT be utilized to define disease progression during the neoadjuvant period to account 
for the unique tumor response seen with immunotherapeutic drugs (i.e. possibility of 
pseudoprogresssion during this 6 week period).  When clinically stable, participants should 
not be discontinued from the trial at this timepoint but instead be allowed to proceed with 
complete surgical resection as planned.  Completion of planned adjuvant trial therapy will be 
allowed at the discretion of the treating physician in this scenario provided that disease 
recurrence is not noted in the post-surgery period.  This allowance to continue treatment 
despite initial radiologic PD takes into account the observation that some participants can 
have a transient tumor flare in the first few months after the start of immunotherapy, and then 
experience subsequent disease response. 
7.1.2.6.1 Initial Tumor Imaging 
Initial screening tumor imaging is required of the chest, abdomen and pelvis as well as any 
other known sites of disease with the exception of clinically measureable cutaneous disease. 
For clinically measurable cutaneous disease, clinical measurements may instead be 
substituted for these areas. 

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Tumor imaging performed as part of routine clinical management is acceptable for use as 
screening tumor imaging if they are of diagnostic quality and performed within 28 days prior 
to the date of allocation and can be assessed by the central imaging vendor.  
7.1.2.6.1 Tumor Imaging During the Study 
For patients with measurable disease, the first and only follow-up on-study imaging 
assessment should be performed at the time of the pre-operative evaluation, i.e. 6 weeks (42 
days ±7 days]) from the date of C1D1, and should include all known sites of disease with the 
exception of clinically measureable cutaneous disease. For clinically measurable cutaneous 
disease, clinical measurements may instead be substituted for these areas.  For patients 
without measurable disease at baseline, tumor imaging is not required at this time point but 
may be implemented at the discretion of the treating physician.  Following the pre-operative 
restaging scan, patients who continue on study will have undergone complete surgical 
resection and therefore be followed only with surveillance imaging.   
7.1.2.6.2 Surveillance Imaging 
Surveillance imaging should first be performed prior to the start of adjuvant systemic 
therapy.  This first post-surgical surveillance imaging should be performed within 28 days of 
the start of the first adjuvant systemic therapy cycle (Cycle #3).  Subsequent surveillance 
imaging should be performed every 3 months (90 days ±14 days) including during the 
follow-up period. 
7.1.2.7 Tumor Tissue Collection and Correlative Studies Blood Sampling 
Correlative blood will include collection of 40mL of blood in green top tubes at serial 
timepoints (see section 6.1). This collection will be separated for PBMC and plasma and 
banked for later use with the Kenneth Tsai laboratory at Moffitt Cancer Center.  At 
screening, Cycle #2, post-operative, Cycle #4 and end of treatment timepoints correlative 
studies will also include anti merkel cell panel (AMERK) testing if the screening AMERK 
test has detectable levels of Merkel cell polyomavirus oncoprotein. 
Tumor tissue will be collected either archival or newly obtained at the time of screening and 
will be collected as well as from the surgical specimen when the patient undergoes complete 
surgical resection.   
7.1.3 Laboratory Procedures/Assessments 
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below.  
Laboratory tests for hematology, chemistry, urinalysis, and others are specified in Table 6.   

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Table 6 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 
 
 
 
Calcium 
 
 
 
Chloride 
 
Blood for correlative studies 
 
Glucose 
 
  
 
Phosphorus 
 
  
 
Potassium   
 
  
 
Sodium 
 
  
 
Magnesium 
 
  
 
Total Bilirubin 
 
  
 
Direct Bilirubin (If total bilirubin is 
elevated above the upper limit of 
normal) 
 
 
 
Total protein 
 
 
 
Blood Urea Nitrogen 
 
 
† Perform on women of childbearing potential only. If urine pregnancy results cannot be confirmed as negative, a serum pregnancy test will be required.   
‡ If considered standard of care in your region. 
 
 
 

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For treatment cycles laboratories, 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.  
 
7.1.4 Other Procedures 
7.1.4.1 Withdrawal/Discontinuation 
When a participant 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.  After discontinuing treatment following completion of study 
therapy, participants 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 7.1.5.3.2). 
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 Post-Treatment Visits 
7.1.5.3.1 Safety Follow-Up Visit 
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the 
last dose of study 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.  
Participants 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-cancer therapy, whichever occurs first.  SAEs that 
occur within 90 days of the end of treatment or before initiation of a new anti-cancer 
treatment should also be followed and recorded.   
7.1.5.3.2 Follow-up Visits 
Participants who discontinue study treatment for a reason other than disease progression will 
move into the Follow-Up Phase and should be assessed every 3 months (90 ± 14 days) by 
radiologic imaging to monitor disease status.  After 3 years of follow-up (starting post 
complete resection), patients will be transitioned to survival follow-up. Every effort should 
be made to collect information regarding disease status until the start of new anti-cancer 
therapy, disease progression, death, or end of the study.  Information regarding post-study 
anti-cancer treatment will be collected if new treatment is initiated. 

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7.1.5.3.3 Survival Follow-up 
Participants who complete the planned follow-up interval, or those who experience disease 
progression or start a new anticancer therapy, will move into the Survival Follow-Up Phase 
and should be contacted by telephone every 6 months (180 days ± 14 days) to assess for 
survival status until death, withdrawal of consent, or the end of the trial, whichever occurs 
first.  
 
7.2 Assessing and Recording Adverse Events 
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation participant administered a pharmaceutical product and which does not 
necessarily have to have a causal relationship with this treatment. An adverse event can 
therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, 
for example), symptom, or disease temporally associated with the use of a medicinal product 
or protocol-specified procedure, whether or not considered related to the medicinal product 
or protocol-specified procedure.  Any worsening (i.e., any clinically significant adverse 
change in frequency and/or intensity) of a preexisting condition that is temporally associated 
with the use of the Merck’s product, is also an adverse event. 
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  
Examples of this may include, but are not limited to, teething, typical crying in infants and 
children and onset of menses or menopause occurring at a physiologically appropriate time. 
Merck product includes any pharmaceutical product, biological product, device, diagnostic 
agent or protocol-specified procedure, whether investigational (including placebo or active 
comparator medication) or marketed, manufactured by, licensed by, provided by or 
distributed by Merck for human use.  For the purposes of this study both pembrolizumab and 
lenvatinib are considered Merck products. 
Adverse events may occur during the course of the use of Merck product in clinical trials, or 
as prescribed in clinical practice, from overdose (whether accidental or intentional), from 
abuse and from withdrawal. 
All AEs, SAEs and other reportable safety events that occur after the consent form is signed 
but before treatment allocation/randomization must be reported by the investigator if the 
participant is receiving placebo run-in or other run-in treatment, if the event cause the 
participant to be excluded from the study, or is the result of a protocol-specified intervention, 
including but not limited to washout or discontinuation of usual therapy, diet, or a procedure.  
● All AEs from the time of treatment allocation/randomization through 30 days following 
cessation of study treatment must be reported by the investigator.  

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● All AEs meeting serious criteria, from the time of treatment allocation/randomization 
through 90 days following cessation of study treatment, or 30 days following cessation of 
study treatment if the participant initiates new anticancer therapy, whichever is earlier must 
be reported by the investigator.  
● All pregnancies and exposure during breastfeeding, from the time of treatment 
allocation/randomization through 120 days following cessation of study treatment, or 30 days 
following cessation of study treatment if the participant initiates new anticancer therapy  
must be reported by the investigator.  
● Additionally, any SAE brought to the attention of an investigator at any time outside of the 
time period specified above must be reported immediately by the investigator if the event is 
considered to be drug-related. 
Investigators are not obligated to actively seek AE or SAE or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study treatment or study participation, the 
investigator must promptly notify Merck. 
7.2.1 Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor and to Merck 
For purposes of this study, 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. In the event of overdose, the participant should 
be observed closely for signs of toxicity.  Appropriate supportive treatment should be 
provided if clinically indicated. 
For purposes of this study, an overdose of lenvatinib will be defined as any dose of 40 mg or 
greater (≥2 times the indicated dose).  No specific information is available on the treatment 
of overdose of lenvatinib.  In the event of overdose, the participant should be observed 
closely for signs of toxicity and subsequent dose(s) may be held at the discretion of the 
treating physician.  Appropriate supportive treatment should be provided if clinically 
indicated. 
If an adverse event(s) is associated with (“results from”) the overdose of a Merck product, 
the adverse event(s) is reported as a serious adverse event, even if no other seriousness 
criteria are met. 
If a dose of Merck’s product meeting the protocol definition of overdose is taken without any 
associated clinical symptoms or abnormal laboratory results, the overdose is reported as a 
non-serious Event of Clinical Interest (ECI), using the terminology “accidental or intentional 
overdose without adverse effect.” 

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All reports of overdose with and without an adverse event must be reported within 24 hours 
to the Sponsor and within 2 working days hours to Merck Global Safety. (Attn: Worldwide 
Product Safety; FAX 215-661-6229) 
7.2.2 Reporting of Pregnancy and Lactation to the Sponsor and to Merck 
Although pregnancy and infant exposure during breast feeding are not considered adverse 
events, it is the responsibility of investigators or their designees to report any pregnancy or 
lactation in a participant (spontaneously reported to them) that occurs during the study. 
Pregnancies and infant exposures during breastfeeding that occur after the consent form is 
signed but before treatment allocation/randomization must be reported by the investigator if 
they cause the participant to be excluded from the trial, or are the result of a protocol-
specified intervention, including but not limited to washout or discontinuation of usual 
therapy, diet, placebo treatment or a procedure.   
Pregnancies and infant exposures during breastfeeding that occur from the time of treatment 
allocation/randomization through 120 days following cessation of Sponsor’s product, or 30 
days following cessation of treatment if the participant initiates new anticancer therapy, 
whichever is earlier, must be reported by the investigator.  All reported pregnancies 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 215-661-6229) 
7.2.3 Immediate Reporting of Adverse Events to the Sponsor and to Merck 
7.2.3.1 Serious Adverse Events 
A serious adverse event is any adverse event occurring at any dose or during any use of 
Merck’s product that: 
• Results in death; 
• Is life threatening; 
• Results in persistent or significant disability/incapacity; 
• Results in or prolongs an existing inpatient hospitalization; 
• Is a congenital anomaly/birth defect; 
• Is another important medical event  
• Note: In addition to the above criteria, adverse events meeting either of the below 
criteria, although not serious per ICH definition, are reportable to the Merck in the 
same timeframe as SAEs to meet certain local requirements. Therefore, these events 
are considered serious by Merck for collection purposes. 

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• Is a new cancer (that is not a condition of the study); 
• Is associated with an overdose. 
 
Refer to Table 7 for additional details regarding each of the above criteria. 
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any serious adverse event, or follow up to a serious adverse event, 
including death due to any cause that occurs to any participant must be reported within 24 
hours to the Sponsor and within 2 working days to Merck Global Safety if it causes the 
participant to be excluded from the trial, or is the result of a protocol-specified intervention, 
including but not limited to washout or discontinuation of usual therapy, diet, placebo 
treatment or a procedure. 
For the time period beginning at treatment allocation/randomization through 90 days 
following cessation of treatment, or 30 days following cessation of treatment if the 
participant initiates new anticancer therapy, whichever is earlier, any serious adverse event, 
or follow up to a serious adverse event, including death due to any cause whether or not 
related to the Merck product, must be reported within 24 hours to the Sponsor and within 2 
working days to Merck Global Safety. 
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to Merck product that is brought to the attention of the investigator at 
any time following consent through the end of the specified safety follow-up period specified 
in the paragraph above, or at any time outside of the time period specified in the previous 
paragraph also must be reported immediately to Merck Global Safety. 
All participants with serious adverse events must be followed up for outcome. 
SAE reports and any other relevant safety information are to be forwarded to the Merck 
Global Safety facsimile number:  +1-215-661-6229 
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 215-661-6229) at the time of submission to FDA. 
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 reported within 2 working days to Merck Global Safety. (Attn: Worldwide 
Product Safety; FAX 215-661-6229). 
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any ECI, or follow up to an ECI, that occurs to any participant 
must be reported within 2 working days to Merck Global Safety if it causes the participant to 

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be excluded from the trial, or is the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure. 
For the time period beginning at treatment allocation/randomization through 90 days 
following cessation of treatment, or 30 days following cessation of treatment if the 
participant initiates new anticancer therapy, whichever is earlier, any ECI, or follow up to an 
ECI, whether or not related to Merck product, must be reported within 2 working days to 
Merck Global Safety. 
Events of clinical interest for this trial include: 
1.  an overdose of Merck product, as defined in Section 7.2.1 - Definition of an Overdose for 
This Protocol and Reporting of Overdose to the 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.  
 
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 5.0. 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 7 Evaluating Adverse Events 
An investigator who is a qualified physician, will evaluate all adverse events as to: 
V5.0 CTCAE 
Grading 
Grade 1 
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention not indicated. 
 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL. 
 
Grade 3 
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation or hospitalization indicated; 
disabling; limiting self-care ADL. 
 
Grade 4 
Life threatening consequences; urgent intervention indicated. 
 
Grade 5 
Death related to AE 
Seriousness 
A serious adverse event is any adverse event occurring at any dose or during any use of Merck product that: 
 
†Results in death; or 
 
†Is life threatening; or places the participant, 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 for an elective procedure to treat a pre-existing condition that has not 
worsened is not a serious adverse event.  A pre-existing condition is a clinical condition that is diagnosed prior to the use of a Merck product and is documented in 
the patient’s medical history.); or 
 
†Is a congenital anomaly/birth defect (in offspring of participant taking the product regardless of time to diagnosis);or 
 
Is a new cancer (that is not a condition of the study) (although not serious per ICH definition, is reportable to the Sponsor within 24 hours and to Merck within 2 
working days to meet certain local requirements); or 
 
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event for collection purposes. 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 to the Sponsor and to 
Merck within 2 working days.. 
 
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 participant and may require medical or surgical intervention to prevent one of the outcomes 

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listed previously (designated above by a †). 
Duration 
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units 
Action taken  
Did the adverse event cause Merck product to be discontinued? 
Relationship to 
Merck Product  
Did Merck product cause the adverse event? The determination of the likelihood that 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 Merck product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely Merck product caused the adverse event (AE): 
 
Exposure 
Is there evidence that the participant was actually exposed to 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 
Merck 
product?  
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal product)? 
 
Likely Cause 
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or environmental factors 
 

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Relationship 
The following components are to be used to assess the relationship between the test drug and the AE: (continued) 
to Merck 
Product 
(continued)  
Dechallenge 
Was Merck product discontinued or dose/exposure/frequency reduced? 
If yes, did the AE resolve or improve? 
If yes, this is a positive dechallenge. If no, this is a negative dechallenge. 
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the AE resolved/improved despite continuation of 
the Sponsor’s product; or (3) the trial is a single-dose drug trial); or (4) Sponsor’s product(s) is/are only used one time.) 
 
Rechallenge 
Was the participant re-exposed to 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) Sponsor’s 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 MERCK PRODUCT, OR IF REEXPOSURE TO MERCK PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT RISK 
TO THE PARTICIPANT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE SPONSOR 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 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 Merck product relationship). 
Yes, there is a reasonable 
possibility of Merck product 
relationship. 
There is evidence of exposure to Merck product.  The temporal sequence of the AE onset relative to the administration of Merck product is 
reasonable.  The AE is more likely explained by Merck product than by another cause. 
No, there is not a reasonable 
possibility of Merck product 
relationship 
Participant did not receive the Merck  product OR temporal sequence of the AE onset relative to administration of Merck product is not reasonable 
OR the AE is more likely explained by another cause than the Merck product.  (Also entered for a participant with overdose without an associated 
AE.) 

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7.2.5 Sponsor Responsibility for Reporting Adverse Events 
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations.  
8.0 STATISTICAL ANALYSIS PLAN 
8.1 Statistical Analysis Plan Summary 
The study will follow a Simon's two-stage minimax design following the primary outcome of 
pathologic complete response rate with 12 patients in the first stage with expansion to 26 
total patients in the second stage.   
8.2 Sample Size Determination and Accrual  
The primary endpoint is pathological complete response (CR). The null hypothesis is that the 
CR is 40% and the alternative hypothesis is that the CR is 65%. The assumptions for the 
response rate are based on the study conducted by Topalian et al (2018).  Using a Minimax 
design with alpha 0.05 and 80% power yields a 12 patient in first stage with expansion to 26 
total patients in stage II if at least 6 patients achieve pathologic complete response in the first 
stage.  Assuming the second stage is completed, if 15 or more patients achieve pathologic CR 
the drug will be considered worthy of further study in this patient population.   
8.3 Population for Analyses 
For purposes of analysis, the following populations are defined.  
Population 
Description 
Enrolled 
All participants who sign the informed consent form.  
Per-Protocol 
All participants who have completed a minimum of disease evaluations and 
who do not have any major deviations, including but not limited to efficacy 
assessments or compliance. This data will be used to analyze the primary 
endpoint.  
Safety 
All participants assigned to study treatment and who take at least one dose of 
study treatment 
 
 

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8.4 Data Analysis Plan 
For this phase 2 study, the primary endpoint is pathological complete response in the per-
protocol population. It will be summarized with the point estimate and corresponding exact 
2-sided 95% confidence interval.   
The secondary endpoint of progression free survival (PFS) will be assessed by Kaplan-Meier 
method utilizing the definition for progression defined in section 7.2.1.6.  Participants who 
do not meet the criterial for progression will be censored at the last follow-up date. The 
median PFS will be estimated along with the corresponding 95% confidence interval.  
Feasibility of treatment will be defined by the percentage of patients able to complete both 
neoadjuvant cycles of trial therapy and be able to complete surgical resection as planned.    
 
 
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. 
Pembrolizumab and lenvatinib will be provided by Merck. 
 
9.2 Packaging and Labeling Information 
Supplies will be labeled in accordance with regulatory requirements. 
9.3 Clinical Supplies Disclosure 
This trial is open-label; therefore, the participant, 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.   

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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 participants and the 
amount remaining at the conclusion of the trial.  
Upon completion or termination of the study, all unused and/or partially used 
investigational product will be destroyed at the site per institutional policy. It is the 
Investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, 
local and institutional guidelines and procedures, and provided that appropriate records of 
disposal are kept. 
10.0 ADMINISTRATIVE AND REGULATORY DETAILS 
10.1.  Internal Monitoring 
Regulatory documents and case report forms will be monitored internally according to 
Moffitt Cancer Center Monitoring Policies. Monitoring will be performed regularly by the 
MCC Clinical Monitoring Core for accuracy, completeness, and source verification of data 
entry, validation of appropriate informed consent process, reporting of SAEs, and adherence 
to the protocol, Good Clinical Practice (GCP) guidelines, and applicable regulatory 
requirements. 
10.2  Quality Assurance and Quality Control 
Each clinical site will perform internal quality management of study conduct, data and 
biological specimen collection, documentation and completion.  
 
Quality control (QC) procedures will be implemented beginning with the data entry system 
and data QC checks that will be run on the database will be generated. Any missing data or 
data anomalies will be communicated to the site(s) for clarification/resolution. 
 
Following written Standard Operating Procedures (SOPs), the monitors will verify that the 
clinical trial is conducted and data are generated and biological specimens are collected, 
documented (recorded), and reported in compliance with the protocol, International 
Conference on Harmonisation Good Clinical Practice (ICH GCP), and applicable regulatory 
requirements (e.g., Good Laboratory Practices (GLP), Good Manufacturing Practices 
(GMP)).  
 

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The investigational site will provide direct access to all trial related sites, source 
data/documents, and reports for the purpose of monitoring and auditing by the sponsor, and 
inspection by local and regulatory authorities. 
 
10.3 Data Collection and Management Responsibilities 
Data will be captured in OnCore and/or Moffitt’s electronic Clinical Trials Management 
System. For each subject enrolled, the electronic CRF must be completed by the assigned 
data manager or other authorized study staff. Clinical data will be entered directly from the 
source documents. Any paper forms should be typed or filled out indelible ink and must be 
legible. Errors should be crossed out but not obliterated, the correction inserted, and the 
change initialed and dated by the investigator or his/her authorized delegate. This also applies 
to records for those subjects who fail to complete the study. If a subject stops dosing or 
terminates from the study, the dates and reasons must be noted on the CRF. If a subject 
terminates from the study because of a DLT, thorough efforts should be made to clearly 
document the outcome. 
 
Data collection is the responsibility of the clinical trial staff at the site under the supervision 
of the site investigator. The investigator is responsible for ensuring the accuracy, 
completeness, legibility, and timeliness of the data reported. 
 
10.4  Study Records Retention 
Study documents should be retained for a minimum of 10 years after the last approval of a 
marketing application in an International Conference on Harmonisation (ICH) region and 
until there are no pending or contemplated marketing applications in an ICH region or until 
at least 10 years have elapsed since the formal discontinuation of clinical development of the 
study intervention. These documents should be retained for a longer period, however, if 
required by local regulations. No records will be destroyed without the written consent of the 
sponsor, if applicable. It is the responsibility of the sponsor to inform the investigator when 
there is no longer a need for these documents to be retained. Permission must be acquired 
from the State of Florida for document destruction after the 10-year minimum record-
retention period described above has elapsed. 
10.5 Protocol Monitoring Committee 
Protocol Monitoring Committee (PMC): The PMC meets monthly and reviews accrual, 
patterns and frequencies of all adverse events, protocol violations and when applicable, 
internal audit results. 
 
10.6 External Sites  
 
10.6.1. Compliance to the Protocol and Adherence to Moffitt External Site 
Coordination Handbook 

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Moffitt is responsible for monitoring each sites compliance to adherence to applicable 
Moffitt External Site Coordination Handbook. In coordination with the Monitoring office, 
the ESC Office assists to monitor compliance to the protocol.  
10.6.2.  External Site Access to Clinical Trial Database 
To obtain access to OnCore, the External Site Coordinator will supply forms required to be 
completed by the site staff. Once the completed forms are received, the site coordinator will 
receive VPN access, logon/password, and information on how to access OnCore. The 
ESC office will provide OnCore training to the site once initial access is granted and on an 
ongoing basis, as needed.  
10.6.3.  Registration Procedures for External Sites 
All external enrolled subjects must be registered with the External Site Coordination (ESC) 
office to be able to participate in a trial. The participating site must email the completed 
c u r r e n t  eligibility checklist, registration form, all supporting documents, and signed, 
unredacted informed consent to the Coordinating Center. Unsigned or incomplete forms 
will be returned to the site. Once documents are received, the ESC Coordinator will 
review them to confirm eligibility and complete the registration process. If eligibility 
cannot be confirmed, the research coordinator will query the site for clarification or 
additional documents as needed. Subjects failing to meet all study eligibility 
requirements will not be registered and will be unable to participate in the trial. 
 
Upon completion of registration, the ESC Coordinator will provide the participating site 
with the study sequence number and, when applicable, randomization information. Within 
48 hours after registration, it is the site’s responsibility to: 
Enter the on-study patient information into the Oncore database 
Order investigational agent(s) if indicated per protocol 
It is the responsibility of the participating Investigator or designee to inform the subject of 
the research treatment plan and to conduct the study in compliance with the protocol as 
agreed upon with Moffitt Cancer Center and approved by the site’s IRB. 
To register a patient send the completed signed eligibility checklist along with the patient 
registration 
form 
and 
supporting 
documentation 
to 
the 
ESC 
via 
email 
at 
ESC_Partnerships@Moffitt.org, Monday through Friday between 8:00AM and 5:00PM 
(EST). If a short turnaround time is required between registration and first treatment, please 
consider discussing this with you ESC Coordinator and, if possible, submit a partial 
submission.  
10.6.4. Required Documentation for External Sites 

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Before the study can be initiated at any site, the site will be required to provide regulatory 
documentation to the External Site Coordination (ESC) office at Moffitt Cancer Center. Sites 
must provide a copy of their informed consent to the ESC office for review and 
approval prior to submission of any documents to the site’s IRB. Any changes requested by 
the site’s IRB must be provided to the ESC staff for review and approval prior to 
resubmission to the IRB. 
The ESC office must receive the following trial specific documents either by hardcopy  or 
email before a site can be activated for any trial. All corresponding updates to these 
documents are required to be submitted to the ESC office throughout the trial: 
• IRB Approval Letter that includes the protocol version and date 
• FDA Form 1572Protocol Signature Page 
• Investigator Brochure (or Package Insert) Signature Page(s) 
• IRB Approved Consent Form 
• Site Delegation of Authority Log 
• Signed Financial Interest Disclosure Forms ( For all individuals listed on the 
1572) 
• Investigator/Personnel documents (CVs, licenses, GCP and HSP training 
certificates, etc.) as needed 
• Laboratory Documents (certifications, normal ranges, etc.) as needed  
• Signed Clinical Trial Agreement 
• Protocol specific documentation as needed 
 
A study initiation teleconference will be held prior to the start of any study related activity at 
the site. Attendance is required for:  
The site PI and appropriate research staff 
Moffitt PI and ESC Coordinator 
The requirements of the protocol and all associated procedures and processes will be 
reviewed and agreed upon prior to the activation of the study. The ESC utilizes the EDC 
system, OnCore. OnCore training will be scheduled, if indicated, with the appropriate staff 
from the site. 
External sites are required to send updated documentation to the ESC Office at 
ESC_Partnerships@Moffitt.org within 10 business days of updating.   
10.6.5.  SAE Reporting Special Language for External Sites 
Information about all serious adverse events will be collected and recorded. To ensure patient 
safety, each serious adverse event must be reported to the PI and to the sponsor 
expeditiously. Moffitt Cancer Center and all participating sites will report SAEs by 
completing an SAE report in OnCore, the electronic data capture system. The SAE Report 

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from OnCore must be signed and reported by email (ESC_Partnerships@moffitt.org) to the 
External Site Coordination (ESC) office within 2 working days. If applicable, the site should 
also follow protocol guidelines for additional reporting to Financial Sponsors and 
government agencies. 
10.6.6. External Site Monitoring and Reporting  
The Coordinating Center will implement ongoing monitoring activities to ensure that 
Participating Institutions are complying with regulatory and protocol requirements, data 
quality, and participant safety. Monitoring practices may include but are not limited to source 
data verification, and review and analysis of eligibility requirements, informed consent 
procedures, adverse events and all associated documentation, review of study drug 
administration/treatment, regulatory files, protocol departures reporting, pharmacy records, 
response assessments, and data management. All monitoring efforts will occur based on the 
protocol specific monitoring plan. 
 
Following each monitoring visit, a monitoring follow-up report will be provided to the 
Participating Site (i.e. Site PI and Coordinator). The monitoring report will summarize any 
issued queries or data clarification requests, identify any reportable events or required 
follow-up on prior events and will specify details of any non-compliance. Participating Sites 
are requested to respond to all queries and data clarifications requests within 20 business 
days. The Moffitt Cancer Center Protocol Monitoring Committee will review all monitoring 
reports and issue resolution. This Committee reserves the right to close accrual for non-
compliance to monitoring. 
 
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with immunoreceptor tyrosine-based switch motif of programmed death 1 upon primary 
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D’Angelo SP, Russell J, Lebbe C, et al.  Efficacy and safety of first-line avelumab 
treatment in patients with stage IV metastatic merkel cell carcinoma: a preplanned interim 
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Fernandez-Figueras MT, Puig L, Musulen E, et al.  Expression profiles associated with 
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Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and autoimmunity. 
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Greenwald RJ, Freeman GJ, Sharpe AH. The B7 family revisited. Annu Rev Immunol 
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Gupta SG, Wang LC, Penas PF, et al.  Sentinal lymph node biopsy for evaluation and 
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Hodgson NC.  Merkel cell carcinoma: changing incidence trends.  J Surg Oncol.  2005; 
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Heusinkveld M, van der Burg SH. Identification and manipulation of tumor associated 
macrophages in human cancers. J Transl Med. 2011;9:216. doi: 10.1186/1479-5876-9-216. 
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Hunder NN, Wallen H, Cao J, Hendricks DW, Reilly JZ, Rodmyre R, et al. Treatment of 
metastatic melanoma with autologous CD4+ T cells against NY-ESO-1. N Engl J Med 
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Joyce JA, Pollard JW. Microenvironmental regulation of metastasis. Nat Rev 
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12.0 APPENDICES 
Appendix 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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Appendix 2: Common Terminology Criteria for Adverse Events V5.0 (CTCAE) 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 5.0 will be utilized for adverse event reporting. 
(http://ctep.cancer.gov/reporting/ctc.html) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Appendix 3: Contraceptive Guidance and Pregnancy Testing 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below)  
Women in the following categories are not considered WOCBP: 
● 
Premenarchal 
● 
Premenopausal female with 1 of the following: 
○ Documented hysterectomy 
○ Documented bilateral salpingectomy 
○ Documented bilateral oophorectomy 
Note:  Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview. 
● 
Postmenopausal female 
○ A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.  
▪ 
A high follicle stimulating hormone (FSH) level in the postmenopausal range may 
be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence 
of 12 months of amenorrhea, confirmation with two FSH measurements in the 
postmenopausal range is required.  
○ Females on HRT and whose menopausal status is in doubt will be required to use one 
of the non-hormonal highly effective contraception methods if they wish to continue 
their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment. 
Contraception Requirements 
Male Participants: 
Male participants with female partners of childbearing potential are eligible to participate if 
they agree to one of the following during the protocol defined time frame in section X:  
● Be abstinent from penile-vaginal intercourse as their usual and preferred lifestyle 
(abstinent on a long term and persistent basis) and agree to remain abstinent 
● Use a male condom plus partner use of a contraceptive method with a failure rate of <1% 
per year as described in Table 9 when having penile-vaginal intercourse with a woman of 
childbearing potential who is not currently pregnant. 
○ Note: Men with a pregnant or breastfeeding partner must agree to remain abstinent 
from penile-vaginal intercourse or use a male condom during each episode of penile 
penetration. 
 

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Female Participants: 
Female participants of childbearing potential are eligible to participate if they agree to use a 
highly effective method of contraception consistently and correctly as described in Table 10 
during the protocol-defined time frame in Section X.  
 
Table 10 
Highly Effective Contraception Methods 
 
Highly Effective Contraceptive Methods That Are User Dependent a  
Failure rate of <1% per year when used consistently and correctly. 
● Combined (estrogen- and progestogen- containing ) hormonal contraception b, c 
○ Oral  
○ Intravaginal  
○ Transdermal  
○ Injectable 
● Progestogen-only hormonal contraception b, c 
○ Oral  
○ Injectable  
Highly Effective Methods That Have Low User Dependency  
Failure rate of <1% per year when used consistently and correctly. 
● Progestogen- only contraceptive implant b, c  
● Intrauterine hormone-releasing system (IUS) b  
● Intrauterine device (IUD) 
● Bilateral tubal occlusion 
● Vasectomized partner  
A vasectomized partner is a highly effective contraception method provided that the partner is the sole 
male sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, an additional 
highly effective method of contraception should be used.  
● Sexual abstinence  
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study treatment. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the 
preferred and usual lifestyle of the participant.)  
Notes:  
Use should be consistent with local regulations regarding the use of contraceptive methods for 
participants of clinical studies.  
 
a) Typical use failure rates are lower than perfect-use failure rates (i.e. when used consistently and 
correctly).  

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b) If hormonal contraception efficacy is potentially decreased due to interaction with study treatment, 
condoms must be used in addition to the hormonal contraception during the treatment period and for at 
least 30 days after the last dose of study treatment . 
c) If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, 
acceptable hormonal contraceptives are limited to those which inhibit ovulation.  
 
Pregnancy Testing 
WOCBP should only be included after a negative highly sensitive urine or serum pregnancy 
test and in accordance with local requirements.  When applicable this test should be repeated 
a maximum of 24-hours before the first dose/vaccination. 
Following initiation of treatment additional pregnancy testing will be performed at monthly 
intervals during the treatment period and at 30 days after the last dose of study treatment and 
as required locally. 
Pregnancy testing will be performed whenever an expected menstrual cycle is missed or 
when pregnancy is otherwise suspected.