WINSHIP4955-20: Perioperative Lenvatinib With Pembrolizumab in Patients With Locally Advanced Nonmetastatic Clear Cell Renal Cell Carcinoma
Phase: PHASE2
Conditions: Kidney Cancer, Stage III Renal Cell Cancer AJCC v8, Stage IV Renal Cell Cancer AJCC v8
Sponsor: Emory University

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SPONSOR: Mehmet Asim Bilen, MD
TITLE: Perioperative Lenvatinib with Pembrolizumab in Patients with Locally Advanced 
Nonmetastatic Clear Cell Renal Cell Carcinoma
IND NUMBER: 147484
Co-Principal Investigator:
Mehmet Asim Bilen, MD
Winship Cancer Institute of Emory University
Department of Hematology and Medical Oncology
1365 Clifton Road NE, B4301, Atlanta, GA 30322
Phone: 404-778-3693
Fax: 404-778-3366
Email: mbilen@emory.edu
Co-Principal Investigator:
Viraj Master, MD, PhD
Emory University
Department of Urology
1365 Clifton Rd, Atlanta, GA 30322
Phone: 404-778-4898
Email: vmaster@emory.edu
Co-Investigators:
Jacqueline Theresa Brown, MD
Winship Cancer Institute of Emory University
Department of Hematology and Medical Oncology
1365 Clifton Road NE, Atlanta, GA 30322
Phone: 404-778-1900
Email: jacqueline.theresa.brown@emory.edu
Omer Kucuk, MD
Winship Cancer Institute of Emory University
Department of Hematology and Medical Oncology
1365 Clifton Road NE, Atlanta, GA 30322
Phone: 404-778-1900
Email: omer.kucuk@emory.edu
Bradley C. Carthon, MD, PhD
Winship Cancer Institute of Emory University
Department of Hematology and Medical Oncology
1365 Clifton Road NE, Atlanta, GA 30322
Phone: 404-778-1900
Email: bradley.c.carthon@emory.edu

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Bassel Nazha, MD, MPH
Winship Cancer Institute of Emory University
Department of Hematology and Medical Oncology
1365 Clifton Road NE, Atlanta, GA 30322
Phone: 404-778-1900
Email: bassel.nazha@emory.edu 
Haydn T. Kissick, PhD
Emory University
Department of Urology
1462 Clifton Rd, Room 420
Atlanta, Georgia, 30322
Phone: 617 259 8364
Email: haydn.kissick@emory.edu
Statistician: 
Yuan Liu, PhD, MS
Winship Cancer Institute of Emory University
718 Gatewood Rd NE
Atlanta, GA 30322
Phone: 404-778-1989
Email: yliu31@emory.edu
Study Coordinator:
Sierra Williams
Supplied Agent: 
pembrolizumab (Merck), lenvatinib (Merck)

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1.0 TRIAL SUMMARY
Abbreviated Tit
Perioperative Lenvatinib Plus Pembrolizumab in Locally Advanced, 
Non-Metastatic Clear Cell Renal Cell Carcinoma
Trial Phase
Phase 2
Clinical Indication
Neoadjuvant and adjuvant therapy
Trial Type
Single-Arm
Type of control
N/A
Route of administration
PO (lenvatinib) and IV (pembrolizumab)
Trial Blinding
N/A
Treatment Groups 
Single-Arm
Number of trial participants
17
Estimated enrollment period
1 year
Estimated duration of trial
3 years
Estimated average length of 
treatment per patient
1 year
2.0 TRIAL DESIGN
2.1
Trial Design
Patients with locally advanced, non-metastatic clear cell renal cell carcinoma (T3Nx or TanyN+) 
will be enrolled to receive neoadjuvant lenvatinib plus pembrolizumab for 4 cycles (12 weeks) 
followed by surgical resection which will then be followed by 13 cycles of adjuvant 
pembrolizumab. 
Each subject’s course will consist of four periods, all of which are depicted in the Trial Flow 
Chart (Section 6.0):

A Pre-Treatment Period in which subjects are consented and undergo screening 
assessments to be qualified for the study.

A Treatment Period which includes three sub-periods: neoadjuvant phase which includes 
treatment with lenvatinib and pembrolizumab (4 cycles), kidney surgery after at least 7 
days wash-out after last treatment dose, and adjuvant treatment with pembrolizumab (13 
cycles). Subjects undergo study assessments during this time. This period will end at the 
time of completion of adjuvant treatment, or when the patient withdraws consent or 
experiences unacceptable toxicity. 

A Post-Treatment Period in which subjects no longer receive study treatment and 
complete post-treatment study assessments.  

A Long-Term Follow-up Period in which subjects will be followed after treatment until 
the patient’s withdrawal of consent or loss to follow up, death, or study termination.

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2.2
Trial Diagram
3.0 OBJECTIVE(S) & HYPOTHESIS(ES)
3.1
Primary Objective & Hypothesis
(1) Objective: To assess the objective response rate (complete and partial responses), following 
the administration of lenvatinib and pembrolizumab for a total of 4 cycles (12 weeks) in 
patients with locally-advanced, biopsy-proven non-metastatic ccRCC prior to undergoing 
nephrectomy (partial or radical). 
(2) Hypothesis: Patients with non-metastatic ccRCC who are treated with 12 weeks of 
neoadjuvant lenvatinib with pembrolizumab will achieve an objective response rate >= 25%.
3.2
Secondary Objectives
(1) Objectives:  

To assess the safety and tolerability of neoadjuvant lenvatinib plus pembrolizumab in a 
presurgical population as well as the safety of adjuvant pembrolizumab post-surgery. 

To determine the clinical outcomes including disease-free survival (DFS) and overall 
survival (OS) of patients with non-metastatic ccRCC treated with neoadjuvant lenvatinib 
and pembrolizumab and adjuvant pembrolizumab. 

To evaluate surgery-related complications and outcomes as per the Clavien-Dindo 
classification system [1] 

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3.3
Exploratory Objectives
(1) Objectives: 

To evaluate changes in biomarkers of immune activation and gene expression before, 
during and after treatment

To assess the quality of life, frailty and sarcopenia of patients before and after treatment
4.0 BACKGROUND & RATIONALE
4.1
Background 
4.1.1
Introduction
In the United States in 2018, there were approximately 65,340 new cases of kidney or renal 
pelvis cancer diagnosed with 14,970 deaths attributable to the disease [2]. Renal cell carcinomas 
(RCC) arising from the renal cortex make up about 85% of kidney cancers in adults with clear 
cell histology making up as many as 85% of RCC [3]. Tumor pathogenesis in clear cell renal cell 
carcinoma (ccRCC) is most often related to deletion, mutation or silencing of the von Hippel-
Lindau (VHL) tumor suppressor gene, either through spontaneous deletion of chromosome 3p 
(on which VHL lies) or in the autosomal dominant VHL disease [4]. When VHL is defective, 
this leads to the accumulation of hypoxia inducible factors (HIFs) which in turn induces the 
production of multiple factors implicated in RCC tumorigenesis including vascular endothelial 
growth factor (VEGF), a main driver of angiogenesis. VEGF is a major molecular target in the 
treatment of RCC in those with unresectable disease or poor surgical candidates for nephrectomy 
[5-9].
4.1.2
Lenvatinib in RCC
Lenvatinib is an oral multi-kinase inhibitor of the vascular endothelial growth factor receptor 
(VEGFR 1-3), fibroblast growth factor receptor (FGFR1-4), platelet growth factor receptor α 
(PDGFR α), RET and KIT. Lenvatinib was approved by the FDA in May 2016 in combination 
with the mTOR inhibitor everolimus in the treatment of advanced RCC based on the 
randomized, open-label phase II trial investigating lenvatinib, everolimus or the combination of 
the two agents (in a 1:1:1 ratio) in patients with metastatic disease who had previously received 
at least one VEGFR inhibitor. Lenvatinib plus everolimus produced a significantly higher 
progression-free survival (PFS) compared to everolimus alone (median 14.6 months versus 5.5 
months). Even lenvatinib alone prolonged PFS to 7.4 months compared to everolimus alone, 
although the difference was not as robust as when compared to the combination [10]. Overall 
survival (OS) was a secondary endpoint and was 25.5 months for lenvatinib plus everolimus, 
18.4 months for single agent lenvatinib and 17.5 months for single agent everolimus; these 
differences were not significant at the time of primary data cutoff. Of note, lenvatinib has an 
acceptable safety profile and is also indicated as a single agent in the first line treatment of 
unresectable hepatocellular carcinoma as well as differentiated thyroid carcinoma that has 
progressed despite radioactive iodine therapy [11, 12]. Recently, combination of lenvatinib and 

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pembrolizumab is approved by FDA for patients with advanced endometrial carcinoma [13]. For 
more details on specific indications refer to the Investigator Brochure and prescribing 
information from Eisai. 
4.1.3
Checkpoint inhibitors in RCC 
Other than molecularly targeted agents such as anti-VEGF agents, the other primary therapeutic 
approach to RCC lies in immunotherapy with checkpoint inhibitors. Such an approach evolved 
after observation that removal of primary kidney lesion could result in spontaneous regression of 
metastatic lesions and demonstration that immunologic agents such as interferon gamma-1b and 
interleukin-2 (IL-2) have the capacity to induce relatively rare but durable complete responses in 
RCC [14-16]. RCC has been shown to demonstrate a penchant for attracting both tumor 
infiltrating lymphocytes (TILs) and NK cells to the tumor [17]. The goal of checkpoint inhibition 
is to counteract the T-cell exhaustion that happens at the tumor bed by disrupting the 
immunosuppressive interactions between programmed cell death receptor-1 (PD-1), a 
coinhibitory molecule expressed on activated B and T cells, and its ligand (PD-L1) on the tumor 
cell surface [18]. RCC also relatively highly expresses PD-L1 at tumor bed, also making it an 
attractive target for checkpoint inhibition [19]. Motzer, et al. (2018) on behalf of the CheckMate 
214 investigators conducted an open-label, phase III trial investigating the combination of 
ipilimumab, a humanized monoclonal antibody (mAb) against cytotoxic T-lymphocyte-
associated protein 4 (CTLA-4), and the anti-programmed cell death 1 (PD-1) monoclonal 
antibody nivolumab compared to standard-of-care sunitinib in the first line setting for 
intermediate and poor risk unresectable RCC. They showed an overall survival advantage with 
nivolumab plus ipilimumab vs sunitinib in patients with previously untreated advanced renal cell 
carcinoma. In an intent-to-treat analysis of all 1,096 randomized patients, the 30-month overall 
survival rate was 64% with the immunotherapy combination vs 56% with sunitinib (P = .0003). 
The objective response rates in the intent-to-treat population was 41% vs 34% (P = .015), 
respectively, including complete response rates of 11% vs 2%. Based on the primary CheckMate 
214 data analysis, the U.S. Food and Drug Administration approved the combination of 
nivolumab and ipilimumab in April 2018 as front-line treatment for intermediate- and poor-risk 
patients with advanced renal cell carcinoma [20]. 
4.1.4
Immunotherapy and targeted therapy combinations in RCC
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 (IB).
There is data to suggest that combining immunotherapy with targeted therapy has the potential to 
create synergy in its anti-tumor effect. Angiogenesis as a mechanism for tumor development 

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requires immune tolerance and the antiangiogenic effects of targeted therapy in RCC may also be 
immunomodulatory; pazopanib, axitinib and sunitinib have all been shown to reduce the in vitro 
expression of myeloid-derived suppressive macrophages [21] and pazopanib was shown to 
increase the expression of PD-1 and PD-L1, potentially increasing concurrent or future 
responsiveness to checkpoint inhibition [22]. More recently, Kimura, et al. showed that lenatinib 
combined with an anti-PD-1 antibody in a pre-clinical mouse model showed an increased 
response rate compared to either single treatment and that lenvatinib regardless of the presence 
of the anti-PD-1 agent led to decreased monocyte/macrophage populations and increased CD8+ 
T cells at the tumor in a hepatocellular carcinoma model [23]. With these mechanisms in mind, 
pembrolizumab was recently FDA approved in combination with axitinib, another multi-kinase 
inhibitor of VEGFR 1-3, in April 2019 for metastatic RCC for all risk groups. This was based on 
the phase III data comparing this combination to sunitinib and showing a median PFS of 15.1 
months in the combination cohort versus 11.1 months in the sunitinib group; the median OS was 
not reached in either group but death-related hazard ratio was 0.53 (95% CI 0.38-0.74; 
P<0.0001) for the combination compared to sunitinib [24]. These data were the first leading to 
FDA approval of an immunotherapy and targeted therapy combination in RCC but have not been 
the last. Since that time, the FDA approved the combination of axitinib and avelumab (a mAb 
against PD-L1) in May 2019 based on a phase III trial showing improved PFS in patients with 
PD-L1 positive tumors of 13.8 months compared to 7.2 months with sunitinib (HR 0.61, CI 0.47-
0.79, P<0.001) [25]. In 2018, Lee, et al. published RCC-specific data from a phase 1b/2 trial of 
lenvatinib plus pembrolizumab in selected solid tumors in the metastatic setting and of the 30 
patients with RCC enrolled, overall response rate at 24 weeks of 66.7% and only 4 patients 
(13%) discontinued the treatment due to adverse events [26]. The phase III CLEAR clinical trial 
investigating lenvatinib combined with either everolimus or pembrolizumab compared to 
sunitinib in metastatic RCC was recently published and showed an improvement in median PFS 
for lenvatinib plus pembrolizumab over sunitinib of 23.9 months v 9.2 months (HR 0.39, CI 
0.32-0.49, P<0.001). Median OS was also longer in those treated with lenvatinib plus 
pembrolizumab compared to sunitinib (HR 0.66; CI 0.49-0.88, P=0.005). While there was a PFS 
benefit noted for lenvatinib plus everolimus over sunitinib, there was no significant increase in 
OS with this combination [27]. Thus, combination therapy with checkpoint inhibitors and 
targeted therapy represents a new horizon in the treatment of RCC.  
4.2
Rationale
4.2.1
Rationale for the Trial and Selected Population
The above discussion involves the application of targeted and immunotherapy agents in the 
metastatic setting. This is because as of June 2019, the NCCN Clinical Practice Guidelines in 
Oncology have no recommendation for kidney cancer neoadjuvant therapy in stage I through III 
disease. There is a category 3 recommendation for sunitinib as an adjuvant treatment in stage III 
disease which is infrequently used due to a lack of overall survival benefit and notable toxicity 
[28, 29]. Most recently, data from phase III KEYNOTE-564 trial was presented at the 2021 
ASCO Annual meeting which showed that adjuvant pembrolizumab conferred a disease-free 
survival at 24 months of 77.3% compared to 68.1% with placebo, positioning itself as a likely 
new standard of care in the near future. [30] However, potential advantages of neoadjuvant 
therapy include downsizing and/or downstaging tumors with the goal of allowing resection of 

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previously unresectable tumors or minimally-invasive approaches, decreasing surgical morbidity 
(e.g. decreasing blood loss, recovery time, need to resect continguous structures), and treating 
micrometastatic disease if present. Phase II data on molecularly targeted agents in the 
neoadjuvant setting have been accumulating. Lane, et al. reported presurgical sunitinib in 72 
patients with RCC [31]. Median tumor size decreased from 7.2 cm to 5.3 post treatment, 
downsizing occurred in 65 tumors (83%) with 15 partial responses (19%). Rini, et al. reported a 
phase II study of pazopanib in patients with localized RCC in which 6 of 13 patients for whom 
partial nephrectomy was not possible pre-treatment proceeded to successful partial nephrectomy 
[32]. Karam, et al. showed that 12 weeks of neoadjuvant axitinib in 24 patients with locally 
advanced RCC led to 11 partial responses and 13 with stable disease (and no disease 
progression) [33]. In terms of neoadjuvant immunotherapy in RCC, there is currently an ongoing 
phase III randomized clinical trial investigating perioperative nivolumab in at least T2 disease 
with two doses given prior to nephrectomy and 9 months of therapy following surgery [34]. 
Pembrolizumab itself has been applied in the neoadjuvant setting in bladder cancer but not yet 
RCC. Necchi, et al. recently published data investigating the use of pembrolizumab in the 
neoadjuvant setting in patients with muscle-invasive bladder carcinoma. Fifty patients received 3 
cycles of pembrolizumab prior to radical cystectomy (RC). 23 patients achieved a complete 
pathologic response (42%) at the time of RC and 27 patients (54%) who had a PD-L1 combined 
positive score of ≥ 10% achieved the same [35]. 
Taken together, there is ample data to support the use of immunotherapy in the management of 
mRCC and the combination of immunotherapy and targeted therapy has recently begun and 
represents a promising new approach by attacking two mechanisms of tumorigenesis 
simultaneously: immunosuppression and angiogenesis. However, this combination has yet to be 
applied in the neoadjuvant setting and there remains gaps in our knowledge of how to best 
approach the management of patients with locally advanced RCC. We have phase Ib/II data on 
the combination of pembrolizumab and lenvatinib in the mRCC with promising response rates 
and manageable adverse events. Thus, we propose the novel application of this combination in 
the neoadjuvant setting for locally advanced RCC and based on existing data that adjuvant 
pembrolizumab confers an improved DFS, we propose completing a total of 1 year of adjuvant 
pembrolizumab in the adjuvant setting. 
4.2.2
Justification for Dose
The planned dose of lenvatinib for this study is 20 mg daily. In the phase 1b/II trial of these two 
therapeutics together in selected metastatic solid tumors including RCC, patients received one of 
three lenvatinib dose levels including 24 mg, 20 mg and 14 mg daily. The maximum tolerated 
dose was determined to be 20 mg daily in combination with pembrolizumab [26]. This is the 
dose of lenvatinib applied in the currently enrolling phase III CLEAR triple-arm trial which 
examines the efficacy of lenvatinib 20 mg daily plus pembrolizumab versus lenvatinib 18 mg 
daily plus everolimus versus sunitinib in metastatic RCC [36]. 
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 

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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 in melanoma and NSCLC indications 
demonstrating flat dose- and exposure-efficacy relationships from 2 mg/kg Q3W to 10 
mg/kg  Q2W, representing an approximate 5- to 7.5-fold exposure range (refer to IB, 
Section 5.2.2)

Population PK analysis showing that both fixed dosing and weight-based dosing provides 
similar control of PK variability with considerable overlap in the distributions of exposures, 
supporting suitability of 200 mg Q3W

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
4.2.3
Rationale for Endpoints
4.2.3.1
Efficacy Endpoints

Primary endpoint: 
Objective response rate was chosen as the primary endpoint to allow us to assess the proportion 
of patients with a reduction in overall tumor burden from baseline after 12 weeks of treatment 
with neoadjuvant lenvatinib and pembrolizumab. This endpoint can be assessed after just 12 
weeks of treatment and has immediate implications on surgical planning and potentially long-
term effects on DFS and OS. 

Secondary endpoints:
The safety and tolerability of lenvatinib in combination with pembrolizumab have been assessed 
in the Phase 2 and now Phase 3 trial of these drugs in tandem in metastatic RCC. However, we 
are seeking to assess their tolerability in the neoadjuvant setting where a patient is being treated 
with curative intent with the goal of nephrectomy followed by 39 weeks of pembrolizumab in the 
adjuvant setting to complete 1 year of total anti-PD-L1 therapy.  
We hypothesized that the downsizing/downstaging of primary after neoadjuvant treatment has 
the potential to allow for conversion from radical to partial nephrectomy. Thus, the assessment of 
any perioperative adverse events such as anemia, bleeding, wound dehiscence, or post-operative 
pneumonia or pulmonary embolism, among many others, will be important to understand the 
potential impact this neoadjuvant therapy may have on decreasing surgical morbidity [1]. 
In addition, if tumor burden can be reduced significantly prior to surgery and if the adjuvant 
component of the pembrolizumab leads to a decrease in post-surgery micrometastatic disease, it 

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is possible that patients may ultimately experience improved DFS and OS as a result. We seek to 
address these outcomes in our Long-Term Follow-up period. 

Exploratory endpoints:
Given that patients enrolled in this trial are being treated with curative intent, it is important to 
assess how experimental neoadjuvant therapy affects their quality of life, frailty and degree of 
sarcopenia. Thus, we will be assessing quality of life will be studied using the Functional 
Assessment of Cancer Therapy-Kidney Specific Index-19 (FKSI-19) questionnaire (Appendix 
4), frailty using the Fried Frailty score (Appendix 5), and degree of sarcopenia by assessment of 
pre-, on- and post-treatment imaging via SliceOmatic v5.0 by TomoVision program. 
4.2.3.2
Biomarker Research

Tumor tissue from prior to trial allotment (in the form of archival tissue or new biopsy if 
archival tissue is not available) compared to post-treatment nephrectomy specimen will 
be evaluated for assessment of mutations and/or immune markers including PD-1/PD-L1 
and other relevant biomarkers (e.g. tumor infiltrating lymphocytes, T- cell repertoire, 
RNA signature profiles). We will also use flow cytometry to assess the phenotypic 
characteristics of cell populations in the tumor microenvironment and changes occurring 
throughout the course of neoadjuvant VEGF inhibition and immunotherapy. Tissue will 
be preserved for future exploratory studies including genomic profiling. Stool sample will 
be collected for microbiome analysis and will be stored in the Winship CTO -80 freezer.
Correlative peripheral blood samples will be collected prior to study drug allotment, throughout 
treatment and post-treatment (both before and after nephrectomy). These samples will be 
assessed for

Circulating tumor DNA (ctDNA) to explore genetic alterations that are present are 
baseline and/or emerge during treatment

Analysis of peripheral blood mononuclear cells (PBMCs) to assess for 
phenotypic/functional changes in T-cells or myeloid markers during and after treatment

Nuclear acid analysis for gene expression profiling
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:

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1. Patients with a renal mass consistent with a clinical stage ≥ T3Nx or TanyN+ or deemed 
unresectable by surgeon 
2. Renal cell carcinoma with clear cell component on pre-treatment biopsy of the primary 
tumor
3. The subject is ≥ 18 years of age on the day of signing informed consent
4. The participant (or legally acceptable representative if applicable) provides written 
informed consent and the willingness and ability to comply with all aspects of the 
protocol
5. Have an Eastern Cooperative Oncology Group (ECOG) performance status  1 
6. 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)
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 

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7. Female particiants:
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 120 days after the last dose of study treatment.
8. Male participants: 
A male participant must agree to use a contraception as detailed in Appendix 3 of this 
protocol during the treatment period and for at least 120 days after the last dose of study 
treatment and refrain from donating sperm during this period.
5.1.2
Participant Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
1. Evidence of metastatic disease on pre-treatment imaging
2. The subject has received of any type of cytotoxic, biologic or other systemic anticancer 
therapy for kidney cancer
3. The subject has received any other type of investigational agent within 28 days before the 
first dose of study treatment
4. Excluding the primary tumor leading to enrollment in this study, any other active 
malignancy (except for localized prostate cancer, definitively treated melanoma in-situ, 
basal or squamous cell carcinoma of the skin, or carcinoma in-situ of the bladder or 
cervix) within the past 24 months; 
5. Prior treatment with lenvatinib or any agent directed against PD-1, PD-L1 or PD-L2, or 
another stimulatory or co-inhibitory T-cell receptor (e.g. CTLA-4, OX-40, CD137)
6. 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.
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.

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7. Subjects having >1+ proteinuria on urinalysis will undergo 24-hour urine collection for 
quantitative assessment of proteinuria. Subjects with urine protein ≥1 g/24-hour will be 
ineligible. 
8. Gastrointestinal malabsorption, gastrointestinal anastomosis, or any other condition that 
might affect the absorption of lenvatinib 
9. The subject has uncontrolled, significant intercurrent or recent illness including, but not 
limited to, the following conditions:
a.
Cardiovascular disorders:
i. New York Heart Association congestive heart failure of grade II or above, 
unstable angina, myocardial infarction within the past 6 months, or serious 
cardiac arrhythmia associated with significant cardiovascular impairment 
within the past 6 months 
ii.  Uncontrolled hypertension defined as sustained blood pressure (BP) > 
150 mm Hg systolic or > 90 mm Hg diastolic despite optimal 
antihypertensive treatment
iii. Prolongation of QTc interval to >480 msec per electrocardiogram (ECG) 
within 28 days before first dose of study treatment. 
b. Clinically significant hematemesis, or hemoptysis of > 0.5 teaspoon (2.5 ml) of red blood, or 
other history of significant bleeding (e.g. pulmonary hemorrhage) within 3 weeks prior to the 
first dose of study drug
c.
Serious non-healing wound/ulcer/bone fracture
d. History of organ allograft (subject has had an allogenic tissue/solid organ transplant) 
10. Biologic response modifiers (e.g. granulocyte colony-stimulating factor) within 4 weeks 
before study entry. Chronic erythropoietin therapy is permitted provided that no dose 
adjustments were made within 2 months before first dose of study treatment. 
11. Subjects must have recovered adequately from any toxicity and/or complications from 
major surgery prior to starting therapy. 
12. Has received a live or live-attenuated 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.  

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13. 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.
14. Has active autoimmune disease that has required systemic treatment in the past 2 years 
(i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). 
Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement 
therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic 
treatment. 
15. Has a history of (non-infectious) pneumonitis/interstitial lung disease that required 
steroids or has current pneumonitis/interstitial lung disease.
16. Has an active infection requiring systemic therapy.
17. Has a known history of active Hepatitis B (e.g., hepatitis B surface antigen [HBsAg]) or 
hepatitis C (e.g., HCV RNA qualitative is detected)
18. Has uncontrolled HIV defined by a CD4+ count < 350 cells/uL, an AIDS-defining 
opportunistic infection within the last 12 months prior to study enrollment or documented 
multidrug resistance that prevents effective HIV therapy
19. 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.  
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
Lenvatinib and pembrolizumab may have adverse effects on a fetus in utero. Refer to Appendix 
3 for approved methods of contraception for WOCBP and men with WOCBP as sexual partners. 
5.1.4
Pregnancy
If a participant inadvertently becomes pregnant while on treatment with pembrolizumab and 
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 (e.g., death, abortion, 
congenital anomaly, or other disabling or life-threatening complication to the mother or 

                                                                     Page 15               Version Date: 02/07/2024
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 lenvatinib or pembrolizumab are excreted in human milk.  It is known 
that lenvatinib and its metabolites are excreted in rat 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.
5.2
Trial Treatments 
The treatment to be used in this trial is outlined below in Table 1.
Table 1.  Trial Treatment
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 x 4 cycles prior 
to surgery and 13 
cycles following 
surgery
Experimental
Lenvatinib
20 mg
Daily
PO with 
water
QD in 21 day cycles 
x 4 cycles prior to 
surgery
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.
5.2.2
Lenvatinib
Lenvatinib will be administered with water orally once a day (with or without food) in 21-day 
cycles at approximately the same time each day. Treatment cycles will be counted continuously 
regardless of dose interruptions. On Day 1 of each cycle, it will be administered approximately 1 
hour after completion of pembrolizumab administration. 
Lenvatinib will be provided as 4 mg and 10 mg capsules. Lenvatinib is formulated with calcium 
carbonate, mannitol, microcrystalline cellulose, hydroxypropylcellulose, low-substituted 
hydroxypropylcellulose, and talc. 

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Lenvima is the mesylate salt of lenvatinib. Its chemical name is 4-[3-chloro-4-(N’- 
cyclopropylureido)phenoxy]-7-methoxyquinoline-6 carboxamide methanesulfonate.  The 
molecular formula is C21H19ClN4O4•CH4O3S and the molecular weight is 522.96. The 
chemical structure of lenvatinib mesylate is:
5.2.2.1
Criteria for Interruption of Treatment, Dose Reduction and Resumption of 
Treatment
Lenvatinib dose reduction and interruption for subjects who experience lenvatinib-related 
toxicity will be in accordance with the guidelines provided in Table 3. Once the dose has been 
reduced, it may not be increased at a later date. 
As this is a neoadjuvant study culminating in the potentially curative surgery, we will allow no 
more than one dose-limiting toxicity for each drug including lenvatinib and pembrolizumab. The 
lenvatinib dose may be lowered once to 14 mg. If the patient has a 2nd occurrence (same or new 
toxicity) of an intolerable grade 2 or any grade 3-4 event, the patient should stop both study 
drugs immediately and proceed with nephrectomy at least 7 days after the last dose of lenvatinib. 
Those patients will be in-evaluable and be replaced.

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For management of hypertension and proteinuria, refer to main protocol text for instructions 
before consulting the table below, as appropriate. 
Table 3. Dose Modifications for Lenvatinib Treatment-Related Toxicity 
Lenvatinib Treatment-Related 
Toxicitya,b
During Therapy 
Adjusted Dosef
Grade 1, Tolerable Grade 2
Continue treatment
No change
Intolerable Grade 2
c,d and Grade 3
g
1st occurrence
Interrupt lenvatinib until resolved to 
tolerable Grade 2 or Grade 0-1 
Reduce lenvatinib dose to 
14mg
2nd occurrence (same toxicity or 
new toxicity)
Discontinue lenvatinib and pembrolizumab and proceed to nephrectomy at 
least 7 days after the last dose of lenvatinib
Grade 4:
 e,f
Discontinue lenvatinib and pembrolizumab and proceed to nephrectomy at least 7 days after the last dose of 
lenvatinib
a.
An interruption of lenvatinib treatment for more than 21 days (due to lenvatinib treatment-related toxicities) will require a 
discussion with the sponsor before treatment can be resumed. 
b.
Excluding alopecia. Initiate optimal medical management for nausea, vomiting, hypothyroidism, hypertension and/or diarrhea 
prior to any lenvatinib interruption or dose reduction. For treatment-related hypertension, refer to Management of Hypertension 
(Section 5.2.2.2.1) for dose modification guidelines. 
c.
Applicable only to Grade 2 toxicities judged by subject and/or physician to be intolerable. 
d.
Obese subjects with weight loss do not need to return to the baseline weight or 10% of baseline weight (i.e., Grade 1 weight loss). 
These subjects will restart the study drug(s) at a lower dose once their weight remains stable for at least 1 week and they reached 
the normal BMI (if the weight loss occurred but it is still above normal BMI, they can restart the study treatment at a lower dose 
once the weight has been stable for at least 1 week). Normal BMI should be used as the new baseline for further dose reductions. 
e.
Excluding laboratory abnormalities judged to be non-life-threatening, in which case manage as Grade 3. 
f.
For asymptomatic Grade ≥3 elevations of amylase and lipase, treatment may resume per investigator discretion.   
g.
Refer to Table 4 for dose adjustments
General guidelines for holding periods of lenvatinib due to procedures: 
For minor procedures, lenvatinib should be stopped 2 days before the procedure and restarted 2 
days after, once there is evidence of adequate healing and no risk of bleeding. Needle biopsies 
(fine needle aspirations and core needle aspiration) are usually considered minor procedures. 
For major procedures, lenvatinib should be stopped 1 week (5 half-lives) before the procedure 
and then restarted once there is clear wound healing and no risk of bleeding, but at least 1 week 
after the procedure. It is up to the investigator to determine if it is a major or minor procedure. 
Usually a major procedure implies general anesthesia. 

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5.2.2.2
Management of Potential Adverse Events Associated with Lenvatinib
5.2.2.2.1 Management of Hypertension
Hypertension is a potential adverse event when using any drug active against the VEGF 
pathway, including lenvatinib. To minimize the need for lenvatinib dose interruptions and 
reduction, a blood pressure of ≤ 150/90 is required at the time of enrollment and subjects known 
to be hypertensive should be on a stable dose of antihypertensive therapy for at least 1 week 
before receiving Cycle 1 Day 1. The management of hypertension occurring during trial is 
outlined below in Table 5. 
Table 4. Recommendations for management of hypertension during trial
Blood pressure level
Management
Systolic BP ≥140 mmHg up to 160 mmHg or diastolic 
BP ≥90 mmHg up to 100 mmHga,b
Continue lenvatinib and institute antihypertensive 
therapy for subjects not already receiving 
antihypertensive medicationc,d
OR 
For those subjects already on antihypertensive 
medication, dose of the current agent may be increased, 
if appropriate, or 1 or more agents of a different class 
of antihypertensive should be addedc,d
Systolic BP ≥160 mmHg or diastolic BP ≥100 mmHg 
and not on optimal antihypertensive therapy
Continue lenvatinib and institute antihypertensive 
therapy for subjects not already receiving 
antihypertensive medicationc,d
OR 
For those subjects already on antihypertensive 
medication, dose of the current agent may be increased, 
if appropriate, or 1 or more agents of a different class 
of antihypertensive should be addedc,d
Systolic BP ≥160 mmHg or diastolic BP ≥100 mmHg 
despite optimal antihypertensive therapy
1.  Withhold lenvatinib 
2. When systolic BP ≤150 mmHg, diastolic BP ≤95 
mmHg, and patient has been on a stable dose of 
antihypertensive therapy for at least 48 hours, resume 
lenvatinib at reduced dosee
Life-threatening consequences (malignant 
hypertension, neurological deficit, or hypertensive 
crisis) 
Urgent intervention is indicated. Discontinue lenvatinib 
and institute appropriate medical management.
a. Confirmed on 2 assessments a minimum of 1 hour apart
b.  One BP assessment is defined as the mean value of 3 measurements at least 5 minutes apart
c. Choice of antihypertensive treatment should be individualized to the subjects’ clinical circumstances and follow standard medical practice. 
d.  For subjects with hypertension and proteinuria, management with an angiotensin-converting enzyme inhibitor or angiotensin-II receptor 
antagonist is preferred [37]
e. During the treatment period, subjects with systolic BP ≥160 mm Hg or diastolic BP ≥100 mm Hg must have their BP monitored every 2 
weeks or more frequently as clinically indicated until systolic BP has been ≤150 mm Hg and diastolic BP has been ≤95 mm Hg for 3 

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consecutive months. If a repeat event of systolic BP ≥160 mm Hg or diastolic BP ≥100 mm Hg occurs, the subject must resume evaluation 
every 2 weeks until systolic BP has been ≤150 mm Hg and diastolic BP has been ≤95 mm Hg for 3 consecutive months. 
BP = blood pressure
5.2.2.2.2 Management of Proteinuria
Proteinuria has been reported in patients receiving lenvatinib. Regular assessment of proteinuria 
should be conducted as detailed in the Trial Flow Chart (Section 6.0) and as clinically indicated. 
Guidelines for the assessment and management of proteinuria:
1. If urine dipstick of ≥2+ proteinuria is detected, a 24-hour urine collection should be 
completed within 72 hours for protein quantitation in the following situations: 

The initial occurrence of ≥2+ proteinuria on urine dipstick while receiving lenvatinib

A subsequent increase in severity of urine dipstick proteinuria occurring on the same 
lenvatinib dose level 

When there has been a lenvatinib dose reduction and at the new dose level the urine 
protein dipstick result is ≥2+ 
2. Grading of proteinuria will be performed according to CTCAE 4.0 (Appendix 2) and 
based on the 24-hour urine collection for total protein if available from that time point. 
3. Urine dipstick testing for subjects with proteinuria ≥2+ should be performed every 2 
weeks or more frequently as clinically indicated until the results have been 1+ or negative 
for 3 consecutive months or until the end of neoadjuvant treatment part. 
4. Management of lenvatinib administration will be based on the grade of proteinuria 
according to instructions contained in Table 3 (Dose Modifications for Lenvatinib 
Treatment-Related Toxicity).
5.2.2.2.3 Management of QT interval prolongation
The effect of a single 32 mg dose of lenvatinib on the QT/QTc interval was evaluated in a 
thorough QT study in healthy subjects (E7080-A001-002). In this study lenvatinib did not 
prolong the QT/QTc interval. QT/QTc interval prolongation has been reported at a higher rate in 
patients treated with lenvatinib. Monitor ECG in patients with congenital long QT syndrome, 
congestive heart failure, bradyarrhythmias, and drugs known to prolong the QT interval, 
including Class Ia and III antiarrhythmics. Monitor and correct electrolyte abnormalities in all 
patients as per the Trial Flow Sheet (Section 6.0). If QTc prolongation is noted, withhold drug 
and resume at reduce dose of lenvatinib as per Table 3 (Dose Modifications for Lenvatinib 
Treatment-Related Toxicity).
5.2.2.2.4 Management of hepatotoxicity
The most commonly reported liver-related adverse reactions in patients treated with lenvatinib 
are increases in alanine aminotransferase (ALT), aspartate aminotransferase (AST) and serum 
bilirubin. Liver-related adverse reactions were reported at a high frequency in lenvatinib-treated 

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patients with HCC than with RCC. Across clinical studies enrolling 1327 LENVIMA-treated 
patients with malignancies other than HCC, serious hepatic adverse reactions occurred in 1.4% 
of patients. Fatal events, including hepatic failure, acute hepatitis and hepatorenal syndrome, 
occurred in 0.5% of patients. Patients with worse hepatic impairment and/or greater liver tumor 
burden at baseline had a higher risk of developing hepatic encephalopathy and hepatic failure. 
Hepatic encephalopathy also occurred more frequently in patients aged 75 years and older. 
Approximately half of the events of hepatic failure were reported in patients with disease 
progression.
Regular monitoring of liver function should be monitored as per the Trial Flow Chart (Section 
6.0). As per standard of care, we plan to monitor liver enzymes (including AST and ALT) every 
2 weeks for the first 2 months of lenvatinib administration.
Any change in liver function should be graded according to CTCAE v4.0 (Appendix 2). In the 
case of a decrease in liver function by 1 grade or more from baseline, Table 3 (Dose 
Modifications for Lenvatinib Treatment-Related Toxicity) should be followed. If hepatic failure 
occurs, the study drug must be discontinued. 
5.2.2.2.5 Management of Thromboembolic Events
Both venous and arterial thromboembolism have been reported at an increased frequency in 
patients receiving lenvatinib. Study participants should be advised to self-assess for any 
symptoms consistent with venous thromboembolism (VTE) including symptoms of acute onset 
of dyspnea, chest pain, tachycardia, tachypnea, fever, hemoptysis, and cough and symptoms of 
lower extremity deep venous thrombosis (DVT) such as unilateral swelling, tenderness, 
erythema or warmth. If a thromboembolic event is diagnosed, appropriate supportive care should 
be provided together with close monitoring. The instructions for managing study drug described 
in Table 3 (Dose Modifications for Lenvatinib Treatment-Related Toxicity) should be followed. 
If a subject experiences life-threatening (Grade 4) thromboembolic reactions, including 
pulmonary embolism, the study drug must be discontinued. 
5.2.2.2.6 Management of Hemorrhagic Events
Serious hemorrhagic events have been reported in patients treated with lenvatinib. History, 
physical exam and complete blood count (CBC) measurements should be serially assessed as per 
the Trial Flow Chart (Section 6.0). Lenvatinib should be discontinued in subjects with serious 
and life-threatening bleeding events or recent hemoptysis (≥ 2.5 mL of red blood).
5.2.2.2.7 Management of Wound Healing Complications
No formal studies of the effect of lenvatinib on wound healing have been conducted but impaired 
wound healing has been reported in patients receiving lenvatinib. To prevent difficulty with 
wound healing, lenvatinib should be held for 2 days prior to a minor procedure (e.g. needle 
biopsy) and restarted 2 days after given evidence of adequate healing and hemostasis. For major 
procedures (e.g. requiring general anesthesia), lenvatinib should be stopped 1 week (5 half-lives) 

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before the procedure and then restarted once there is clear wound healing and adequate 
hemostasis (at least 1 week after the procedure). Any wounds should be monitored for wound 
dehiscence, wound infection and other signs of impaired wound healing after lenvatinib is 
resumed. If dehiscence occurs, lenvatinib should be interrupted until complete healing has taken 
place. 
5.2.2.2.8 Management of Gastrointestinal (GI) Disorders
5.2.2.2.8.1 Fistula Formation and GI Perforation
Events of fistula formation or gastrointestinal perforation and their sequelae have been reported 
in patients treated with lenvatinib. Fistulas (e.g. gastrointestinal, bronchopleural, trachea-
esophageal, cutaneous, pharyngeal, female genital tract fistula) have been reported in lenvatinib 
clinical trials and in post-marketing experience. In addition, pneumothorax has been reported 
with and without clear evidence of a bronchopleural fistula. Some reports of gastrointestinal 
perforation, fistula and pneumothorax occurred in association with tumor regression or necrosis. 
In most cases of fistula formation or gastrointestinal perforation, risk factors such as prior 
surgery or radiotherapy were present. 
Discontinue treatment with lenvatinib and initiate appropriate management in subjects who have 
been diagnosed with GI perforation or fistula.
5.2.2.2.8.2 Diarrhea
Diarrhea is one of the most common AEs noted during lenvatinib treatment and should be 
managed as per Table 6.
Table 5. Management of Diarrhea Associated with Lenvatinib

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Status
Management
Tolerable Grade 1-2 
(duration < 48 h)

Continue lenvatinib and consider dose reduction

Initiate treatment with an antidiarrheal agent (e.g. loperamide 4 mg followed 
by 2 mg after each episode of diarrhea with maximum 16 mg loperamide per 
day)

Dietary modifications (e.g. small, bland meals such as the BRAT diet 
[bananas, rice, applies, toast])

Increase intake of isotonic fluids (1-1.5 L/day orally)

Reassess after 24 hours:
o
Resolving to baseline: advance diet and decrease antidiarrheal 
treatment after 12 h without diarrhea
o
Not resolving: Continue/resume antidiarrheal treatment 
Intolerable Grade 2,
Grade 2 > 48 h, 
or ≥ Grade 3

Interrupt study treatment

Evaluation participant in clinic

Rule out infection (e.g. C. difficile toxin, stool culture)
o
Administer antibiotics as needed (e.g. if fever or evidence of 
neutropenic enterocolitis)

Administer fluids (1-1.5 L/day orally or IV) for hydration

Correct electrolyte abnormalities if present

Consider hospitalization and IV hydration for grade 3-4 diarrhea 

Re-assess after 24 h
o
Resolving to baseline or Grade ≤ 1: consider restarting study 
treatment at reduced dose
o
Not resolving: Start and or continue antidiarrheal treatment. 
Consider starting or adding second line antidiarrheal or referral to 
gastroenterologist
5.2.2.2.8.3 Nausea and Vomiting
Treat with antiemetic agents as clinically appropriate. Administer supportive care including PO 
or IV fluids and electrolyte supplementation as indicated. 
5.2.2.2.9 Management of Thyroid Dysfunction
Hypothyroidism has been reported in patients treated with lenvatinib. Thyroid function, T3, T4 
and TSH should be monitored serially as per the Trial Flow Chart (Section 6.0). Hypothyroidism 
should be treated according to standard medical practice to maintain euthyroid state. 
5.2.2.2.10   Management of Posterior Reversible Encephalopathy Syndrome (PRES)
Events of reversible posterior leukoencephalopathy syndrome (RPLS), also known as posterior 
reversible encephalopathy syndrome (PRES), have been reported (<1%) in patients treated with 
lenvatinib. PRES is a neurological disorder that can present with headache, seizure, lethargy, 
confusion, altered mental function, blindness, and other visual or neurological disturbances. Mild 
to severe hypertension may be present. Magnetic resonance imaging is necessary to confirm the 
diagnosis of PRES. Appropriate measures should be taken to control blood pressure. 

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In patients with signs or symptoms of PRES, dose interruptions, adjustments, or discontinuation 
may be necessary as per Table 3 (Dose Modifications for Lenvatinib Treatment-Related 
Toxicity).
5.2.2.2.11 Management of Hypocalcemia
Hypocalcemia has been reported in patients taking lenvatinib. Calcium is to be monitored 
regularly as per the Trial Flow Chart (Section 6.0) and more frequently if clinically necessary. 
Hypocalcemia should be treated per institutional guidelines (e.g., using, as appropriate, calcium, 
magnesium, and Vitamin D supplementation) until resolution. Interrupt and adjust lenvatinib 
dosing as necessary depending on severity, presence of ECG changes, and persistence of 
hypocalcemia.
5.2.3
Pembrolizumab 
Pembrolizumab 200 mg will be administered as a 30 minute IV infusion every 3 weeks (+/- 3 
days).  Sites should make every effort to target infusion timing to be as close to 30 minutes as 
possible.  However, given the variability of infusion pumps from site to site, a window of -5 
minutes and +10 minutes is permitted (i.e., infusion time is 30 minutes: -5 min/+10 min). The 
Pharmacy Manual contains specific instructions for the preparation of the pembrolizumab 
infusion fluid and administration of infusion solution.
Pembrolizumab may be provided as a sterile, preservative-free, white to off-white lyophilized 
powder in single-use vials. Each vial will be reconstituted and diluted for intravenous infusion. 
Each 2 mL of reconstituted solution contains 50 mg of pembrolizumab and is formulated in L-
histidine (3.1 mg), polysorbate-80 (0.4 mg), sucrose (140 mg). The solution may contain 
hydrochloric acid/sodium hydroxide to adjust pH to 5.5. 
Pembrolizumab will be provided as a sterile, preservative-free, clear to slightly opalescent, 
colorless to slightly yellow solution that requires dilution for intravenous infusion. Each vial 
contains 100 mg of pembrolizumab in 4 mL of solution. Each 1 mL of solution contains 25 mg 
of pembrolizumab and is formulated in: L-histidine (1.55 mg), polysorbate 80 (0.2 mg), sucrose 
(70 mg), and Water for Injection. 
5.2.3.1
Dose Modification and Toxicity Management for Immune-Related AEs Associated 
with pembrolizumab 
AEs associated with pembrolizumab exposure, including coadministration with additional 
compounds, may represent an immunologic aetiology. These immune-related AEs (irAEs) may 
occur shortly after the first dose or several months after the last dose of 
pembrolizumab/combination treatment and may affect more than one 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 interruptions of pembrolizumab/combination treatment, 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, 

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endoscopy, skin biopsy may be included as part of the evaluation. Dose modification and toxicity 
management guidelines for irAEs associated with pembrolizumab/combination treatment are 
provided in Table 6.
Attribution of Toxicity:
When study interventions are administered in combination, attribution of an adverse event to a 
single component is likely to be difficult.  Therefore, while the investigator may attribute a 
toxicity event [to the combination, to lenvatinib alone or to pembrolizumab alone], for adverse 
events listed in Table 6, both interventions must be held according to the criteria in Table 6 Dose 
Modification and Toxicity Management Guidelines for Immune-Related Adverse Events 
Associated with Pembrolizumab.
Holding Study Interventions:
When study interventions are administered in combination, if the AE is considered immune-
related, both interventions should be held according to recommended dose modifications.
Restarting Study Interventions:
Participants may not have any dose modifications (no change in dose or schedule) of 
pembrolizumab in this study, as described in Table 6.

If the toxicity does not resolve or the criteria for resuming treatment are not met, the participant 
must be discontinued from all study interventions.

If the toxicities do resolve and conditions are aligned with what is defined in [Table 6], the 
combination of lenvatinib and pembrolizumab may be restarted at the discretion of the 
investigator.[In these cases where the toxicity is attributed to[the combination or to lenvatinib 
alone, re-initiation of pembrolizumab as a monotherapy may be considered at the principal 
investigator’s discretion .]
As this is a neoadjuvant study culminating in the potentially curative surgery, we will allow no 
more than one dose-limiting toxicity for each drug including lenvatinib and pembrolizumab. Any 
more than one dose-limiting toxicity for each drug will result in discontinuation of both study 
drugs and early nephrectomy at least 7 days after the last dose of lenvatinib.  Those patients will 
be in-evaluable and be replaced. 

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Table 6. Dose Modification and Toxicity Management Guidelines for Immune-Related AEs Associated with Pembrolizumab 
Monotherapy and IO Combinations
General instructions:
1.
Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other immunosuppressive treatment should 
begin if the irAEs are not controlled by corticosteroids.
2.
Study intervention must be permanently discontinued if the irAE does not resolve or the corticosteroid dose is not ≤10 mg/day within 12 weeks of 
the last study intervention treatment. 
3.
The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks.
4.
If study intervention has been withheld, study intervention may resume after the irAE decreased to ≤ Grade 1 after corticosteroid taper.
irAEs
Toxicity 
Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Grade 2
Withhold 
Pneumonitis 
Recurrent 
Grade 2, 
Grade 3 or 4 
Permanently 
discontinue
  Administer corticosteroids (initial dose of 
1 to 2 mg/kg prednisone or equivalent) 
followed by taper
  Add prophylactic antibiotics for 
opportunistic infections
  Monitor participants for signs and symptoms of 
pneumonitis
  Evaluate participants with suspected 
pneumonitis with radiographic imaging and 
initiate corticosteroid treatment
Diarrhea/Colitis 
Grade 2 or 3
Withhold
  Administer corticosteroids (initial dose of 
1 to 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) 

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irAEs
Toxicity 
Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Recurrent 
Grade 3 or 
Grade 4
Permanently 
discontinue
and of bowel perforation (ie, peritoneal signs 
and ileus)
  Participants with ≥Grade 2 diarrhea 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
Grade 2 a
Withhold
  Administer corticosteroids (initial dose of 
0.5 to 1 mg/kg prednisone or equivalent) 
followed by taper
AST or ALT 
Elevation or 
Increased 
Bilirubin
Grade 3 b or 4 c
Permanently 
discontinue
  Administer corticosteroids (initial dose of 
1 to 2 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)
T1DM or 
Hyperglycemia
New onset 
T1DM or 
Grade 3 or 4 
hyperglycemia 
associated with 
Withhold d
  Initiate insulin replacement therapy for 
participants with T1DM
  Monitor participants for hyperglycemia or other 
signs and symptoms of diabetes

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irAEs
Toxicity 
Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
evidence of 
-cell failure
  Administer antihyperglycemic in 
participants with hyperglycemia
Grade 2
Withhold
Hypophysitis
Grade 3 or 4
Withhold or 
permanently 
discontinue d
  Administer corticosteroids and initiate 
hormonal replacements as clinically 
indicated
  Monitor for signs and symptoms of hypophysitis 
(including hypopituitarism and adrenal 
insufficiency)
Grade 2
Continue
Hyperthyroidism
Grade 3 or 4
Withhold or 
permanently 
discontinue d
  Treat with nonselective beta-blockers 
(eg, propranolol) or thionamides as 
appropriate
  Monitor for signs and symptoms of thyroid 
disorders
Hypothyroidism
Grade 2, 3 or 4
Continue
  Initiate thyroid replacement hormones 
(eg, levothyroxine or liothyronine) per 
standard of care
  Monitor for signs and symptoms of thyroid 
disorders
Grade 2
Withhold
Nephritis:
grading 
according to 
increased 
creatinine or 
acute kidney 
injury
Grade 3 or 4
Permanently 
discontinue
  Administer corticosteroids (prednisone 1 
to 2 mg/kg or equivalent) followed by 
taper
  Monitor changes of renal function
Neurological 
Grade 2
Withhold
  Based on severity of AE administer 
  Ensure adequate evaluation to confirm etiology 

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irAEs
Toxicity 
Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Toxicities
Grade 3 or 4
Permanently 
discontinue
corticosteroids
and/or exclude other causes
Grade 1
Withhold
Myocarditis
Grade 2, 3 or 4
Permanently 
discontinue
  Based on severity of AE administer 
corticosteroids
  Ensure adequate evaluation to confirm etiology 
and/or exclude other causes
Suspected SJS, 
TEN, or 
DRESS
Withhold
Exfoliative 
Dermatologic 
Conditions
Confirmed SJS, 
TEN, or 
DRESS
Permanently 
discontinue
  Based on severity of AE administer 
corticosteroids
  Ensure adequate evaluation to confirm etiology 
or exclude other causes
Persistent Grade 2 Withhold
Grade 3
Withhold or 
discontinue based 
on the event e 
All Other irAEs
Recurrent 
Grade 3 or 
Grade 4 
Permanently 
discontinue
  Based on severity of AE administer 
corticosteroids
  Ensure adequate evaluation to confirm etiology 
or exclude other causes
AE(s)=adverse event(s); ALT= alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common Terminology Criteria for Adverse Events; DRESS=Drug 
Rash with Eosinophilia and Systemic Symptom; GI=gastrointestinal; IO=immuno-oncology; ir=immune related; IV=intravenous; SJS=Stevens-Johnson Syndrome; 
T1DM=type 1 diabetes mellitus; TEN=Toxic Epidermal Necrolysis; ULN=upper limit of normal.
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations.
a
AST/ALT: >3.0 to5.0 x ULN if baseline normal; >3.0 to 5.0 x baseline, if baseline abnormal; 
bilirubin:>1.5 to 3.0 x ULN if baseline normal; >1.5 to 3.0 x baseline if baseline abnormal
b
AST/ALT: >5.0 to 20.0 x ULN, if baseline normal; >5.0 to 20.0 x baseline, if baseline abnormal; bilirubin:>3.0 to 10.0 x ULN if baseline normal; >3.0 to 10.0 x baseline 
if baseline abnormal

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irAEs
Toxicity 
Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
c
AST/ALT: >20.0 x ULN, if baseline normal; >20.0 x baseline, if baseline abnormal; 
bilirubin: >10.0 x ULN if baseline normal; >10.0 x baseline if baseline abnormal
d
The decision to withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician. If control achieved or ≤ Grade 2, 
pembrolizumab may be resumed.
e
Events that require discontinuation include, but are not limited to: encephalitis and other clinically important irAEs.
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 
7. 
Table 7.  Pembrolizumab Infusion Reaction Dose modification and Treatment Guidelines

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NCI CTCAE Grade
Treatment
Premedication at Subsequent Dosing
Grade 1
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated
Increase monitoring of vital signs as medically indicated until the 
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 
pembrolizumab 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 v4.0 (CTCAE) at http://ctep.cancer.gov
5.2.3.2
Other Allowed Dose Interruptions 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. 

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5.3
Randomization or Treatment Allocation
This is an open-label, single-arm study. All subjects who provide signed informed consent to 
participate in this study and satisfy all eligibility requirements will receive lenvatinib in 
combination with pembrolizumab. There is no randomization in this study. 
5.4
Stratification
There will be no stratification as this is a single-arm trial. 
5.5
Concomitant Medications/Vaccinations
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.
5.5.1
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 
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. Any medication that is considered 
necessary for the subject’s health and that is not expected to interfere with the evaluation of 
or interact with lenvatinib or pembrolizumab may be continued during the study.
For clarification, the following concomitant medications are also allowed: 

Antiemetics and antidiarrheal medications are allowed according to standard clinical 
practice if indicated

Granulocyte colony-stimulating factors (G-CSF or GM-CSF) are allowed if used per 
clinical guidelines (e.g. ASCO guidelines)

Erythropoietin (e.g. epoetin alfa and darbepoetin alfa ) is allowed if used per clinical 
guidelines (e.g. ASCO guidelines) but the subject should be carefully monitored for 
increases in red blood cell (RBC) counts

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
Transfusions if clinically indicated

Thyroid hormone suppressive therapy (including therapy to treat hypothyroidism and 
hyperthyroidism) 

Adjuvant hormonal therapy for history of definitively treated breast cancer or 
localized prostate cancer 

Low-molecular-weight heparin

Aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), and anticoagulants 
including low-molecular-weight heparin, warfarin, anti-Xa agents or direct thrombin 
inhibitors are permissible but should be used with caution

Bisphosphonates or denosumab 

Medications for treatment of infusion reaction associated with pembrolizumab (see 
Section 5.2.3.2) 

Antihypertensive therapy (including additional antihypertensive treatment as 
appropriate if BP increases once the patient has been enrolled) 
5.5.1.1
Drug-Drug Interactions
Lenvatinib’s weak in vitro inhibitory and induction potential on cytochrome P450 (CYP 
P450) enzymes (Study No. XT063020) suggests a low risk of lenvatinib interference with the 
PK of other drugs metabolized by CYP P450 enzymes which are co-administered in usual 
clinic practice. Nonclinical studies identify CYP3A4 as an important enzyme responsible for 
human hepatic metabolism of lenvatinib. However, clinical studies conducted to test these 
findings showed that co-administration of lenvatinib with CYP3A4/P-glycoprotein (P-gp) 
inhibitors or inducers is not of clinical concern. 
No formal pharmacokinetic drug interaction studies have been conducted with 
pembrolizumab. Pembrolizumab is a monoclonal antibody; pharmacokinetic interactions 
with lenvatinib (and vice-versa) are not expected. 
5.5.2
Prohibited Concomitant Medications
Participants are prohibited from receiving the following therapies during the Pre-Treatment 
and Treatment Phases 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

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
Radiation therapy 

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 (e.g., 
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.
o
Note: Inhaled steroids are allowed for management of asthma or seasonal 
allergies. 
Participants should avoid drugs that are known to prolong the QTc interval until the study 
treatment has been discontinued, although these agents are not specifically prohibited if there 
is a clinical indication for their use as long as the QTc has been < 480 ms as per monitoring 
based on the Trial Flow Chart (Section 6.0). 
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.
There are no prohibited therapies during the Long-Term Follow-Up Phase. 
5.5.3
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 5.2.3.1, [Table 6].  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 

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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.  
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event. 
5.6
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 7.1.5.1 (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 radiographic disease progression outlined in Section 7.1.4.1.4.

Any progression of any malignancy, or any occurrence of another malignancy that 
requires active treatment

Unacceptable adverse experiences as described in 5.2.2.2 (lenvatinib) and 5.2.3.1 
(pembrolizumab).

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

Sexually active subjects of childbearing potential who refuse to use medically 
accepted barrier methods of contraception (e.g. male condom) during the course of 
the study and for 4 months after discontinuation of study treatment

Noncompliance with study treatment or procedure requirements

Recurrent Grade 2 pneumonitis

The participant is lost to follow-up

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
Administrative reasons
5.7
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
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
6.1
Study Flow Chart

                                        Page 38
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Treatment Phaseb
Trial Phase:
Pre-treatment Phase
Neoadjuvant Phase
Surgical Phase
Adjuvant 
Phasew,x
Post-
Treatment 
Phase
Long-term 
Follow-up 
Phase
Treatment Cycle/Title:
Screening
(Visit 1)a,b
Baseline 
(Visit 2)a,b
1
2
3
4
Post-
neoadjuvant 
therapy safety 
visit
Surgery
Cycles 5-17
Post-adjuvant 
therapy safety 
visit
Day:
-28 to 1
-3 to 1
1
8
15
22
29
36
43
50
57
64
71
78
Within 7 days 
of last dose of 
lenvatinib
At least 7 
days after 
last dose of 
lenvatinib
Day 1 of 
each cycle
Within 14 days 
of last dose of 
pembrolizumab
Every 12 
weeks +/- 14 
daysc
Administrative Procedures
Informed Consent
X
Inclusion/Exclusion Criteria
X
X
Demographics and Medical History
X
Prior and Concomitant Medication 
Review
X
X
X
X
X
X
X
Xd
Assessment of Trial Compliance
X
X
X
X
X
X
X
Lenvatinib Administration
Throughout (daily)
Pembrolizumab Administration
X
X
X
X
X
Clinical Procedures/Assessments
Review Adverse Events
X (throughout)
X
Full Physical Examination
X
Focused Physical Exam
X
X
X
X
X
X
X
Vital Signs, Height and Weighte
X
X
X
X
X
X
X
X
ECOG Performance Statusf
X
X
X
X
X
X
X
X
MUGA or echocardiogram
X
Xg
Xg
12-lead EKG
X
X
X
X
X
X
X
X
Sarcopenia Assessmenth
X
Xh
Xh
Xh
Quality of Life Assessmenti
X
X
X
Xz
X
Frailty Assessmentj
X
X
X
Xz
X
Laboratory Procedures/Assessments: analysis performed by LOCAL laboratory
Pregnancy Test – Urine or serum -
HCGk
X
X
X
X
X
X
X
X
X
PT/INR and aPTT
X
X
X
X
X
X
X
X
X

                                        Page 39
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Clinical laboratory testsl
X
X
X
X
X
X
X
X
X
Liver enzymesm
X
X
X
X
X
X
X
X
X
X
Urinalysisn,o
X
X
X
X
X
X
X
X
X
T3, FT4 and TSH
X
X
X
X 
X
X
X
X
X
Efficacy Measurements
Tumor Imaging
MRI brainp
X
CT chestq
X
Xy
Xy
CT or MRI abdomen/pelvisr
X
Xy
Xy
X
Survival
X (throughout)
X
Xc
Tumor Biopsies/Archival Tissue Collection/Correlative Studies Blood
Archival or Newly Obtained Tissue 
Collections
X
Nephrectomy
Xt,u
Correlative Studies Blood Collection
X
X
X
X
X
X
Xv
Xv
XCC
X
Stool sample for microbiome
X
X
Xaa
X
a.
The screening period extends from Day -28 to Day 1 Subjects must be screened within 28 days prior to Cycle 1/Day 1. The screening assessment can serve as the baseline assessment, if performed within 72 h before Cycle 
1/Day 1. The baseline assessment can be performed from Day -3 to Cycle 1/Day 1 (prior to the first dose of study drug). Informed consent may be obtained up to 8 weeks prior to the start of study drug.
b.
Efforts should be made to conduct study visits and clinical procedures on the day scheduled (±3 days). Treatment cycles will be counted continuously regardless of dose interruptions. Clinical laboratory assessments may be 
conducted anytime within 72 h prior to the scheduled visit, unless otherwise specified. 
c.
Long-term follow-up should continue until the patient’s withdrawal of consent or loss to follow up, death, or study termination. Patients in long term follow-up can be seen by medical oncology or urology team, have chart 
reviewed, or phone call to determine current status every 12 weeks. 
d.
Concomitant meds are recorded for 30 days after last dose
e.
Assessments will include vital signs (resting BP, HR, RR, and body temperature), weight, and height. Height will be measured at the Screening Visit only. Elevated BP assessment (i.e., systolic BP ≥140 mmHg or diastolic 
BP ≥90 mmHg) should be confirmed by a repeat assessment after a minimum of 1 hour. One BP assessment is defined as the mean value of 3 measurements at least 5 minutes apart. Subjects with systolic BP ≥160 mmHg or 
diastolic BP ≥100 mmHg must have their BP monitored every 2 weeks until systolic BP has been ≤150 mmHg and diastolic BP has been ≤95 mmHg for 3 consecutive months. If a new event of systolic BP ≥160 mmHg or 
diastolic BP ≥100 mmHg occurs, the subject must resume the evaluation every 2 weeks until systolic BP has been ≤150 mmHg and diastolic BP has been ≤95 mmHg for 3 consecutive months.
f.
Appendix 1
g.
If clinically indicated
h.
Sarcopenia assessment will be completed using baseline, on-treatment and post-treatment scans via SliceOmatic v5.0 by TomoVision program after completion of study. 
i.
Appendix 4
j.
Appendix 5
k.
Only necessary in women of child bearing potential
l.
Clinical laboratory tests include a standard hematology panel (WBC with differential [including absolute count of neutrophils, basophils, eosinophils, lymphocytes, monocytes at minimum], hemoglobin/hematocrit, platelet 
count), chemistry panel (albumin, alkaline phosphatase, ALT, amylase, AST, bicarbonate, bilirubin, blood urea nitrogen, calcium, chloride, creatinine, γ-glutamyltransferase [GGT], glucose, lactate dehydrogenase, lipase, 
magnesium, phosphorus, potassium, sodium, total protein, uric acid), and CRP

                                        Page 40
Version Date: 02/07/2024
m.
As per standard of care while initiating lenvatinib, transaminases including AST and ALT need to be monitored every 2 weeks for the first 2 months of treatment. For this reason, the patient will have these checked at the 
time of each cycle start but also between days 8 and 15, days 29 and 36, and days 50 and 57 (This test can be done locally if patient is traveling). 
n.
Urinalysis includes appearance, color, pH, specific gravity, ketones, protein, UPCR, glucose bilirubin, nitrite, creatinine, urobilinogen, occult blood (microscopic examination of sediment will be performed only if the results 
of the urinalysis dipstick evaluation are positive)
o.
If urine dipstick has 2+ proteinuria, a 24-hour urine collection will be collected for protein quantification and adverse effect grading
p.
Screening brain scans will be performed by MRI pre- and post- gadolinium within 28 days prior to C1D1. During the Treatment Phase, CT/MRI of the brain will be performed if clinically indicated
q.
Screening tumor assessments using CT of the chest can be done with or without IV iodinated contrast 
r.
Screening and post-treatment tumor assessments of the abdomen pelvis can be done with MRI or CT. CT should be performed with iodinated IV contrast and MRI scans should be done with IV gadolinium chelate unless 
there is a medical contraindication to contrast. 
s.
An archival tumor tissue sample must be available prior to first dose. If an archival tumor sample for biomarker analysis is not available, then a newly obtained tumor biopsy must be obtained prior to the first dose. Subjects 
must have recovered adequately from the biopsy prior to starting therapy. 
t.
Patients will undergo kidney surgery a minimum 7 days after the last dose of lenvatinib
u.
Analysis of intraoperative and post-operative complications using the universally used Clavien-Dindo perioperative classification of adverse events [1]
v.
Blood for correlative studies will be collected in the within 7 days prior to nephrectomy and within 7-42 days post nephrectomy
w.
Patients who completed combination neoadjuvant therapy and underwent nephrectomy prior to the amendment including 13 cycles of adjuvant pembrolizumab will not receive adjuvant therapy. Subjects who are currently 
receiving treatment prior to new protocol amendment will be offered the option to receive adjuvant pembrolizumab after reconsented. All patients enrolled after the amendment including adjuvant pembrolizumab will 
receive adjuvant pembrolizumab if they enroll in the trial. 
x.
The 1stdose of adjuvant pembrolizumab (cycle 5 pembrolizumab) should be initiated within 4 to 12 weeks after nephrectomy depending on the patient’s recovery from surgery and readiness for therapy as determined by the 
investigator. 
y.
Cross-sectional imaging as per superscript q and r will be conducted after the last dose of Lenvatinib but before nephrectomy. Beginning with adjuvant pembrolizumab cycle 5, cross-sectional imaging will be completed 
within 7 days before or after the time of initiation of cycle 5 pembrolizumab and every 12 weeks thereafter until completion of study drug, after which time local guidelines on surveillance imaging can be followed. 
z.
Quality of life and frailty assessments will be made every 12 weeks while receiving pembrolizumab cycles 5-13. 
aa.
Stool samples will be collected during cycle 9 only during the adjuvant phase
bb.
Blood samples will be collected cycle 5, 9, 13

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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 must obtain documented consent from each potential participant prior to 
participating in a clinical trial. This must be done within 8 weeks of Cycle 1 Day 1. 
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.  
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations 
and Sponsor requirements.

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7.1.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the participant qualifies for the trial. 
7.1.1.3
Demographics and Medical History
Patient demographics and 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.  
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
Trial compliance
Compliance will be assessed by the investigator and/or study personnel at each patient visit 
and information provided by the patient and/or caregiver (collection of drug diary) will be 
captured in the Drug Accountability Form (Appendix 6). This information must be captured 
in the source document at each patient visit.  Dose changes and interruptions of study drug 
must be specifically documented in the patient’s CRF. 
7.1.1.6
Lenvatinib Administration
Lenvatinib will be administrated daily during cycles 1 through 4 (with each cycle lasting 21 
days). The initiation of Cycle 1 Day 1 should align with the first pembrolizumab 
administration +/- 3 days. Lenvatinib will not be administered post-surgery. 
7.1.1.7
Pembrolizumab Administration
Pembrolizumab will be administered on the 1st day of each 21-day cycle for a total of four 
cycles prior to surgery and a total of 13 cycles after surgery (for a total of 17 cycles 
pembrolizumab in total). The 5th cycle (which is the 1st adjuvant cycle administered after 
nephrectomy) will be administered between 4 and 12 weeks post-nephrectomy. The exact 

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time of initiation of cycle 5 will be left up to investigator discretion based on the patient’s 
recovery after surgery. 
Patients who completed combination neoadjuvant therapy and underwent nephrectomy prior 
to the amendment including 13 cycles of adjuvant pembrolizumab will not receive adjuvant 
therapy. Those who are currently receiving treatment will be offered the option to receive 
adjuvant pembrolizumab and will be reconsented. All patients enrolled after the amendment 
including adjuvant pembrolizumab will receive adjuvant pembrolizumab if they enroll in the 
trial. 
7.1.2
Clinical Procedures and 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 4.0 (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 the Screening visit. 
7.1.2.3
Focused Physical Exam
For cycles that do not require a full physical exam per the Trial Flow Chart, the investigator 
or qualified designee will perform a directed physical exam as clinically indicated prior to 
trial treatment administration.  
7.1.2.4
Vital Signs, Height and Weight
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.

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7.1.2.5
Eastern Cooperative Oncology Group (ECOG) Performance Scale
The investigator or qualified designee will assess ECOG status at screening, prior to the 
administration of each dose of trial treatment and after discontinuation of trial treatment as 
specified in the Trial Flow Chart. ECOG classification groups are referenced in Appendix 1. 
7.1.2.6
Multigated acquisition scan (MUGA) or echocardiogram
A MUGA scan (using technetium-99m-pertechnetate) or an echocardiogram to assess left 
ventricular ejection fraction (LVEF) will be performed as designated in the Study Flow 
Chart. MUGA or echocardiogram scans should be performed locally in accordance with the 
institution’s standard practice. MUGA scans are the preferred modality; however, whichever 
modality is used for an individual subject at baseline should be repeated for all subsequent 
LVEF assessments for that subject. 
All scans performed during the study should be archived in accordance with the standard 
local practice. They must be accessible in the event of a sponsor request to submit them for 
central review. 
7.1.2.7
12-lead Electrocardiogram (EKG)
Electrocardiograms will be obtained as designated in the Study Flow Chart. Complete, 
standardized, 12-lead ECG recordings that permit all 12 leads to be displayed on a single 
page with an accompanying lead II rhythm strip below the customary 3 × 4 lead format are to 
be used. In addition to a rhythm strip, a minimum of 3 full complexes should be recorded 
from each lead simultaneously. Subjects must be in the recumbent position or sitting for a 
period of 5 minutes prior to the ECG. 
An ECG abnormality may meet the criteria of an AE as described in this protocol (see 
Section 7.2). In these instances, the AE corresponding to the ECG abnormality will be 
recorded as an Adverse Event. 
7.1.2.8
Sarcopenia Assessment
Sarcopenia assessment will be completed using baseline, on-treatment, and post-treatment 
imaging via SliceOmatic v5.0 by TomoVision program after completion of study. 
7.1.2.9
Frailty Assessment
Frailty assessment will be studies using the Fried Frailty score (Appendix 5), which will be 
obtained at baseline, halfway through neoadjuvant treatment (Cycle 3 Day 1) and prior to 
surgery. During the adjuvant pembrolizumab phase, frailty assessment will be obtained every 
12 weeks and at the post-treatment visit.  

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7.1.2.10 Quality of Life Assessment
Quality of life will be studied using the Functional Assessment of Cancer Therapy-Kidney 
Specific Index-19 (FKSI-19) questionnaire (Appendix 4), which will be filled out at baseline, 
halfway through neoadjuvant treatment treatment (Cycle 3 Day 1) and prior to surgery. 
During the adjuvant pembrolizumab phase, frailty assessment will be obtained every 12 
weeks and at the post-treatment visit.  
7.1.3
Laboratory Procedures and Assessments
The schedule regarding specific laboratory procedures/assessments to be performed in this 
trial are noted in the Study Flow Chart.  
All hematology, blood chemistry (including pregnancy test, as applicable), and urinalysis 
samples are to be obtained prior to study drug administration and results reviewed prior to 
administration/dispensing of study drug at the beginning of each treatment cycle. Clinical 
laboratory assessments during the treatment period may be conducted anytime within 72 h 
prior to the scheduled visit, unless otherwise specified. 
A laboratory abnormality may meet the criteria to qualify as an AE as described in this 
protocol (see Section 7.2). In these instances, the AE corresponding to the laboratory 
abnormality will be recorded. 
Laboratory tests for hematology, chemistry, urinalysis, and others are specified in Table 7.

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Table 7. Trial-Related Laboratory Tests
Hematology
Chemistry
Urinalysis
Other
Hematocrit
Albumin
Appearance
β-human chorionic gonadotropin†
Hemoglobin
Alkaline phosphatase
Color
PT (INR)
Platelet count
Alanine aminotransferase (ALT)
pH 
aPTT
WBC (total and differential)
Aspartate aminotransferase (AST)
Specific gravity 
Total triiodothyronine (T3)
Red Blood Cell Count
Lactate dehydrogenase (LDH)
Ketones
Free thyroxine (T4)
Absolute Neutrophil Count
Bicarbonate
Protein
Thyroid stimulating hormone (TSH)
Absolute Lymphocyte Count
Uric Acid
UPCR
CRP
Absolute Monocyte Count
Calcium
Glucose
 
Absolute Eosinophil Count 
Chloride
Bilirubin
Blood for correlative studies
Absolute Basophil Count
Glucose
Nitrite
Phosphorus
Creatinine
Potassium  
Urobilinogen
Sodium
Occult blood
 
Magnesium
(microscopic examination of sediment will 
be performed only if the results of the 
urinalysis dipstick evaluation are positive)
 
Bilirubin
Urine pregnancy test †
 
Total protein
Blood Urea Nitrogen
Amylase
Lipase
γ-glutamyltransferase (GGT)
† Perform on women of childbearing potential only. Urine or serum testing is allowed. If urine pregnancy results cannot be confirmed as negative, a serum 
pregnancy test will be required.  
7.1.4
Efficacy Measurements
7.1.4.1
Tumor Imaging and Assessment of Disease
Tumor imaging is strongly preferred to be acquired by computed tomography (CT).  For the abdomen and pelvis, contrast-enhanced 
magnetic resonance imaging (MRI) may be used when CT with iodinated contrast is contraindicated, or when local practice mandates 

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it.  MRI is the strongly preferred modality for imaging the brain. CT of the brain with IV iodinated contrast is acceptable only if MRI 
is medically 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.
Expedited confirmation of measurable disease based on RECIST 1.1 at Screening should be used to determine participant eligibility.  
Confirmation that the participant’s imaging shows at least 1 lesion that is appropriate for selection as a target lesion per RECIST 1.1 is 
required to participant treatment allocation.   
7.1.4.1.1 Initial Tumor Imaging
Initial tumor imaging of the brain, chest, abdomen and pelvis at Screening must be performed within 28 days prior to the date of study 
drug allocation. The site study team must review screening images to confirm the participant has measurable disease per RECIST 1.1. 
Brain imaging is required to rule out radiographically detectable brain metastases.  Magnetic resonance imaging is preferred; however, 
CT imaging will be acceptable if MRI is medically contraindicated. 
7.1.4.1.2 Tumor Imaging During the Study
Imaging assessment during the study can be performed as clinically indicated but there is no scheduled time for assessment within the 
12 weeks between Cycle 1 Day 1 and the completion of 12 weeks of neoadjuvant study treatment. Imaging will be done within 14 
days after completion of the last dose of lenvatinib but before surgical resection. Post nephrectomy, repeat imaging will occur at the 
time of initiation of cycle 5 of pembrolizumab and every 12 weeks while receiving therapy.  
7.1.4.1.3 End of Treatment and Follow-up Tumor Imaging
Imaging should be completed within 14 days of completing the final cycle (13) of adjuvant pembrolizumab. If a subject prematurely 
discontinues study treatment prior to completion of the last dose of pembrolizumab, tumor imaging should be performed within 2 
weeks of treatment discontinuation if that is  4 weeks from Cycle 1 Day 1 of therapy and their last imaging timepoint. 
Post-nephrectomy and in the long-term follow-up period, every effort should be made to continue monitoring subjects disease status 
by tumor imaging as per NCCN guidelines for stage III RCC [29]. This includes surveillance imaging every 3 to 6 months for at least 
3 years and then annually for up to 5 years. Imaging beyond 5 years should be performed as clinically indicated. 

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7.1.4.1.4 RECIST 1.1 
Objective response rate (ORR) is the primary endpoint for this study which will be evaluated. ORR will be based on the tumor 
assessment performed by the investigators using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. This assessment will be 
made based on the imaging obtained after the completion of 12 weeks of therapy but before nephrectomy as per the Trial Flow Chart. 

Target lesions:
All tumor measurements will be recorded in centimeters. RECIST references a maximum of 5 lesions in total and 2 per organ that 
should be identified as target lesions and recorded and measured at baseline. Non-lymph nodes must be at least 10mm in the longest 
diameter and lymph nodes must be at least 15mm in short axis to be included as a target lesion. Target lesions should be selected on 
the basis of their size (those with the longest diameter) and their suitability for accurate repeated measurements (either by imaging 
techniques or clinically). A sum of the longest diameter for all target lesions will be calculated and reported as the baseline sum 
longest diameter. The baseline sum of longest diameters will be used as the reference by which the objective tumor response is 
characterized. Given that inclusion criteria for this study specifies that participants must have T3Nx or TanyN1 disease, it is likely that 
only target lesion assessment will be required.  

Non-target lesions:
All other lesions (or sites of disease) should also be recorded at baseline. There is no limit to the number of non-target lesions that can 
be recorded at baseline. This may include lesions that are felt to represent neoplastic tissue but are difficult to measure in a 
reproducible manner (e.g. bone metastases, leptomeningeal metastasis, ascites) although these are not expected as this is a trial of 
locally advanced and not metastatic disease. Measurements of these lesions are not required, but the presence or absence of each 
should be noted throughout follow-up.

New lesions:
Any lesion that was not recorded at baseline. There is no minimum size criteria to identify a new lesion and clinical judgment may be 
used by the investigator. A new lesion should be unequivocal and not due to differences in scanning technique. 
Target and non-target lesions will be evaluated after treatment as per Table 8. 

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Table 8. RECIST 1.1 evaluation of target and non-target lesions
Type of response
Definition
Complete response (CR)
Complete disappearance of all measurable and non-measurable lesions (from 
baseline) and there are no unequivocal new lesions.
Lymph nodes must decrease to <10 mm in short axis. 
Partial response (PR)
SODpost-treatment of target lesions (TLs) decreases by ≥30 % compared to 
SODbaseline and there are no unequivocal new lesions, and no progression of 
nontarget disease.
Stable disease (SD)
Failure to meet criteria for CR or PR in the absence of PD. 
If the sum of the TLs and the status of the nontarget lesions do not reach the 
criteria to meet PR or PD (increase ≥20% and at least 5 mm absolute increase in 
SOD compared to baseline), the response is SD. 
SD = neither 30% decrease compared to SODbaseline or 20% increase and at 
least 5 mm absolute change compared to nadir.
Progressive disease (PD)
Minimum 20% increase and a minimum 5 mm absolute increase in SOD 
compared to nadir, or PD for nontarget lesion(s) or unequivocal new lesion(s).  
Not evaluable (NE)
Used in exceptional cases where insufficient data exists due to poor quality of 
scans or missed scans or procedure 
SODbaseline = Sum of diameters at baseline = longest diameter of all non-nodal + shortest diameter of all nodal target lesions 
Best overall response after the completion of treatment will be evaluated as per Table 9. 
Table 9. Evaluation of Best Overall Response per RECIST 1.1 
Target Lesions (% change in 
SOD)a
Non-Target Lesions Status
New Lesions Status
Overall Response (RECIST)
 100
Absent
Absent
CR
 100
Present/NE
Absent
PR
  30
Present/Absent/NE
Absent
PR
 100
  30
 < 30 to  < 20
Present/Absent/NE
Present
PD

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NE
 100
  30
 < 30 to  < 20
NE
Unequivocal progressionb
Any
PD
  20 from nadir
Any
Any
PD
NE
Present/Absent/NE
Absent
NE
a. Decreases assessed relative to baseline, including measurable lesions only
b. In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as disease progression
Note:  Patients with a global deterioration of health status requiring discontinuation of treatment without objective evidence of disease progression at that time should be reported as “symptomatic 
deterioration.”  Every effort should be made to document the objective progression even after discontinuation of treatment.

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7.1.4.2
Survival
Survival will be assessed throughout treatment as well as in the post-treatment period and 
long-term follow-up period until the patient’s withdrawal of consent or loss to follow up, 
death, or study termination. 
7.1.4.3
Tumor Tissue Collection and Correlative Studies Blood Sampling
7.1.4.3.1 Tumor Tissue Collection
Tumor tissue will be collected prior to trial enrollment and allotment in the form of archival 
tissue. If archival tissue is not available, tumor biopsy must be obtained prior to the first 
dose. Subjects must have recovered adequately from the biopsy prior to starting therapy. 
Tissue will be obtained during nephrectomy and will serve as the post-treatment specimen. 
Any obtained tissues will be handled as follows: 

RNAlater for RNA stabilization and tissue storage

Formalin-fixed paraffin-embedded (FFPE) block with one cut H&E stained 
slide

Liquid nitrogen frozen tissue in cryo-preservation vials
All collected tissues are stabilized and stored in -80°C freezers (RNAlater stabilized, OCT 
embedded, short term storage) or the vapor phase of a liquid nitrogen freezer (long term 
storage) in single use aliquots. All FFPE tissue blocks are stored in a climate-controlled 
storage room that is temperature (less than 27ºC) and humidity controlled.
Tissue will be evaluated for assessment of mutations and/or immune markers including PD-
1/PD-L1 and other relevant biomarkers (e.g. tumor infiltrating lymphocytes, T- cell 
repertoire, RNA signature profiles). When sufficient quantities of fresh tissue are available, it 
will also be dissociated and flow cytometry will be used to determine the phenotypic 
characteristics of cell populations in the tumor microenvironment. Tissue will be preserved 
for future exploratory studies including genomic profiling. 
7.1.4.3.2 Correlative Studies Blood Sampling
Correlative peripheral blood samples will be collected prior to study drug allotment, on Cycle 
1 Day 1 of each cycle, on Cycle 1 Day 8 to assess for any immune-related changes occurring 
in the immediate period following checkpoint inhibitor exposure, and in the post-treatment 
period (both pre- and post-nephrectomy) as expanded in the Trial Flow Chart. Approximately 
60 mL of peripheral blood will be collected at each time point. The samples will be stored in 
-80°C freezers until analysis. Stool sample for microbiome analysis will be collected at 
baseline, and post-treatment phase within the 14 days after the last dose of lenvatinib. 
Analysis may include but is not limited to:

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
Circulating tumor DNA (ctDNA) to explore genetic alterations that are present are 
baseline and/or emerge during treatment

Analysis of peripheral blood mononuclear cells (PBMCs) to assess for 
phenotypic/functional changes in T-cells or myeloid markers during and after 
treatment

Nuclear acid analysis for gene expression profiling

Stool sample for microbiome analysis
Shipping and handling instructions
After appropriate processing, the blood samples, tissue blocks, slides or frozen tissue samples 
will be sent to:
Kissick Laboratory
1462 Clifton Rd, Room 420
Atlanta, Georgia, 30322
ph: 617 259 8364
email: haydn.kissick@emory.edu
On the day that the specimens are to be shipped, notify Dr. Haydn Kissick of the pending 
specimen shipments. Include the Fed-Ex tracking number in the email.
Research blood contact Information:
Kissick Laboratory
ph: 617 259 8364
email: haydn.kissick@emory.edu
7.1.5
Other Procedures
7.1.5.1
Local Registration/Enrollment Procedures
7.1.5.1.1 Registration
Study personnel will notify Winship Central Subject Registration (WCSR) by email at 
winshipcsr@emory.edu, once subject has been consented for a trial. Email notification must 
be done within 24 hours after consent has been obtained and it will include scanned copies 
of:

Signed patient consent form

HIPAA authorization form

Emory Research Management System (ERMS; https://erms.emory.edu) 
Enrollment Fax Cover 

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The WCSR will enter the subject into the OnCore Research Management System, which is 
the system of record for Winship Cancer Institute Clinical Trials.
7.1.5.1.2 Enrollment
Enrolling a subject requires careful screening and determination of eligibility. 
Eligible patients will be enrolled on study at Winship Cancer Institute by the Study 
Coordinator.  When all required test results are available, complete the eligibility checklist 
and provide the checklist and the supporting documentation to the IRB approved investigator 
for review and sign-off. Once the investigator (sub-investigator, Co-Investigator) has signed 
the eligibility checklist, randomization and or enrollment may proceed. Oncore and ERMS 
must be updated to reflect eligibility and on treatment status. 
7.1.5.2
Withdrawal/Discontinuation
When a participant discontinues/withdraws prior to trial completion, all applicable/necessary 
activities, per investigator’s discretion, 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, these participants should return to the site for a Safety Follow-up Visit (Section 
7.1.6.3.1) and then proceed to nephrectomy (if the discontinuation happened during the 
neoadjuvant phase of treatment) and then the Follow-Up Period of the study (Section 
7.1.5.4).
7.1.5.3
Blinding/Unblinding
Not applicable to this unblinded study. 
7.1.6
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.
7.1.6.1
Screening Period
The screening period extends from Day -28 to Day 1. Subjects must be screened at a visit 
within 28 days prior to Cycle 1/Day 1. The screening assessment can serve as the baseline 
assessment, if performed within 72 h before Cycle 1/Day 1. The baseline assessment must be 
performed at a visit and can be performed anywhere between Day -3 to Cycle 1/Day 1 (prior 
to the first dose of study drug). Informed consent may be obtained up to 8 weeks prior to the 
start of study drug.
7.1.6.2
Treatment Period

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7.1.6.2.1 Neoadjuvant Phase
A visit is required at the start of each cycle of treatment beginning with Cycle 1 Day 1. 
Efforts should be made to conduct study visits on the day scheduled (±3 days). Treatment 
cycles will be counted continuously regardless of dose interruptions.  
7.1.6.2.2 Surgical Phase
7.1.6.2.2.1 Post neoadjuvant therapy Safety Follow-Up Visit
The mandatory post-neoadjuvant therapy safety visit will be conducted within 7 days of the 
last dose of lenvatinib and prior to nephrectomy. Laboratory and physical examinations will 
be performed including peripheral blood collection for correlative studies. Remaining 
Lenvatinib will be returned by the subject, and treatment compliance will be assessed and 
documented. Additional follow-up will occur for subjects with AEs related to study treatment 
that are ongoing at the time of this visit, and for subjects with SAEs related to study 
treatment that occur after the time of this visit. 
7.1.6.2.2.2 Nephrectomy
Patients will wait at least 7 days from the last dose of lenvatinib before undergoing 
nephrectomy. Patients will be analyzed for intraoperative and post-operative complications 
using the Clavien-Dindo perioperative classification of adverse events [1]. Our 
documentation will include but not be limited to complications such as anemia, chylous 
ascites, pulmonary embolism, ileus, bleeding, superficial wound dehiscence, fascial 
dehiscence, pleural effusion, pneumonia, urinary retention, gastroparesis, and post- operative 
delirium. We will also collect data regarding the details of the surgical procedure (e.g. extent 
of nephrectomy). 
7.1.6.2.3 Adjuvant Phase
Cycle 5 of pembrolizumab will begin between 4 and 12 weeks after nephrectomy and exact 
timing will be at investigator’s discretion based on the subject’s recovery from nephrectomy, 
etc. A visit is required at the start of each cycle of adjuvant treatment beginning with Cycle 5 
Day 1. Efforts should be made to conduct study visits on the day scheduled (±3 days). 
Treatment cycles will be counted continuously regardless of dose interruptions.  

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7.1.6.3
Post-Treatment Period
7.1.6.3.1 Post adjuvant therapy Safety Follow-Up Visit
The mandatory post-adjuvant therapy Safety Follow-Up Visit should be conducted within 
approximately 14 days after the last dose of study treatment (pembrolizumab). Laboratory 
and physical examinations will be performed including peripheral blood collection for 
correlative studies.. Additional follow-up will occur for subjects with AEs related to study 
treatment that are ongoing at the time of this visit, and for subjects with SAEs related to 
study treatment that occur after the time of this visit.  
7.1.6.4
Long Term Follow-Up Period
After the post-adjuvant therapy safety follow-up visit, patients enter the long-term follow-up 
period. During this time, they can be seen by the medical oncology or urology team via clinic 
visit, chart review, or phone call to determine current status every 12 weeks (+/- 14 days) 
until disease recurrence, initiation of new antineoplastic or investigational therapy whichever 
occurs first. Patients removed from study for unacceptable adverse event(s) will be followed 
until resolution or stabilization of the adverse event.
Long-term follow-up should continue until the patient’s withdrawal of consent or loss to 
follow up, death, or study termination. 
7.1.6.4.1 Loss to Follow-Up
A study participant will be considered lost to follow-up if he/she does not present for three 
scheduled visits and is unable to be contacted by the trial team after three attempts at contact 
by phone. 
The following actions will be taken a participant fails to return to the clinic for a required 
study visit:

The study team will attempt to contact the subject and reschedule the missed visit. 
They will counsel the subject on the importance of keeping scheduled visits and 
determine whether the subject wishes to or should remain in the study. 

Before being labeled as lost to follow-up, the investigator or study designee with 
make every effort to regain contact with the subject including 3 telephone calls and, if 
necessary, a certified letter to their last known mailing address. These attempts will 
be recorded in the subject’s file. 

If these attempts are unsuccessful, the subject will be considered to have withdrawn 
from the study with the reason of lost to follow-up. 

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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 Merck product, is also an adverse event.
From the time of treatment allocation through 90 days following cessation of treatment, all 
adverse events, that begin or worsen after informed consent, must be recorded by the 
investigator or designee at each examination on the Adverse Event case report 
forms/worksheets.  
The investigator will make every attempt to follow all subjects with non-serious adverse 
events for outcome.
Conditions that were already present at the time of informed consent should be recorded in 
the Medical History page of the patient’s CRF/worksheet.
Adverse events will be assessed and graded according to the Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.0. Grade 1 to 5 will be used to characterize the 
severity of the Adverse Event. 
If CTCAE grading does not exist for an adverse event, the severity of mild, moderate, severe, 
and life-threatening, death related to the AE corresponding respectively to Grades 1 - 5, will 
be used. Information about any deaths (related to an Adverse Event or not) will also be 
collected through a Death form (or EOT/SEC/Survival Information in NOVDD). The 
occurrence of adverse events should be sought by non-directive questioning of the patient 
(patient) during the screening process after signing informed consent and at each visit during 
the study. Adverse events also may be detected when they are volunteered by the patient 
(patient) during the screening process or between visits, or through physical examination, 
laboratory test, or other assessments. As far as possible, each adverse event should be 
evaluated to determine: 
1. The severity grade (CTCAE Grade 1-5) 
2. Its duration (Start and end dates)  
3. Its relationship to the study treatment (Definitely Related, Probably Related, Potentially 
Related, Unlikely to be related, Not Related)
4. Action taken with respect to study or investigational treatment (none, dose adjusted, 
temporarily interrupted, permanently discontinued, unknown, not applicable) 
5. Whether medication or therapy was given (no concomitant medication/non-drug therapy, 
concomitant medication/non-drug therapy) 
6. Whether it is serious, where a serious adverse event (SAE) is defined as in Section 9.2 and 
which seriousness criteria have been met (include for NCDS trials) 

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Outcome (not recovered/not resolved, recovered/resolved, recovering/resolving, 
recovered/resolved with sequelae, fatal, unknown)  
If the event worsens the event should be reported a second time in the CRF noting the start 
date when the event worsens in toxicity. For grade 3 and 4 adverse events only, if 
improvement to a lower grade is determined a new entry for this event should be reported in 
the CRF noting the start date when the event improved from having been Grade 3 or Grade 4.  
All adverse events should be treated appropriately. If a concomitant medication or non-drug 
therapy is given, this action should be recorded on the Adverse Event CRF.
Once an adverse event is detected, it should be followed until its resolution or until it is 
judged to be permanent, and assessment should be made at each visit (or more frequently, if 
necessary) of any changes in severity, the suspected relationship to the study treatment, the 
interventions required to treat it, and the outcome. Progression of malignancy (including fatal 
outcomes), if documented by use of appropriate method (for example, as per RECIST criteria 
for solid tumors), should not be reported as a serious adverse event. 
Adverse events separate from the progression of malignancy (example, deep vein thrombosis 
at the time of progression or hemoptysis concurrent with finding of disease progression) will 
be reported as per usual guidelines used for such events with proper attribution regarding 
relatedness to the drug.
Laboratory abnormalities that constitute an Adverse event in their own right (are considered 
clinically significant, induce clinical signs or symptoms, require concomitant therapy or 
require changes in study treatment), should be recorded on the Adverse Events CRF.
Laboratory abnormalities, that do not meet the definition of an adverse event, should not be 
reported as adverse events. A Grade 3 or 4 event (severe) as per CTCAE does not 
automatically indicate a SAE unless it meets the definition of serious as defined below and/or 
as per investigator’s discretion. A dose hold or medication for the lab abnormality may be 
required by the protocol in which case the lab abnormality would still, by definition, be an 
adverse event and must be reported as such.
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 
Principal Investigator 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.

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Due to the high plasma protein binding, lenvatinib is not expected to be dialyzable. Death 
due to multiorgan dysfunction occurred in a patient who received a single dose of lenvatinib 
120mg orally. 
If an adverse event(s) is associated with (“results from”) the overdose of a Merck product, 
the adverse event(s) is reported as a serious adverse event, even if no other seriousness 
criteria are met.
If a dose of Merck’s product meeting the protocol definition of overdose is taken without any 
associated clinical symptoms or abnormal laboratory results, the overdose is reported as a 
non-serious Event of Clinical Interest (ECI), using the terminology “accidental or intentional 
overdose without adverse effect.”
All reports of overdose with and without an adverse event must be reported within 24 hours 
to the principal investigator (PI) 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 Principal Investigator 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 Supporter`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 PI and within 2 working days to Merck 
Global Safety. (Attn: Worldwide Product Safety; FAX 215-661-6229)

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7.2.3
Immediate Reporting of Adverse Events to the Principal Investigator and to 
Merck
7.2.3.1
Serious Adverse Events
An adverse event (AE) or suspected adverse reaction is considered "serious" if, in the view of 
either the investigator or sponsor, it results in any of the following outcomes: 

Death

Life-threatening adverse event 

Inpatient hospitalization or prolongation of existing hospitalization

A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions, or a congenital anomaly/birth defect. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the participant and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition. (Examples of such medical events 
include allergic bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse).
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:

submitted on a Winship SAE form and assessed by PI in order to determine 
reporting criteria to regulatory authorities 

reported 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 through 90 days following cessation of 
treatment, or 30 days following cessation of treatment if the subject 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 study drug, must be:

submitted on a Winship SAE form and assessed by PI in order to determine 
reporting criteria to regulatory authorities,. 

 reported within 2 working days to Merck Global Safety
Both lenvatinib and pembrolizumab are Merck products. All SAEs will be followed until 
satisfactory resolution or until the site investigator deems the event to be chronic or the 
adherence to be stable. Other supporting documentation of the event may be requested by the 
study sponsor and should be provided as soon as possible. The study sponsor-Investigator 
will be responsible for notifying FDA and Merck of any unexpected fatal or life-threatening 
suspected adverse reaction as soon as possible but in no case later than 7 calendar days after 
the PI’s initial receipt of the information..

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All subjects with serious adverse events must be followed up for outcome.
Any additional information for the SAE including complications, progression of the initial 
SAE, and recurrent episodes must be submitted on a new Winship SAE form and assessed 
by PI in order to determine reporting criteria to regulatory authorities, (IRB, DSMC, FDA) 
and submitted to Merck as follow-up to the original episode. 
An SAE occurring at a different time interval or otherwise considered completely unrelated 
to a previously reported one should be reported separately as a new event. 
Any SAEs experienced after the reporting period described above should only be reported to 
FDA/IRB and  Merck if the investigator suspects a causal relationship to the study treatment.   
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The investigator must assess and record the relationship of each SAE to 
each specific study treatment (Pembrolizumab and/or Lenvatinib), complete the SAE Report 
Form, and submit the completed form.  
Each reoccurrence, complication, or progression of the original event should be reported as a 
follow-up to that event regardless of when it occurs. The follow-up information should 
describe whether the event has resolved or continues, if and how it was treated, whether the 
blind was broken or not, and whether the patient continued or withdrew from study 
participation. 
All SAE must be recorded on a MedWatch 3500 Form. SAE reports and any other relevant 
safety information are to be forwarded to the following 
MedWatch 3500 Reporting Guidelines:
Note:  MedWatch 3500 forms and other information related to MedWatch reporting are 
available at http://www.fda.gov/medwatch/index.html.
A copy of all 15 Day Reports and Annual Progress Reports is submitted as required by FDA. 
Investigators will cross reference this submission according to local regulations to the 
Investigational Compound Number (IND, CSA, etc.) at the time of submission. 
An investigator who is a qualified physician will evaluate all adverse events according to the 
NCI Common Terminology for Adverse Events (CTCAE), version 4.0. Any adverse event 
which changes CTCAE grade over the course of a given episode will have each change of 
grade recorded on the adverse event case report forms/worksheets. All adverse events 
regardless of CTCAE grade must also be evaluated for seriousness.
Reporting Requirements for IND holder
For Investigator-sponsored IND studies, reporting requirements for the FDA apply in 
accordance with the guidance set forth in 21 CFR, Part 312.32.  Events meeting the following 
criteria need to be submitted to the FDA as Expedited IND Safety Reports.
7 Calendar-Day Telephone or Fax Report
The Sponsor-Investigator is required to notify the FDA of a fatal or life-threatening adverse 
event that is unexpected and assessed by the investigator to be possibly related to the use of 
investigational agents.  An unexpected adverse event is one that is not already described in 
the most recent Guidance for Investigator section of the Investigator’s Brochure.  Such 

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reports are to be telephoned or faxed to the FDA, within 7 calendar days of the first learning 
of the event.
15 Calendar-Day Written Report
The Sponsor-Investigator is also required to notify the FDA and all participating 
investigators, in a written IND Safety Report, of any serious unexpected adverse event that is 
considered reasonably or possibly related to the use of investigational agent.
Written IND Safety Reports with analysis of similar events are to be submitted to the FDA, 
within 15 calendar days of first learning of the event.  The FDA prefers these reports on a 
MedWatch 3500 Form but alternative formats (e.g., summary letter) are acceptable.
FDA Fax number of IND Safety Reports: 1-(800)-FDA-1078.
The IND sponsor will also make an assessment of whether the event constitutes an 
unanticipated problem posing risks to subjects or others (UP). This assessment will be 
provided to the Emory University IRB, which, in turn will make a final determination.  If the 
Emory IRB determines an event is a UP it will notify the appropriate regulatory agencies and 
institutional officials.
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations.
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 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
Both lenvatinib and pembrolizumab are Merck products. 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, 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 be excluded from the trial, or is the 

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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 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 Supporter, 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 4.0. Any adverse event 
which changes CTCAE grade over the course of a given episode will have each change of 
grade recorded on the adverse event case report forms/worksheets.
All adverse events regardless of CTCAE grade must also be evaluated for seriousness.

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Table 10. Evaluating Adverse Events
An investigator who is a qualified physician, will evaluate all adverse events as to:
V4.0 CTCAE 
Grading
Grade 1
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention not indicated.
Grade 2
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL.
Grade 3
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation or hospitalization indicated; 
disabling; limiting self-care ADL.
Grade 4
Life threatening consequences; urgent intervention indicated.
Grade 5
Death related to AE
Seriousness
A serious adverse event is any adverse event occurring at any dose or during any use of Merck product that:
†Results in death; or
†Is life threatening; or places the 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

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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 
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 Supporter`s product; or (3) the trial is a single-dose drug trial); or (4) Supporter`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) Supporter`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 INFORMED IN ADVANCE BY THE SUPPORTER 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).

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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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8.0 STATISTICAL ANALYSIS PLAN
8.1
Statistical Analysis Plan Summary
The primary outcome is objective response rate (complete and partial responses) at week 12 
after the administration of lenvatinib and pembrolizumab. The Simon’s two-stage design will 
be adopted for a possible early termination for futility.  The null hypothesis that the true 
response is 5% will be tested against a one-sided alternative. In the first stage, 9 patients will 
be accrued, and if there is no responses among them, the study will be stopped for futility. 
Otherwise, additional 8 patients will be accrued for a total of 17 patients (This does not 
include screen failures and in-evaluable patients). We anticipate enrolling 30 patients total to 
account for screen-failures in order to have 17 evaluable patients complete the protocol as 
required. The null hypothesis will be rejected if there are 3 or more responses in 17 patients. 
The design yields a type I error rate of 0.05 and power of 80% when the true response rate is 
25%. The final response rate will be estimated with 95% confidence interval by binomial 
test. The power calculation was from web-based calculation developed by UNC Lineberger 
Comprehensive Cancer Center [38]. 
For the secondary objectives, the safety profile of the treatment will be documented and 
summarized by summary statistics as frequency and percentage for each AE at patient’s 
level. Disease free survival (DFS), which was defined as the interval between time of surgery 
and the first tumor recurrence, or death. For overall survival, death from any cause will be 
defined as the event. Patients will be censored at time of last follow-up. OS and DFS will be 
estimated with the Kaplan-Meier method. The DFS and OS of each patient group at specific 
time points such as 6 months, 1 year, 3 years, etc. and will be also estimated alone with 95% 
CI. 
For the exploratory endpoint, paired t-test or Wilcoxon singed-rank test will be used to 
compare the biomarkers change before, during, and after treatment.  Summary statistics will 
be applied to all items in the measurements for quality of life, frailty, and degree of 
sarcopenia. Their change over time will be modeled in longitudinal data analyses (e.g., GEE 
or mixed effect models) along with data visualization for the trajectory of change over time. 
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 as summarized in Table 11. 

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Table 11. Product Descriptions
Product Name & Potency
Dosage Form
Pembrolizumab 100 mg/ 4mL
Solution for Injection
Lenvatinib 10 mg and 4 mg
Capsule
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.  
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 Data Reporting
Study staff are responsible for submitting data and/or data forms in the clinical management 
system - Online Collaborative Research Environment (ONCORE) - per Winship SOP 4.2 
Data Completion Metrics.  Data completion will be reviewed monthly. In situations where 

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there are significant delays of data completion, the Associate Director of Clinical Research or 
the Director of Clinical Trials may temporarily suspend enrollment. Data entry is to be 
completed within the designated timeframe, not to exceed 30 days of the subject visit. 
Queries will be resolved by the research staff within the time frame specified by the protocol, 
not to exceed 2 weeks. 
10.1.1 Source Data and Documents
In accord with section 1.51 of the ICH E6 document all information in original records and 
certified copies of original records or clinical findings, observations, or other activities 
necessary for the reconstruction and evaluation of the trial is considered source data. Source 
data are contained in source documents, which can be original records or certified copies of 
hospital records, clinical and office charts, laboratory notes, memoranda, subjects' diaries of 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies or transcriptions certified after verification as being accurate and 
complete, microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject 
files, and records kept at the pharmacy, at the laboratories, and at medico-technical 
departments involved in the clinical trial.
Case Report Forms (CRFs) - Source data may be collected in the source documents or 
entered directly onto the case report forms.
Protocol Adherence
By signing the Form FDA 1572, the Investigator agrees to conduct the study according to the 
protocol and the FDA regulations set forth in 21 CFR Parts 50, 54, 56, and 312.
Retention of Study Documents
All documentation of adverse events, records of study drug receipt and dispensation, and all 
IRB correspondence will be maintained for at least 2 years after the investigation is 
completed.
10.2 Data and Safety Monitoring Plan
The Data and Safety Monitoring Committee (DSMC) of the Winship Cancer Institute will 
provide oversight for the conduct of this study.  The DSMC functions independently within 
Winship Cancer Institute to conduct internal monitoring functions to ensure that research 
being conducted by Winship Cancer Institute Investigators produces high-quality scientific 
data in a manner consistent with good clinical practice (GCP) and appropriate regulations 
that govern clinical research.    Depending on the risk level of the protocol, the DSMC 
review may occur every 6 months or annually.  For studies deemed High Risk, initial study 
monitoring will occur within 6 months from the date of the first subject accrued, with 2 of the 
first 5 subjects being reviewed.  For studies deemed Moderate Risk, initial study monitoring 
will occur within 1 year from the date of the first subject accrued, with 2 of the first 5 

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subjects being reviewed.  Subsequent monitoring will occur in routine intervals per the 
Winship Data and Safety Monitoring Plan (DSMP). 
The DSMC will review pertinent aspects of the study to assess subject safety, compliance 
with the protocol, data collection, and risk-benefit ratio. Specifically, the Winship Cancer 
Institute Internal Monitors assigned to the DSMC may verify informed consent, eligibility, 
data entry, accuracy and availability of source documents, AEs/SAEs, and essential 
regulatory documents.  Following the monitoring review, monitors will provide a preliminary 
report of monitoring findings to the PI and other pertinent individuals involved in the conduct 
of the study.  The PI is required to address and respond to all the deficiencies noted in the 
preliminary report.  Prior to the completion of the final summary report, monitors will 
discuss the preliminary report responses with the PI and other team members (when 
appropriate).  A final monitoring summary report will then be prepared by the monitor.  Final 
DSMC review will include the final monitoring summary report with corresponding PI 
response, submitted CAPA (when applicable), PI Summary statement, and available 
aggregate toxicity and safety data.  
The DSMC will render a recommendation and rating based on the overall trial conduct.  The 
PI is responsible for ensuring that instances of egregious data insufficiencies are reported to 
the IRB.  Continuing Review submissions will include the DSMC recommendation letter.  
Should any revisions be made to the protocol-specific monitoring plan after initial DSMC 
approval, the PI will be responsible for notifying the DSMC of such changes.  The 
Committee reserves the right to conduct additional audits if necessary. 
The PI and the investigators, the clinical research coordinator and the regulatory affairs 
coordinator will meet to review and discuss study data to ensure subject safety. During the 
meetings the PI or co-I will review the eligibility criteria for each new patient. In addition, 
during these meeting the group will review all the toxicity (AE/SAE) logs, random checks of 
case report form completion and roadmap for each patient on the trial. All study personnel 
will be trained on the protocol by the PI or co-I. Study personnel will sign training log prior 
to being included on delegation of authority log. All AE and SAE will be handled according 
to Section 7.2 which provides detailed instructions on reporting requirements. 
10.3 Ethical Aspects
10.3.1 Ethical standard
The investigator will ensure that this study is conducted in full conformity with Regulations 
for the Protection of Human Subjects of Research codified in 45 CFR Part 46, 21 CFR Part 
50, 21 CFR Part 56, as well as the federal regulations pertaining to ICH E6.

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10.3.2 Informed Consent
Consent forms describing in detail the study agent, study procedures, and risks are given to 
the participant and written documentation of informed consent is required prior to starting 
intervention/administering study product. 
Informed consent is a process that is initiated prior to the individual consent to participate in 
the study and continues throughout the individual’s participation. Extensive discussion of 
risks and possible benefits of participation will be provided to the participants and their 
families. Consent forms will be IRB approved and the participant will be asked to read and 
review the document. The investigator will explain the research study to the participant and 
answer any questions that may arise. All participants will receive a verbal explanation in 
terms suited to their comprehension of the purposes, procedures, and potential risks of the 
study and of their rights as research participants.  Participants will have the opportunity to 
carefully review the written consent form and ask questions prior to signing.
The participants should have the opportunity to discuss the study with their surrogates or 
think about it prior to agreeing to participate. The participant will sign the informed consent 
document prior to any procedures being done specifically for the study. The participants may 
withdraw consent at any time throughout the course of the trial. A copy of the informed 
consent document will be given to the participants for their records. The rights and welfare of 
the participants will be protected by emphasizing to them that the quality of their medical 
care will not be adversely affected if they decline to participate in this study.
10.3.3 Institutional Review Board/Ethics Committee
The protocol, informed consent form, recruitment materials, and all participant materials will 
be submitted to the IRB for review and approval. Approval of both the protocol and the 
consent form must be obtained before any participant is enrolled. Any amendment to the 
protocol will require review and approval by the IRB before the changes are implemented to 
the study. All changes to the consent form will be IRB approved; a determination will be 
made regarding whether previously consented participants need to be re-consented.
10.3.4 Participant and data confidentiality
Participant confidentiality is strictly held in trust by the participating investigators, their staff, 
and the sponsor(s) and their agents. This confidentiality is extended to cover testing of 
biological samples and genetic tests in addition to the clinical information relating to 
participants. Therefore, the study protocol, documentation, data, and all other information 
generated will be held in strict confidence. No information concerning the study or the data 
will be released to any unauthorized third party without prior written approval of the 
sponsor.
The study monitor, other authorized representatives of the sponsor, representatives of the IRB 
or pharmaceutical company supplying study product may inspect all documents and records 
required to be maintained by the investigator, including but not limited to, medical records 
(office, clinic, or hospital) and pharmacy records for the participants in this study. The 
clinical study site will permit access to such records.

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The study participant’s contact information will be securely stored at each clinical site for 
internal use during the study. At the end of the study, all records will continue to be kept in a 
secure location for as long a period as dictated by local IRB and Institutional regulations.
Study participant research data, which is for purposes of statistical analysis and scientific 
reporting, will be transmitted to and stored. This will not include the participant’s contact or 
identifying information. Rather, individual participants and their research data will be 
identified by a unique study identification number. The study data entry and study 
management systems used by clinical sites and research staff will be secured and password 
protected. At the end of the study, all study databases will be de-identified and archived.
10.3.5 Research use of stored samples, specimens, or data
Samples and data collected under this protocol may be used to study RCC. Access to stored 
samples will be limited to IRB-approved investigators. Samples and data will be stored using 
codes assigned by the investigators or their designees. Data will be kept in password-
protected computers. Only investigators will have access to the samples and data.
All stored samples will be maintained in the laboratory to which it was sent initially for 
analysis. Study participants who request destruction of samples will be notified of 
compliance with such request and all supporting details will be maintained for tracking.
10.4 Conditions for Modifying the Protocol
Protocol modifications (including protocol amendments) may be made and will be prepared, 
reviewed, and approved by representatives of the principal investigator. Protocol 
modifications or amendments must be reviewed and approved by Merck prior to 
implementation.
All protocol modifications must be submitted to the IRB/EC for information and approval in 
accordance with local requirements and to regulatory agencies if required. Approval must be 
obtained before any changes can be implemented, except for changes necessary to eliminate 
an immediate hazard to study subjects or those that involve only logistical or administrative 
aspects of the trial (e.g. change in monitor or change of telephone number).
10.5 Conditions for Terminating the Study
At any time, the study may be terminated by the investigator, the IRB, or by Merck. Should 
this be necessary, Merck and the investigator will arrange the procedures on an individual 
study basis after review and consultation. In terminating the study, Merck and the 
investigator will ensure that adequate consideration is given to the protection of the subjects’ 
interests. Upon study termination, the investigator(s) shall cease enrolling subjects into the 
study, and shall discontinue conduct of the study as soon as is medically practical.

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11.0 REFERENCES
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a new proposal with evaluation in a cohort of 6336 patients and results of a survey. 
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Siegel, R.L., K.D. Miller, and A. Jemal, Cancer statistics, 2018. CA Cancer J Clin, 
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Storkel, S. and E. van den Berg, Morphological classification of renal cancer. World 
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4.
Gnarra, J.R., et al., Mutations of the VHL tumour suppressor gene in renal 
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5.
Sufan, R.I., M.A. Jewett, and M. Ohh, The role of von Hippel-Lindau tumor 
suppressor protein and hypoxia in renal clear cell carcinoma. Am J Physiol Renal 
Physiol, 2004. 287(1): p. F1-6.
6.
Motzer, R.J., et al., Sunitinib versus interferon alfa in metastatic renal-cell 
carcinoma. N Engl J Med, 2007. 356(2): p. 115-24.
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Sternberg, C.N., et al., Pazopanib in locally advanced or metastatic renal cell 
carcinoma: results of a randomized phase III trial. J Clin Oncol, 2010. 28(6): p. 
1061-8.
8.
Rini, B.I., et al., Bevacizumab plus interferon alfa compared with interferon alfa 
monotherapy in patients with metastatic renal cell carcinoma: CALGB 90206. J Clin 
Oncol, 2008. 26(33): p. 5422-8.
9.
Choueiri, T.K., et al., Cabozantinib Versus Sunitinib As Initial Targeted Therapy for 
Patients With Metastatic Renal Cell Carcinoma of Poor or Intermediate Risk: The 
Alliance A031203 CABOSUN Trial. J Clin Oncol, 2017. 35(6): p. 591-597.
10.
Motzer, R.J., et al., Lenvatinib, everolimus, and the combination in patients with 
metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial. 
Lancet Oncol, 2015. 16(15): p. 1473-82.
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Kudo, M., et al., Lenvatinib versus sorafenib in first-line treatment of patients with 
unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. 
Lancet, 2018. 391(10126): p. 1163-1173.
12.
Schlumberger, M., et al., Lenvatinib versus placebo in radioiodine-refractory thyroid 
cancer. N Engl J Med, 2015. 372(7): p. 621-30.
13.
https://investors.merck.com/news/press-release-details/2019/FDA-Approves-
KEYTRUDA-pembrolizumab-plus-LENVIMA-lenvatinib-Combination-Treatment-
for-Patients-with-Certain-Types-of-Endometrial-Carcinoma/default.aspx.
14.
Gleave, M.E., et al., Interferon gamma-1b compared with placebo in metastatic 
renal-cell carcinoma. Canadian Urologic Oncology Group. N Engl J Med, 1998. 
338(18): p. 1265-71.
15.
Vogelzang, N.J., E.R. Priest, and L. Borden, Spontaneous regression of histologically 
proved pulmonary metastases from renal cell carcinoma: a case with 5-year 
followup. J Urol, 1992. 148(4): p. 1247-8.
16.
Fyfe, G., et al., Results of treatment of 255 patients with metastatic renal cell 
carcinoma who received high-dose recombinant interleukin-2 therapy. Journal of 
Clinical Oncology, 1995. 13(3): p. 688-696.

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17.
Wierecky, J., et al., Immunologic and clinical responses after vaccinations with 
peptide-pulsed dendritic cells in metastatic renal cancer patients. Cancer Res, 2006. 
66(11): p. 5910-8.
18.
Labriola, M.K., et al., Immunotherapy Is Changing First-Line Treatment of 
Metastatic Renal-Cell Carcinoma. Clin Genitourin Cancer, 2019. 17(3): p. e513-
e521.
19.
Yarchoan, M., et al., PD-L1 expression and tumor mutational burden are independent 
biomarkers in most cancers. JCI Insight, 2019. 4(6).
20.
Motzer, R.J., et al., Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-
Cell Carcinoma. N Engl J Med, 2018. 378(14): p. 1277-1290.
21.
Unnikrishnan, R.R., P.; Yang, Y.; Diaz-Montero, C. M.; and Finke, J., Pazopanib, 
sunitinib, and axitinib reduce expansion of in vitro induced suppressive macrophages 
The Journal of Urology, 2015. 193(4S): p. 3712.
22.
Bracarda, S., et al., Angiogenic and immunological pathways in metastatic renal cell 
carcinoma: A counteracting paradigm or two faces of the same medal? The GIANUS 
Review. Crit Rev Oncol Hematol, 2019. 139: p. 149-157.
23.
Kimura, T., et al., Immunomodulatory activity of lenvatinib contributes to antitumor 
activity in the Hepa1-6 hepatocellular carcinoma model. Cancer Sci, 2018. 109(12): 
p. 3993-4002.
24.
Rini, B.I., et al., Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-
Cell Carcinoma. N Engl J Med, 2019. 380(12): p. 1116-1127.
25.
Motzer, R.J., et al., Avelumab plus Axitinib versus Sunitinib for Advanced Renal-Cell 
Carcinoma. N Engl J Med, 2019. 380(12): p. 1103-1115.
26.
Lee, C.-H., et al., Lenvatinib + pembrolizumab in patients with renal cell carcinoma: 
Updated results. Journal of Clinical Oncology, 2018. 36(15_suppl): p. 4560-4560.
27.
Motzer, R., et al., Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal 
Cell Carcinoma. New England Journal of Medicine, 2021. 384(14): p. 1289-1300.
28.
Ravaud, A., et al., Adjuvant Sunitinib in High-Risk Renal-Cell Carcinoma after 
Nephrectomy. N Engl J Med, 2016. 375(23): p. 2246-2254.
29.
NCCN, Kidney Cancer (Version 2.2020). National Comprehensive Cancer Network, 
2019.
30.
Choueiri, T.K., et al., Pembrolizumab versus placebo as post-nephrectomy adjuvant 
therapy for patients with renal cell carcinoma: Randomized, double-blind, phase III 
KEYNOTE-564 study. Journal of Clinical Oncology, 2021. 39(18_suppl): p. LBA5-
LBA5.
31.
Lane, B.R., et al., Presurgical sunitinib reduces tumor size and may facilitate partial 
nephrectomy in patients with renal cell carcinoma. Urol Oncol, 2015. 33(3): p. 
112.e15-21.
32.
Rini, B.I., et al., A Phase II Study of Pazopanib in Patients with Localized Renal Cell 
Carcinoma to Optimize Preservation of Renal Parenchyma. J Urol, 2015. 194(2): p. 
297-303.
33.
Karam, J.A., et al., Phase 2 trial of neoadjuvant axitinib in patients with locally 
advanced nonmetastatic clear cell renal cell carcinoma. Eur Urol, 2014. 66(5): p. 
874-80.
34.
Harshman, L.C., et al., PROSPER: A phase III randomized study comparing 
perioperative nivolumab (nivo) versus observation in patients with localized renal 

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cell carcinoma (RCC) undergoing nephrectomy (ECOG-ACRIN 8143). Journal of 
Clinical Oncology, 2019. 37(7_suppl): p. TPS684-TPS684.
35.
Necchi, A., et al., Pembrolizumab as Neoadjuvant Therapy Before Radical 
Cystectomy in Patients With Muscle-Invasive Urothelial Bladder Carcinoma (PURE-
01): An Open-Label, Single-Arm, Phase II Study. J Clin Oncol, 2018: p. Jco1801148.
36.
Grunwald, V., et al., Lenvatinib plus everolimus or pembrolizumab versus sunitinib in 
advanced renal cell carcinoma: study design and rationale. Future Oncol, 2019. 
15(9): p. 929-941.
37.
Sarafidis, P.A., N. Khosla, and G.L. Bakris, Antihypertensive therapy in the presence 
of proteinuria. Am J Kidney Dis, 2007. 49(1): p. 12-26.
38.
http://cancer.unc.edu/biostatistics/program/ivanova/SimonsTwoStageDesign.aspx.
39.
Oken, M.M., et al., Toxicity and response criteria of the Eastern Cooperative 
Oncology Group. Am J Clin Oncol, 1982. 5(6): p. 649-55.

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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 Oken, et al (1982) [39] 

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Appendix 2: Common Terminology Criteria for Adverse Events V4.0 (CTCAE)
The descriptions and grading scales found in the revised NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.0 will be utilized for adverse event reporting. 
(http://ctep.cancer.gov/reporting/ctc.html)

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Appendix 3: Contraceptive Guidance and Pregnancy Testing
(1) 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.
(2) Contraception Requirements
Male Participants:
Male participants with female partners of childbearing potential are eligible to participate if 
they agree to one of the following beginning at least 1 menstrual cycle prior to starting study 
drugs, throughout the entire study period, and for 120 days after the last dose of study drug:
●
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 14 when having penile-vaginal intercourse with a woman 
of childbearing potential who is not currently pregnant.

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○
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.
Female Participants:
Female participants of childbearing potential are eligible to participate if they agree to use a 
highly effective method of contraception that has a low user dependency consistently and 
correctly as described in Table 13 during the entire study period and for 120 days after the 
last dose of study drug:
Table 13
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
●
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.) 
a. Typical use failure rates are lower than perfect-use failure rates (i.e. when used consistently and correctly). 
b. If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, acceptable hormonal contraceptives are limited to 
those which inhibit ovulation. 
c. Must be on a stable dose of the same oral hormonal contraceptive product for at least 4 weeks before dosing with study drug and for the 
duration of the study.

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(3) Pregnancy Testing
WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L 
or equivalent units of beta-human chorionic gonadotropin [β-hCG]) at the Screening Visit 
and the Baseline Visit. A pregnancy test needs to be performed within 72 hours of the first 
dose of study drug. If urine pregnancy results cannot be confirmed as negative, a serum 
pregnancy test will be required.  
Following initiation of treatment, pregnancy testing will be performed at the time points 
specified in the Trial Flow Chart. 
Pregnancy testing will also be performed whenever an expected menstrual cycle is missed or 
when pregnancy is otherwise suspected.

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Appendix 4:  Quality of Life Assessment (NCCN-FACT FKSI-19 V2)
Below is a list of statements that other people with your illness have said are important. Please circle or mark 
one number per line to indicate your response as it applies to you the past 7 days.
Not at 
all
A little 
bit
Some-
what
Quite
a bit
Very 
much
G
P1
I have a lack of energy
......................................................................................
0
1
2
3
4
G
P4
I have pain
......................................................................................
0
1
2
3
4
C2
I am losing weight
......................................................................................
0
1
2
3
4
HI
7
I feel fatigued
......................................................................................
0
1
2
3
4
B1
I have been short of breath
......................................................................................
0
1
2
3
4
BR
M3
I am bothered by fevers (episodes of high body 
temperature)
......................................................................................
0
1
2
3
4
BP
1
I have bone pain
......................................................................................
0
1
2
3
4
L2
I have been coughing
......................................................................................
0
1
2
3
4
HI
12
I feel weak all over
......................................................................................
0
1
2
3
4
R
C
C2
I have had blood in my urine
......................................................................................
0
1
2
3
4
C6
I have a good appetite
......................................................................................
0
1
2
3
4
G
F5
I am sleeping well
......................................................................................
0
1
2
3
4
G
E6
I worry that my condition will get worse
......................................................................................
0
1
2
3
4
G
P2
I have nausea
......................................................................................
0
1
2
3
4
D
R
S-
P
D
R
S-
E

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C5
I have diarrhea (diarrhoea)
......................................................................................
0
1
2
3
4
G
P5
I am bothered by side effects of treatment
......................................................................................
0
1
2
3
4
G
F1
I am able to work (include work at home)
......................................................................................
0
1
2
3
4
G
F3
I am able to enjoy life
......................................................................................
0
1
2
3
4
G
F7
I am content with the quality of my life right now
......................................................................................
0
1
2
3
4
T
S
E
F
W
B

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Appendix 5:  Frailty Assessment 

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Appendix 6:  Lenvatinib Pill Diary 
Lenvatinib Pill Diary
 Subject Initials:_______      Subject ID: _______  Cycle: _______  Current Dose:________
Instruction: 
1. Take ___ of the 4mg capsules once per day. Take___ of the 10 mg capsules once per day.                                                             
2. Caregivers should not open the capsule, in order to avoid repeated exposure to the contents of the capsule.                             
3. You should take your dose at approximately the same time every day.                                                                                              
4. If a dose is missed and cannot be taken within 12 hours, skip that dose and take the next dose at usual time of 
administration.                                          5. Please return any empty packaging and unused product at your next visit. Do not 
throw away any medicines via wastewater or household waste. 
Da
y
Date 
Time
# of 4 mg 
tablets taken
# of 10 mg 
tablets taken
Comments
1
 
 
 
2
 
 
 
3
 
 
 
4
 
 
 
5
 
 
 
6
 
 
 
7
 
 
 
8
 
 
 
9
 
 
 
10
 
 
 
11
 
 
 
12
 
 
 
13
 
 
 
14
 
 
 
15
 
 
 
16
 
 
 
17
 
 
 
18
 
 
 
19
 
 
 
20
 
 
 
21
 
 
 
Patient Signature: _____________________________________________     Date: 
______________________
This section to be completed by a Research Nurse / Research Coordinator: 
__________________________________
Dosing Cycle Start Date: 
_________________
 
Dosing Cycle End Date:___________

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Lot Number: 
___________________________
 
 # of Tablets Dispensed:________
Any Interruptions? □ Yes □ No 
 
Any Dose reduction? □ YES  □ NO