Conditions: GastroEsophageal Cancer Gastric Cancer
Keywords: Pebrolizumab Lenvatinib
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 24
Healthy volunteers: no

Brief summary:
This is an open label, single arm phase II study, to determine the overall response rate for the combination of lenvatinib and pemrolizumab in patients with metastatic gastroesophageal cancer who have progressed on first or subsequent line therapies. Given the significant cross talk between angiogenesis and the immune response, combined therapy with lenvatinib and pemrolizumab in advanced gastroesophageal cancer patient will provide improved outcomes compared to standard treatment with currently approved agents.

Detailed description:
The objective of this study is to determine the progression free survival (PFS), overall survival (OS) and toxicity rates in advanced gastroesophageal patients treated with lenvatinib and pemrolizumab.

Arms:
arm 1: None

Interventions: intervention 1: Lenvatinib intervention 2: Pembrolizumab
Intervention descriptions: intervention 1: Lenvatinib 20 mg orally each day on days 1-7 intervention 2: Pembrolizumab 200mg intravenously, to be initiated on day 8, and continued every 3 weeks, in combination with daily lenvatinib 20 mg

Protocol document:
Prot_SAP_000.pdf: 
 
 
Official Title: 
A Phase II a Study of Lenvatinib, a Multi-targeted Tyrosine Kinase 
Inhibitor, Combined With Pembrolizumab (PD-1 Inhibitor) for the 
Treatment of Metastatic Gastroesophageal Cancer Patients Who Have 
Progressed on First or Subsequent Line Therapies   
NCT Number: 
NCT03321630 
Study Number: 
17-00626 
Document Type:  
Study Protocol and Statistical Analysis Plan 
Date of the 
Document: 
• 
December 29, 2021 
 


 
Page 1 of 115 
 
Clinical Research Protocol  
 
A PHASE II STUDY OF LENVATINIB, A MULTI-TARGETED TYROSINE KINASE 
INHIBITOR, COMBINED WITH PEMBROLIZUMAB FOR THE TREATMENT OF 
METASTATIC GASTROESOPHAGEAL CANCER PATIENTS WHO HAVE 
PROGRESSED ON FIRST OR SUBSEQUENT LINE THERAPIES 
 
Regulatory Sponsor: 
The Laura and Isaac Perlmutter Cancer Center 
NYU Langone Medical Center  
160 E 34th Street 
New York, NY 10016 
(212) 731-5001 
 
Funding Sponsor: 
Eisai Inc. (Headquarters) 
100 Tice Blvd. 
Woodcliff Lake, NJ 07677 
Telephone: 201-692-1100 
Fax: 201-692-1804 
 
Merck Corporate Headquarters 
2000 Galloping Hill Road 
Kenilworth, NJ 07033 U.S.A. 
Telephone: 908-740-4000 
 
Study Product: 
Lenvatinib (Lenvima) 
Pembrolizumab (Keytruda) 
Coordinating Center: 
 
 
Principal Investigator: 
NYU Langone Health 
The Laura and Isaac Perlmutter Cancer Center 
NYU Langone Health  
 
Paul Oberstein, MD 
The Laura and Isaac Perlmutter Cancer Center 
NYU Langone Health 
160 East 34th Street 
New York, NY, 10016 
Paul.Oberstein@nyulangone.org 
Principal Investigator: 
Mount.Sinai Health System 
 
 
 
 
 
 
Deirdre J. Cohen MD 
The Tisch Cancer Institute 
Icahn School of Medicine at Mount Sinai  
1425 Madison Avenue 
New York, NY 10029 
Deirdre.Cohen@mssm.edu 
 
 


 
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Clinical Research Protocol  
 
NYU Protocol Number: 
 
s17-00626 
NYULH Medical Monitor: 
Stella Lymberis, MD 
NYU Langone Health 
160 East 34th Street 
New York, NY 10016 
Email:  Stella.Lymberis@nyulangone.org 
 
IND Number: 
 
Participating Sites: 
 
133212 
 
 
NYU Perlmutter Cancer Center and Bellevue Hospital 
The Mount. Sinai Hospital 
 
Version: 
 
 
January 10, 2020 v1.0 
 
 
 
 
May 18, 2020 v2.0 
 
 
 
 
November 19, 2021 v 3.0 
 
 
 
 
 


 
Page 3 of 115 
 
Clinical Research Protocol  
INVESTIGATOR SIGNATURE PAGE 
 
I have read this protocol, including all appendices, and I agree to conduct the study in 
compliance with all applicable regulations (including 21 CFR Part 312).  I will also make a 
reasonable effort to complete the study within the time designated.  I will provide all study 
personnel under my supervision copies of the protocol and access to all information provided 
by Eisai/Merck.  I will discuss this material with them to ensure that they are fully informed 
about the drug and the study. 
I am aware that, prior to the commencement of this study, the Institutional Review Board must 
approve this protocol and the informed consent document associated with the clinical facility 
where the study will be conducted.  I agree to make all reasonable efforts to adhere to the 
attached protocol.  I agree to provide all subjects with a signed and dated copy of their informed 
consent document, as required by FDA and ICH regulations.  I further agree to report to 
Eisai/Merck any adverse events in accordance with the terms of this protocol and FDA 
regulation 21 CFR 312.64.   
Nothing in this document is intended to limit the authority of a physician to provide emergency 
medical care under applicable regulations.  
 
 
 
 
Investigator Signature 
 
 Date of Signature 
(DD/MM/YYYY) 
__________________________________________________ 
Name of Investigator (please print) 
 
 
 
 


 
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Clinical Research Protocol  
Table of Contents 
INVESTIGATOR SIGNATURE PAGE............................................................................... 3 
1.0 TRIAL SUMMARY ........................................................................................................ 19 
2.0 TRIAL DESIGN .............................................................................................................. 19 
2.1 Trial Design ................................................................................................................ 19 
2.2 Trial Diagram - Figure 1 ............................................................................................ 19 
3.0 OBJECTIVES & HYPOTHESES ................................................................................. 21 
3.1 Primary Objective & Hypothesis ............................................................................... 21 
3.2 Secondary Objective & Hypothesis ........................................................................... 21 
3.3 Exploratory Objective ................................................................................................ 21 
4.0 BACKGROUND & RATIONALE ................................................................................ 21 
4.1 Pembrolizumab and Lenvatinib Background ............................................................. 21 
4.1.1 Pembrolizumab Pharmaceutical and Therapeutic Background .......................... 21 
4.1.2 Pembrolizumab Preclinical and Clinical Trial Data ........................................... 23 
4.1.3 Lenvatinib Pharmaceutical and Therapeutic Background .................................. 30 
4.1.4 Lenvatinib Preclinical and Clinical Trial Data ................................................... 31 
4.2 Rationale ..................................................................................................................... 41 
4.2.1 Rationale for the Trial and Selected Subject Population .................................... 41 
4.2.2 Rationale for Dose Selection .............................................................................. 44 
4.2.3 Rationale for Study Endpoints ............................................................................ 46 
4.2.4 Research Risks and Benefits ............................................................................... 47 
5.0 METHODOLOGY .......................................................................................................... 48 
5.1 Entry Criteria .............................................................................................................. 48 
5.1.1 Diagnosis and Conditions for Entry into the Trial .............................................. 48 
5.1.2 Subject Inclusion Criteria.................................................................................... 48 
5.1.3 Subject Exclusion Criteria .................................................................................. 49 
5.1.4 Inclusion of Women and Minorities ................................................................... 52 
5.2 Registration Procedures .............................................................................................. 52 
5.2.1 General Guidelines .............................................................................................. 52 
5.2.2 Process of Consent .............................................................................................. 52 


 
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Clinical Research Protocol  
5.2.3 Documentation of Consent ................................................................................. 55 
5.2.4 Multi-Site Surveillance ........................................ Error! Bookmark not defined. 
5.2.5 Patient Informed Consent at Additional Sites ...... Error! Bookmark not defined. 
5.2.6 Patient Registration at Other Participating InstitutionsError! 
Bookmark 
not 
defined. 
5.3 Trial Treatments ......................................................................................................... 55 
5.3.1 Dose Selection and Modification ........................................................................ 55 
5.3.2 Timing of Dose Administration .......................................................................... 59 
5.3.3 Trial Blinding/Masking ....................................................................................... 60 
5.4 Concomitant Medications and Vaccinations Allowed and Prohibited ....................... 60 
5.4.1 Acceptable Concomitant Medications ................................................................ 60 
5.4.2 Prohibited Concomitant Medications.................................................................. 60 
5.5 Rescue Medications and Supportive Care .................................................................. 61 
5.5.1 Supportive Care Guidelines ................................................................................ 61 
5.6 Diet, Activity, and Other Considerations ................................................................... 64 
5.6.1 Diet ...................................................................................................................... 64 
5.6.2 Contraception ...................................................................................................... 65 
5.6.3 Use in Pregnancy ................................................................................................ 66 
5.6.4 Use in Nursing Women ....................................................................................... 67 
5.7 Subject Withdrawal/Discontinuation Criteria ............................................................ 67 
5.8 Subject Replacement Strategy .................................................................................... 68 
5.9 Clinical Criteria for Early Trial Termination ............................................................. 68 
6.0 Table 10: Study Flow Chart ........................................................................................... 69 
7.0 TRIAL PROCEDURES ................................................................................................. 72 
7.1 Trial Procedures ......................................................................................................... 72 
7.1.1 Administrative Procedures .................................................................................. 72 
7.1.2 Clinical Procedures and Assessments ................................................................. 74 
7.1.3 Laboratory Procedures/Assessments .................................................................. 78 
7.1.4 Other Procedures ................................................................................................. 80 


 
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Clinical Research Protocol  
7.1.5 Visit Requirements .............................................................................................. 80 
7.2 Assessing and Recording Adverse Events ................................................................. 87 
7.2.1 Reporting of Pregnancy and Lactation................................................................ 89 
7.2.2 Reporting of Serious Adverse Events ................................................................. 90 
7.2.3 Events of Clinical Interest ................................................................................... 96 
7.2.4 Protocol-Specific Exceptions to Serious Adverse Event Reporting ................... 97 
7.2.5 Evaluating Adverse Events ................................................................................. 97 
7.2.6 Responsibility for Reporting Adverse Events ................................................... 101 
7.2.7 Stopping Rules .................................................................................................. 101 
7.2.8 Medical Monitoring Plan .................................................................................. 101 
8.0 STATISTICAL ANALYSIS PLAN ............................................................................. 102 
8.1 Statistical Analysis Plan ........................................................................................... 102 
9.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ............................................................................................................... 103 
9.1 Investigational Products ........................................................................................... 103 
9.2 Packaging and Labeling Information ....................................................................... 104 
9.3 Clinical Supplies Disclosure .................................................................................... 104 
9.4 Storage and Handling Requirements ........................................................................ 104 
9.5 Returns and Reconciliation ...................................................................................... 104 
10.0 
ADMINISTRATIVE AND REGULATORY DETAILS ..................................... 105 
10.1 Confidentiality .......................................................................................................... 105 
Confidentiality and HIPAA .............................................................................................. 105 
10.2 Compliance with Financial Disclosure Requirements ............................................. 106 
10.3 Ethical Considerations, and Compliance with Law, Audit and Debarment ............. 106 
10.4 Compliance with Trial Registration and Results Posting Requirements ................. 107 
10.5 Quality Management System ................................................................................... 107 
10.6 Data Management .................................................................................................... 108 
10.6.1 Source Documents ................................................................................................. 108 
10.6.2 Data and Source Documentation ........................................................................... 108 
10.6.3 Case Report Forms ................................................................................................. 108 
10.6.4 Records Retention .................................................................................................. 109 
10.7 Monitoring of the study, Auditing and Inspecting ................................................... 109 
Study Monitoring Plan ...................................................................................................... 110 


 
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Clinical Research Protocol  
Auditing and Inspecting .................................................................................................... 110 
11.0 
Study Finances ........................................................................................................ 110 
11.1 Funding Source ........................................................................................................ 110 
11.2 Subject Stipends or Payments .................................................................................. 110 
12.0 
Publication Plan ...................................................................................................... 110 
13.0 
APPENDICES ......................................................................................................... 112 
13.1 Table 16: ECOG Performance Status ....................................................................... 112 
13.2 Common Terminology Criteria for Adverse Events V4.03 (CTCAE) .................... 112 
TABLES 
Table 1: Clinical Efficacy Results of Patients with Melanoma Treated with 
Pembrolizumab ........................................................................................................... 29 
Table 2:  Efficacy Results: Response Rates (Pembrolizumab) ............................................... 30 
Table 3: Kinase IC50 Values .................................................................................................... 32 
Table 4: Summary of Anti-Tumor Effects of Lenvatinib Monotherapy................................... 33 
Table 5: Adequate Organ Function Laboratory Values ......................................................... 48 
Table 6: Trial Treatments ....................................................................................................... 51 
Table 7: Dose Modification Guidelines for Pembrolizumab-Related Adverse Events ........... 52 
Table 8: Dose Modification Guidelines for Lenvatinib-Related Adverse Events ................... 55 
Table 9: Infusion Reaction Treatment Guidelines .................................................................. 59 
Table 10: Study Flow Chart .................................................................................................... 65 
Table 11: Estimation of Overall Response: RECIST v. 1.1 .................................................... 71 
Table 12: Laboratory Tests  .................................................................................................... 73 
Table 13: Evaluating Adverse Events  .................................................................................... 90 
Table 14: Product Description: Pembrolizumab .................................................................... 94 
Table 15: Product Description: Lenvatinib ............................................................................ 94 
Table 16: ECOG Performance Status................................................................................... 102 
 
FIGURES 
Figure 1: Trial Diagram ......................................................................................................... 20 
Figure 2: Kaplan Meier Curve for Overall Survival of Patients Treated with 
Pembrolizumab ........................................................................................................... 29 
 
 
 


 
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Clinical Research Protocol  
List of Abbreviations and Definition of Terms 
Abbreviation  Explanation  
% 
Percent 
µg 
microgram(s) 
14C 
Carbon-14: radioactive carbon isotope of mass 14, used as a tracer in biochemistry 
5-FU 
5-Fluorouracil 
ADA 
Anti-Drug Antibodies 
ADCC 
Antibody-Dependent Cell-Mediated Cytotoxicity 
ADL 
Activities of Daily Living 
AE 
Adverse Event 
AEOSI 
Adverse Event of Significant Interest 
aFGF 
acidic Fibroblast Growth Factor 
AGITG 
Australian Gastrointestinal Trials Group 
ALK 
Anaplastic Lymphoma Kinase (CD 246), 
ALT/SGPT 
Alanine 
transaminase 
or 
alanine 
aminotransferase/serum 
glutamate-pyruvate 
transaminase, a liver function test 
ANC 
Absolute Neutrophil Count 
AO 
Aldehyde Oxidase 
aPTT 
Activated Partial Thromboplastin Time: a test that characterizes blood coagulation 
AST/SGOT 
Aspartate transaminase or aspartate aminotransferase/Serum glutamic oxaloacetic 
transaminase, a liver function test 
ATP 
Adenosine Triphosphate 
AUC 
Area Under the Curve 
AUCss 
Area Under the Curve at steady state 
BCG Vaccine Bacillus Calmette–Guérin vaccine: used primarily against tuberculosis 


 
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Clinical Research Protocol  
BCRP 
Breast Cancer Resistance Protein 
BICR 
Blinded Independent Central Review 
BOR 
Best Overall Response 
BP  
Blood Pressure 
BRAF 
A human gene that encodes the B-Raf protein, which is involved in directing cell growth.  
BSEP 
Bile Salt Export Pump 
C 
Cycle 
CBC 
Complete Blood Count 
CBR 
Clinical Benefit Rate 
CD28 
Cluster of Differentiation 28: one of the proteins expressed on T cells that provide co-
stimulatory signals required for T cell activation and survival. 
CD3 
Cluster of Differentiation 3: a T-cell co-receptor that helps to activate the cytotoxic T-Cell. 
CD3ζ 
CD3zeta or CD247: a T-cell surface glycoprotein and effector molecule involved in the 
CD3 T-cell signalling cascade important for T-cell activation.  Plays an important role in 
coupling antigen recognition to several intracellular signal-transduction pathways.  
CD4 
Cluster of Differentiation 4: a glycoprotein found on the surface of immune cells such as 
T helper cells, monocytes, macrophages, and dendritic cells. 
CD8 
Cluster of Differentiation 8: a transmembrane glycoprotein that serves as a co-receptor for 
the T cell receptor.  
CDC 
Complement-Dependent Cytotoxicity 
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
CIN  
Chromosomal Instability 
CL 
Clearance 
Cmax 
Peak Concentration 
Cmin 
Trough concentration  


 
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Clinical Research Protocol  
CNS 
Central Nervous System 
CO2 
Carbon Dioxide 
CR 
Complete Response 
CrCl 
Creatinine Clearance 
CRF 
Case Report Form 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTLA-4 
Cytotoxic T-lymphocyte associated antigen 4: a protein receptor that, functioning as an 
immune checkpoint, downregulates the immune system.  
CTO 
Clinical Trials Office 
CV 
Coefficient of Variation 
CYP3A4 
Cytochrome P450 3A4  
D 
Day 
DCR 
Disease Control Rate 
Discon. 
Discontinuation 
dL 
Deciliter(s) (10-1 Liters) 
DLT 
Dose Limiting Toxicity 
DMC  
Data Monitoring Committee 
DRAE 
Drug Related Adverse Event 
DTC 
Differentiated Thyroid Cancer 
EBV 
Epstein Barr Virus 
EC 
Esophageal Cancer 
EC50 
Effective Concentration 
ECG 
Electrocardiogram 
ECI  
Event of Clinical Interest 


 
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Clinical Research Protocol  
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EGFR 
Epidermal Growth Factor Receptor 
Epo 
Erythropoietin 
ERC 
Ethics Review Committee 
ERK1/2 
Extracellular signal–regulated kinases 1 and 2 
et al.  
et alia, a Latin phrase meaning "and others" 
Etc. 
Et cetera: a Latin expression meaning "and other things", or "and so forth".  It is used at 
the end of a list to indicate that further, similar items are included. 
EU  
European Union 
FDA 
The US Food and Drug Administration  
FDAAA 
Food and Drug Administration Amendments Act  
FDAMA 
Food and Drug Administration Modernization Act  
FGF 
Fibroblast Growth Factor 
FGFR1/2/3/4 
Fibroblast Growth Factor Receptors 1, 2, 3, and 4 
FOXP3 
Forkhead box P3, a protein involved in immune system responses and regulation of the 
development and function of regulatory T cells. 
FSH 
Follicle Stimulating Hormone 
fT4 
Free Thyroxine, a thyroid function test 
GBM 
Glioblastoma, Malignant 
GC 
Gastric Cancer 
GCP 
Good Clinical Practice 
GEJ 
Gastroesophageal Junction 
GFR 
Glomerular Filtration Rate, a kidney function test 


 
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Clinical Research Protocol  
GLP 
Good Laboratory Practices 
GS 
Genomically Stable 
GSH 
Glutathione  
Gy 
Gray: a derived unit of ionizing radiation dose in the International System of Units (SI). It 
is defined as the absorption of one joule of radiation energy per kilogram of matter. 
HBsAg 
Hepatitis B virus surface antigen 
HCC 
Hepatocellular Carcinoma 
HCV 
Hepatitis C Virus 
hERG 
human Ether-à-go-go-Related Gene 
HGF 
Hepatocyte Growth Factor 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human Immunodeficiency Virus 
HR 
Hazard Ratio 
Hr 
Hour 
HUVECS 
Human Umbilical Vein Endothelial Cells 
i.e. 
id est, a Latin phrase meaning “that is” 
IB 
Investigator's Brochure 
IC50 
The concentration of an inhibitor required to reduce the rate of an enzymatic reaction by 
50%. It is a measure of how effective a drug is. 
ICAM1 
Intercellular Adhesion Molecule 1 
ICH 
International Conference on Harmonisation  
ICOS 
Inducible T Cell Co-stimulator 
IEC 
Independent Ethics Committee 
IFNγ 
Interferon Gamma 
IgC 
Constant immunoglobulin domain 


 
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Clinical Research Protocol  
IgG4 κ 
Immunoglobulin G4 kappa 
IgV 
Variable immunoglobulin domain 
IHC 
Immunohistochemistry 
IIR 
Independent Imaging Review 
IL-2 
Interleukin 2: an interleukin, a type of cytokine signaling molecule in the immune system. 
It is a protein that regulates the activities of white blood cells that are responsible for 
immunity.  
IL-8 
Interleukin 8: a chemoattractant cytokine that attracts neutrophils, basophils, and T-cells.  
It is also involved in neutrophil activation.  
IND 
Investigational New Drug 
INR 
International Normalized Ratio: a blood coagulation test 
IRB 
Institutional Review Board 
IRR 
Independent Radiologic Review 
ITIM 
Immunoreceptor tyrosine-based inhibition motif  
ITSM 
Immunoreceptor tyrosine-based switch motif  
IUD  
Intrauterine Device 
IUO 
Investigational Use Only 
IV 
Intravenous 
Kg 
Kilogram(s) 
KIT 
Tyrosine Protein Kinase Kit (CD117) 
L 
Liter 
LMWH 
Low Molecular Weight Heparin 
M 
Meter(s) 
mAb 
Monoclonal Antibody 
MAPK 
Mitogen-Activated Protein Kinase 
mcL 
Microliters (10-6 Liter) 


 
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Clinical Research Protocol  
MDR 
Multi-Drug Resistance Protein 
MDSC 
Myeloid-Derived Suppressor Cell 
MedWatch 
The FDA Safety Information and Adverse Event Reporting Program 
Mg 
Milligram(s)  (10-3 grams) 
Min 
Minute 
mL 
Milliliter(s)  (10-3 liters) 
Mm 
Millimeter(s) (10-3 meters) 
mm/hg 
Millimeters of mercury: unit of measure for blood pressure 
Mmol 
Millimolar (10-3 molar) 
MRI 
Magnetic Resonance Imaging 
mRNA 
Messenger Ribonucleic Acid 
ms  
Milliseconds (10-3 seconds) 
MSI 
Microsatellite Instability 
MTC 
Medullary Thyroid Cancer 
MTD 
Maximum Tolerated Dose 
mTOR 
Mammalian Target of Rapamycin: a serine/threonine protein kinase that regulates cell 
growth, cell proliferation, cell motility, cell survival, protein synthesis, autophagy, and 
transcription 
MVD 
Microvessel Density 
N 
Number 
NCI 
National Cancer Institute 
NK 
Natural Killer Cells: a type of lymphocyte (white blood cell) and a component of the innate 
immune system. NK cells play a major role in the host-rejection of both tumors and virally 
infected cells. 
nM or nmol 
Nanomolar (10-9 molar) 
NOAEL 
No Observed Adverse Effect Level 


 
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Clinical Research Protocol  
NSAIDs 
Non-Steroidal Anti-Inflammatory Drugs 
NSCLC 
Non-Small Cell Lung Cancer 
NT 
Not Tested 
NYHA 
New York Heart Association 
NYU  
New York University 
NYULH 
NYU Langone Health 
NYULMC 
NYU Langone Medical Center 
OAT 
Organic Anion Transporter 
OATP 
Organic Anion Transporter Polypeptide 
OOL 
Optional Open Label 
ORR 
Overall Response Rate 
OS 
Overall Survival 
OTC 
Over The Counter 
PBMCs 
Peripheral Blood Mononuclear Cells 
PD-1 
Programmed cell death protein 1, a cell surface receptor of the immunoglobulin 
superfamily and expressed on T cells and pro-B cells.  It binds two ligands: PD-L1 and 
PD-L2. 
Pdcd1 
Gene encoding PD-1 
PDGF 
Platelet-Derived Growth Factor 
PDGFRα 
Platelet-Derived Growth Factor Receptor alpha polypeptide 
PD-L1 
Programmed Death Ligand 1 
PD-L2 
Programmed Death Ligand 2 
PFS 
Progression-Free Survival 
P-gp 
P-glycoprotein 
PHI 
Protected Health Information 


 
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Clinical Research Protocol  
PK 
Pharmacokinetics 
PKCθ 
Protein Kinase C, an effector molecule involved in the CD3 T-cell signalling cascade 
important for T-cell activation. 
PMDA 
Pharmaceutical and Medical Devices Agency 
PO 
Per os, or by mouth (oral) 
PPE 
Palmar-Plantar Erythrodysesthesia 
PR 
Partial Response 
PS 
Performance Status 
PT 
Prothrombin Time: a blood coagulation test 
PVC 
Polyvinylchloride 
Q or q 
Every 
QD 
Every Day / Daily 
QTc 
Corrected QT interval 
QTcF 
Corrected QT interval according to Fridericia's Correction Formula: A formula which 
takes into account the physiologic shortening of the QT interval which occurs as the heart 
rate increases. It is mathematically defined as: QTcF = QT/CubeRootRR(seconds)  
RCC 
Renal Cell Carcinoma 
RECIST v. 
1.1 
Response Evaluation Criteria in Solid Tumors version 1.1 
RET 
Receptor tyrosine kinase for members of the glial cell line-derived neurotrophic factor 
(GDNF) family of extracellular signalling molecules 
RNA 
Ribonucleic acid 
RPSFT 
Rank-Preserving Structural Failure Time 
RR 
Response Rate 
RTK 
Receptor Tyrosine Kinase 
S6  
A ribosomal protein. 


 
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Clinical Research Protocol  
S6K 
Ribosomal protein S6 kinase: an enzyme and serine/threonine protein kinase.  Its target 
substrate is the S6 ribosomal protein. Phosphorylation of S6 induces protein synthesis at 
the ribosome. The kinase activity of this protein leads to an increase in protein synthesis 
and cell proliferation. Amplification of the region of DNA encoding this gene and 
overexpression of this kinase are seen in some cancer cell lines. 
SAE 
Serious Adverse Event 
SAS 
Statistical Analysis System 
SD 
Stable Disease 
SHP-1/2 
Src homology region 2 domain-containing phosphatase-1 and 2: tyrosine phosphatases  
T/C 
Treatment / Control 
t1/2 
Terminal Half-Life 
T1DM 
Type 1 Diabetes Mellitus 
T3 
Total Triiodothyronine, a thyroid function test 
TB 
Bacillus Tuberculosis 
TCGA 
The Cancer Genome Atlas 
TIL 
Tumor Infiltrating Lymphocytes 
TK 
Toxicokinetic 
TKI 
Tyrosine Kinase Inhibitor 
TNFα 
Tumor Necrosis Factor Alpha 
TPS 
Tumor Proportion Score 
Treg 
Regulatory T Cell 
TSH 
Thyroid Stimulating Hormone, a thyroid function test 
Tx. 
Treatment 
ULN 
Upper Limit of Normal 
US 
United States 
VCAM1 
Vascular cell adhesion protein 1  


 
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Clinical Research Protocol  
VEGF 
Vascular Endothelial Growth Factor 
VEGFR-1 
(FLT-1) 
Vascular Endothelial Growth Factor Receptor 1 (Fms-Related Tyrosine Kinase 1): a 
receptor tyrosine kinase that is important for the control of cell proliferation and 
differentiation. 
VEGFR-2 
(KDR) 
Vascular Endothelial Growth Factor Receptor 2 (Kinase insert domain receptor), a 
receptor tyrosine kinase that is important for the control of cell proliferation and 
differentiation. 
VEGFR-3 
(FLT-4) 
Vascular Endothelial Growth Factor Receptor 3 (Fms-related tyrosine kinase 4): a receptor 
tyrosine kinase that is important for the control of cell proliferation and differentiation. 
Vs 
Versus 
W  
Week 
ZAP70 
Zeta-chain-associated protein kinase 70 is a protein normally expressed near the surface 
membrane of T cells and natural killer cells. It is part of the T cell receptor, plays a critical 
role in T-cell signaling, and serves as an effector molecule involved in the CD3 T-cell 
signalling cascade important for T-cell activation. 
β-HCG 
Beta Human Chorionic Gonadotropin 
μmol/L 
Micromolar (10-6 molar) 
 


 
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Clinical Research Protocol  
1.0 TRIAL SUMMARY 
Abbreviated Title 
Lenvatinib and pembrolzumab in advanced gastroesophageal cancer 
Trial Phase 
Phase II 
Clinical Indication 
Gastric and gastroesophageal junction adenocarcinoma  
Trial Type 
Single arm 
Type of control 
n/a 
Route of administration 
Lenvatinib PO, Pembrolizumab IV 
Trial Blinding 
n/a 
Treatment Groups  
n/a 
Number of trial subjects 
29 
Estimated enrollment period 
18 months 
Estimated duration of trial 
30 months 
Duration of Participation 
8 months 
Estimated average length of 
treatment per subject 
6 months 
 
 
 
 
 
2.0 TRIAL DESIGN 
2.1 
Trial Design 
This is an open label, single arm, phase II study. 
2.2 
Trial Diagram - Figure 1 
 
 
 
 


 
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Clinical Research Protocol  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
Screening and Registration 
 
 
 
Subjects with advanced gastroesophageal carcinoma 
who have progressed on one or more lines of therapy 
Lenvatinib 20 mg orally each day on days 1-7 
 
 
Pembrolizumab  200 mg intravenously, to be initiated on 
day 8, and continued every 3 weeks, in combination 
with daily lenvatinib 20 mg  
1. One cycle: 21  days 
2. Treatment until progression of disease, development of unacceptable toxicity, or at the discretion 
of the treating physician 
3. Once off-treatment, subjects will be followed every 12 weeks (+/- 1 week) from the date of last 
dose of pembrolizumab and/or lenvatinib until death or lost to follow up or until study closure 
(approximately 6 months after the final subject completes treatment). 
Response Assessment every 3 cycles (9 weeks) 
Follow Up 


 
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Clinical Research Protocol  
 
3.0 OBJECTIVES & HYPOTHESES 
3.1 
Primary Objective & Hypothesis 
Objective:  
To determine the overall response rate as measured by RECIST 1.1 for the combination 
of lenvatinib and pembrolizumab in patients with metastatic gastroesophageal cancer 
who have progressed on first or subsequent line(s) therapies. 
        Hypothesis:   
Given the significant cross talk between tumor angiogenesis and the immune response, 
combined therapy with lenvatinib and pembrolizumab in advanced gastroesophageal 
cancer patients will provide improved outcomes compared to standard treatment with 
currently approved agents. 
3.2 
Secondary Objective & Hypothesis 
 
Objective:   
 
To determine the progression free survival (PFS), overall survival (OS), and toxicity rates 
in advanced gastroesophageal patients treated with lenvatinib and pembrolizumab. 
3.3 
Exploratory Objective 
Objective:  
To characterize changes in the immune cell phenotype, immune pathway activity, and 
immune response following lenvatinib only, and then with the addition of 
pembrolizumab. 
4.0 BACKGROUND & RATIONALE 
4.1 
Pembrolizumab and Lenvatinib Background  
Pemborlizumab and lenvatinib are briefly described below.  Refer to the current Investigator’s 
Brochures (IB)/approved labeling for details. 
4.1.1 Pembrolizumab Pharmaceutical and Therapeutic Background 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades.  Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue, and favorable prognosis in 
various malignancies.  In particular, the presence of CD8+ T-cells and the ratio of CD8+ 
effector T-cells / FoxP3+ regulatory T-cells seems to correlate with improved prognosis and 
long-term survival in many solid tumors. 


 
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The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control.  The normal function of PD-1, expressed on the cell surface of activated T-
cells under healthy conditions, is to down-modulate unwanted or excessive immune responses, 
including autoimmune reactions.  PD-1 (encoded by the gene Pdcd1) is an Ig superfamily 
member related to CD28 and CTLA-4 which has been shown to negatively regulate antigen 
receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2).  The structure of 
murine PD-1 has been resolved.  PD-1 and family members are type I transmembrane 
glycoproteins containing an Ig Variable-type (V-type) domain responsible for ligand binding 
and a cytoplasmic tail which is responsible for the binding of signaling molecules.  The 
cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an immunoreceptor 
tyrosine-based inhibition motif (ITIM) and an immunoreceptor tyrosine-based switch motif 
(ITSM).  Following T-cell stimulation, PD-1 recruits the tyrosine phosphatases SHP-1 and 
SHP-2 to the ITSM motif within its cytoplasmic tail, leading to the dephosphorylation of 
effector molecules such as CD3ζ, PKCθ and ZAP70 which are involved in the CD3 T-cell 
signaling cascade.  The mechanism by which PD-1 down modulates T-cell responses is similar 
to, but distinct from that of CTLA-4 as both molecules regulate an overlapping set of signaling 
proteins.  PD-1 was shown to be expressed on activated lymphocytes including peripheral 
CD4+ and CD8+ T-cells, B-cells, T regs and Natural Killer cells.  Expression has also been 
shown during thymic development on CD4-CD8- (double negative) T-cells as well as subsets 
of macrophages and dendritic cells.  The ligands for PD-1 (PD-L1 and PD-L2) are 
constitutively expressed or can be induced in a variety of cell types, including non-
hematopoietic tissues as well as in various tumors .  Both ligands are type I transmembrane 
receptors containing both IgV- and IgC-like domains in the extracellular region and contain 
short cytoplasmic regions with no known signaling motifs.  Binding of either PD-1 ligand to 
PD-1 inhibits T-cell activation triggered through the T-cell receptor.  PD-L1 is expressed at 
low levels on various non-hematopoietic tissues, most notably on vascular endothelium, 
whereas PD-L2 protein is only detectably expressed on antigen-presenting cells found in 
lymphoid tissue or chronic inflammatory environments.  PD-L2 is thought to control immune 
T-cell activation in lymphoid organs, whereas PD-L1 serves to dampen unwarranted T-cell 
function in peripheral tissues.  Although healthy organs express little (if any) PD-L1, a variety 
of cancers were demonstrated to express abundant levels of this T-cell inhibitor.  PD-1 has 
been suggested to regulate tumor-specific T-cell expansion in subjects with melanoma.  This 
suggests that the PD-1/PD-L1 pathway plays a critical role in tumor immune evasion and 
should be considered as an attractive target for therapeutic intervention. 
Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of the 
IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, 
PD-L1 and PD-L2.  KeytrudaTM (pembrolizumab) has been approved in the United Stated for 
multiple indications including: the treatment of patients with unresectable or metastatic 
melanoma,  patients with metastatic non-small cell lung cancer (NSCLC) previously untreated 
or who have had disease progression on or after platinum-containing chemotherapy and  whose 
tumor express PD-L1 as determined by an FDA-approved test, patients with recurrent or 
metastatic head and neck squamous cell cancer with disease progression on or after platinum-
containing chemotherapy, and patients with advanced urothelial carcinoma who are either 
ineligible or who have progressed on cisplatin-containing chemotherapy. . 


 
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4.1.2 Pembrolizumab Preclinical and Clinical Trial Data 
4.1.2.1  Nonclinical Pharmacology 
Pembrolizumab binds to human and Cynomolgus monkey PD-1 with comparable affinity and 
blocks the binding of human and Cynomolgus monkey PD-1 to PD-L1 and PD-L2 with 
comparable potency. Pembrolizumab does not cross-react with dog, rat, or mouse PD-1. 
Pembrolizumab does not bind immunoglobulin superfamily members cluster of differentiation 
28 (CD28), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), or inducible T-cell 
costimulator (ICOS).  
 
Pembrolizumab strongly enhances T-lymphocyte immune responses in cultured blood cells 
from healthy human donors, cancer subjects, and nonhuman primates. In T-cell activation 
assays using human donor blood cells, the half-maximal effective concentration (EC50) has 
been approximately 0.1 to 0.3 nM. In addition to interleukin-2 (IL-2), tumor necrosis factor 
alpha (TNFα), interferon gamma (IFNγ), and levels of other cytokines were found to be 
modulated by pembrolizumab. The antibody potentiates existing immune responses only in the 
presence of antigen and does not nonspecifically activate T-cells. In the in vitro peripheral 
blood mononuclear cell (PBMC) and whole blood cytokine release assays, the cytokine levels 
induced by pembrolizumab were low and comparable to those induced by trastuzumab. 
Pembrolizumab does not induce antibody-dependent cell-mediated cytotoxicity (ADCC) or 
complement-dependent cytotoxicity (CDC).  
 
Using anti–murine PD-1 surrogate antibodies, PD-1 blockade has been shown to significantly 
inhibit tumor growth in a variety of syngeneic murine tumor models. In these experiments in 
mice, anti–PD-1 therapy is synergistic with chemotherapeutic agents such as gemcitabine and 
5-fluorouracil (5-FU), and combination therapy results in increased complete tumor regression 
rates in vivo. Studies also revealed that immunosuppressive doses of dexamethasone included 
in combination with agents used in standard-of-care treatment for 
NSCLC do not reduce the anti-tumor efficacy of an anti–murine PD-1 surrogate antibody. 
4.1.2.2  Nonclinical Pharmacokinetics 
The pharmacokinetics (PK) of pembrolizumab were evaluated in a non–Good Laboratory 
Practices (GLP) single dose PK study and two GLP repeat-dose toxicokinetic (TK) studies (1 
month and 6 month) in Cynomolgus monkeys. Pembrolizumab stability as a modified IgG4 
molecule was evaluated in vivo in mice. 
 
After single-dose IV administration at 0.3, 3, or 30 mg/kg in Cynomolgus monkeys, decline of 
serum concentration followed multiphasic kinetics. Anti–drug antibodies (ADAs) were 
detected in most of the treated animals. Clearance (CL) and terminal half-life (t1/2) appeared to 
be dose-dependent in the dose range tested with t1/2 varying from 4 to 10 days. In the 1-month 
repeat-dose (once weekly) GLP toxicity study at 6, 40, or 200 mg/kg in Cynomolgus monkeys, 
ADAs were detected in most of the low-dose (6 mg/kg) treated animals. The systemic exposure 
over the 7-day dosing interval (AUC0-7 days) was sex-independent and increased with increasing 
dose. The mean t1/2 values in individual 
ADA-negative animals ranged from 15.7 to 22.3 days across doses. 
 
In the 6-month repeat-dose (every other week) GLP toxicity study at 6, 40, or 200 mg/kg in 


 
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Cynomolgus monkeys, ADAs were detected in most of the low-dose (6 mg/kg) treated animals. 
The systemic exposure to pembrolizumab was independent of sex and was approximately 
dose-proportional across all doses. The mean t1/2 values in individual 
ADA-negative animals ranged from 21 to 22 days across doses. 
 
IgG4 wild type molecule can undergo in vivo molecular rearrangement called Fab-arm (or 
half molecule) exchange by swapping their half molecule with other IgG4 half molecules, 
thereby generating bispecific or hybrid antibodies. Pembrolizumab is a hinge mutated IgG4 
(S228P), which prevents in vivo half-molecule swap (formation of hybrid ). An in vivo mice 
experiment has demonstrated that pembrolizumab did not form hybrid antibody with another 
wild type IgG4 molecule. 
 
4.1.2.3  Safety Pharmacology/Toxicology 
The potential for systemic toxicity of pembrolizumab was assessed in a 1-month repeat-dose 
toxicity study with a 4-month recovery in Cynomolgus monkeys and in a 6-month repeat-dose 
toxicity study with a 4-month recovery period in Cynomolgus monkeys. In the 
1-month toxicity study, Cynomolgus monkeys were administered an IV dose of 6, 40, or 200 
mg/kg once weekly for a total of 5 doses. Four monkeys/sex/group were euthanized during 
Week 5. The remaining 2 monkeys/sex/group were euthanized during Week 23, after a 4-
month post-dose period. In this study, pembrolizumab was well-tolerated in monkeys with the 
systemic exposure (AUC) up to approximately 170,000 μg·day/mL over the course of the 
study. There was no test article–related mortality, and test article–related changes were limited 
to an increased incidence of inguinal swelling, and increased splenic weights in males 
receiving 200 mg/kg. Both of these findings were not considered adverse and there was no 
histopathologic correlation. Splenic weights were normal at the post-dose necropsy. 
 
Anti–pembrolizumab antibodies were detected in 7 out of 8 animals in the 6 mg/kg dose group 
and 1 animal out of 8 in the 40 mg/kg dose group and were associated with an apparent increase 
in clearance of pembrolizumab. The presence of ADA in monkeys in the low-dose group and 
in 1 monkey in the mid-dose group did not impact the pharmacodynamic response, because 
sufficient target engagement was demonstrated for the duration of the study (with the exception 
of 1 low-dose monkey). Additionally, anti–pembrolizumab antibodies were not detected in any 
monkeys in the high-dose group, suggesting that potential toxicity has been evaluated at the 
highest exposure levels in the study. Based on the lack of adverse test article–related findings 
in this study, the no observed adverse effect level (NOAEL) was ≥200 mg/kg. 
 
In the 6-month toxicity study, the potential for systemic toxicity was assessed in Cynomolgus 
monkeys administered an IV dose of 6, 40, or 200 mg/kg once every other week for 
approximately 6 months (a total of 12 doses) followed by a 4-month treatment-free period. 
Three animals/sex/group were designated for interim necropsy at the end of the 6-month dosing 
phase (3 days after receiving the last dose in Study Week 23); and the remaining 
monkeys were designated for final necropsy following the 4-month treatment-free period. 
Pembrolizumab was well tolerated at all dose levels. There were no test article–related ante 
mortem findings, electrocardiographic or ophthalmic findings, changes at injection sites, gross 
observations or organ weight changes at the interim or final necropsy. Because there were no 
test article–related histomorphologic findings at interim necropsy, histomorphologic 


 
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evaluation of tissues collected at final necropsy was not conducted. The presence of ADA was 
observed in 5 out of 10 animals at 6 mg/kg/dose during the dosing phase, which correlated 
with an apparent increased rate of elimination of pembrolizumab in these animals. 
No anti–pembrolizumab antibodies were detected at 40 or 200 mg/kg/dose during the dosing 
phase, and no pembrolizumab serum concentration profiles in these 2 groups suggested an 
effect of ADA on pembrolizumab elimination rate. During the treatment-free period, anti– 
pembrolizumab antibodies were detected in 2 animals at the 6 mg/kg/dose, which already had 
ADA present during the dosing phase, and in 2 additional animals (1 at the 6 mg/kg/dose and 
1 at the 200 mg/kg/dose), which were ADA-negative during the dosing phase. The detection 
of anti-pembrolizumab antibodies had a minimal effect on the mean group systemic exposure 
to pembrolizumab during the study and did not impact the evaluation of potential toxicity of 
pembrolizumab for the duration of the 6-month study, because there were no test article– 
related effects on any of the parameters examined and no monkey in the mid- and high-dose 
groups developed ADA during the dosing phase. In conclusion, pembrolizumab administered 
once every other week over a 6-month duration to Cynomolgus monkeys was well tolerated 
and the NOAEL was ≥200 mg/kg/dose (the highest dose tested). 
 
In addition, tissue cross-reactivity studies using monkey and human specimens were conducted 
to evaluate the potential cross reactivity of pembrolizumab with cryosections of 
Cynomolgus monkey tissues and normal human tissues. Results demonstrated the expected 
on-target staining of the membranes of mononuclear leukocytes in both species. The off-target 
staining (cytoplasmic and stromal) that occurred in many tissues of both species was 
considered spurious binding inherent to the experimental conditions of the in vitro tissue cross-
reactivity studies with no in vivo toxicological significance. 
 
4.1.2.4  Clinical Summary of Results 
As of the data cutoff dates for the IB (dated 17-FEB-2017) pembrolizumab monotherapy and 
combination therapies have been administered to approximately 9833 subjects with 
hematologic malignancies and solid tumors in Merck-sponsored trials  
 
4.1.2.5  Clinical Pharmacology 
The pharmacokinetic profile of pembrolizumab, with low clearance and limited volume of 
distribution, is typical for therapeutic antibodies. Exposure to pembrolizumab is approximately 
linear in the dose range of clinical relevance (1 to 10 mg/kg and at 200mg). Furthermore, 
pembrolizumab has a low potential of eliciting the formation of anti-drug antibodies. 
 
The pharmacokinetics of pembrolizumab was studied in 2195 patients who received doses of 
1 to 10 mg/kg every 2 weeks or 2 to 10 mg/kg every 3 weeks. Based on population 
pharmacokinetic analyses in patients with solid tumors, the geometric mean [% coefficient of 
variation (CV%)] for clearance, steady state volume of distribution, and terminal half-life were 
202 mL/day (37%), 7.38 L (19%) and 27 days (38%), respectively. 
Steady-state concentrations of pembrolizumab were reached by 19 weeks of repeated dosing 
with an every 3-week regimen and the systemic accumulation was 2.2-fold. The peak 
concentration (Cmax), trough concentration (Cmin), and area under the plasma concentration 


 
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versus time curve at steady state (AUCss) of pembrolizumab increased dose proportionally in 
the dose range of 2 to 10 mg/kg every 3 weeks. 
4.1.2.6  Safety 
Pembrolizumab has a positive benefit-risk profile and is well tolerated in the approved 
indications, as evidenced by a low rate of toxicity Grade 3 to 5 drug-related AEs (13.8%), 
discontinuations due to AEs (11.9%), and deaths due to drug-related AEs (0.4%). 
Furthermore, the frequency of immune-mediated AEOSIs is low, and these events are readily 
managed in the clinical setting. The safety and efficacy data generated to date provide a 
favorable benefit-risk assessment for the use of pembrolizumab as a treatment for subjects with 
advanced/metastatic melanoma, NSCLC, and HNSCC.  
In the pembrolizumab monotherapy trials (P001/P002, P012, P013, and P028, plus the P011 
monotherapy arm), the overall incidence of AEs ranged from 83.0% (73 of 88 subjects in P012) 
to 100% (10 of 10 subjects in P011). The most commonly reported AEs included fatigue, 
diarrhea, decreased appetite, nausea, and anemia. The incidence of drug -related AEs (DRAEs) 
ranged from 39.8% (35 of 88 subjects in P013) to 80.0% (8 of 10 subjects in P011). The most 
commonly reported DRAEs across all studies were nausea, fatigue, and diarrhea. The 
incidence of Grade 3-5 DRAEs across studies ranged from 6.8% (6 of 88 in P013) to 12.0% 
(187 of 1562 subjects) in P001/P002. The most commonly reported Grade 3-5 DRAEs were 
anemia, increased alanine aminotransferase, and increased aspartate aminotransferase . Most 
subjects who experienced an AE continued in the study, with the incidence of AEs leading to 
discontinuation ranging from 1.9% (8 of 430 subjects in P028) to 12.3% (192 of 1562 subjects 
in P001/P002). The majority of AEs leading to discontinuation were not considered drug 
related. Discontinuations due to a DRAE were infrequent and ranged from 0% (no subjects in 
P011) to 4.5% (4 of 88 subjects in P013). The most commonly reported DRAEs leading to 
discontinuation were pneumonitis, alanine increased aminotransferase, and increased aspartate 
aminotransferase. 
 
The overall pattern of AEs observed in melanoma subjects enrolled in P002 demonstrates 
favorable safety profile when this immune therapy is compared to chemotherapy. Consistent 
with prior observations from randomized comparisons of the 2 mg/kg and 10 mg/kg dose levels 
when given every 3 weeks, there are no important differences in the safety profile of 
pembrolizumab at these 2 dose levels, and both doses appear to have a favorable safety profile 
compared to chemotherapy. 
 
In the combination therapy trials (P021 and P023), the overall incidence of AEs was 95.4% 
(62 of 65 subjects) in P021 and 80% (8 of 10 subjects) in P023. In P021, the most commonly 
reported AEs in this population across the dose regimens were fatigue (49.2%), constipation 
and nausea (26.2% each), decreased appetite (23.1%), diarrhea (18.5%), and anemia and 
alopecia (15.4% each). In P023, the most commonly reported AEs experienced in this 
population across the dose regimens were neutropenia and thrombocytopenia (50.0% each), 
followed by anemia, respiratory tract infection, and back pain (30.0% each). The incidence of 
DRAEs was 86.2% (56 of 65 subjects in this population) in P021 and 60.0% (6 of 10 subjects 
in this population) in P023. In P021, the most commonly reported DRAEs experienced in this 
population across the dose regimens are fatigue (35.4%); nausea, decreased appetite, and 
alopecia (13.8% each); diarrhea (12.3%); and constipation and aspartate aminotransferase 
increased (10.8% each). In P023, the most commonly reported DRAEs experienced in this 


 
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population across the dose regimens were neutropenia and thrombocytopenia (50.0% each), 
anemia (30.0%), dysphonia, hiccups, and pruritis (20.0% each). 
 
Grade 3-5 DRAEs were reported in 23.1% (15 of 65 subjects in this population) in P021 and 
50.0% (5 of 10 subjects in this population) in P023. In P021, the most common Grade 3-5 
DRAEs in this population across dose regimens were aspartate aminotransferase increased 
(6.2%) and anemia and alanine aminotransferase increased (4.6% each). In P023, the only 
Grade 3-5 DRAEs that occurred in more than 1 subject in this population across dose regimens 
were neutropenia (40.0%) and anemia (20.0%). 
 
In P021, most subjects continued treatment despite AEs, and only 4.6% discontinued due to an 
AE. Only 3.1% of subjects discontinued study treatment due to an AE that was considered 
related to study treatment by Investigators. Adverse events resulting in discontinuation were 
reported in 3.1% (2 of 65 subjects). Interstitial lung disease, dermatitis allergic, and drug 
eruption were the only AEs resulting in discontinuation and were reported in 1 subject each 
(1.5%). In P023, no subjects discontinued due to an AE. 
 
In general, the incidence of drug-related serious adverse events (DRSAEs) was low. Many of 
the events occurred in 1 subject each and/or <1.0% each. 
 
In the pembrolizumab monotherapy trials, the most commonly reported DRSAEs (those that 
occurred in 3 or more subjects overall in at least 1 study) were pneumonitis (range of 0.7% to 
1.3% of subjects); colitis (range of 0.3% to 0.9% of subjects), pyrexia (range of 0.3% to 0.5% 
of subjects); diarrhea (range of 0.2% to 0.4%); hepatitis (0.7% of subjects); nausea, adrenal 
insufficiency, hyponatraemia, hyperthyroidism, hypophysitis, vomiting, and dyspnea (0.3% of 
subjects each); and dehydration, generalized edema, hypothyroidism, renal failure acute, and 
pericardial effusion (0.2% of subjects each). The remaining DRSAEs occurred in 
1 or 2 subjects each per study. 
 
In the combination therapy trials, all DRSAEs were reported in 1 subject each. In P021, 8 
subjects experienced DRSAEs; the DRSAEs were as follows: anemia, febrile neutropenia, 
atrial fibrillation, colitis, pyrexia, hypersensitivity, alanine aminotransferase increased, 
aspartate aminotransferase increased, drug eruption, rash, and urticaria. In P023, 2 subjects 
experienced DRSAEs; 1 subject had an event of pneumonia and the other had an event of 
tumor lysis syndrome. 
 
Due to the fact that P021 and P023 were combination studies, and also because of the small 
sample size, comparative evaluation of the AE profile of pembrolizumab combination therapy 
from those protocols to pembrolizumab monotherapy or to chemotherapy monotherapy in 
other studies cannot be made. 
 
Among P001 and P002 studies, the incidence of Adverse Events of Significant Interest 
(AEOSI) was 16.1%. Overall, the most commonly reported AEOSI included hypothyroidism 
(7.2% of subjects), pneumonitis (2.9% of subjects), infusion reaction (2.5% of subjects), and 
hyperthyroidism (2.2% of subjects). The incidences of the remaining AEOSI were low (range 
of 0.1 to 1.3% of subjects). The overall incidence of drug-related AEOSI was 14.3%. Overall, 


 
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2.6% of subjects discontinued treatment due to an AEOSI and the most commonly reported 
drug-related. 
 
AEOSI leading to discontinuation was pneumonitis (1.3% of subjects). Only one subject died 
of AEOSI (pneumonitis, 0.1% of subjects). No corticosteroids were used to manage myositis, 
pericarditis, thyroiditis, type 1 diabetes mellitus, uveitis and vasculitis. 
 
4.1.2.7 Clinical Efficacy: Melanoma 
The safety and efficacy of pembrolizumab were evaluated in a randomized (1:1:1), open-label, 
multicenter, active-controlled trial in patients with ipilimumab-naive melanoma Patients were 
randomized to receive pembrolizumab at a dose of 10 mg/kg every 2 weeks or 10mg/kg every 
3 weeks as an intravenous infusion until disease progression or unacceptable toxicity or to 
ipilimumab 3 mg/kg every 3 weeks as an intravenous infusion for 4 doses unless discontinued 
earlier for disease progression or unacceptable toxicity. Patients with disease progression could 
receive additional doses of treatment unless disease progression was symptomatic, was rapidly 
progressive, required urgent intervention, occurred with a decline in performance status, or 
was confirmed at 4 to 6 weeks with repeat imaging. Randomization was stratified by line of 
therapy (0 vs.1), ECOG PS (0 vs. 1), and PD-L1 expression (≥1% of tumor cells [positive] vs. 
<1% of tumor cells [negative]) according to an investigational use only (IUO) assay. Key 
eligibility criteria were unresectable or metastatic melanoma with progression of disease; no 
prior ipilimumab; and no more than one prior systemic treatment for metastatic melanoma. 
Patients with BRAF V600E mutation-positive melanoma were not required to have received 
prior BRAF inhibitor therapy. Patients with autoimmune disease; a medical condition that 
required immunosuppression; previous severe hypersensitivity to other monoclonal antibodies; 
and HIV, hepatitis B or hepatitis C infection, were ineligible. Assessment of tumor status was 
performed at 12 weeks, then every 6 weeks through Week 48, followed by every 12 weeks 
thereafter. The major efficacy outcome measures were overall survival (OS) and progression-
free survival (PFS), as assessed by blinded independent central review (BICR) using Response 
Evaluation Criteria in Solid Tumors [RECIST v1.1]). Additional efficacy outcome measures 
were overall response rate (ORR) and response duration. 
A total of 834 patients were randomized: 277 patients to the pembrolizumab 10 mg/kg every 
3 weeks arm, 279 to the pembrolizumab 10 mg/kg every 2 weeks arm, and 278 to the 
ipilimumab arm.  The study demonstrated statistically significant improvements in OS and 
PFS for patients randomized to pembolizumab as compared to ipilimumab (see below, Table 
1 and Figure 1). 
 
 
 
 
Table 1: Efficacy results  


 
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Figure 2: Kaplan-Meier Curve for Overall Survival 
 
 
4.1.2.8 Clinical Efficacy: Non-Small Cell Lung Cancer (NSCLC) 
The efficacy of pembrolizumab was investigated in a sub-group of a cohort of 280 patients 
enrolled in a multicenter, open-label multi-cohort, activity-estimating study. The cohort 
consisted of patients with metastatic NSCLC that had progressed following platinum-
containing chemotherapy, and if appropriate, targeted therapy for ALK or EGFR mutations 
and any evidence of PD-L1 expression by a clinical trial immunohistochemistry assay. Patients 


 
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with autoimmune disease; a medical condition that required immunosuppression; or who had 
received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible. 
A prospectively defined sub-group was retrospectively analyzed using an analytically 
validated test for PD-L1 expression tumor proportion score (TPS). This retrospectively 
identified sub-group of 61 patients accounts for 22% of the 280 patients in the cohort. Patients 
included in this sub-group had a PD-L1 expression TPS of greater than or equal to 50% tumor 
cells as determined by the PD-L1 IHC 22C3 pharmDx Kit. Patients received KEYTRUDA 10 
mg/kg every 2 (n=27) or 3 (n=34) weeks until unacceptable toxicity or disease progression that 
was symptomatic, was rapidly progressive, required urgent intervention, occurred with a 
decline in performance status, or was confirmed at 4 to 6 weeks with repeat imaging. 
Assessment of tumor status was performed every 9 weeks. The major efficacy outcome 
measures were ORR according to RECIST 1.1 as assessed by BICR and duration of response. 
Among the 61 patients with a TPS greater than or equal to 50%, the baseline characteristics 
were: 
median age 60 years (34% age 65 or older); 61% male; 79% White; and 34% and 64% with an 
ECOG PS 0 and 1, respectively. Disease characteristics were squamous (21%) and non-
squamous (75%); M1 (98%); brain metastases (11%); one (26%), two (30%), or three or more 
(44%) prior therapies; and the incidence of genomic aberrations was EGFR (10%) or ALK 
(0%). 
Efficacy results are summarized in Table 2. The ORR and duration of response were similar 
regardless of schedule (every 2 weeks or every 3 weeks) and thus the data below are pooled. 
Table 2: Efficacy Results 
 
4.1.3 Lenvatinib Pharmaceutical and Therapeutic Background 
Angiogenesis, the formation of new blood vessels from a pre-existing vascular network, is 
essential for tumor growth and metastasis.  Many molecules have been implicated as positive 
regulators of angiogenesis including vascular endothelial growth factor (VEGF), acidic 
fibroblast growth factor (aFGF), basic FGF, hepatocycte growth factor (HGF), interleukin 
(IL)-8, and platelet-derived growth factor (PDGF).   
Of the numerous molecules that have been shown to have angiogenic properties, VEGF has 
been identified as a crucial regulator of both physiologic and pathologic angiogenesis with 
increased expression being associated with a poor prognosis in many human tumor types, 
including gastroesophageal cancers.  VEGF acts primarily on endothelial cells to promote their 


 
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proliferation and three-dimensional organization for tube formation and is thought to be the 
most potent and specific proangiogenic factor.  VEGF exerts its effects through two cell 
membrane bound receptors, VEGFR1 and 2, of which VEGFR2 is thought to be more 
important. There is substantial evidence that VEGFR2 is the major mediator of endothelial cell 
proliferation and survival as well as tube formation and microvascular permeability.  VEGFR2 
undergoes dimerization and ligand-dependent tyrosine phosphorylation, producing a 
mitogenic, chemotactic and pro-survival signal.  An inhibitor of VEGFR2 would therefore be 
expected to exert a potent inhibitory effect on tumor growth and metastasis formation. 
Lenvatinib is an oral, multiple receptor tyrosine kinase (RTK) inhibitor that selectively inhibits 
the kinase activities of VEGF receptors VEGFR1, VEGFR2, and VEGFR3. Lenvatinib also 
inhibits other receptor tyrosine kinases that have been implicated in pathogenic angiogenesis, 
tumor growth, and cancer progression in addition to their normal cellular functions. These 
include FGF receptors FGFR1, 2, 3, and 4; PDGFRα, KIT, and RET. Lenvatinib interacts with 
VEGFR2 with a novel binding mode recently categorized as Type V resulting in high 
selectivity, rapid association kinetics and relatively slow dissociation kinetics for the target.[1] 
Lenvatinib binds to the adenosine triphosphate (ATP)-binding site and the neighboring 
allosteric region in the kinase domain adopting the aspartic acid-phenylalanine-glycine (DFG)-
in conformation. This results in superior binding affinity of lenvatinib to VEGFR2. Most of 
the known receptor tyrosine kinase inhibitors are categorized as: 1) Type I inhibitors which 
bind the kinase in the DFG-in configuration and only bind to the ATP-binding site; or 2) Type 
II inhibitors which bind the kinase in the DFG-out conformation and bind to both the ATP-
binding site and the neighboring regions. 
 
The results of in vitro receptor binding assays, cell-based assays, and an in vivo angiogenesis 
models as well as the results of recent studies in human xenograft models in athymic mice 
suggest that in most tumors, the mode of action for lenvatinib antitumor activity is primarily 
related to the inhibition of both VEGF and FGF-dependent angiogenesis.[2, 3] Specifically, 
intracellular signal transduction analysis for MAPK/Erk1/2, S6K, S6, and their phosphorylated 
forms in HUVECs revealed that lenvatinib inhibited the MAPK pathway and the mTOR-S6K-
S6 pathway triggered by activated VEGFR and FGFR, both of which are important 
intracellular signaling pathways for angiogenesis. Since cross talk between the VEGF 
signaling pathway and the FGF signaling pathway may accelerate angiogenesis in the tumor, 
this mode of dual inhibition may more effectively inhibit tumor angiogenesis. In addition, 
recent data from preclinical studies suggest that the FGFR pathway is also a driver resistance 
to antiangiogenic drugs.[4]  Lenvatinib targets both VEGFR- and FGFR-induced 
angiogenesis thereby blocking this mechanism of tumor resistance. 
Lenvatinib has been approved in the US for the treatment of patients with locally recurrent or 
metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer (DTC). 
4.1.4 Lenvatinib Preclinical and Clinical Trial Data 
4.1.4.1 Nonclinical Pharmacology 
A cell free kinase inhibition profiling study revealed that lenvatinib is a potent multiple 
tyrosine kinase inhibitor. The most sensitive kinases with half-maximal inhibitory 


 
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concentration (IC50) values below 10 nmol/L include VEGF receptors (VEGFR1, VEGFR2, 
VEGFR3) and RET. The second most sensitive group includes FGF receptors (FGFR1 - 4), 
PDGFRα, and KIT with IC50 values below 100 nmol/L. All are typical pro-angiogenic and 
oncogenic pathway-related receptor tyrosine kinases. 
 
Table 3: Kinase IC50 Values 
 
Kinase 
IC50 (nmol/L) 
VEGFR3 (FLT4) 
2.3 
VEGFR2 (KDR) 
3.0 
VEGFR1 (FLT1) 
4.6 
RET 
6.4 
FGFR2 
27 
PDGFRα 
29 
FGFR4 
43 
FGFR3 
52 
FGFR1 
61 
KIT 
85 
FGFR= Fibroblast Growth Factor Receptor 
IC50 = with half-maximal Inhibitory Concentration 
PDGFRα = Platelet-Derived Growth Factor Receptor alpha 
VEGFR = Vascular Endothelial Growth Factor 
 
 
In cell-based assays, lenvatinib inhibited VEGF-driven VEGFR2 phosphorylation, 
proliferation, and tube formation in human umbilical vein endothelial cell (HUVEC) models 
with IC50 values of 0.25, 3.4, and 2.1 nmol/L, respectively. Lenvatinib also inhibited FGF-
driven HUVEC tube formation of with an IC50 value of 7.3 nmol/L. These results indicated 
that lenvatinib inhibits both VEGF- and FGF-driven angiogenesis in vitro. 
 
In human tumor xenograft models in athymic mice, orally administered lenvatinib 
(administered as lenvatinib mesylate) significantly inhibited the growth of many different 
tumors at doses between 1 and 100 mg/kg (see Table 4). 
 
 
 
 
 
 
 
 
 
 
 
 
Table 4: Summary of the Anti-Tumor Effects of Lenvatinib Monotherapy 
 


 
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4.1.4.2  Nonclinical Pharmacokinetics 
 
The PK of lenvatinib in mice, rats, dogs, and monkeys were characterized by a low plasma 
clearance and a small to moderate volume of distribution. After oral administration of 
lenvatinib at 3 mg/kg as a solution, lenvatinib was absorbed rapidly and exhibited good oral 
bioavailability in mice (64.4%), rats (68.7%), dogs (70.4%), and monkeys (78.4%). 
 
In vitro plasma protein binding of lenvatinib (0.3 – 30 μg/mL) was highest in humans (97.87% 
– 98.62%), followed by rats, athymic mice, monkeys, and dogs. In humans, lenvatinib mainly 
bound to albumin. In vitro blood to plasma ratios of lenvatinib (0.1 - 10 μg/mL) remained 
constant in humans (0.589 – 0.608); in contrast, the ratios in animals were lower with 
increasing concentration. 
 
In human liver microsomes, the demethylated form of lenvatinib was identified as the major 
metabolite. This metabolite was also detected after incubation with mouse, rat, dog, and 
monkey liver microsomes. Cytochrome P450 (CYP)3A4 was the predominant (>80%) CYP 
isoform involved in the metabolism of lenvatinib. Aldehyde oxidase (AO) in human liver 
9000×g supernatant of homogenate (S9) generated M3´ from lenvatinib and M2´ from M2. 
About 50 metabolites were detected in plasma, tissues, urine, feces, and bile samples after a 
single oral administration of [14C]lenvatinib (radiolabeled on the quinoline ring) to rats and 


 
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monkeys at 3 mg/kg. More than 50% of methanol extractable radioactivity in plasma was 
parent drug, lenvatinib, and oxidative metabolism was one of the main metabolic pathways of 
lenvatinib. In addition to oxidative metabolism, glutathione (GSH) conjugation with 
elimination of the O-aryl group followed by further biotransformations (hydrolysis of the 
glutathione moiety, degradation of the cysteine moiety, and intramolecular rearrangement of 
the cysteinylglycine and cysteine conjugates and subsequent dimerization) were the major 
metabolic pathways after [14C]lenvatinib administration. Cleavage of the O-aryl bond 
followed by further biotransformations (conjugate with glucuronic acid, glutathione, and N-
acetyl glucosamine with or without hydroxylation) were the major metabolic pathways after 
[14C]CB-lenvatinib (radiolabeled on the chlorobenzene ring). In human plasma, lenvatinib and 
its metabolite, the N-cysteine conjugate of the quinoline moiety in lenvatinib, could form 
covalent bonds with human plasma protein(s) via the thioether and disulfide bonds, 
respectively. Nucleophiles such as GSH and cysteine successfully released lenvatinib-related 
components which covalently bound to human plasma protein as the corresponding conjugates 
via a substitution reaction, suggesting that the covalent binding would be reversible in humans 
in vivo. 
 
After a single oral administration of [14C]lenvatinib (3 mg/kg) to rats and monkeys, 
radioactivity was mainly excreted in feces, and 90% or more of the radioactive dose was 
recovered by 7 days post-dose. In rats, oral absorption of radioactivity was at least 65%, which 
coincided with oral bioavailability of lenvatinib. Tissue distribution and elimination of 
radioactivity in most tissues were parallel with that in blood or plasma in rats and monkeys, 
while the elimination of radioactivity in the melanin-containing tissues was slow in monkeys. 
 
The placental transfer of lenvatinib after a single oral administration of [14C]lenvatinib (3 
mg/kg) to pregnant rats was very low in rats on Days 13 and 18 of pregnancy. The radioactivity 
in milk was approximately 2 times higher than that in plasma after a single oral administration 
of [14C]lenvatinib mesylate to lactating rats (3 mg/kg), and the radioactivity in the milk 
decreased in parallel with that in plasma. Radioactivity detected in the milk and plasma was 
primarily attributed to the parent drug, lenvatinib. 
 
Lenvatinib exhibited a potent inhibitory effect on CYP2C8 (IC50: 10.1 μmol/L), a weak 
inhibitory effect on CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A and 
virtually no inhibitory effect on CYP2A6 and CYP2E1 in human liver microsomes. Time-
dependent inhibition by lenvatinib of the formation of 1'-hydroxymidazolam from midazolam 
(CYP3A4) was observed. The results of the simulations using Simcyp® suggested that there 
is no significant drug-drug interaction risk between lenvatinib and midazolam (CYP3A 
substrate) or repaglinide (CYP2C8 substrate) at the clinical dose of 24 mg of lenvatinib. 
 
Treatment of cultured human hepatocytes with up to 3 μmol/L of lenvatinib had a tendency 
towards a slight increase in CYP3A enzyme activity or CYP3A4 mRNA expression. No effects 
on CYP1A1, CYP1A2, CYP2C9, and CYP2B6 based on enzyme activities or messenger 
(mRNA) expression. 
 
In 
human 
liver 
microsomes, 
lenvatinib 
directly 
inhibited 
5´-diphospho-
glucuronosyltransferase (UGT)1A1 and UGT1A4 with IC50 values of 10.6 and 14.0 μmol/L, 


 
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respectively. Lenvatinib showed no or little evidence of direct inhibition of UGT1A6, 
UGT1A9, and UGT2B7 (IC50 values greater than 30.0 μmol/L). Treatment of cultured human 
hepatocytes with up to 3 μmol/L of lenvatinib did not induce UGT1A1, UGT1A4, UGT1A6, 
UGT1A9, and UGT2B7 enzyme activities or mRNA expression. 
 
Lenvatinib was a substrate for multidrug resistance protein 1 (MDR1, = P-glycoprotein [P-gp]) 
and breast cancer resistance protein (BCRP) and showed inhibitory activity toward P-gp-
mediated and BCRP-mediated transports (IC50>30 μmol/L). Lenvatinib was not a substrate 
for organic anion transporter (OAT)1, OAT3, organic anion transporting polypeptide 
(OATP)1B1, OATP1B3, organic cation transporter (OCT)1, OCT2, or bile salt export pump 
(BSEP). Lenvatinib showed an inhibitory effect on OAT1, OAT3, OCT1, OCT2, OATP1B1, 
and BSEP with the IC50 values of 4 to 15 μmol/L, and no inhibitory effect on OATP1B3 (IC50 
>30 μmol/L). Treatment of cultured human hepatocytes with up to 3 μmol/L of lenvatinib 
showed no induction potency on P-gp mRNA expression. In human liver cytosol, lenvatinib 
did not inhibit AO activity (IC50 >100 μmol/L). 
 
4.1.4.3 Safety Pharmacology/Toxicology 
In the chronic toxicity studies in rats and cynomolgus monkeys, target organ toxicity was 
primarily observed in the kidneys (glomerulopathy, sometimes with proteinuria), 
gastrointestinal tract (duodenal lesions), artery/arterioles (arterial fibrinoid necrosis, medial 
degeneration, or hemorrhage) in various organs, bone (increased epiphyseal growth 
plate/cartilage), and male and female reproductive organs (testicular hypocellularity and 
ovarian follicular atresia and decreased menstruation [monkeys]) in both species, and in the 
incisor (dysplasia) and adrenals (sinusoidal dilatation, cortical necrosis) in rats. All of these 
findings were not unexpected as similar findings have been reported in animals treated with 
other TKIs and are considered to be related to the pharmacologic (antiangiogenic) effects of 
lenvatinib. These findings were reversible and most were not evident at the end of the 4- 
week recovery period. 
 
The effects of lenvatinib on the cardiovascular, respiratory, and central nervous system (CNS) 
were evaluated in rats and dogs. Two in vitro electrophysiology studies were also conducted 
to assess the effect of lenvatinib on human ether-à-go-go-related gene (hERG) potassium 
current or action potential parameters. No significant adverse effects were observed in these 
studies except for a weak inhibitory effect on hERG potassium current (IC50 = 11.89 μmol/L). 
 
In view of these results, lenvatinib is anticipated to have a low risk of cardiovascular, 
respiratory, and CNS adverse effects in humans. However, hypertension is an identified 
clinical risk associated with clinical use of lenvatinib and other VEGF inhibitors. 
 
 
4.1.4.4 Clinical Summary of Results 
 
As of the data cutoff date of 27 Apr 2015, a total of 31 clinical studies in the Clinical 
Development Program have enrolled subjects.  Of these 31 studies, 22 are completed (14 Phase 
1/1b, 7 Phase 2, and 1 Phase 3), 8 are ongoing (1 Phase 1, 5 Phase 2, 1 Phase 3, and 1 Expanded 
Access Program), and 1 was discontinued.  


 
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4.1.4.5 Clinical Pharmacology 
Data from the clinical pharmacology studies showed lenvatinib: 
• Exhibits linear PK and minimal accumulation at clinically relevant doses 
• Is extensively metabolized with no major metabolites 
• Has an elimination half-life of approximately 28 hours 
• Has no clinically significant drug-drug interactions 
• Has no food effect 
• Does not prolong QTc interval in healthy volunteers (increases >10 msec excluded) 
 
Absorption: After oral administration of lenvatinib, time to peak plasma concentration (Tmax) 
typically occurs from 1 to 4 hours post-dose. Administration with food does not affect the 
extent of absorption, but decreases the rate of absorption and delays the median Tmax from 2 
hours to 4 hours.  
 
In patients with solid tumors administered single and multiple doses of lenvatinib once daily, 
the maximum lenvatinib plasma concentration (Cmax) and the area under the concentration- 
time curve (AUC) increased proportionally over the dose range of 3.2 to 32 mg with a median 
accumulation index of 0.96 (20 mg) to 1.54 (6.4 mg).  
 
Distribution: In vitro binding of lenvatinib to human plasma proteins ranged from 98% to 99% 
(0.3 – 30 μg/mL). In vitro, the lenvatinib blood-to-plasma concentration ratio ranged from 
0.589 to 0.608 (0.1 – 10 μg/mL).  
 
Based on in vitro data, lenvatinib is a substrate of P-gp and BCRP but not a substrate for 
organic anion transporter (OAT) 1, OAT3, organic anion transporting polypeptide (OATP) 
1B1, OATP1B3, organic cation transporter (OCT) 1, OCT2, or the bile salt export pump 
(BSEP).  
 
Elimination: Plasma concentrations declined bi-exponentially following Cmax. The terminal 
elimination half-life of lenvatinib was approximately 28 hours. 
 
Metabolism: CYP3A is one of the main metabolic enzymes of lenvatinib. The main metabolic 
pathways for lenvatinib in humans were identified as enzymatic (CYP3A and aldehyde 
oxidase) and non-enzymatic processes.  
 
Excretion: Ten days after a single administration of radiolabeled lenvatinib to 6 patients with 
solid tumors, approximately 64% and 25% of the radiolabel were eliminated in the feces and 
urine, respectively. 
 
 
4.1.4.6 Safety 
 
Safety data obtained in 1,108 patients with advanced solid tumors who received lenvatinib as 
a single agent across multiple clinical studies was used to further characterize risks of serious 
adverse drug reactions. 
 


 
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The most common adverse reactions observed in lenvatinib-treated patients (greater than or 
equal to 30%) were, in order of decreasing frequency, hypertension, fatigue, diarrhea, 
arthralgia/myalgia, decreased appetite, weight decreased, nausea, stomatitis, headache, 
vomiting, proteinuria, palmar-plantar erythrodysesthesia (PPE) syndrome, abdominal pain, 
and dysphonia. The most common serious adverse reactions (at least 2%) were pneumonia 
(4%), hypertension (3%), and dehydration (3%). 
 
Adverse reactions led to dose reductions in 68% of patients receiving lenvatinib and 5% of 
patients receiving placebo; 18% of patients discontinued lenvatinib and 5% discontinued 
placebo for adverse reactions. The most common adverse reactions (at least 10%) resulting in 
dose reductions of lenvatinib were hypertension (13%), proteinuria (11%), decreased appetite 
(10%), and diarrhea (10%); the most common adverse reactions (at least 1%) resulting in 
discontinuation of lenvatinib were hypertension (1%) and asthenia (1%) 
 
 
4.1.4.7 Clinical Efficacy 
 
4.1.4.7.1 Phase I /Ib studies 
There were a total of 34 confirmed PRs observed in four studies across all doses as of the cutoff 
date of 27 Apr 2014, including 7 (20.6%) in Study E7080-E044-101, 10 (29.4%) in Study 
E7080-A001-102 (Schedules 1 and 2), 1 (2.9%) in Study E7080-J081-103, and 16 (47.1%) in 
Study E7080-J081-110. One CR was observed in Study E7080-J081-110.  
Study E7080-J081-110 is completed. Objective response rate (ORR [CR + PR]) was 60.7% 
(17 of 28 subjects) overall, 68.2% (15 of 22 subjects) in the combined 4 mg BID group (dose-
escalation cohort and expansion cohort combined), and 33.3% (2 of 6 subjects) in the 6 mg 
BID group. 
4.1.4.7.2 Phase II studies 
There were a total of 13 Phase 2 studies: 7 are completed, 5 are ongoing, and 1 was closed to 
enrollment. Of the 7 completed studies, 2 were conducted in subjects with melanoma (E7080-
G000-206, E7080-702), one was in DTC and medullary thyroid cancer (MTC) (E7080-G000-
201), one in Advanced Hepatocellular Carcinoma (HCC) (E7080-J081-202), one in recurrent 
Grade 3 or 4 GBM (glioblastoma, malignant) (E7080-G000-203), and one in advanced 
endometrial cancer (E7080-G000-204), and one in ATC or DTC or MTC (E7080-J081-208]). 
Study E7080-701 was conducted in ovarian cancer and was closed to enrollment. Completed 
studies are those for which enrollment has been completed and the primary analysis has been 
conducted. In some cases, subjects will continue to receive treatment if they are receiving 
clinical benefit. 
Study E7080-G000-203 showed modest antitumor activity and no clinical or OS advantage for 
lenvatinib over bevacizumab in subject with Grade 4 GBM. PFS and OS results showed no 
difference in these outcomes between recurrent Grade 4 GBM subjects treated with lenvatinib 
and those treated with bevacizumab (Cohort 1). Although OS rates at 12 and 18 months were 
numerically higher in the lenvatinib than in the bevacizumab arm (lenvatinib 37% and 24% vs 
bevacizumab 22% and 9%), in the context of a PFS-6 of 21.2%, median OS of only 7.5 months 


 
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for lenvatinib, and the difference in median OS of only 1.5 months between lenvatinib and 
bevacizumab, the DMC and Eisai concurred that lenvatinib does not provide additional benefit 
over bevacizumab in these subjects. The activity of lenvatinib was limited in subjects with 
recurrent Grade 3 GBM (Cohort 2), with a 6-month PFS rate of 8.0%, median PFS of 2.8 
months, and median OS of 12.0 months (median 17.7 months of follow-up). The activity of 
lenvatinib was unimpressive in subjects with recurrent Grade 4 GBM who failed prior 
bevacizumab therapy (Cohort 3), with a 6-month PFS rate of 7.6%, median PFS of 1.8 months, 
and median OS of 4.1 months (median 23.4 months of follow-up) in these subjects. 
In Study E7080-G000-204, treatment with lenvatinib resulted in antitumor activity in subjects 
with recurrent metastatic endometrial cancer with evidence of disease progression following 
platinum-based chemotherapy. The primary endpoint of the study was the ORR; 19 (14.3%) 
subjects achieved a best overall response of CR (1 subject) or PR (18 subjects) based on the 
assessments by the independent radiologic review (IRR), and 28 (21.1%) subjects achieved 
CR (2 subjects) or PR (26 subjects) based on investigator assessments in the Full Analyses Set. 
Results from the Per Protocol Analysis Set were similar, with an ORR of 15.7% (19 subjects) 
based on the assessments by the IRR and 22.3% (27 subjects) based on investigator 
assessments, indicating that lenvatinib is active as a second-line treatment in subjects with 
advanced endometrial cancer. Median OS was 9.6 months (median follow-up was 9.6 months). 
The median OS increased to 10.6 months based on an updated survival assessment at 59.4% 
of events and a median follow-up at 15.2 months that took place approximately 6 months later. 
The median estimate of PFS was 5.6 months based on IRR assessment. The 3- and 6-month 
PFS rates were 66.1% and 41.0%, respectively, based on IRR assessment. 
Study E7080-G000-206 primary objective was to assess the objective response rate (ORR; 
complete response + partial response [CR + PR]) of lenvatinib in subjects with unresectable 
Stage III or Stage IV melanoma not harboring the V600E BRAF mutation and disease 
progression following up to 2 prior systemic anticancer regimens for unresectable Stage III or 
Stage IV melanoma (Cohort 1) and in in subjects with unresectable Stage III or Stage IV 
melanoma harboring the activating BRAF mutations (mainly the V600E mutation) and disease 
progression following BRAF V600E-targeted therapy (Cohort 2). The ORR was similar for 
both subjects with or without the V600 E BRAF mutation. The ORR was 8.6% (8 subjects) in 
Cohort 1 and 9.0% (8 subjects) in Cohort 2. All were partial responses. Treatment with 
lenvatinib resulted in some antitumor activity in subjects with unresectable Stage III or Stage 
IV melanoma and evidence of disease progression. For the Cohort 1 the median estimate of 
PFS was 3.7 month and the 6-month PFS rate was 26.1%. The estimated Kaplan-Meier median 
OS was 8.9 months. The overall survival rate was 40.9% at 12 months and was not estimable 
at 18 and 24 months. The median follow-up time was 8.7 months. Based on assessments by 
the IRR, the disease control rate (DCR) was 52.7% and the CBR was 31.2%. The durable SD 
rate was 22.6%. The assessments for time to response and duration of response were not 
reliable given the small number of responses. For the Cohort 2 the median estimate of PFS was 
1.8 months and the 6-month PFS rate was 17.2%. The estimated Kaplan-Meier median OS was 
6.3 months. The overall survival rate was 26.8% at 12 months, 19.9% at 18 months and 16.4% 
at 24 months. The median follow-up time was 14.0 months. Based on assessments by the IRR, 
the DCR was 34.8% and the CBR was 14.6%. The durable SD rate was 5.6%. The assessments 
for time to response and duration of response were not reliable given the small number of 
responses. 


 
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In Study E7080-701, 7 subjects with platinum-sensitive ovarian cancer were enrolled. Due to 
the early termination of the study, no efficacy analysis was performed. 
Although efficacy was not an endpoint for the Phase 1b portion of Study E7080-702, tumor 
response was recorded. The data presented were from local reads only; thus, caution should be 
used when interpreting the data. Some encouraging clinical activity was noted at the MTD 
(Cohort 2, 20 mg daily, n=7), with a best overall response of partial response (PR) for 2 
subjects, stable disease (SD) for 4 subjects, and unevaluable for 1 subject. 
Although Study E7080-702 was not powered or designed to determine superiority of the 
lenvatinib plus dacarbazine combination (L+D arm) compared with dacarbazine alone (D arm) 
in Phase 2, the study did provide promising efficacy results. The median PFS (imputed) for the 
L+D arm was 19.1 weeks (95% CI: 9.57, 25.57) compared with 7.0 weeks (95% CI: 5.57, 
15.57) for the D arm, with a hazard ratio of L+D versus D alone of 0.4 (95% CI: 0.23, 0.75), a 
2.7-fold increase in PFS, and 60% reduction in progression risk. Time to progression favored 
the L+D arm (n=30), with an imputed median TTP of 19.1 weeks (95% CI: 9.57, 24.43) 
compared with 7.0 weeks (95% CI: 5.57, 15.57) in the D arm (n=30), with a hazard ratio of 
L+D versus D alone of 0.4 (95% CI: 0.25, 0.79). In the L+D arm, 31 subjects (77.5%; 95% CI: 
64.6%, 90.4%) were recorded as having PD or death at six months compared with 34 subjects 
(91.9%; 95% CI: 83.1%, 100.0%) in the D arm. An overall response (confirmed CR or PR) 
was reported for eight subjects (ORR: 20.0%; 95% CI: 7.6%, 32.4%) in the L+D arm compared 
with three subjects (ORR: 8.1%; 95% CI: 0.0%, 16.9%) in the D arm for an ORR difference 
comparing the L+D arm with the D arm of 11.9% (95% CI: -3.3%, 27.1%). In the L+D arm, 
the disease control rate (CR + PR + SD [confirmation of CR or PR not required]) was 60.0% 
(95% CI: 44.8%, 75.2%) compared with 40.5% (95% CI: 24.7%, 56.4%) in the D arm. 
A meaningful clinical benefit was observed in Study E7080-G000-201. Lenvatinib showed 
antitumor activity in both the DTC and MTC histological cohorts. The primary endpoint of the 
study, ORR based on the assessments by the independent imaging review (IIR), was 50% in 
the DTC cohort and 36% in the MTC cohort. A favorable benefit was also observed in the 
secondary efficacy endpoints of median PFS and overall survival. For the DTC cohort, with a 
follow-up time of 14 months, the median estimate of PFS was 12.6 months, and for the MTC 
cohort, with a follow-up time of 8.0 months, the median estimate of PFS was 9.0 months. The 
overall survival rate was 86% for the DTC cohort and 76% for the MTC cohort at 12 months. 
These positive findings have led to pursuing a Phase 3 study, E7080-G000-303, in subjects 
with 131I-refractory DTC and radiographic evidence of disease progression within the prior 
12 months. 
The remaining 6 Phase 2 studies, (E7080-G000-205 in renal cell carcinoma (RCC), E7080-
G000-207 in pediatrics subjects, E7080-G000-209 in adenocarcinoma, E7080-703 in locally 
advanced or metastatic NSCLC, and E7050-G000-901 in combination with lenvatinib in 
subjects with advanced solid tumors (Dose Escalation) and in subjects with recurrent 
glioblastoma or unresectable Stage III or Stage IV melanoma) are currently ongoing. 
4.1.4.7.3 Phase III 
Of the 2 Phase 3 studies, Study E7080-G000-303 is closed to enrollment and the data have 
been analyzed for the primary objective of efficacy. This is a Phase 3 study to compare the 


 
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safety and efficacy of lenvatinib in subjects with 131I-refractory DTC and radiographic 
evidence of disease progression within the prior 12 months. The study cutoff date for the 
primary analysis of this study was 15 Nov 2013. As of this date, 94 (36.0%) subjects in the 
lenvatinib arm and 119 (90.8%) subjects in the placebo arm had completed treatment in the 
Randomized Phase, i.e., had disease progression. Treatment was discontinued prematurely for 
45 (17.2%) subjects in the lenvatinib arm and 4 (3.1%) subjects in the placebo arm. The most 
frequent reason for premature discontinuation in both treatment arms was AEs: 37 (14.2%) 
subjects in the lenvatinib arm and 3 (2.3%) subjects in the placebo arm. Treatment was ongoing 
for 122 (46.7%) lenvatinib subjects compared with 8 (6.1%) placebo subjects. 
All 392 subjects enrolled in the study (261 in the lenvatinib arm and 131 in the placebo arm) 
were included in both the Full Analysis Set and the Safety Analysis Set. The Per Protocol 
Analysis Set comprised 383/392 (97.7%) subjects, 256/261 (98.1%) subjects in the lenvatinib 
arm and 127/131 (96.9%) subjects in the placebo arm. 
Based on IIR assessments using the Full Analysis Set, the median PFS was 18.3 months for 
lenvatinib compared with 3.6 months for the placebo group, with an HR of 0.21 (99% CI: 0.14, 
0.31), as estimated from the stratified Cox proportional hazard model. The difference in PFS 
between the lenvatinib and placebo arms was statistically significant (P<0.0001) using both a 
stratified and unstratified log-rank test. 
The results of the primary efficacy analysis were fully supported by the results of the analysis 
with the Per Protocol Analysis Set. The median PFS and 95% CI were the same for the 2 
analysis sets. The results of the 3 planned sensitivity analyses were consistent with the primary 
PFS analyses (Sensitivity Analysis A [all events and deaths], Sensitivity Analysis B 
[investigators’ assessments], and Sensitivity Analysis C [uniform scheduled date of 
assessment]). The log-rank tests all showed a statistically significant difference between 
lenvatinib treatment and placebo (P<0.0001). The HRs for all the analyses were comparable 
(0.21 to 0.24). 
The median PFS was longer with lenvatinib treatment compared with placebo for all of the 
subgroups evaluated (age group [≤65, >65 years], sex, race, prior VEGF/VEGFR-targeted 
therapy [0, 1], region [Europe, North America, Other], histology [papillary, follicular], and 
TSH level). The HRs and 2-sided 95% CIs showed favorable outcomes for lenvatinib 
compared with placebo for PFS for all the various subgroups. 
Four (1.5%) subjects treated with lenvatinib had a best overall response (BOR) of CR while 
no subjects in the placebo group had a CR, and 165 (63.2%) subjects had a PR compared with 
2 (1.5%) subjects in the placebo group. The secondary endpoint, ORR based on the IIR 
assessments, was significantly higher with lenvatinib treatment. The ORR was 64.8% in the 
lenvatinib arm compared with 1.5% in the placebo arm. The odds ratio was 28.87, which was 
statistically significant (P<0.0001) in favor of lenvatinib. The median duration of objective 
response for the lenvatinib arm was not yet reached at the time of data cutoff. Among the 
responders, 75% had a duration of response of greater than 9.4 months, and the median time 
to the first objective response was 2.0 months for the lenvatinib group. 


 
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Although OS was another secondary endpoint, the study was not designed to demonstrate a 
survival difference with the crossover design and limited statistical power. The analysis for OS 
included data from the placebo-treated subjects with confirmed disease progression who 
entered into the optional open label (OOL) Lenvatinib Treatment Period of the Extension 
Phase. At the data cutoff date, the median OS was not yet reached for either the lenvatinib arm 
or the placebo arm (including crossover subjects). When adjusted for the treatment crossover, 
using the pre-specified rank-preserving structural failure time (RPSFT) model, the HR was 
0.62 (95% CI: 0.40, 1.00), showing a trend toward prolongation of OS with lenvatinib as 
compared with placebo. The difference in OS between the 2 treatment arms was marginally 
significant as determined using the resampling method (bootstrapping) (P=0.0510). The 
adjusted OS rates were numerically higher in the lenvatinib arm compared with the placebo 
crossover arm (6 months: 90.7% vs 85.3%, respectively; 12 months: 81.6% vs 70.0%, 
respectively; 18 months: 72.3% vs 63.0%, respectively). Using the unadjusted stratified Cox 
proportional hazard model, the HR was 0.73 (95% CI: 0.50, 1.07), showing a trend in favor of 
lenvatinib treatment for prolonged OS, as was observed with the adjusted model. 
Study E7080-G000-304 in unresectable HCC is still ongoing as of the 27 Apr 2015 data cutoff 
date. 
 
 
4.2 
Rationale 
4.2.1 Rationale for the Trial and Selected Subject Population 
4.2.1.1 Background: Gastroesophageal Cancer 
With an annual global incidence of more than 952,000 cases of gastric cancer (GC) and 
456,000 cases of esophageal cancer (EC), upper GI malignancies are major worldwide cancer 
risks.[5]  In the United States, predictions for 2015 call for 16,910 new cases of EC, with 
15,690 deaths, and 26,370 new cases of GC, with 10,730 deaths.[6]  Most patients diagnosed 
in the US unfortunately already have advanced incurable disease at the time of presentation.  
Standard cytotoxic chemotherapy with a fluoropyrimidine and platinum is typically used as 
first-line treatment for advanced gastroesophageal adenocarcinoma, with median survival 
ranging from 8 to 10 months.  There is no standard second line treatment and quality of life 
and minimization of side effects are key considerations when choosing the therapeutic 
approach.  Both single agent irinotecan and docetaxel have demonstrated a survival benefit 
compared with best supportive care, with median overall survival rates of 4-5 months.[7]  
There is a clear need for better treatment options in this refractory gastroesophageal cancer 
patient population.   
4.2.1.2 Targeting Angiogenesis 
Angiogenesis plays a major role in the development and progression of gastric cancer.  It has 
been shown that expression of VEGFR2 is a prognostic factor correlated with poor 
prognosis.[8]  Furthermore, the Gastric Cancer Genome Atlas Research Network (TCGA) has 
demonstrated how some subtypes of gastric cancer are associated with a recurrent 
amplification of the VEGF-A gene and with an elevated expression of the angiogenesis-related 
pathways.[9-11] 


 
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Clinically, angiogenesis inhibitors are active and beneficial in the treatment of advanced gastric 
cancer.  A recent meta-analysis of 22 trials exploring targeted therapy for a total of 7,022 
advanced gastric cancer patients demonstrated positive results for anti-angiogenic agents in 
terms of overall survival (HR 0.759; P < 0.001).[12]  Ramucirumab, an anti-VEGFR2 
monoclonal antibody, has been FDA approved as a single agent or in combination with 
paclitaxel for treatment of advanced gastric or gastro-esophageal junction adenocarcinoma, 
with disease progression on or after prior fluoropyrimidine- or platinum-containing 
chemotherapy.  When used as a single agent median overall survival reached 5.2 months and 
in combination with paclitaxel 9.6 months.[13, 14]  In addition, apatinib an oral VEGFR2 
tyrosine kinase inhibitor was approved in China in December 2014 for use in advanced gastric 
patients who have failed two prior lines of chemotherapy, based on a survival benefit of nearly 
two months.[15]  It is currently being investigated in multiple additional ongoing studies in 
China including earlier lines of therapy, in combination with chemotherapy and as a 
maintenance strategy.[16]  Finally, regorafenib an oral multi-targeted tyrosine kinase inhibitor 
including VEGFR1-3, has demonstrated promising activity in refractory gastroesophageal 
patients.  Led by the AGITG group, INTEGRATE was a randomized phase II study of 
regorafenib versus placebo in 152 advanced gastroesophageal cancer patients who had 
progressed on one or more lines of prior therapy.  A significant improvement in progression 
free survival compared to placebo (2.6 vs 0.9 months, p<0.0001) was found in all geographic 
regions and patient subgroups evaluated.[17]   
4.2.1.3 Immune Checkpoint Inhibition 
There is increasing evidence that cancer immunotherapy is active in a wide variety of 
malignancies.  Modulation of the immune checkpoint is one of the key mechanisms by which 
tumors are able to evade the immune response and escape destruction.  Checkpoint pathways 
are regulated by ligand/receptor interactions.  The programmed death-1 (PD-1) receptor is 
present on lymphocytes and negatively regulates T cell responses following binding of PD-1 
ligand (PD-L1), which is frequently expressed on tumor cells.  Blocking the PD-1/PD-L1 
interaction prevents tumors from down regulating the cytotoxic lymphocyte response.  Immune 
checkpoint inhibition has shown early promise in the treatment of gastric cancer.  A phase 1b 
study of single agent pembrolizumab was reported in which patients with advanced PD-L1-
positive gastric cancer who had progressed on at least 1 line of therapy were treated every 2 
weeks until progression or toxicity.  Pembrolizumab had manageable toxicity and 
demonstrated promising efficacy with a 22% response rate and a 12 month overall survival of 
42%.[18]  Single agent pembrolizumab was subsequently evaluated in a large phase II study 
of patients with advanced gastric/GEJ adenocarcinoma who had progressed on 2 or more prior 
chemotherapy regimens.  Of 259 patients enrolled, overall response rate irrespective of tumor 
PD-L1 expression was 11.2%.[19] Grade 3-5 treatment-related adverse events were 
manageable and occurred in 16.6% of patients, leading to treatment discontinuation in 2 
patients and fatalities in 2 patients.  Nivolumab, a similar monoclonal antibody targeting PD-
1, was investigated as a single agent in 59 refractory gastroesophageal cancer patients.  Overall 
response rate was 12%, with a 12 month overall survival rate of 38%.[20]  Single agent 
nivolumab was also evaluated in a randomized placebo controlled phase III study for patients 
with advanced gastric cancer who had progressed on 2 or more chemotherapy regimens.  A 
total of 493 patients were enrolled and randomized 2:1 to nivolumab versus placebo with 
primary endpoint overall survival.  Median OS was 5.32 months with nivolumab versus 4.14 


 
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months with placebo (hazard ratio [HR], 0.63; 95% confidence interval [CI], 0.50-0.78; 
p<0.0001), and OS rates at 6 and 12 month were 46.4% versus 34.7% and 26.6% versus 10.9%, 
respectively.  The overall response rate (ORR) was 11.2% (95% CI, 7.7-15.6) with nivolumab 
versus 0% (95% CI, 0.0-2.8) with placebo (p<0.0001). Grade ≥ 3 drug-related adverse events 
(AEs) occurred in 11.5 % of nivolumab and 5.5 % of placebo; 2.7% and 2.5%, respectively, 
discontinued of study treatment due to drug-related AEs (any grade).[21] 
4.2.1.4 Rationale for a Combined Anti-Angiogenesis and Immune Therapy Strategy 
There is significant interplay between angiogenesis and the immune system.  VEGF has been 
shown to exert multiple effects on the anti-tumor immune response including antigen 
presentation, effector mechanisms and immune cell trafficking.  Specifically, VEGF can 
impair dendritic cell maturation through both VEGFR-1 and 2.[22-24]  VEGF can also induce 
myeloid derived suppressor cell (MDSC) accumulation and regulatory T cell (Treg) 
proliferation in a VEGFR2 dependent manner.[25, 26]  In addition, the extravasation of 
effector immune cells into tumor sites is modulated by VEGF.   VEGF can down-regulate the 
expression of adhesion molecules, including ICAM 1 and VCAM-1, on tumor endothelial cells 
thereby limiting the leukocyte-endothelial interaction.[24]  As a result, in the presence of a 
pro-angiogenic environment, the tumor microenvironment lacks adequate effector T cell 
infiltration and is characterized by hypoxia and acidity, conditions known to foster 
immunosuppressive cells.  In turn, many of the induced immunosuppressive cells themselves 
promote angiogenesis.  Both myeloid derived suppressor cells as well as activated dendritic 
cells directly support tumor neo-angiogenesis.[27-29]  
Given the extensive cross talk between angiogenesis and immune surveillance, a combined 
and targeted approach is warranted for optimal outcomes.  Employing anti-angiogenic therapy 
provides several advantages beyond its own potential anti-tumor effects.   Because 
angiogenesis inhibitors do not deplete all Tregs, but only restore their proportion to physiologic 
levels, there is less likelihood of autoimmune mediated side effects.[26] In addition, targeting 
angiogenesis does not deplete activated T cells while it does inhibit immunosuppressive 
pathways such as MDSC’s and thereby may promote the ideal environment for an immune 
modulated anti-tumor response.[30]    
Proof of principle was demonstrated in a xenograft colon cancer model in which the 
simultaneous blockade of PD1 and VEGFR2 inhibited tumor growth synergistically, without 
any overt toxicities.[31]  It was noted that VEGFR2 blockade did not interfere with T cell 
infiltration and immunological activation induced by PD-1 blockade.  In this study, a 
monoclonal antibody to VEGFR2 was employed; however, it is hypothesized that a VEGFR2 
TKI with additional targets would be superior.  Sunitinib, a multi-targeted TKI with targets 
including VEGFR2, PDGFR and Flt3, demonstrated reversal of immune suppression and 
modulation of the tumor microenvironment in a colon xenograft model.[32]   There was a 
decrease in the number of MDSC’s and Tregs as well as an increase in CD8 and CD4 tumor 
infiltrating cells for sunitinib treated mice. There was also a decrease in expression of 
immunosuppressive cytokines such as IL-10 and TGF-β.  Promising activity for combined PD-
1 and VEGFR2 blockade has been seen in renal cell carcinoma.  In a phase I clinical trial 
combining nivolumab, an anti-PD-1 antibody with sunitinib or pazopanib in patients with 
metastatic renal cell carcinoma the ORR was 52% (17/33) in the sunitinib arm and 45% (9/20) 


 
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in the pazopanib arm.  Responses occurred by first assessment (6 weeks) in 41% (arm S) and 
56% (arm P) of responding patients and were durable (range: arm S: 12.1+ to 54 weeks; arm 
P: 12.1 to 69.1+ weeks).[33] 
 
 
4.2.1.5 Advantage of Lenvatinib in Gastroesophageal Cancer 
Similar to other anti-angiogenic agents found to have single agent activity in advanced 
gastroesophageal cancer, lenvatinib inhibits VEGFR2 with a high affinity and an IC 50 of 
4nM/L.  However, lenvatinib also targets additional tyrosine kinases including FGFR.   
Fibroblast growth factor (FGF) family members are among those linked to escape from the 
effects of inhibition of VEGF signaling.[34, 35]  Therefore, lenvatinib should theoretically 
provide superior anti-angiogenic activity than pure VEGF/VEFR2 inhibitors.  In mice models, 
lenvatinib was shown to inhibit both VEGF- and FGF- induced angiogenesis.[2]   Amongst an 
extended panel of 19 human tumor xenograft models, lenvatinib treatment resulted in 
significant tumor shrinkage with a ΔT/C of -55% in the AZ-521 gastric adenocarcinoma cell 
line.  The anti-tumor activity of lenvatinib in these xenografts was associated with high 
microvessel density (MVD) and low % of pericyte coverage.  Furthermore, when MVD and 
pericyte coverage were examined in 18 different types of human primary tumor specimens, 
stomach adenocarcinoma had one of the highest vascular scores and therefore would be 
predicted to be sensitive to treatment with lenvatinib.[2]  Additionally, alterations in FGFR2 
have been shown in up to 9% of gastric cancer patients and are correlated with poor 
outcome.[9, 36]  Lenvatinib may be especially beneficial in this subset.  Finally, it is interesting 
to note that both VEGFA and FGFR2 alterations are enriched in the chromosomal instability 
(CIN) and genomically stable (GS) molecular subsets defined by the TCGA.[9]   More than 
two thirds of gastric cancers can be classified within these two subtypes which, unlike MSI 
and EBV subtypes, are not typically thought to be “immunogenic” tumors.  Using lenvatinib 
to simultaneously target VEGF and FGF in these common subtypes is hypothesized to improve 
their “immunogenicity” and response to PD-1 blockade.   
 
4.2.2 Rationale for Dose Selection  
4.2.2.1 Pembrolizmuab Fixed Dosing 
An open-label Phase I trial (Protocol 001) was conducted to evaluate the safety and clinical 
activity of single agent pembrolizumab.  The dose escalation portion of this trial evaluated 
three dose levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 weeks (Q2W) in 
subjects with advanced solid tumors.  All three dose levels were well tolerated and no dose-
limiting toxicities were observed.  This first in human study of pembrolizumab showed 
evidence of target engagement and objective evidence of tumor size reduction at all dose levels 
(1 mg/kg, 3 mg/kg and 10 mg/kg Q2W).  No MTD has been identified to date.  10.0 mg/kg 
Q2W, the highest dose tested in PN001, will be the dose and schedule utilized in Cohorts A, 
B, C and D of this protocol to test for initial tumor activity.  Recent data from other clinical 


 
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studies within the pembrolizumab program has shown that a lower dose of pembrolizumab and 
a less frequent schedule may be sufficient for target engagement and clinical activity. 
 
PK data analysis of pembrolizumab administered Q2W and Q3W showed slow systemic 
clearance, limited volume of distribution, and a long half-life (refer to IB).  Pharmacodynamic 
data (IL-2 release assay) suggested that peripheral target engagement is durable (>21 days).  
This early PK and pharmacodynamic data provides scientific rationale for testing a Q2W and 
Q3W dosing schedule.   
 
A population pharmacokinetic analysis has been performed using serum concentration time 
data from 476 patients. Within the resulting population PK model, clearance and volume 
parameters of pembrolizumab were found to be dependent on body weight. The relationship 
between clearance and body weight, with an allometric exponent of 0.59, is within the range 
observed for other antibodies and would support both body weight normalized dosing or a 
fixed dose across all body weights.  Pembrolizumab has been found to have a wide therapeutic 
range based on the melanoma indication.  The differences in exposure for a 200 mg fixed dose 
regimen relative to a 2 mg/kg Q3W body weight based regimen are anticipated to remain well 
within the established exposure margins of 0.5 – 5.0 for pembrolizumab in the melanoma 
indication. The exposure margins are based on the notion of similar efficacy and safety in 
melanoma at 10 mg/kg Q3W vs. the proposed dose regimen of 2 mg/kg Q3W (i.e. 5-fold higher 
dose and exposure). The population PK evaluation revealed that there was no significant 
impact of tumor burden on exposure. In addition, exposure was similar between the NSCLC 
and melanoma indications. Therefore, there are no anticipated changes in exposure between 
different indication settings. 
 
The rationale for further exploration of 2 mg/kg and comparable doses of pembrolizumab in 
solid tumors is based on: 1) similar efficacy and safety of pembrolizumab when dosed at either 
2 mg/kg or 10 mg/kg Q3W in melanoma patients, 2) the flat exposure-response relationships 
of pembrolizumab for both efficacy and safety in the dose ranges of 2 mg/kg Q3W to 10 mg/kg 
Q3W, 3) the lack of effect of tumor burden or indication on distribution behavior of 
pembrolizumab (as assessed by the population PK model) and 4) the assumption that the 
dynamics of pembrolizumab target engagement will not vary meaningfully with tumor type. 
The choice of the 200 mg Q3W as an appropriate dose for the switch to fixed dosing is based 
on simulations performed using the population PK model of pembrolizumab showing that the 
fixed dose of 200 mg every 3 weeks will provide exposures that 1) are optimally consistent 
with those obtained with the 2 mg/kg dose every 3 weeks, 2) will maintain individual patient 
exposures in the exposure range established in melanoma as associated with maximal efficacy 
response and 3) will maintain individual patients exposure in the exposure range established 
in melanoma that are well tolerated and safe.  
A fixed dose regimen will simplify the dosing regimen to be more convenient for physicians 
and to reduce potential for dosing errors.  A fixed dosing scheme will also reduce complexity 
in the logistical chain at treatment facilities and reduce wastage. 
4.2.2.2 Combined Pembrolizumab and Lenvatinib Dosing 


 
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An open label phase 1b/2 trial of lenvatinib plus pembrolizumab in subjects with selected solid 
tumors (NCT02501096) is currently ongoing.  The phase 1b portion was designed to determine 
and confirm the maximum tolerated dose (MTD) for lenvatinib in combination with 200 mg 
(intravenous [IV], every 3 weeks [Q3W]) pembrolizumab in participants with selected solid 
tumors including non-small cell lung cancer, renal cell carcinoma, endometrial cancer, 
urothelial cancer, squamous cell carcinoma of the head and neck, or melanoma. Based on the 
preliminary results from this study, the MTD for lenvatinib was determined to be 20mg PO 
daily.  In the first dosing cohort of lenvatinib 24mg po daily in combination with 
pembrolizumab 200mg IV q3w, 2 DLT’s occurred including 1 grade 3 fatigue and 1 grade 3 
arthralgia.  As a result, the dose was de-escalated to 20mg of daily lenvatinib.  At this dose 
level, no DLT’s have been observed in 10 patients (6 with renal cell carcinoma, 2 with 
endometrial carcinoma, 1 with NSCLC and 1 with melanoma).  Seven of the ten patients have 
not experienced any significant adverse events, have not required any dose reductions, and 
remain on study (range 4-19 weeks).  Three patients did experience adverse events including 
one patient with grade 3 liver function abnormality at week 7 who came off study for 
progression of disease at week 9, one with grade 3 rhabdomyolysis at week 5 which resolved 
with holding treatment and patient currently continues on dose reduced treatment at week 9, 
and one patient with grade 3 hypertension at week 4.  The study has now proceeded to the 
phase 2 expansion portion to evaluate the safety and efficacy of the combination in 6 cohorts 
with lenvatinib 20mg PO daily and pembrolizumab 200mg IV q3w. 
 
4.2.3 Rationale for Study Endpoints 
4.2.3.1 Efficacy Endpoints 
Primary and Secondary Efficacy Assessments 
Objective response as assessed by RECIST v1.1 are standard measures of clinical activity. 
Overall survival is considered the “gold standard” for quantifying clinical benefit, with PFS 
being an acceptable surrogate. 
Safety 
Standard safety parameters (AEs, SAEs, laboratory evaluations, vital signs,  and physical 
examinations) will be employed to assess the safety profile of lenvatinib in combination with 
pembrolizumab. 
4.2.3.2 Biomarker Research 
Candidate biomarkers for subject selection will be assessed to determine whether these 
markers predict which subjects are most likely to respond to treatment with lenvatinib in 
combination with pembrolizumab. 
Tumors can express PD-L1 as a mechanism of adaptive resistance to an activated immune 
response within the tumor microenvironment. PD-L1 protein level in tumor sections, assessed 
by IHC, has been shown to correlate with response to pembrolizumab in multiple tumor types 
including gastroesophageal cancer.[37] Archival pre-treatment biopsies will be collected from 


 
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all subjects and analyzed by IHC to evaluate whether the expression of PD-L1 may be a 
predictive marker for response to treatment with lenvatinib in combination with 
pembrolizumab. 
Previous studies have demonstrated that certain gene expression profiles correlate with clinical 
benefit and represent reproducible and sensitive tools that define common features of the 
immune microenvironment associated with response to pembrolizumab across multiple tumor 
types.[18, 37] Commercially available nanostring technology will be used to look at a 770 gene 
panel which combines markers for 24 different immune cell types and populations, 30 common 
cancer antigens and genes that represent all categories of immune response including key 
checkpoint blockade genes. The 18 gene T-cell inflamed GEP (weighted sum of the normalized 
values for the genes) previously shown to be predictive of response to pembrolizumab will be 
determined.[37]  The 6 gene IFN-γ signature will also be analyzed and correlated with clinical 
outcome.  In addition, the genomic profile of the tissue will be analyzed to determine if there 
are alternations in various genes which may predict response, with special attention to the 
FGFR pathway. 
The general status of the immune system may also affect responsiveness to combination 
treatment with lenvatinib and pembrolizumab.  As a result, changes induced by lenvatinib in 
terms of immune cell phenotype, immune pathway activity, and profile of the immune response 
is planned to see if there is sensitization occurring to PD-1 inhibition.  Blood will be collected 
for correlative biomarker analysis on study day 1 prior to initiation of lenvatinib.  Repeat blood 
draws will be done on day 8, prior to pembrolizumab administration and on C2D1 prior to 
pembrolizumab administration.  The numbers of total T cells, CD4T cells, CD8 T cells, B cells, 
and NK cells per mL of peripheral blood, the relative populations of these lymphocyte subsets, 
and the relative frequency of proliferating, naïve, effector, and memory T cells, will be 
evaluated by flow cytometry. Serum marker levels will be summarized descriptively and 
graphically for the patient population. The time course of expression levels will also be 
summarized graphically by patient. 
 
4.2.4 Research Risks and Benefits 
4.2.4.1 Other Risks of Study Participation 
Additional risks to study participation include breach of confidentiality and risks associated 
with blood draw.  This risk includes weakness, redness, pain, bruising, bleeding or infection 
at the needle site. Privacy protection procedures are in place and good clinical practice 
guidelines are followed for the study to minimize risks associated with research procedures 
and participation. 
 
4.2.4.2 Potential benefits 
The potential benefits to subjects with study participation are improved overall survival.  The 
information obtained from this research may help others with this disease in the future. 
 


 
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5.0 METHODOLOGY 
5.1 
Entry Criteria 
5.1.1 Diagnosis and Conditions for Entry into the Trial 
Patients with advanced gastric and gastroesophageal junction(GEJ) adenocarcinomas who 
have progressed on one or more line(s) of therapy, but not more than 3 lines.  
5.1.2 Subject Inclusion Criteria 
In order to be eligible for participation in this trial, the subject must: 
1. Be willing and able to provide written informed consent/assent for the trial. 
2. Be ≥ 18 years of age on day of signing informed consent. 
3. Have histologically or cytologically confirmed metastatic or recurrent gastric or GEJ 
adenocarcinoma. 
4. Have measurable disease based on RECIST 1.1.   
5. Must have received and have progressed, or are intolerant to at least one systemic 
regimen (platinum- or fluoropyrimidine-based chemotherapy regimen for metastatic or 
recurrent disease or progressed within 6 month of completion of adjuvant therapy with 
a platinum- or fluoropyrimidine-based regimen). 
6. If Her2 positive, must have received and have progressed or are intolerant to treatment 
with trastuzumab for metastatic or recurrent disease. 
7. Subjects must consent to provide archival tumor tissue (initial and subsequent tumor 
biopsy samples, if possible) for correlative biomarker studies.    
8. Have a performance status of 0 or 1 on the ECOG Performance Scale. 
9. Adequately controlled blood pressure with or without antihypertensive medications 
defined as BP < 140/90 mmHg at screening and no change in antihypertensive 
mediation within 1 week prior to the Screening Visit. 
10. Demonstrate adequate organ function as defined in Table 5, all screening labs should 
be performed within 10 days of treatment initiation.   
Table 5:  Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
Hematological 
 
Absolute neutrophil count (ANC) 
≥1,500 /mcL 
Platelets 
≥100,000 / mcL 


 
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Hemoglobin 
≥9 g/dL or ≥5.6 mmol/L without transfusion or EPO 
dependency (within 7 days of assessment) 
Renal 
 
Serum creatinine OR 
Measured or calculateda creatinine 
clearance 
(GFR can also be used in place of 
creatinine or CrCl) 
≤1.5 X upper limit of normal (ULN) OR 
 
≥60 mL/min for subject with creatinine levels > 1.5 X 
institutional ULN 
Hepatic 
 
Serum total bilirubin 
≤ 1.5 X ULN OR 
 
Direct bilirubin ≤ ULN for subjects with total bilirubin 
levels > 1.5 ULN 
AST (SGOT) and ALT (SGPT) 
≤ 3 X ULN  
Coagulation 
International Normalized Ratio 
(INR) or Prothrombin Time (PT) 
 
Activated Partial Thromboplastin 
Time (aPTT) 
≤1.5 X ULN unless subject is receiving anticoagulant 
therapy 
as long as PT or PTT is within therapeutic range of 
intended use of anticoagulants 
≤1.5 X ULN unless subject is receiving anticoagulant 
therapy 
as long as PT or PTT is within therapeutic range of 
intended use of anticoagulants 
aCreatinine clearance should be calculated per institutional standard. 
 
11. Female subject of childbearing potential should have a negative urine or serum 
pregnancy within 72 hours prior to receiving the first dose of study medication.  If the 
urine test is positive or cannot be confirmed as negative, a serum pregnancy test will 
be required.   
12. Female subjects of childbearing potential (Section 5.5.2) must be willing to use an 
adequate method of contraception as outlined in Section 5.5.2 – Contraception,  for the 
course of the study through 120 days after the last dose of study medication. 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for 
the subject. 
13. Male subjects of childbearing potential (Section 5.5.2) must agree to use an adequate 
method of contraception as outlined in Section 5.5.2 - Contraception, starting with the 
first dose of study therapy through 120 days after the last dose of study therapy. 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for 
the subject. 
5.1.3 Subject Exclusion Criteria 
The subject must be excluded from participating in the trial if the subject: 


 
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1. Is currently participating and receiving study therapy or has participated in a study of 
an investigational agent and received study therapy or used an investigational device 
within 4 weeks of the first dose of treatment. 
2. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy (in 
dosing exceeding 10mg daily of prednisone equivalent) or any other form of 
immunosuppressive therapy within 7 days prior to the first dose of trial treatment.  
3. Has a known history of active TB   (Bacillus Tuberculosis) 
 
4. Hypersensitivity to pembrolizumab or lenvatinib or any of its excipients. 
5. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study 
Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due 
to agents administered more than 4 weeks earlier. 
6. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy 
within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at 
baseline) from adverse events due to a previously administered agent. 
- 
Note:  Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and 
may qualify for the study. 
- 
Note:  If subject received major surgery, a minimum of four weeks must have 
passed and they must have recovered adequately from the toxicity and/or 
complications from the intervention prior to starting therapy.   
7. Has a known additional malignancy that is progressing or requires active treatment.  
Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the 
skin that has undergone potentially curative therapy or in situ cervical cancer. 
8. Subjects having >1+ proteinuria on urine dipstick testing will undergo 24h urine 
collection for quantitative assessment of proteinuria.  Subjects with urine protein 
>1g/24h will be ineligible. 
9. Gastrointestinal malabsorption or any other condition in the opinion of the investigator 
that might affect the absorption of lenvatinib. 
10. Prolongation of QTcF interval to >480ms 
11. Significant cardiovascular impairment: history of congestive heart failure greater than 
New York Heart Association (NYHA) Class II, unstable angina, myocardial infarction 
or stroke within 6 months of the first dose of study drug.   
12. Arrhythmias requiring Class Ia and III antiarrhythmics and/or grade >2 bradycardia. 
13. Bleeding disorders or active significant bleeding (i.e. hemoptysis, hematochezia, 
hematemesis) within 3 weeks. 


 
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14. Thrombotic disorders or use of anticoagulants, such as warfarin, requiring therapeutic 
international normalized ratio (INR) monitoring. (treatment with low molecular weight 
heparin (LMWH) or direct acting oral anti-coagulants is allowed.) 
15. History of prior gastrointestinal fistula and/or perforation. 
16. Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis.  Subjects with previously treated brain metastases may participate provided 
they are stable (without evidence of progression by imaging for at least four weeks 
prior to the first dose of trial treatment and any neurologic symptoms have returned to 
baseline), have no evidence of new or enlarging brain metastases, and are not using 
steroids for at least 7 days prior to trial treatment.  This exception does not include 
carcinomatous meningitis which is excluded regardless of clinical stability.   
17. 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 and is allowed.  
18. Has known history of, or any evidence of active, non-infectious pneumonitis. 
19. Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable 
angina pectoris. 
20. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the trial, interfere with the subject’s participation for 
the full duration of the trial, or is not in the best interest of the subject to participate, in 
the opinion of the treating investigator.   
21. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 
22. Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the trial, starting with the screening visit through 120 days after 
the last dose of trial treatment. 
23. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent. 
24. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 
25. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected). 
26. Has received a live vaccine within 30 days of planned start of study therapy. 


 
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Note:  Seasonal influenza vaccines for injection are generally inactivated flu vaccines 
and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live 
attenuated vaccines, and are not allowed. 
5.1.4 Inclusion of Women and Minorities 
Both men and women of all races and ethnic groups are eligible for this trial 
5.2 
Registration Procedures 
5.2.1 General Guidelines 
Each patient must sign and date an informed consent form before undergoing any study 
specific procedure unless a procedure is being performed as part of the patient’s standard of 
care. 
 
Enrollment in the study requires that all inclusion and exclusion criteria have been met.  
Enrolment occurs upon confirmation of registration from the NYULMC PCC Clinical Trials 
Office.  The following materials must be submitted to the Research Coordinator for 
registration: 
 
1.  Complete signed and dated informed consent form 
2. Complete signed and dated eligibility checklist 
3. All supporting documentation verifying each criterion has been met 
 
Registration will occur within 48 hours of research coordinator receipt of all of the above 
documents.  A written confirmation of enrollment including a unique study identification 
number assigned by the research coordinator will be distinguished to the study team upon 
registration. 
 
 
Once eligibility is verified, a unique patient study number will be issued within 24 hours of 
receiving all required registration material.  The patient will not be identified by name.  This 
is the point, at which, the patient is considered accrued on study. 
 
5.2.2 Multi-Site Surveillance 
As the lead investigator in a multi-site trial, the Principal Investigator is responsible for 
organizing and conducting monthly teleconferences with all participating sites. Each 
participating site will be responsible for submitting the results and recommendations from the 
DSMC’s quarterly reviews to their IRB of record at the time of continuing review.  
Additionally, the NYU Langone Health PCC Clinical Trial Office, Quality Assurance Unit 
will provide a remote extensive monitoring including real-time review of all eCRFs to ensure 


 
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completeness and compliance with the protocol (100% source documentation verification).  
Additionally, a first subject audit is to be completed within four weeks of enrollment. Decisions 
from the DSMB will be disseminated to other study sites during routine calls of the 
investigators at each site, which will occur monthly. 
5.2.3 Patient Registrations at Other Participating Institutions 
Enrollment at addition sites can begin once each site’s IRB has approved this 
protocol, a copy of each site’s IRB approval, Citi training certificates, Medical 
Licenses and signed CVs are provided to NYU Langone Health Perlmutter Cancer 
Center (PCC) Clinical Trials Office. Once, all required documents are provided to 
NYU Clinical Trials Office a n d  a n  S I V  i s  c o n d u c t e d ,  an activation 
notification will be sent to the PI and research coordinator of that site. Central 
registration for this study will take place at NYU Langone Health PCC Quality 
Assurance Unit (PCC-QAU@nyulangone.org). 
 
Each patient must sign and date an informed consent form before undergoing any 
study specific procedures unless a procedure is being performed as part of the 
patient’s standard of care. Once a patient has signed consent, each site must notify 
the NYU Langone Health PCC Quality Assurance Unit and forward a copy of the 
signed consent to NYU Langone Health PCC Clinical Trials Office within 24 hours. 
 
Enrollment in the study requires that all inclusion and exclusion criteria have been 
met. Enrollment occurs upon confirmation of registration from the NYU Langone 
Health PCC Clinical Trials Office. The following materials must be submitted to the 
Quality Assurance Unit at NYU Langone Health via email (PCC-
QAU@nyulangone.org): 
 
1. Complete signed and dated informed consent form 
2. Complete signed and dated informed consent checklist 
3. Complete signed and dated eligibility checklist 
4. All supporting documentation verifying each criterion has been met. 
 
Registration will occur once the Senior Research Nurse for Quality Assurance 
conducts a central review of the submitted materials. Once eligibility is verified, a 
unique subject study number will be issued within 48 hours of receiving all required 
registration material. This number is unique to the participant and must be written on 
all data and correspondence for the participant. The NYU Langone Health PCC CTO 
will return a signed eligibility confirmation worksheet email with the subject’s unique 
study number. 
 
The subject will not be identified by name. This is the point, at which, the patient is 
considered accrued on study. Protocol treatment should begin within the designated 
timeframe; issues that would cause treatment delays should be discussed with the 
overall PI, Dr. Oberstein. Subjects must not start any protocol procedures prior to 


 
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registration; each participating institution will order the study agent directly from the 
supplier.  
 
Each site is responsible for reporting all unexpected problems involving risks to 
participants or others to NYU Langone PCC Clinical Trials Office and to their IRB as 
per site institutional policy. 
 
Please email all SAEs to NYUPCCsafetyreports@nyulangone.org, assigned medical 
monitor, and Dr. Paul Oberstein. 
 
5.2.4 Process of Consent 
Consent will be obtained by a participating investigator, or allied health professional/research 
coordinator/research nurse, all of whom have completed requisite training for human subject 
research and have been instructed by the Principal Investigator about the research study and 
consent process.  Investigators will review the informed consent form with patients and address 
any questions or concerns prior to obtaining written informed consent for participation and 
HIPAA authorization. 
Patients who are evaluated and/or treated by physicians in the oncology program will be given 
a consent form (attached) describing participation in the study.  Patients will be given adequate 
time to read the consent form.  After patients have been evaluated by their physician, they will 
be given time to ask questions about the study in private exam rooms.  Questions will be 
answered by a participating physician, physician’s assistant, nurse, or research coordinator, all 
of whom have completed requisite training for human subject research.  Investigators will 
review the informed consent form with patients and address any questions or concerns prior to 
obtaining written informed consent for participation.  Investigators will stress that participation 
in the study is completely voluntary and will not affect the care patients receive or result in any 
loss of benefits to which patients are otherwise entitled. 
For non-English speaking patients, institutional translation services will be utilized.  All 
procedures for consenting non-English speaking patients will be in accordance with NYULMC 
PCC CTO guidelines and policy. 
For patients who cannot read.  A witness, not related to the research study will be present.  The 
consent will be read to the patient.  The patient will also be allowed to ask any questions s/he 
may have.  The investigator will ask the patient questions to ensure s/he understands the study.  
If the investigator determines the subject understands the study, the patient will mark an X 
where his/her name would go and the witness will sign the consent form. 
 


 
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5.2.5 Documentation of Consent 
The Principal Investigator will be responsible for documentation in the medical record that 
consent has been obtained from all participants.  A signed copy of the consent form will be 
given to each participant.  Original consent forms will be stored in the subject’s medical chart. 
 
 
 
 
5.3 
Trial Treatments 
The treatment to be used in this trial is outlined below in Table 6 
Table 6:  Trial Treatment 
Drug 
Dose/Potency 
Dose 
Frequency 
Route of 
Administration 
Regimen/Treatment 
Period 
Use 
Lenvatinib 
20mg 
QD 
PO 
Lead in as single 
agent day 1-7, then to 
continue daily on Q3 
week schedule 
Experimental 
Pembrolizumab 200 mg 
Q3W 
IV infusion 
Day 1 of each 3 week 
cycle, starting 
following 7 day lead 
in with lenvatiinb 
(Day 8 of study) 
Experimental 
 
Trial treatment should begin on the day of randomization or as close as possible to the date on 
which treatment is allocated/assigned. 
5.3.1 
Dose Selection and Modification 
5.3.1.1  Dose Selection 
Dose and schedule are based on phase I results from ongoing study “Phase 1b/2 Trial of 
Lenvatinib Plus Pembrolizumab in Subjects With Selected Solid Tumors” NCT02501096.  
Subjects with non-small cell lung cancer, renal cell carcinoma, endometrial cancer, urothelial 
cancer, squamous cell carcinoma of the head and neck, or melanoma were treated with 
pembrolizumab 200mg IV every three weeks with escalating doses of lenvatinib in order to 
determine the maximum tolerated dose.  The MTD was determined to be 20mg of lenvatinib 
daily in combination with pembrolizumab.    


 
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5.3.1.2 
Dose Modification (Escalation/Titration/Other) 
If one therapeutic agent is either held or permanently discontinued secondary to toxicity, 
then therapy with the other study agent should continue and the subject should remain on-
study with full adherence to all protocol-related requirements.  
 
5.3.1.3   Dose Interruptions and Modifications for Pembrolizumab 
Adverse events (both non-serious and serious) associated with pembrolizumab exposure may 
represent an immunologic etiology.  These adverse events may occur shortly after the first dose 
or several months after the last dose of treatment. Pembrolizumab must be withheld for drug-
related toxicities and severe or life-threatening AEs as per 3 below. See Section 5.5.1 for 
supportive care guidelines, including use of corticosteroids. 
Table 7: Dose Modification Guidelines for Pembrolizumab Adverse Events (AEs) 
Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting Treatment 
Treatment Discontinuation 
Diarrhea/Colitis 
2-3 
 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks 
4 
Permanently discontinue 
Permanently discontinue 
AST, ALT, or 
Increased Bilirubin 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose 
3-4 
Permanently discontinue 
(see exception below)a 
Permanently discontinue 
Type 1 diabetes 
mellitus (if new 
onset) or 
Hyperglycemia 
T1DM or  
3-4 
Hold pembrolizumab for new onset Type 
1 diabetes mellitus or Grade 3-4 
hyperglycemia associated with evidence of 
beta cell failure 
Resume pembrolizumab when patients are clinically and 
metabolically stable 
Hypophysitis 
2-4 
Toxicity resolves to Grade 0-1. Therapy 
with pembrolizumab can be continued 
while endocrine replacement therapy is 
instituted 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks 
Hyperthyroidism  
3 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks 
4 
Permanently discontinue 
Permanently discontinue 
Hypothyroidism 
 
Therapy with pembrolizumab can be 
continued while thyroid replacement 
therapy is instituted 
Therapy with pembrolizumab can be continued while thyroid 
replacement therapy is instituted 
 
Infusion Reaction 
2b 
Toxicity resolves to Grade 0-1  
Permanently discontinue if toxicity develops despite adequate 
premedication  
3-4 
Permanently discontinue 
Permanently discontinue 
Pneumonitis 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks 
Or 
2nd episode  
3-4 
Permanently discontinue 
Permanently discontinue 
Renal Failure or 
Nephritis 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks 
3-4 
Permanently discontinue 
Permanently discontinue 


 
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Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting Treatment 
Treatment Discontinuation 
All Other Drug-
Related Toxicityc 
3 or Severe 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks 
4 
Permanently discontinue 
Permanently discontinue 
Note: Permanently discontinue for any severe or Grade 3 drug-related AE that recurs or any life-threatening event. 
a For patients with liver metastasis who begin treatment with Grade 2 AST or ALT, if AST or ALT increases by greater than or equal to 50% relative to baseline 
and lasts for at least 1 week then patients should be discontinued. 
b If symptoms resolve within one hour of stopping drug infusion, the infusion may be restarted at 50% of the original infusion rate   (e.g., from 100 mL/hr to 50 
mL/hr).  Otherwise dosing will be held until symptoms resolve and the subject should be premedicated for the next scheduled dose. 
c Patients with intolerable or persistent Grade 2 drug-related AE may hold study medication at physician discretion.  Permanently discontinue study drug for 
persistent Grade 2 adverse reactions for which treatment with study drug has been held, that do not recover to Grade 0-1 within 12 weeks of the last dose. 
 
Dosing interruptions are permitted in the case of medical / surgical events or logistical reasons 
not related to study therapy (e.g., elective surgery, unrelated medical events, subject vacation, 
and/or holidays). Subjects should be placed back on study therapy within 3 weeks of the 
scheduled interruption, unless otherwise discussed with the Sponsor (NYU Langone Medical 
Center). The reason for interruption should be documented in the subject's study record. 
 
5.3.1.4  
Dose Interruptions and Modifications for Lenvatinib 
5.3.1.4.1 Management of Hypertension 
Hypertension is a recognized side-effect of treatment with drugs inhibiting VEGF signaling. 
Investigators should therefore ensure that subjects enrolled to receive treatment with lenvatinib 
have BP < 140/90 mmHg at the time of study entry and, if known to be hypertensive, are on 
antihypertensive therapy before they start treatment with lenvatinib. The early detection and 
effective management of hypertension are important to minimize the need for lenvatinib dose 
interruptions and reductions. Antihypertensive agents should be started as soon as the BP is 
confirmed to be > 140/90 mmHg on 2 assessments 1 hour apart.  The choice of antihypertensive 
treatment should be individualized to the subject's clinical circumstances and follow standard 
medical practice. For previously normotensive subjects, monotherapy with one of the classes 
of antihypertensives should be started when BP > 140/90 mmHg is first observed on 2 
assessments 1 hour apart. For those subjects already on antihypertensive medication, the dose 
of the current agent may be increased, if appropriate, or one or more agents of a different class 
of antihypertensive should be added. For subjects with hypertension and proteinuria, treatment 
with an angiotensin-converting enzyme inhibitor or angiotensin-II receptor antagonist is 
preferred. 
 
Lenvatinib should be withheld in any instances where a subject is at imminent risk to 
develop a hypertensive crisis or has significant risk factors for severe complications of 
uncontrolled hypertension (e.g., BP > 160/100 mmHg, significant risk factors for cardiac 
disease, intracerebral hemorrhage, or other significant co-morbidities). Once the blood 
pressure is controlled, lenvatinib should be resumed as described below. 
 


 
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The following guidelines should be followed for the management of systolic BP > 160 mmHg 
or diastolic BP > 100 mmHg confirmed on repeat measurements after an hour:  
 
• Continue study drug and institute antihypertensive therapy for subjects not already 
receiving this. 
• For those subjects already on antihypertensive medication, the dose of the current agent 
may be increased, if appropriate, or one or more agents of a different class of 
antihypertensive should be added. 
• If systolic BP > 160 mmHg or diastolic BP > 100 mmHg persists despite maximal 
antihypertensive therapy, then lenvatinib administration should be interrupted and 
restarted at a dose of 14 mg once daily when BP < 150/95 mmHg. 
• If systolic BP > 160 mmHg or diastolic BP > 100 mmHg recurs on the 14 mg once 
daily dose despite optimal management of hypertension with antihypertensive 
medications (either by dose increase or the addition of a different class of 
antihypertensive), then lenvatinib administration should be interrupted and restarted 
at a dose of 10 mg once daily when BP < 150/95 mmHg. 
• If systolic BP >160 mmHg or diastolic BP > 100 mmHg recurs on the 10mg once 
daily dose despite optimal management of hypertension with antihypertensive 
medications (either by dose increase or the addition of a different class of 
antihypertensive), then study drug administration should be interrupted and additional 
dose reduction should be discussed with the sponsor. 
 
The following guidelines should be followed for the management of Grade 4 hypertension (life 
threatening consequences): 
• Institute appropriate medical management. 
• Discontinue lenvatinib 
 
 
5.3.1.4.2 Management of Proteinuria 
Regular assessment for proteinuria should be conducted as detailed in the Study Flow Chart 
(Section 6.0).  Guidelines for assessment and management of proteinuria are summarized as 
follows: 
 
• If proteinuria > 2+ is detected on urine dipstick testing, study drug will be continued 
and a 24-hour urine collection for total protein will be obtained as soon as possible 
within 72 hours to verify the grade of proteinuria. Grading according to the National 
Cancer Institute's (NCI) Common Terminology Criteria for Adverse Events (CTCAE 
v4.03) will be based on the 24 hour urinary protein result. Management of lenvatinib 
administration will be based on the grade of proteinuria according to the Dose 
Reduction and Interruption Instructions provided in Table 8. 
 
 
 
 
 


 
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Table 8: Dose Modification Guidelines for Lenvatinib-Related Adverse Events 
Treatment-Related Toxicitya,b 
During therapy 
Adjusted Dose 
      Grade 1 
 
                       Continue treatment 
 
       Intolerable Grade 2c 
First occurrence 
Interrupt until resolved to Grade   0-1 or baseline 
No change 
Second occurrence (same toxicity or new 
toxicity) 
Interrupt until resolved to Grade   0-1 or baseline 
14 mg orally once a day 
Third occurrence(same toxicity or new toxicity) 
Interrupt until resolved to Grade   0-1 or baseline 
10 mg orally once a day 
 
                                 Grade 3 
 
First occurrence 
Interrupt until resolved to Grade   0-1 or baseline 
14 mg orally once a day 
Second occurrence (same toxicity or new 
toxicity) 
Interrupt until resolved to Grade   0-1 or baseline 
10 mg orally once a day 
Third occurrence (same toxicity or new toxicity) 
Interrupt until resolved to Grade   0-1 or baseline 
8 mg orally once a day 
Fourth occurrence (same toxicity or new toxicity) 
Interrupt until resolved to Grade   0-1 or baseline 
Discuss with Sponsor 
        Grade 4d 
 
Discontinue Study Treatment 
 
a: A delay of study treatment for more than 28 days (due to treatment-related toxicities) will require a discussion with the sponsor 
before treatment can be resumed. 
b: Initiate optimal medical management for nausea, vomiting, and/or diarrhea prior to any study treatment interruption or dose 
reduction. 
c: Applicable to any grade 2 proteinuria and  to Grade 2 toxicities judged by the subject and physician to be intolerable. 
d: Excluding laboratory abnormalities judged to be non-life-threatening, in which case manage as Grade 3. 
 
5.3.2 Timing of Dose Administration 
Trial treatment should be administered on Day 1 of each cycle after all procedures/assessments 
have been completed as detailed on the Trial Flow Chart (Section 6.0).  Trial treatment may 
be administered up to 3 days before or after the scheduled Day 1 of each cycle due to 
administrative reasons. 
All trial treatments will be administered on an outpatient basis. 
Pembrolizumab 200 mg will be administered as a 30 minute IV infusion every 3 weeks.  Sites 
should make every effort to target infusion timing to be as close to 30 minutes as possible.  
However, given the variability of infusion pumps from site to site, a window of -5 minutes and 
+10 minutes is permitted (i.e., infusion time is 30 minutes: -5 min/+10 min). 
The Pharmacy Manual contains specific instructions for the preparation of the pembrolizumab 
infusion fluid and administration of infusion solution. 


 
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5.3.3 Trial Blinding/Masking 
This is an open-label trial; therefore, the Sponsor (NYU Langone Medical Center), investigator 
and subject will know the treatment administered. 
5.4 
Concomitant Medications and Vaccinations Allowed and Prohibited 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for one of these or other medications 
or vaccinations specifically prohibited during the trial, discontinuation from trial therapy or 
vaccination may be required.  The investigator should discuss any questions regarding this 
with the Merck Clinical team.  The final decision on any supportive therapy or vaccination 
rests with the investigator and/or the subject's primary physician.  
5.4.1 Acceptable Concomitant Medications 
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care.  All concomitant medication will be recorded on the case report form (CRF) 
including all prescription, over-the-counter (OTC), herbal supplements, and IV medications 
and fluids.  If changes occur during the trial period, documentation of drug dosage, frequency, 
route, and date may also be included on the CRF. 
All concomitant medications received within 28 days 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 serious 
adverse events (SAEs) and events of clinical interest (ECIs) as defined in Section 7.2. 
5.4.2 Prohibited Concomitant Medications 
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase (including retreatment for post-complete response relapse) of this trial: 
• Antineoplastic systemic chemotherapy or biological therapy  
• Immunotherapy not specified in this protocol 
• Chemotherapy not specified in this protocol 
• Investigational agents other than pembrolizumab and lenvatinib 
• Radiation therapy  
o Note:  Radiation therapy to a symptomatic solitary lesion or to the brain may 
be allowed at the investigator’s discretion.   
• Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial.  Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and 
typhoid vaccine.  


 
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• Systemic glucocorticoids for any purpose other than to modulate symptoms from an 
event of clinical interest of suspected immunologic etiology.  Replacement therapy 
(e.g., physiologic corticosteroid replacement therapy for adrenal or pituitary 
insufficiency, etc.) is not considered a form of systemic treatment and is allowed with 
dosing not to exceed 10mg daily of prednisone equivalent. 
Subjects who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial.  Subjects 
may receive other medications that the investigator deems to be medically necessary. 
The Exclusion Criteria describes other medications which are prohibited in this trial. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
5.5 
Rescue Medications and Supportive Care 
5.5.1 
Supportive Care Guidelines 
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Suggested supportive care measures for the management of adverse 
events with potential immunologic etiology are outlined below. Where appropriate, these 
guidelines include the use of oral or intravenous treatment with corticosteroids as well as 
additional anti-inflammatory agents if symptoms do not improve with administration of 
corticosteroids.   Note that several courses of steroid tapering may be necessary as symptoms 
may worsen when the steroid dose is decreased. For each disorder, attempts should be made to 
rule out other causes such as metastatic disease or bacterial or viral infection, which might 
require additional supportive care. The treatment guidelines below are intended to be applied 
when the investigator determines the events to be related to pembrolizumab.  
Note: if after the evaluation the event is determined not to be related, the investigator does not 
need to follow the treatment guidance (as outlined below). Refer to Section 5.3.1.3 for dose 
modification.  
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event.  
 
 
 
 
 
 
 


 
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Table 9: Dose Modification & Toxicity Management Guidelines for Immune Related AE’s 
Associated with Pembrolizumab 
 
 
 
 


 
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5.5.2 Management of Infusion Reactions 
Signs and symptoms usually develop during or shortly after drug infusion and generally resolve 
completely within 24 hours of completion of infusion.  
The table below shows treatment guidelines for subjects who experience an infusion reaction 
associated with administration of pembrolizumab. 
 


 
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Table 10: Infusion Reaction Treatment Guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
Grade 1 
Mild reaction; infusion interruption 
not indicated; intervention not 
indicated 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
None 
Grade 2 
Requires infusion interruption but 
responds promptly to symptomatic 
treatment (e.g., antihistamines, 
NSAIDS, narcotics, IV fluids); 
prophylactic medications indicated for 
< =24 hrs 
Stop Infusion and monitor symptoms. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
If symptoms resolve within one hour of stopping 
drug infusion, the infusion may be restarted at 
50% of the original infusion rate (e.g., from 100 
mL/hr to 50 mL/hr).  Otherwise dosing will be 
held until symptoms resolve and the subject 
should be premedicated for the next scheduled 
dose. 
Subjects who develop Grade 2 toxicity despite 
adequate premedication should be 
permanently discontinued from further trial 
treatment administration. 
Subject may be premedicated 1.5h 
(± 30 minutes) prior to infusion of 
pembrolizumab (MK-3475) with: 
 
Diphenhydramine 50 mg po (or 
equivalent dose of antihistamine). 
 
Acetaminophen 500-1000 mg po 
(or equivalent dose of antipyretic). 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly responsive 
to symptomatic medication and/or 
brief interruption of infusion); 
recurrence of symptoms following 
initial improvement; hospitalization 
indicated for other clinical sequelae 
(e.g., renal impairment, pulmonary 
infiltrates) 
Grade 4: 
Life-threatening; pressor or ventilatory 
support indicated 
Stop Infusion. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine 
 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
Hospitalization may be indicated. 
Subject is permanently discontinued from 
further trial treatment administration. 
No subsequent dosing 
Appropriate resuscitation equipment should be available in the room and a physician readily available during the period of drug 
administration. 
 
 
 
5.6 
Diet, Activity, and Other Considerations 
5.6.1 
Diet 
Subjects should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea or vomiting. 


 
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5.6.2 
Contraception 
Pembrolizumab and lenvatinib may have adverse effects on a fetus in utero.  Furthermore, it is 
not known if pembrolizumab and lenvatinib have transient adverse effects on the composition 
of sperm.   
For this trial, male subjects will be considered to be of non-reproductive potential if they have 
azoospermia (whether due to having had a vasectomy or due to an underlying medical 
condition).   
Female subjects will be considered of non-reproductive potential if they are either:  
(1) postmenopausal (defined as at least 12 months with no menses without an alternative 
medical cause; in women < 45 years of age a high follicle stimulating hormone (FSH) level 
in the postmenopausal range may be used to confirm a post-menopausal state in women 
not using hormonal contraception or hormonal replacement therapy. In the absence of 12 
months of amenorrhea, a single FSH measurement is insufficient.);  
OR  
(2) have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or bilateral 
tubal ligation/occlusion, at least 6 weeks prior to screening;  
OR  
(3) has a congenital or acquired condition that prevents childbearing. 
Female and male subjects of reproductive potential must agree to avoid becoming pregnant or 
impregnating a partner, respectively, while receiving study drug and for 120 days after the last 
dose of study drug by complying with one of the following:   
(1) practice abstinence† from heterosexual activity;  
OR  
(2) use (or have their partner use) acceptable contraception during heterosexual activity.   
 
Acceptable methods of contraception are‡: 
 Single method (one of the following is acceptable): 
• intrauterine device (IUD) 
• vasectomy of a female subject’s male partner  
• contraceptive rod implanted into the skin 
  


 
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Combination method (requires use of two of the following): 
• diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide) 
• cervical cap with spermicide (nulliparous women only)   
• contraceptive sponge (nulliparous women only)  
• male condom or female condom (cannot be used together) 
• hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or progestin-
only pill), contraceptive skin patch, vaginal contraceptive ring, or subcutaneous 
contraceptive injection 
 
 †Abstinence (relative to heterosexual activity) can be used as the sole method of contraception 
if it is consistently employed as the subject’s preferred and usual lifestyle and if considered 
acceptable by local regulatory agencies and ERCs/IRBs.  Periodic abstinence (e.g., calendar, 
ovulation, sympto-thermal, post-ovulation methods, etc.) and withdrawal are not acceptable 
methods of contraception.  
‡If a contraceptive method listed above is restricted by local regulations/guidelines, then it 
does not qualify as an acceptable method of contraception for subjects participating at sites in 
this country/region. 
 
Subjects should be informed that taking the study medication may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the study.  In order to participate in 
the study subjects of childbearing potential must adhere to the contraception requirement 
(described above) from the day of study medication initiation (or 14 days prior to the initiation 
of study medication for oral contraception) throughout the study period up to 120 days after 
the last dose of trial therapy.  If there is any question that a subject of childbearing potential 
will not reliably comply with the requirements for contraception, that subject should not be 
entered into the study. 
5.6.3 
Use in Pregnancy 
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab and/or 
lenvatinib, the subject will immediately be removed from the study.  The site will contact the 
subject at least monthly and document the subject’s status until the pregnancy has been 
completed or terminated.  The outcome of the pregnancy will be reported to the Sponsor and 
to Merck and Eisai without delay and within 24 hours to the Sponsor and within 2 working 
days to Merck and Eisai if the outcome is a serious adverse experience (e.g., death, abortion, 
congenital anomaly, or other disabling or life-threatening complication to the mother or 
newborn).   
 
 


 
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If a male subject impregnates his female partner, the study personnel at the site must be 
informed immediately and the pregnancy reported to the Sponsor and to Merck and Eisai 
followed as described above and in Section 5.6.3.  The study investigator will make every 
effort to obtain permission from the male subject’s female partner; to follow the outcome of 
the pregnancy and report the condition of the fetus or newborn to the Sponsor.    
5.6.4 
Use in Nursing Women 
It is unknown whether pembrolizumab or lenvatinib are excreted in human milk.  Since many 
drugs are excreted in human milk, and because of the potential for serious adverse reactions in 
the nursing infant, subjects who are breast-feeding are not eligible for enrollment. 
5.7 
Subject Withdrawal/Discontinuation Criteria 
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur.  In addition, a subject may be 
withdrawn by the investigator or the Sponsor if enrollment into the trial is inappropriate, the 
trial plan is violated, or for administrative and/or other safety reasons.  Specific details 
regarding discontinuation or withdrawal are provided in Section 7.1.4 – Other Procedures. 
A subject must be discontinued from the trial treatment for any of the following reasons: 
• The subject or legal representative (such as a parent or legal guardian) withdraws 
consent. 
• Confirmed radiographic disease progression 
Note: For unconfirmed radiographic disease progression, please see Section 7.1.2.5 
Note: A subject may be granted an exception to continue on treatment with 
confirmed radiographic progression if clinically stable or clinically improved, 
please see Section 7.1.5.3.5. 
• Unacceptable adverse experiences as described in Section 5.3 
• Intercurrent illness that prevents further administration of treatment 
• Investigator’s decision to withdraw the subject 
• The subject has a confirmed positive serum pregnancy test 
• Noncompliance with trial treatment or procedure requirements 
• The subject is lost to follow-up 
• Administrative reasons 


 
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The End of Treatment and Follow-up visit procedures are listed in Section 6.0 (Study Flow 
Chart) and Section 7.1.5 (Visit Requirements).  After the end of treatment, each subject will 
be followed for 30 days for adverse event monitoring (serious adverse events will be collected 
for 90 days after the end of treatment as described in Section 7.2).  Subjects who discontinue 
for reasons other than progressive disease will have post-treatment follow-up for disease status 
until disease progression, initiating a non-study cancer treatment, withdrawing consent or 
becoming lost to follow-up.  After documented disease progression each subject will be 
followed by telephone for overall survival until death, withdrawal of consent, or the end of the 
study, whichever occurs first. 
5.8 
Subject Replacement Strategy 
There are no replacement subjects allowed. 
5.9 
Clinical Criteria for Early Trial Termination 
Early trial termination will be the result of the criteria specified below: 
1. Quality or quantity of data recording is inaccurate or incomplete 
2. Poor adherence to protocol and regulatory requirements 
3. Incidence or severity of adverse drug reaction in this or other studies indicates a potential 
health hazard to subjects 
4. Plans to modify or discontinue the development of the study drug 
In the event of Merck and or Eisai decision to no longer supply study drug, ample notification 
will be provided so that appropriate adjustments to subject treatment can be made. 
 


Product:  Pembrolizumab/MK-3475 
 
Protocol/Amendment No.:  May 18, 2020 v.2.0 
 
 
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6.0 TABLE 11: STUDY FLOW CHART 
Trial Period: 
Screening 
Phase 
Treatment Cycles 
End of 
Treatmentm 
Post-Treatment 
Treatment Cycle/Title: 
 
Main Study 
Screening 
(Visit 1) 
Lead  in 
D1-7 
 
2  
3 
4 
To be repeated beyond 
8 cycles 
Study Treatment 
(Tx.) 
Discontinuation 
(Discon.)  
Safety 
Follow-up 
Follow-Up 
Visitsn 
Survival 
Follow-Upo 
1 
5 
6 
7 
8 
Scheduling Window (Days): 
-28 to -1 
 
 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
At time of  Tx. 
Discon. 
30 Days 
Post Tx. 
Discon. 
Every 6-8 
Weeks Post 
Tx. Discon. 
Every 12 
Weeks  
 
Administrative Procedures 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and Medical History 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Prior and Concomitant Medication Review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Lenvatinib 20 mg PO QDa 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Pembrolizumab 200 mg IV Q 3 Weeksb 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Post-study anticancer therapy status 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Survival Status 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Clinical Procedures/Assessments 
Review Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Review Pill Diary 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Physical Examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Vital Signsc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECOG Performance Status 
X 
Xd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Electrocardiogram 
Xp 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Laboratory Procedures/Assessments 
Urine Pregnancy Testq 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum β-HCG Pregnancy Teste‡ 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Coagulation Studies (PT/INR and aPTT) ‡ 
 X+ 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC with Differentialf 
 X+ 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Comprehensive Serum Chemistry Panelg 
 X+ 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 


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Trial Period: 
Screening 
Phase 
Treatment Cycles 
End of 
Treatmentm 
Post-Treatment 
Treatment Cycle/Title: 
 
Main Study 
Screening 
(Visit 1) 
Lead  in 
D1-7 
 
2  
3 
4 
To be repeated beyond 
8 cycles 
Study Treatment 
(Tx.) 
Discontinuation 
(Discon.)  
Safety 
Follow-up 
Follow-Up 
Visitsn 
Survival 
Follow-Upo 
1 
5 
6 
7 
8 
Scheduling Window (Days): 
-28 to -1 
 
 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
At time of  Tx. 
Discon. 
30 Days 
Post Tx. 
Discon. 
Every 6-8 
Weeks Post 
Tx. Discon. 
Every 12 
Weeks  
Urinalysish 
 X+ 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Thyroid Function Tests (T3, FT4 and TSH)i 
 X+ 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
 
 
Efficacy Measurements 
Tumor Imaging & Disease Assessmentj 
X 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
Tumor Biopsies/Archival Tissue Collection/Correlative Studies Blood 
Archival or Newly Obtained Tissue 
Collectionk 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Correlative Studies Blood Collectionl 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
aLenvatinib 20 mg will be administered as a single agent by mouth each day on Days 1-7 as a lead in dose.  Lenvatinib administration will continue daily on a Q3 week schedule in combination with 
pembrolizumab. 
bPembrolizumab 200 mg IV will be administered on Day 1 of Cycle 1 following the 7-day lead in with Lenvatinib, and on Day 1 of each subsequent 3-week cycle.  
CVital signs include temperature, pulse, respiratory rate, weight, and blood pressure.  Height will be measured at screening only. 
dECOG performance status must be maintained at 0-1 on day of treatment initiation. 
eA serum β-hCG pregnancy test is required for women of childbearing potential at screening only, within 14 days prior to first dose of treatment. 
+Screening laboratory studies to be conducted within 14 days prior to start of protocol therapy. 
‡Required at screening only. 
fCBC with Differential includes: Hemoglobin, Hematocrit, Platelet Count, White Blood Cell Count (Total & Differential), Red Blood Cell Count, Absolute Neutrophil Count, and Absolute Lymphocyte 
Count. 
gComplete Chemistry includes: Albumin, Alkaline Phosphatase, Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), CO2/Bicarbonate, Calcium, Chloride, Glucose, Phosphorus, 
Potassium, Sodium, Total Bilirubin, Direct Bilirubin (if Total Bilirubin is elevated or greater than the upper limit of normal (ULN)), Total Protein, and Blood Urea Nitrogen 
hUrinalysis includes: Blood, Glucose, Protein, Specific Gravity, and Microscopic Exam (if abnormal results are noted) 
iThyroid function test including thyroid stimulating hormone (TSH), triothhyronine (T3) (or free T3) and free thyroxine (FT4) to be done at screening, cycle 1day and then every other cycle, ie cycle 3, 
5, 7 etc. 
jTumor imaging is to include CT of the chest, abdomen, and pelvis.  The preferred method of assessment is CT with contrast.  If this is contraindicated, CT without contrast is preferred over MRI.  The 
same method of imaging is preferred for all subsequent tumor assessments.  Scans and x-rays must be done <4 weeks prior to the start of therapy. Tumor assessments will be based on RECIST v1.1, 


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and will be performed approximately every 6-9 weeks.  Timing of imaging will be based on the start of pembrolizumab on cycle 1, day 1.  First imaging assessment will be done at 6 weeks, prior to 
cycle 3, day1.  Next assessment will be done six weeks thereafter, prior to cycle 5, day1.  Subsequent imaging will be done every 3 cycles (9 weeks) thereafter, ie prior to cycle 8, 11, 14 etc.   
kArchived tumor specimens will be collected at study enrollment.  Receipt of specimens is not required prior to initiating study treatment.  
lBlood for correlative studies will be collected on Day 1 of lead in of lenvatinib and day 1 of Cycle 1 and on Day 1of Cycle 2. Blood will be collected before administration of study treatment.   
m.Subjects who attain a CR or complete 24 months of treatment with pembrolizumab may discontinue treatment with the option of restarting treatment.  Subjects who stop pembrolizumab with stable 
disease may continue treatment for up to 1 year if progression occurs after stopping study treatment, if the study remains open and the conditions in section 7.1.5.3.5 are met.   
n.Follow-Up: Subjects who discontinue study therapy for a reason other than disease progression will undergo radiologic assessment  every 9 weeks (63 ± 7 Days) to monitor disease status. Throughout 
the Follow-Up period, information regarding disease status, subsequent antineoplastic therapy, and survival status will be collected. 
oSurvival Follow-Up will occur via telephone call every 12 weeks until death, withdrawal of consent, or end-of-study, whichever occurs first. 
pAt Screening only, unless as clinically indicated 
qWithin 72 hours prior to C1D1 


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7.0 TRIAL PROCEDURES 
7.1 
Trial Procedures 
The Study 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 and/or Eisai for reasons related to subject safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations 
may require that additional informed consent be obtained from the subject.  In these cases, 
such evaluations/testing will be performed in accordance with those regulations. 
7.1.1 Administrative Procedures 
7.1.1.1 Informed Consent 
The Investigator must obtain documented consent from each potential subject prior to 
participating in a clinical trial. 
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature 
of the person conducting the consent discussion.  
A copy of the signed and dated consent form should be given to the subject before participation 
in the trial. 
The initial informed consent form, any subsequent revised written informed consent form and 
any written information provided to the subject must receive the IRB/ approval opinion in 
advance of use.  The subject or his/her legally acceptable representative should be informed in 
a timely manner if new information becomes available that may be relevant to the subject’s 
willingness to continue participation in the trial.  The communication of this information will 
be provided and documented via a revised consent form or addendum to the original consent 
form that captures the subject’s dated signature or by the subject’s legally acceptable 
representative’s dated signature. 
Specifics about a trial and the trial population will be added to the consent form template at 
the protocol level.   
The informed consent will adhere to IRB requirements, applicable laws and regulations and 
Sponsor requirements. 
 


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7.1.1.2 Inclusion/Exclusion Criteria 
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the trial.  
7.1.1.3 Medical History 
A medical history will be obtained by the investigator or qualified designee.  Medical history 
will include all active conditions, and any condition diagnosed within the prior 10 years that 
are considered to be clinically significant by the Investigator.  Details regarding the disease for 
which the subject has enrolled in this study will be recorded separately and not listed as medical 
history.   
7.1.1.4 Prior and Concomitant Medications Review 
7.1.1.4.1 Prior Medications 
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the subject 
within 28 days before starting the trial.  Treatment for the disease for which the subject has 
enrolled in this study will be recorded separately and not listed as a prior medication.  
7.1.1.4.2 Concomitant Medications 
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial.  All medications related to reportable SAEs and ECIs should be recorded as 
defined in Section 7.2. 
7.1.1.5 Disease Details and Treatments 
7.1.1.5.1 Disease Details 
The investigator or qualified designee will obtain prior and current details regarding disease 
status.  
7.1.1.5.2 Prior Treatment Details 
The investigator or qualified designee will review all prior cancer treatments including 
systemic treatments, radiation and surgeries. 
7.1.1.5.3 Subsequent Anti-Cancer Therapy Status 
The investigator or qualified designee will review all new anti-neoplastic therapy initiated after 
the last dose of trial treatment.  If a subject initiates a new anti-cancer therapy within 30 days 
after the last dose of trial treatment, the 30 day Safety Follow-up visit must occur before the 
first dose of the new therapy.  Once new anti-cancer therapy has been initiated the subject will 
move into survival follow-up.  


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7.1.2 Clinical Procedures and Assessments 
7.1.2.1 Adverse Event (AE) Monitoring 
The investigator or qualified designee will assess each subject to evaluate for potential new or 
worsening AEs as specified in the Trial Flow Chart and more frequently if clinically indicated.  
Adverse experiences will be graded and recorded throughout the study and during the follow-
up period according to NCI CTCAE Version 4.03 (see Section 11.2).  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 Physical Exam 
The investigator or qualified designee will perform a physical exam during the screening 
period and subsequent visits.  Clinically significant abnormal findings should be recorded as 
medical history.    
7.1.2.3 Vital Signs 
The investigator or qualified designee will take vital signs at screening, prior to the 
administration of each dose of trial treatment and at treatment discontinuation as specified in 
the Study Flow Chart (Section 6.0).  Vital signs should include temperature, pulse, respiratory 
rate, weight and blood pressure.  Height will be measured at screening only. 
7.1.2.4 Eastern Cooperative Oncology Group (ECOG) Performance Scale 
The investigator or qualified designee will assess ECOG status (see Section 11.1) at screening, 
prior to the administration of each dose of trial treatment and discontinuation of trial treatment 
as specified in the Trial Flow Chart.   
7.1.2.5 Tumor Imaging and Assessment of Disease 
Tumor assessments will be based on RECIST v1.1 and will be performed according to the 
schedule presented in Sections 6.0 and 7.0.  Tumor assessments should include the following 
evaluations: physical examination and CT of chest, abdomen, and pelvis.  The preferred 
method of disease assessment is CT with contrast. If CT with contrast is contraindicated, CT 
without contrast is preferred over MRI. The same method is preferred for all subsequent tumor 
assessments. 
 
Measurability of Tumor Lesions 
Tumor lesions will be categorized as follows: 
 
• Measurable Lesions - Must be accurately measured in at least one dimension (longest 
diameter in the plane of measurement is to be recorded) with a minimum size of: 


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◦ 10 mm by CT scan (irrespective of scanner type) and MRI (no less than double the 
   slice thickness and a minimum of 10 mm) 
◦ 10 mm caliper measurement by clinical exam (when superficial) 
◦ Malignant lymph nodes are considered pathologically enlarged and measurable, a 
   lymph node must be ≥ 15 mm in short axis when assessed by CT scan (CT scan 
   slice thickness recommended to be no greater than 5 mm) 
 
• Nonmeasurable Lesions - Nonmeasurable lesions are defined as all other lesions (or sites of 
disease), including small lesions (longest diameter < 10 mm or pathological lymph nodes with 
≥ 10 to < 15 mm in short axis). Lesions considered truly nonmeasurable include the following: 
leptomeningeal disease, ascites, pleural/pericardial effusion, and inflammatory breast disease, 
lymphangitic involvement of skin or lung, abdominal masses/abdominal organomegaly 
identified by physical exam that is not measurable by reproducible imaging techniques. 
 
• Target Lesions - All lesions up to a maximum of 5 lesions total (and a maximum of 2 lesions 
per organ) representative of all involved organs should be identified as target lesions. It may 
be the case that, on occasion, the largest lesion does not lend itself to reproducible measurement 
in which circumstance the next largest lesion which can be measured reproducibly should be 
selected. 
 
• Non-target Lesions - It is possible to record multiple non-target lesions involving the same 
organ as a single item on the case report form (e.g., “multiple enlarged pelvic lymph nodes” or 
“multiple liver metastases”). 
 
Evaluation of Target Lesions 
 
• Complete Response - Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to < 10 mm (the sum may 
not be “0” if there are target nodes). 
 
• Partial Response - At least a 30% decrease in the sum of the diameters of target lesions, 
taking as reference the baseline sum diameters. 
 
• Progressive Disease - At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate 
an absolute increase of at least 5 mm. (Note: The appearance of one or more 
new lesions may be considered progression.) 
 
• Stable Disease - Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum of diameters while on study. 
 
Evaluation of Non-target Lesions 


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• Complete Response - Disappearance of all non-target lesions and normalization of tumor 
marker level. All lymph nodes must be non-pathological in size (< 10 mm in short 
axis). 
 
• Non-complete Response/Non-progressive Disease - Persistence of 1 or more non-target 
lesion(s) and/or maintenance of tumor marker level above the normal limits. 
 
• Progressive Disease - Unequivocal progression of existing non-target lesions will be defined 
as the overall level of substantial worsening in non-target disease such that, even in presence 
of SD or PR in target disease, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy. In the absence of measurable disease, change in nonmeasurable 
disease comparable in magnitude to the increase that would be required to declare PD for 
measurable disease. Examples include an increase in a pleural effusion from “trace” to “large,” 
an increase in lymphangitic disease from localized to widespread. 
 
Appearance of New Lesions 
The appearance of new lesions is considered PD according to RECIST v1.1. Considering the 
unique response kinetics that have been observed with immunotherapy, new lesions may not 
represent true disease progression. In the absence of rapid clinical deterioration, subjects may 
continue to receive study treatment until confirmed PD. 
 
Evaluation of Overall Response 
Treatment of subjects may continue 
after the initial assessment of PD if the investigator determines the subject is clinically 
improving and is deriving benefit from treatment. In the absence of clinical deterioration, such 
modifications to the RECIST criteria may discourage the early discontinuation of 
pembrolizumab in combination with lenvatinib and provide a more complete evaluation of the 
combination activity than would be seen with conventional response criteria. 
 
Table 11: Estimation of Overall Response: RECIST v. 1.1 
 
Target Lesions  
Non-target Lesions  
New Lesions  
Overall Response 
Complete response 
Complete response 
No 
Complete response 
Complete response 
Not evaluable 
No 
Partial response 
Complete response 
Non-complete response/ 
Non-progressive disease 
No 
Partial response 
Partial response 
Non-progressive disease 
and not evaluable 
No 
Partial response 
Stable disease 
Non-progressive disease 
and not evaluable 
No 
Stable disease 
Progressive disease 
Any 
Yes or No 
Progressive disease 
Any 
Progressive disease 
Yes or No 
Progressive disease 
 


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7.1.2.6 Tumor Tissue Collection and Correlative Studies Blood Sampling 
Archived tumor specimens will be collected at study enrollment.  Receipt of specimens is 
not required prior to initiating on study treatment.   
A total of 15 unstained 5 micron slides cut from an FFPE tissue block will be collected.  The 
sections will be treated as follows: 
PDL-1 Immunohistochemistry (5 slides) 
Tumor tissue for biomarker analysis should be provided as five (5) unstained slides cut from 
an FFPE tissue block. Three (3) sectioned slides per sample are necessary for H&E, PD-L1, 
and isotype control staining. The 4th and 5th sections are for a repeat staining if needed.  
 
Please refer to MISP Sample handling manual for additional sampling handling and 
shipping instructions. 
Biomarker samples will be stored for at least 10 years, linking keys of the subject’s unique 
identification number to their PHI will be maintained by the principal investigator and stored 
on the NYULMC secure drive.  A subject can withdraw their samples at any time, by 
making a formal request to the principal investigator in writing. 
Multiplexed-gene expression profiling (5 slides) 
Research biopsies will be subjected to RNA extraction and analysis to assess expression of 
immune-related genes. The NanoString technology is a variation on the DNA microarray, 
and permits analysis of up to 800 transcripts in a single reaction. This platform has been 
validated for application to both RNA from frozen tissue and RNA extracted from FFPE 
samples. The nCounter®PanCancer Immune Profile Panel developed by NanoString, Inc. 
allows analysis of 770 genes for 24 different immune cell types and populations, 30 common 
cancer antigens and functional markers including checkpoint blockade genes 
(http://www.nanostring.com/).  
RNA will be isolated from 5 X 5um sections of formalin-fixed, paraffin embedded material. 
RNA will be extracted from tissue at the NYU Translational Research Laboratory using the 
RNeasy® kit (Qiagen). The resulting RNA will be quantified using a bioanalyzer and 250ng 
used for targeted gene expression analysis following manufacturer's protocols. The resulting 
data will be interrogated to establish whether a limited and defined gene-expression 
signature is predictive of clinical responses to therapy. The gene expression analysis will be 
performed at the NYU Genome Technology Center. We will plan to assess several immune 
signatures, including the immune signatures cited above, section 4.2.3.2. 
Tumor Genomic analysis (5 slides) 
Whole genome sequencing will be performed on tumor tissue.  Nucleic acid will be obtained 
from tumor cellular material from 5x5um sections of formalin-fixed, paraffin embedded 
material using standard operating procedures and then analyzed at the NYU Genome 


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Technology Center, led by Adriana Heguy, PhD.  Genomic alterations, with special 
attention to the FGFR and VEGFR pathways will be evaluated to determine if there are any 
associations with clinical outcome. 
Peripheral Blood Collection 
Blood will be collected for correlative biomarker analysis on study day 1 of the lead in 
phase, prior to initiation of lenvatinib.  Repeat blood draws will be done on Cycle 1, day 1, 
prior to pembrolizumab administration and on C2D1 prior to pembrolizumab 
administration. Three tall 10ml K2 EDTA tubes will be collected at each aforementioned 
time point. Peripheral blood specimens for correlative studies will be submitted to Dr. Debra 
Morrison, Director of the NYU Office of Collaborative Science (OCS) Immune Monitoring 
Core for processing.    
Peripheral blood mononuclear cells (PBMCs) will be isolated from whole blood to assess 
immune cell populations. Flow cytometry analysis will be done at the NYU Cytometry and 
Cell Sorting Laboratory.  Surface staining with a panel of antibodies (CD3, CD4, CD8, 
CD25, FoxP3, CD11c, CD83, CD86, CD56) and intracytoplasmatic cytokine staining, 
followed by flow cytometry will be performed in order to identify different T cell 
populations, their activation status, and the production of different cytokines as well as other 
immune cell populations. Serum marker levels will be summarized descriptively and 
graphically for the subject population.  
7.1.3 Laboratory Procedures/Assessments 
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below. 
Laboratory tests for hematology, chemistry, urinalysis, and others are specified in Table 12.   


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Table 12:  Laboratory Tests 
Hematology 
Chemistry 
Urinalysis 
Other 
Hematocrit 
Albumin 
Blood 
Serum β-human chorionic gonadotropin  (β-hCG)† ‡ 
Hemoglobin 
Alkaline phosphatase 
Glucose 
PT (INR) ‡ 
Platelet count 
Alanine aminotransferase (ALT) 
Protein 
aPTT‡ 
WBC (total and differential) 
Aspartate aminotransferase (AST) 
Specific gravity  
Total thriiodothyronine (T3) 
Red Blood Cell Count 
Carbon Dioxide  
Microscopic exam (If abnormal  Free thyroxine (T4) 
Absolute Neutrophil Count 
  (CO2 or bicarbonate) 
results are noted) 
Thyroid stimulating hormone (TSH) 
Absolute Lymphocyte Count 
Calcium 
 
Blood for correlative studies  
 
Chloride 
 
 
 
Glucose 
 
 
 
Phosphorus 
 
 
 
Potassium   
 
  
 
Sodium 
 
  
 
Total Bilirubin 
 
  
 
Direct Bilirubin (If total bilirubin is 
elevated above the upper limit of 
normal) 
 
  
 
Total protein 
 
  
 
Blood Urea Nitrogen 
 
  
† Perform on women of childbearing potential only. A serum pregnancy test will be required.   
‡ Screening only 
 
 
 


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Laboratory tests for screening should be performed within 14 days prior to the first dose of 
treatment.  After Cycle 1, pre-dose laboratory procedures can be conducted up to 72 hours 
prior to dosing.  Results must be reviewed by the investigator or qualified designee and found 
to be acceptable prior to each dose of trial treatment.  
7.1.4 Other Procedures 
7.1.4.1 Withdrawal/Discontinuation 
A subject has the right to voluntarily discontinue study treatment or withdraw from the study 
at any time, for any reason, and without repercussion.  The investigator and sponsor have the 
right to discontinue a subject from the study treatment or withdraw a subject from the study at 
any time. 
When a subject discontinues/withdraws prior to trial completion, all applicable activities 
scheduled for the final trial visit should be performed at the time of discontinuation.  Any 
adverse events which are present at the time of discontinuation/withdrawal should be followed 
in accordance with the safety requirements outlined in Section 7.2: Assessing and Recording 
Adverse Events.  Subjects who a) attain a CR or b) complete 24 months of treatment with 
pembrolizumab may discontinue treatment with the option of restarting treatment if they meet 
the criteria specified in Section 7.1.5.3.5.  After discontinuing treatment following assessment 
of CR, these subjects should return to the site for a Safety Follow-up Visit (described in Section 
7.1.5.3.2) and then proceed to the Follow-Up Period of the study (described in Section 
7.1.5.3.3). 
7.1.5 Visit Requirements 
Visit requirements are outlined in Section 6.0 - Study Flow Chart.   Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures. 
7.1.5.1 Screening 
The study flow chart (Section 6.0) shows all procedures to be conducted at the screening visit. 
Screening procedures are required for subjects at initial enrollment. 
The following will be performed during the screening period: 
• Informed Consent 
• Confirmation of Eligibility Criteria 
• Collection of Demographic Information and Medical History 
• Collection of Prior and Concomitant Medication Information 
• Collection of Adverse Event Information 
• Physical Examination 
• Vital Signs (including Height)  
• ECOG Performance Status 


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• Serum β-hCG Pregnancy Test for Women of Child-Bearing Potential 
• PT/INR and aPTT 
• Complete Blood Count (CBC) with Differential  
• Comprehensive Serum Chemistry Panel  
• Urinalysis 
• Thyroid Function Tests (T3, FT4, and TSH) 
• Tumor Imaging and Disease Assessment 
• Archival or Newly Obtained Tissue Collection 
 
7.1.5.2 Treatment Period 
Procedures to be conducted during the treatment period are presented in study flow chart 
(Section 6.0) for Cycles 1-8 and beyond. All samples are collected pre-dose unless otherwise 
indicated. 
The following will be performed during the treatment period: 
7.1.5.2.1 Lead in with Lenvatinib, Day 1-7 
• Collection of Demographic Information and Medical History 
• Collection of Prior and Concomitant Medication Information 
• Collection of Adverse Event Information 
• Physical Examination 
• Vital Signs 
• ECOG Performance Status 
• CBC with Differential  
• Comprehensive Serum Chemistry Panel  
• Blood Collection for Correlative Studies 
• Administration of Lenvatinib 20 mg, by mouth, daily (given alone on Days 1-7) 
 
7.1.5.2.2 Cycle 1 Day 1 
• Collection of Demographic Information and Medical History 
• Collection of Prior and Concomitant Medication Information 
• Collection of Adverse Event Information 
• Review Pill Diary 
• Physical Examination 
• Vital Signs 


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• ECOG Performance Status 
• CBC with Differential  
• Comprehensive Serum Chemistry Panel  
• Thyroid Function Tests (T3, FT4, and TSH) 
• Urinalysis 
• Blood Collection for Correlative Studies (prior to treatment) 
• Administration of Lenvatinib 20 mg, by mouth, daily, on a q 3 week schedule   
• Administration of Pembrolizumab 200 mg IV  
 
7.1.5.2.3 Cycle 2 Day 1 
• Collection of Demographic Information and Medical History 
• Collection of Prior and Concomitant Medication Information 
• Collection of Adverse Event Information 
• Review Pill Diary 
• Physical Examination 
• Vital Signs 
• ECOG Performance Status 
• CBC with Differential  
• Comprehensive Serum Chemistry Panel  
• Urinalysis 
• Blood Collection for Correlative Studies (prior to treatment) 
• Administration of Lenvatinib 20 mg, by mouth, daily, on a q 3 week schedule  
• Administration of Pembrolizumab 200 mg IV, on Day 1 of each 3 week cycle 
 
7.1.5.2.4 Day 1 of Each Subsequent Cycle 
• Collection of Demographic Information and Medical History 
• Collection of Prior and Concomitant Medication Information 
• Collection of Adverse Event Information 
• Review Pill Diary 
• Physical Examination  
• Vital Signs 
• ECOG Performance Status 
• CBC with Differential  
• Comprehensive Serum Chemistry Panel  


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• Thyroid Function Tests (T3, FT4, and TSH) (odd cycles) 
• Urinalysis 
• Tumor Imaging and Disease Assessment (prior to Cycle 3, Cycle 5, and every 3 cycles 
[9weeks] thereafter, ie cycle 8, 11, 14, etc.) 
• Administration of Lenvatinib 20 mg, by mouth, daily, on a q 3 week schedule  
• Administration of Pembrolizumab 200 mg IV, on Day 1 of each 3 week cycle 
 
7.1.5.3 Post-Treatment Visits 
The study flow chart (Section 6.0) shows all procedures to be conducted during the end of 
treatment visit and follow-up period. All subjects are to complete the end of treatment visit, all 
follow-up visits, and be contacted for survival status in accordance with the schedule of study 
procedures. However, if a subject discontinues study treatment and moves onto alternative 
anticancer treatment, follow-up visits will no longer be required; however, survival follow-up 
assessments would be required as indicated in the schedule of study procedures unless the 
subject withdraws consent for further survival follow-up. Survival follow-up will continue 
until the end of study as defined as 5 years after the final subject is enrolled, or the date the 
study is closed by the sponsor, whichever occurs first.  
 
7.1.5.3.1 End of Treatment Visit 
The following will be performed at the End-of-Treatment Visit: 
• Collection of Demographic Information and Medical History 
• Collection of Prior and Concomitant Medication Information 
• Collection of Adverse Event Information 
• Review of Pill Diary 
• Physical Examination  
• Vital Signs 
• ECOG Performance Status 
• CBC with Differential  
• Comprehensive Serum Chemistry Panel  
• Thyroid Function Tests (T3, FT4, and TSH) 
 
7.1.5.3.2  Safety Follow-Up Visit 
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the 
last dose of trial treatment or before the initiation of a new anti-cancer treatment, whichever 


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comes first.  All AEs that occur prior to the Safety Follow-Up Visit should be recorded.  
Subjects with an AE of Grade > 1 will be followed until the resolution of the AE to Grade 0-1 
or until the beginning of a new anti-neoplastic therapy, whichever occurs first.  SAEs that occur 
within 90 days of the end of treatment or before initiation of a new anti-cancer treatment should 
also be followed and recorded.  Subjects who are eligible for retreatment with pembrolizumab 
(as described in Section 7.1.5.3.5) may have up to two safety follow-up visits, one after the 
Treatment Period and one after the Second Course Phase. 
The following will be performed at the Safety Follow-Up Visit (30 days post study treatment 
discontinuation): 
• Collection of Demographic Information and Medical History 
• Collection of Prior and Concomitant Medication Information 
• Collection of Adverse Event Information 
• Physical Examination  
• Vital Signs 
• ECOG Performance Status 
• CBC with Differential  
• Comprehensive Serum Chemistry Panel  
• Thyroid Function Tests (T3, FT4, and TSH) 
 
7.1.5.3.3 Follow-up Visits 
Study subjects will receive up to 24 months of Pembrolizumab, and then will continue on 
Lenvatinib only.  Subjects will then be followed every 9 weeks (± 7 days) with radiologic 
imaging (CT scan or MRI).  If a subject experiences disease progression on single agent 
lenvatinib, then that subject will have the option to restart Pembrolizumab if all the other 
criteria are met (please see section 7.1.5.3.5 below entitled “Second Course Phase (Retreatment 
Period)” for more information). 
Every effort should be made to collect information regarding disease status until the start of 
new anti-neoplastic therapy, disease progression, death, end of the study or if the subject begins 
retreatment with pembrolizumab as detailed in Section 7.1.5.3.5.  Information regarding post-
study anti-neoplastic treatment will be collected if new treatment is initiated. 
Subjects who are eligible to receive retreatment with pembrolizumab according to the criteria 
in Section 7.1.5.3.5 will move from the follow-up phase to the Second Course Phase when they 
experience disease progression.  Details are provided in Section 6.0 – Trial Flow Chart for 
Retreatment.    
The following will be performed at Follow-Up Visits (every 6-8 weeks after study treatment 
discontinuation): 


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• Collection of Demographic Information and Medical History 
• Collection of Prior and Concomitant Medication Information 
• Collection of Adverse Event Information 
• Physical Examination  
• Vital Signs 
• ECOG Performance Status 
• CBC with Differential  
• Comprehensive Serum Chemistry Panel  
• Thyroid Function Tests (T3, FT4, and TSH) 
• Tumor Imaging and Disease Assessment 
• Collection of Post-Study Antineoplastic Therapy Information 
• Collection of Survival Status Information 
 
7.1.5.3.4 Survival Follow-up 
Once a subject experiences confirmed disease progression or starts a new anti-cancer therapy, 
the subject moves into the survival follow-up phase and should be contacted by telephone 
every 12 weeks to assess for survival status until death, withdrawal of consent, or the end of 
the study, whichever occurs first.  
The following will be performed during Survival Follow-Up telephone calls (every 12 weeks 
after confirmed disease progression or start of a new anti-cancer therapy until death, 
withdrawal of consent, or end of study, whichever occurs first): 
• Collection of Post-Study Antineoplastic Therapy Information 
• Collection of Survival Status Information 
 
7.1.5.3.5 Second Course Phase (Retreatment Period) 
 
Subjects who stop pembrolizumab with SD or better may be eligible for up to one year of 
additional pembrolizumab therapy if they progress after stopping study treatment.  This 
retreatment is termed the Second Course Phase of this study and is only available if the study 
remains open and the subject meets the following conditions: 
• Either  
o Stopped initial treatment with pembrolizumab after attaining an investigator-
determined confirmed CR according to RECIST 1.1, and 
 Was treated for at least 24 weeks with pembrolizumab before discontinuing 
therapy 


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 Received at least two treatments with pembrolizumab beyond the date when 
the initial CR was declared 
 
 
OR 
o Had SD, PR or CR and stopped pembrolizumab treatment after 24 months of study 
therapy for reasons other than disease progression or intolerability 
AND 
• Experienced an investigator-determined confirmed radiographic disease progression 
after stopping their initial treatment with pembrolizumab 
• Did not receive any other anti-cancer treatment besides lenvatinib since the last dose 
of pembrolizumab 
• Has a performance status of 0 or 1 on the ECOG Performance Scale 
• Demonstrates adequate organ function as detailed in Section 5.1.2 
• Female subject of childbearing potential should have a negative serum or urine 
pregnancy test within 72 hours prior to receiving retreatment with study medication.   
• Female subject of childbearing potential should be willing to use 2 methods of birth 
control or be surgically sterile, or abstain from heterosexual activity for the course of 
the study through 120 days after the last dose of study medication (Reference Section 
5.5.2).  Subjects of child bearing potential are those who have not been surgically 
sterilized or have been free from menses for > 1 year.  
• Male subject should agree to use an adequate method of contraception starting with the 
first dose of study therapy through 120 days after the last dose of study therapy.   
• Does not have a history or current evidence of any condition, therapy, or laboratory 
abnormality that might interfere with the subject’s participation for the full duration of 
the trial or is not in the best interest of the subject to participate, in the opinion of the 
treating investigator. 
Subjects who restart treatment will be retreated at the same dose and dose interval as when 
they last received pembrolizumab.  Treatment will be administered for up to one additional 
year. 
Visit requirements are outlined in Section 6.0 – Trial Flow Chart. 
 


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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 subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol-
specified procedure, whether or not considered related to the medicinal product or protocol-
specified procedure.  Any worsening (i.e., any clinically significant adverse change in 
frequency and/or intensity) of a preexisting condition that is temporally associated with the use 
of study drug(s), is also an adverse event. 
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  Examples 
of this may include, but are not limited to, teething, typical crying in infants and children and 
onset of menses or menopause occurring at a physiologically appropriate time. 
Adverse events may occur during the course of the use of investigational product(s) in clinical 
trials, or as prescribed in clinical practice, from overdose (whether accidental or intentional), 
from abuse and from withdrawal. 
Progression of the cancer under study is not considered an adverse event.  
All adverse events that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject 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. 
From the time of treatment allocation/randomization through 30 days following cessation of 
treatment, all adverse events must be reported by the investigator. Such events will be 
recorded at each examination on the Adverse Event case report forms/worksheets.  The 
reporting timeframe for adverse events meeting any serious criteria is described in section 7.2. 
The investigator will make every attempt to follow all subjects with non-serious adverse 
events for outcome. 
Adverse events will not be collected for subjects during the pre-screening period (for 
determination of archival tissue status) as long as that subject has not undergone any protocol-
specified procedure or intervention.  If the subject requires a blood draw, fresh tumor biopsy 
etc., the subject is first required to provide consent to the main study and AEs will be captured 
according to guidelines for standard AE reporting.  
Pembrolizumab Overdose: Definition of an Overdose for This Protocol and Reporting of 
Overdose to the Sponsor and to Merck. 
For purposes of this trial, an overdose of pembrolizumab will be defined as any dose of 1,000 
mg or greater (≥5 times the indicated dose).  No specific information is available on the 
treatment of overdose of pembrolizumab. Appropriate supportive treatment should be provided 


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if clinically indicated. In the event of overdose, the subject should be observed closely for signs 
of toxicity.  Appropriate supportive treatment should be provided if clinically indicated. 
If an adverse event(s) is associated with (“results from”) the overdose of a Merck product, the 
adverse event(s) is reported as a serious adverse event, even if no other seriousness criteria are 
met. 
If a dose of Merck’s product meeting the protocol definition of overdose is taken without any 
associated clinical symptoms or abnormal laboratory results, the overdose is reported as a non-
serious Event of Clinical Interest (ECI), using the terminology “accidental or intentional 
overdose without adverse effect.” 
All reports of overdose with and without an adverse event must be reported within 24 hours to 
the Sponsor and within 2 working days hours to Merck Global Safety. (Attn: Worldwide 
Product Safety; FAX 215 993-1220) 
At each contact with the subject, the investigator must seek information on adverse events by 
specific questioning and, as appropriate, by examination.  Information on all adverse events 
should be recorded immediately in the source document, and also in the appropriate adverse 
event module of the case report form (CRF).  All clearly related signs, symptoms, and abnormal 
diagnostic procedures results should recorded in the source document, though should be 
grouped under one diagnosis. 
All adverse events occurring during the study period must be recorded.  The clinical course of 
each event should be followed until resolution, stabilization, or until it has been determined 
that the study treatment or participation is not the cause.  Serious adverse events that are still 
ongoing at the end of the study period must be followed up to determine the final outcome.  
Any serious adverse event that occurs after the study period and is considered to be possibly 
related to the study treatment or study participation should be recorded and reported 
immediately. 
Lenvatinib overdose: Definition of an Overdose for This Protocol and Reporting of Overdose 
to the Sponsor and to Eisai: 
The highest tested doses of lenvatinib in clinical studies were 32 mg QD and 20 mg BID. There 
have been reports of overdose with lenvatinib involving single administrations of 6 to 10 times 
the recommended daily dose. Adverse reactions associated with these reports were consistent 
with the AEs reported in clinical studies at the recommended 24 mg dose. There is no specific 
antidote for overdose with lenvatinib. In case of suspected overdose, lenvatinib should be 
withheld and supportive care initiated. There is no specific antidote for overdose with 
lenvatinib. Due to the high plasma protein binding, lenvatinib is not expected to be dialyzable. 
Adverse reactions in subjects receiving single doses of lenvatinib as high as 40 mg were similar 
to the adverse events reported in the clinical studies at the recommended dose for DTC and 
RCC. 
 


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If an adverse event(s) is associated with (“results from”) the overdose of a Eisai product, the 
adverse event(s) is reported as a serious adverse event, even if no other seriousness criteria are 
met. 
If a dose of Eisai’s product meeting the protocol definition of overdose is taken without any 
associated clinical symptoms or abnormal laboratory results, the overdose is reported as a non-
serious Event of Clinical Interest (ECI), using the terminology “accidental or intentional 
overdose without adverse effect.” 
All reports of overdose with and without an adverse event must be reported within 24 hours to 
the Sponsor and within 2 working days hours to Eisai, Inc.: 
Eisai Medical Affairs  
100 Tice Blvd.  
Woodcliff Lake, NJ 07677  
Tel: 1-888-274-2378  
Fax: -1-732-791-1111  
Email: ESI_Safety@eisai.com 
At each contact with the subject, the investigator must seek information on adverse events by 
specific questioning and, as appropriate, by examination.  Information on all adverse events 
should be recorded immediately in the source document, and also in the appropriate adverse 
event module of the case report form (CRF).  All clearly related signs, symptoms, and abnormal 
diagnostic procedures results should recorded in the source document, though should be 
grouped under one diagnosis. 
All adverse events occurring during the study period must be recorded.  The clinical course of 
each event should be followed until resolution, stabilization, or until it has been determined 
that the study treatment or participation is not the cause.  Serious adverse events that are still 
ongoing at the end of the study period must be followed up to determine the final outcome.  
Any serious adverse event that occurs after the study period and is considered to be possibly 
related to the study treatment or study participation should be recorded and reported 
immediately. 
 
 
7.2.1 Reporting of Pregnancy and Lactation  
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them) that occurs during the trial. 
Pregnancies and lactations that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 


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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 lactations that occur from the time of treatment allocation/randomization 
through 120 days following cessation of Sponsor’s product, or 30 days following cessation of 
treatment if the subject 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. 
 
Should a pregnancy occur, it must be reported immediately to the regulatory specialist, 
research coordinator, and NYUPCCsafetyreport@nyumc.org in accordance with the 
procedures described below.  Pregnancy in itself is not regarded as an adverse event unless 
there is a suspicion that the investigational product may have interfered with the effectiveness 
of a contraceptive medication.  This will be reported to the IRB if necessary. 
Such events must be reported within 24 hours to the Sponsor and within 2 working days to 
Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220) 
7.2.2 Reporting of Serious Adverse Events 
A serious adverse event is any adverse event occurring at any dose or during any use of study 
drug(s) that: 
• Results in death; 
• Is life threatening; 
• Results in persistent or significant disability/incapacity; 
• Results in or prolongs an existing inpatient hospitalization; 
• Is a congenital anomaly/birth defect; 
• Is an other important medical event  
• Note: In addition to the above criteria, adverse events meeting either of the below 
criteria, although not serious per ICH definition, are reportable to the Merck in the same 
timeframe as SAEs to meet certain local requirements. Therefore, these events are 
considered serious by Merck for collection purposes. 
● 
Is a new cancer (that is not a condition of the study); 
● 
Is associated with an overdose. 
 
Refer to Table 13 for additional details regarding each of the above criteria. 
All SAEs must be reported to the sponsor, NYU Langone Medical Center within 24 hours and 
to Merck Global Safety and Eisai within 2 working days. 


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Initial Report: within 24 hours: 
The following events must be reported to the CTO via email within 24 hours of awareness of the 
event:  
• 
Unanticipated problems related to study participation,  
• 
Serious adverse events, regardless of whether they are unexpected.  
   
 
Email:  NYUPCCsafetyreports@nyumc.org 
Tel:  212-263-4427 
 
AND 
 
Paul Oberstein, MD 
The Laura and Isaac Perlmutter Cancer Center 
NYU Langone Medical Center 
160 East 34th Street 
New York, NY, 10016 
Telephone: (212) 731-6120 
AND 
 
PCC Assigned Medical Monitor  
 
For the time period beginning when the consent form is signed until treatment allocation any 
serious adverse event, or follow up to a serious adverse event, including death due to any cause 
other than progression of the cancer under study (reference Section 7.2. for additional details) 
that occurs to any subject must be reported within 24 hours to the Sponsor (NYU Langone 
Medical Center) and within 2 working days to Merck Global Safety and Eisai if it causes the 
subject to be excluded from the trial, or is the result of a protocol-specified intervention, 
including but not limited to washout or discontinuation of usual therapy, diet, placebo 
treatment or a procedure. 
For the time period beginning at treatment allocation/randomization through 90 days following 
cessation of treatment, or 30 days following cessation of treatment if the 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 other than progression of the cancer under 
study (reference Section 7.2.. for additional details) whether or not related to the investigational 
product(s), must be reported within 24 hours to the Sponsor (NYU Langone Medical Center) 
and within 2 working days to Merck Global Safety and Eisai. 
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to either investigational agent that is brought to the attention of the 
investigator at any time following consent through the end of the specified safety follow-up 
period specified in the paragraph above, or at any time outside of the time period specified in 
the previous paragraph also must be reported immediately to the Sponsor and to Merck Global 
Safety and Eisai. 
All subjects with serious adverse events must be followed up for outcome. 


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SAE reports and any other relevant safety information are to be forwarded to the Merck 
Global Safety facsimile number:  +1-215-993-1220 and 
To Eisai, Inc.:  
Eisai Medical Affairs  
100 Tice Blvd.  
Woodcliff Lake, NJ 07677  
Tel: 1-888-274-2378  
Fax: -1-732-791-1111  
Email: ESI_Safety@eisai.com 
A copy of all Reports and Progress Reports is submitted as required by FDA, European Union 
(EU), Pharmaceutical and Medical Devices agency (PMDA) or other local regulators. 
Investigators will cross reference this submission according to local regulations to the Merck 
Investigational Compound Number (IND, CSA, etc.) at the time of submission.  Additionally 
investigators will submit a copy of these reports to Merck & Co., Inc. (Attn: Worldwide 
Product Safety; FAX 215 993-1220) at the time of submission to FDA. 
Additionally, an FDA MEDWATCH Form 3500A (download form and instructions at 
http://www.fda.gov/Safety/MEDWATCH/HowToReport/DownloadForms/ucm2007307.htm
) must be completed by the investigator and faxed to the study sponsor within 24 hours.  The 
investigator shall maintain a copy of the MEDWATCH Form on file at the study site. If 
supplied as in a narrative format, the minimum information to be supplied is as follows: 
• Study identifier 
• Study Center 
• Subject number 
• A description of the event 
• Date of onset 
• Current status 
• Whether study treatment was discontinued 
• The reason why the event is classified as 
serious 
• Investigator assessment of the association 
between the event and study treatment 
 
Follow-up report: within 48 hours: 
As a follow-up to the initial report, within the following 48 hours of awareness of the event, 
the investigator shall provide further information, as applicable, on the unanticipated event or 
the unanticipated problem in the form of a written narrative.  This should include a copy of the 
completed Unanticipated Problem form, and any other diagnostic information that will assist 
the understanding of the event.  Significant new information on ongoing unanticipated adverse 
device effects shall be provided promptly to the study sponsor. 
 
IND Safety Reports: 


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The study sponsor is required to report certain study events in an expedited fashion to the FDA.  
These written notifications of adverse events are referred to as IND safety reports. The 
following describes the safety reporting requirements by timeline for reporting and associated 
type of event: 
• Within 7 calendar days (via telephone or facsimile report) 
Any study event that is: 
– associated with the use of the study drug 
– unexpected,  
– fatal or life-threatening 
 
• Within 15 calendar days (via written report) 
Any study event that is: 
– associated with the use of the study drug, 
– unexpected, and 
– serious, but not fatal or life-threatening 
-or- 
– a previous adverse event that was not initially deemed reportable but is later found 
to fit the criteria for reporting (reporting within 15 calendar days from when event 
was deemed reportable). 
Any finding from tests in laboratory animals that:  
– suggest a significant risk for human subjects including reports of mutagenicity, 
teratogenicity, or carcinogenicity. 
 
Additional reporting requirements 
Sponsors are also required to identify in IND safety reports all previous reports concerning 
similar adverse events and to analyze the significance of the current event in light of the 
previous reports. 
 
Reporting Process 
Adverse events may be submitted on FDA Form 3500A (download form and instructions at 
http://www.fda.gov/Safety/MEDWATCH/HowToReport/DownloadForms/ucm2007307.htm
), or in a narrative format. If supplied as in a narrative format, the minimum information to be 
supplied is as follows: 


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• Study identifier 
• Study Center 
• Subject number 
• A description of the event 
• Date of onset 
• Current status 
• Whether study treatment was discontinued 
• The reason why the event is classified as 
serious 
• Investigator assessment of the association 
between the event and study treatment 
 
Other Reportable events: 
• Deviations from the study protocol 
Deviations from the protocol must receive both Sponsor (NYU Langone Medical 
Center) and the investigator’s IRB approval before they are initiated. Any protocol 
deviations initiated without Sponsor and the investigator’s IRB approval that may 
affect the scientific soundness of the study, or affect the rights, safety, or welfare of 
study subjects, must be reported to the Sponsor and to the investigator’s IRB as soon 
as a possible, but no later than 5 working days of the protocol deviation. 
• Withdrawal of IRB approval 
An investigator shall report to the sponsor a withdrawal of approval by the 
investigator’s reviewing IRB as soon as a possible, but no later than 5 working days 
of the IRB notification of withdrawal of approval. 
Federal regulations require timely reporting by investigators to their local IRB of unanticipated 
problems posing risks to subjects or others.  The following describes the NYULMC IRB 
reporting requirements, though Investigators at participating sites are responsible for meeting 
the specific requirements of their IRB of record.  
This section also specifies the NYULMC IRB requirements for investigator reporting of 
unanticipated problems posing risk to subjects or others, including adverse events.  The IRB 
requirements reflect the current guidance documents released by the Office of Human 
Research Protections (OHRP), and the Food and Drug Administration (FDA) and are 
respectively entitled “Guidance on Reviewing and Reporting Unanticipated Problems 
Involving Risks to Subjects or Others and Adverse Events” and “Guidance for Clinical 
Investigators, Sponsors, and IRBs:  Adverse Event Reporting – improving Human Subject 
Protection”. 
 
The NYU IRB address is: 
NYU School of Medicine IRB 
1 Park Avenue, 6th Floor 
New York, NY 10016  
 


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Report Promptly, but no later than 5 working days: 
Researchers are required to submit reports of the following problems promptly but no later 
than 5 working days from the time the investigator becomes aware of the event: 
• Unanticipated problems including adverse events that are unexpected and related 
– Unexpected: An event is “unexpected” when its specificity and severity are not 
accurately reflected in the protocol-related documents, such as the IRB-approved 
research protocol, any applicable investigator brochure, and the current IRB-
approved informed consent document and other relevant sources of information, 
such as product labeling and package inserts.  
– Related to the research procedures: An event is related to the research procedures 
if in the opinion of the principal investigator or sponsor, the event was more likely 
than not to be caused by the research procedures.  
– Harmful: either caused harm to subjects or others, or placed them at increased risk 
 
Other Reportable events: 
The following events also require prompt reporting to the IRB, though no later than 5 working 
days: 
• Complaint of a research subject when the complaint indicates unexpected risks or the 
complaint cannot be resolved by the research team. 
• Protocol deviations or violations (includes intentional and accidental/unintentional 
deviations from the IRB approved protocol) for any of the following situations:  
– one or more participants were placed at increased risk of harm  
– the event has the potential to occur again 
– the deviation was necessary to protect a subject from immediate harm 
• Breach of confidentiality 
• Incarceration of a participant when the research was not previously approved under 
Subpart C and the investigator believes it is in the best interest of the subject to remain 
on the study. 
• New Information indicating a change to the risks or potential benefits of the research, 
in terms of severity or frequency. (e.g. analysis indicates lower-than-expected response 
rate or a more severe or frequent side effect; Other research finds arm of study has no 
therapeutic value; FDA labeling change or withdrawal from market) 
 


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Reporting Process 
The reportable events noted above will be reported to the IRB using the form: “Reportable 
Event Form” or as a written report of the event (including a description of the event with 
information regarding its fulfillment of the above criteria, follow-up/resolution and need for 
revision to consent form and/or other study documentation). 
Copies of each report and documentation of IRB notification and receipt will be kept in the 
Clinical Investigator’s study file. 
 
Notifying participating investigators 
It is the responsibility of the study sponsor to notify all participating investigators of any 
adverse event that meets the FDA 15-day reporting requirement criteria as noted above.  The 
same materials and timeline used to report to the FDA are used for notifying participating 
investigators. 
 
7.2.3 Events of Clinical Interest 
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported within 24 hours to the Sponsor and within 2 working days to Merck 
Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220). 
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any ECI, or follow up to an ECI, that occurs to any subject must be 
reported within 24 hours to the Sponsor and within 2 working days to Merck Global Safety if 
it causes the subject to be excluded from the trial, or is the result of a protocol-specified 
intervention, including but not limited to washout or discontinuation of usual therapy, diet, 
placebo treatment or a procedure. 
For the time period beginning at treatment allocation/randomization through 90 days following 
cessation of treatment, or 30 days following cessation of treatment if the subject 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 24 hours to the Sponsor and within 24 hours to 
Merck Global Safety. 
Events of clinical interest for this trial include: 
1.  an overdose of Merck product, as defined in Section 7.2. - Definition of an Overdose for 
This Protocol and Reporting of Overdose to the Sponsor, that is not associated with clinical 
symptoms or abnormal laboratory results.  
2.  an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the upper 


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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 Protocol-Specific Exceptions to Serious Adverse Event Reporting  
Efficacy endpoints as outlined in this section will not be reported to Merck as described in 
Section 7.2.3 - Immediate Reporting of Adverse Events to the Sponsor and to Merck, unless 
there is evidence suggesting a causal relationship between the drug and the event. Any such 
event will be submitted to the Sponsor within 24 hours and to Merck Global Safety within 2 
working days either by electronic or paper media. 
Specifically, the suspected/actual events covered in this exception include any event that is 
disease progression of the cancer under study. 
The Sponsor will monitor unblinded aggregated efficacy endpoint events and safety data to 
ensure the safety of the subjects in the trial. Any suspected endpoint which upon review is not 
progression of the cancer under study will be forwarded to Merck Global Safety as a SAE 
within 2 working days of determination that the event is not progression of the cancer under 
study 
Hospitalization related to convenience (e.g. transportation issues etc.) will not be considered a 
SAE. 
 
7.2.5 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 4.03. 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 13:  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 subject, in the view of the investigator, at immediate risk of death from the event as it occurred (Note: This does not include an 
adverse event that, had it occurred in a more severe form, might have caused death.); or 
 
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or 
 
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation. (Note: Hospitalization 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 subject taking the product regardless of time to diagnosis);or 
 
Is a new cancer (that is not a condition of the study) (although not serious per ICH definition, is reportable to the Sponsor within 24 hours and to Merck within 2 
working days to meet certain local requirements); or 
 
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event for collection purposes. An 
overdose that is not associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24 hours to the Sponsor and to 
Merck within 2 working days.. 


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Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes listed 
previously (designated above by a †). 
Duration 
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units 
Action taken  
Did the adverse event cause 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 subject was actually exposed to Merck product such as: reliable history, acceptable compliance assessment (pill count, 
diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen? 
 
Time Course 
Did 
the 
AE 
follow 
in 
a 
reasonable 
temporal 
sequence 
from 
administration 
of 
Merck 
product?  
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal product)? 
 
Likely Cause 
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or environmental factors 
 


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Relationship 
The following components are to be used to assess the relationship between the test drug and the AE: (continued) 
to Merck 
Product 
(continued)  
Dechallenge 
Was Merck product discontinued or dose/exposure/frequency reduced? 
If yes, did the AE resolve or improve? 
If yes, this is a positive dechallenge. If no, this is a negative dechallenge. 
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the AE resolved/improved despite continuation of 
the Sponsor’s product; or (3) the trial is a single-dose drug trial); or (4) Sponsor’s product(s) is/are only used one time.) 
 
Rechallenge 
Was the subject re-exposed to Merck product in this study? 
If yes, did the AE recur or worsen? 
If yes, this is a positive rechallenge. If no, this is a negative rechallenge. 
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, or (2) the trial is a single-dose drug trial); or (3) 
Sponsor’s product(s) is/are used only one time). 
NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN 
CAUSED BY MERCK PRODUCT, OR IF REEXPOSURE TO MERCK PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT RISK 
TO THE SUBJECT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE SPONSOR AS PER DOSE MODIFICATION 
GUIDELINES IN THE PROTOCOL. 
 
Consistency 
with Trial 
Treatment 
Profile 
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding Merck product or drug class pharmacology or 
toxicology? 
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to his/her best clinical judgment, including 
consideration of the above elements. 
Record one of the following 
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of Merck product relationship). 
Yes, there is a reasonable 
possibility of Merck product 
relationship. 
There is evidence of exposure to Merck product.  The temporal sequence of the AE onset relative to the administration of Merck product is reasonable.  
The AE is more likely explained by Merck product than by another cause. 
No, there is not a reasonable 
possibility of Merck product 
relationship 
Subject 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 subject with overdose without an associated AE.) 


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7.2.6 Responsibility for Reporting Adverse Events 
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations.  
The Principal Investigator is responsible for reporting all unexpected problems involving risk 
to participants or others to NYU Perlmutter Cancer Center CTO. 
7.2.7 Stopping Rules 
As no adverse events are anticipated given the low level of risk in this trial, there are no 
formalized stopping rules. However, should any serious and unexpected adverse events 
occur, the principal investigator will consider whether early stopping is appropriate. 
7.2.8 Medical Monitoring Plan 
It is the responsibility of the Principal Investigator to oversee the safety of the study at his/her 
site.  This safety monitoring will include careful assessment and appropriate reporting of 
adverse events as noted above, as well as the construction and implementation of a site data 
and safety-monitoring plan.  The Data Safety and Monitoring Committee (DSMC) will 
review the study at least annually.  Medical monitoring will include a regular assessment of 
the number and type of serious adverse events. 
7.2.8.1  Data and Safety Monitoring Plan 
Per the NYU PCC Institutional Data Safety and Monitoring Plan, this phase II trial will be 
monitored by DSMC at least annually (from the date the first subject is enrolled), at dose 
escalation point and subsequent cohort activation, and at the completion of the study prior to 
study closure. This review includes accrual data, subject demographics and adverse events.  
Principal Investigators are required to attend the review of their studies. Additional reviews 
can be scheduled based on SAE reports, investigator identified issues, external information, 
etc.  
7.2.9 Monitoring of Other Participating Institutions 
Monitoring visits are done remotely unless otherwise specified, via remote EMR access. If not 
possible, secure email exchange will be utilized. The quality assurance specialist will confirm 
an upcoming monitoring visit with a Site Investigator and staff. If remote EMR access is 
not available, then the Site Coordinator will ensure that all source documents for subjects 
are de-identified and labeled only with the subject ID number(s), and emails all requested 
documents to the quality assurance specialist by the specified visit date. All documents 
are reviewed and a monitoring report is submitted within 5 business days from the date of 
the visit. Any outstanding documents will be listed in the report as a high- priority request 
for the next monitoring visit. It is expected that response to data clarification requests and 
other trial-related inquiries will occur throughout the course of the study through regular 


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communication with the site monitor, the Sponsor or representatives, and review/entry of 
data into the electronic study database. Continued non-compliance and failure to submit 
documentation will result in the suspension of 
subject enrollment at the site, until the 
documents have been received. 
 
 
8.0 STATISTICAL ANALYSIS PLAN 
8.1 
Statistical Analysis Plan 
The Simon optimal two-stage design to test the null hypothesis of <10% RR (CR+PR) versus 
the alternative hypothesis of >30% overall response rate requires an overall sample size of 29 
subjects in order to achieve 80% power with a significance level of 5%.  After testing the 
combination therapy on 10 response evaluable subjects in the first stage, the trial will be 
terminated if there are 1 or fewer responses. If there are 2 or more responses (including non-
confirmed responses) the trial will continue on to second stage. A response evaluable subject 
is defined as having received both investigational agents for at least 2 cycles and had one CT 
scan for disease evaluation on therapy, or evidence of early (prior to 2 cycles) clear progression 
on physical examination, or death prior to 2 cycles. Best overall response for the interim 
analysis will be assessed up to 6 months on treatment.  If the trial goes on to the second stage, 
then if there are 5 or fewer responses  out of 29 response evaluable subjects, the combination 
therapy will be rejected. If there are 6 or more responses (including non-confirmed responses) 
over the entire treatment duration - the combination will be studied further.  
At the end of the study, toxicities, as measured by the NCI CTCAE Version 4.03, will be 
described by frequency and grade, by cycle and over all cycles, with the maximum grade over 
all cycles used as the summary measure per patient. Overall response rates (defined as PR plus 
CR) will be estimated with exact 95% confidence intervals. PFS and OS will be described 
using Kaplan-Meier curves.  
All subjects who receive at least one dose of the lenvatinib and/or pembrolizumab combination 
will be evaluable for toxicity. 
Efficacy Measures 
Response rate (RR): Best overall response will be calculated as the best response (CR or PR) 
recorded from the start of treatment for each subject, and will be used for the summaries of 
objective response. Best overall response will be determined programmatically based on the 
RECIST 1.1 criteria. For this study confirmation of response within 4 weeks will not be 
required. 
Progression Free Survival (PFS): is defined as the interval between the date of start of treatment 
and the earlier date of objective disease progression per RECIST 1.1 criteria or death due to 
any cause in the absence of progression. 


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Overall Survival (OS): is calculated as the interval from the start of treatment to the date of 
subject death (any cause). 
RECIST 1.1 assessments (including Target Lesion measurements) will be used to determine 
ORR and PFS.  Imaging assessments will be made every 6-9 weeks. 
Safety Measures 
AEs and SAEs will be collected throughout the study from informed consent until 30 days 
after study treatment is discontinued. Investigators must continue to report all SAEs to the 
NYU CTO until 30 days after study treatment is discontinued. 
If a subject discontinues study treatment for reasons other than disease progression, and 
therefore continues to have tumor assessments using RECIST following the 30 days after the 
last dose of the last study treatment, only study drug-, or study procedure-related SAEs will be 
captured until the subject is considered to have progressive disease. 
AEs will be graded according to the National Cancer Institute Common Terminology Criteria 
for AEs. 
AEs will be coded using MedDRA (Medical Dictionary for Regulatory Activities). 
 
Biomarker/Exploratory Objectives 
All biomarker analyses will consist of descriptive statistical summaries at baseline (means, 
medians, standard deviations, quantiles, ranges, etc.) and graphical displays (e.g. boxplots). 
Similar summaries will be provided by changes from baseline and response status for each of 
the biomarkers under study. We will use non-parametric tests to assess the relationships 
between PDL1 status, gene expression profiles of interest, and response to combination 
treatment of pembrolizumab and lenvatinib. Outcome relationships will be largely explorative 
and descriptive. 
 
 
9.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES 
9.1 
Investigational Products  
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and 
regulations. 


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Clinical Supplies of pembrolizumab will be provided by Merck as summarized in Table 14. 
Table 14:  Pembrolizumab Product Description  
Product Name & Potency 
Dosage Form 
Pembrolizumab 50 mg 
Lyophilized Powder for Injection 
Pembrolizumab 100 mg/ 4mL 
Solution for Injection 
 
Clinical Supplies of lenvatinib will be provided by Eisai as summarized in Table 15. 
Table 15: Lenvatinib Product Description 
Product Name & Potency 
Dosage Form 
Lenvatinib 10 mg 
Capsule 
Lenvatinib 4mg 
Capsule 
 
9.2 
Packaging and Labeling Information 
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements. 
9.3 
Clinical Supplies Disclosure 
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or 
designee are not blinded to treatment. Drug identity (name, strength) is included in the label 
text; random code/disclosure envelopes or lists are not provided. 
9.4 
Storage and Handling Requirements 
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.   
Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site. 
Clinical supplies may not be used for any purpose other than that stated in the protocol. 
9.5 
Returns and Reconciliation 
The investigator is responsible for keeping accurate records of the clinical supplies received 
from Merck and Eisai, the amount dispensed to and returned by the subjects and the amount 
remaining at the conclusion of the trial.  


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Upon completion or termination of the study, all unused and/or partially used investigational 
product will be destroyed at the site per institutional policy. It is the Investigator’s 
responsibility to arrange for disposal of all empty containers, provided that procedures for 
proper disposal have been established according to applicable federal, state, local and 
institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept. 
10.0 ADMINISTRATIVE AND REGULATORY DETAILS 
10.1 Confidentiality 
All samples will be stored in a secure place.  Samples will be identified by a unique identifier.  
The subject’s name will not be used on the sample.  This unique identifier will be put into the 
sponsor database and will link in the sponsor database only to de-identified subject data 
(subject number).  Personal health information (PHI) will not be identifiable in the sponsor 
database or on the stored samples.  Besides protecting confidentiality, this system will allow 
the sponsor to destroy the sample if the subject requests this.  Samples will be retained and 
used until they are exhausted. The log to PHI will be maintained at the study site.  Information 
will be stored in a secure, locked room and in a secure, password-protected database.  Only 
approved study personnel will have access to the samples.   
 
The informed consent form (ICF) will incorporate (or, in some cases, be accompanied by a 
separate document incorporating) wording that complies with relevant data protection and 
privacy legislation. 
Confidentiality and HIPAA 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  
Those regulations require a signed subject authorization informing the subject of the following:  
• What protected health information (PHI) will be collected from subjects in this study 
• Who will have access to that information and why 
• Who will use or disclose that information  
• The rights of a research subject to revoke their authorization for use of their PHI.  
 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization.  For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect at least vital status (i.e. that the subject is alive) 
at the end of their scheduled study period. 
 


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10.2 Compliance with Financial Disclosure Requirements 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or 
financial gain greater than the minimum allowable by their institution, etc.) must have the 
conflict reviewed by a properly constituted Conflict of Interest Committee with a Committee-
sanctioned conflict management plan that has been reviewed and approved by the study 
sponsor prior to participation in this study.  All NYULMC investigators will follow the 
applicable University conflict of interest policies. 
 
10.3 Ethical Considerations, and Compliance with Law, Audit and Debarment 
This study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with International Conference on Harmonisation 
(ICH), US government regulations, international standards of Good Clinical Practice (GCP), 
applicable regulatory requirements, the sponsor policy on Bioethics and Human Biological 
Samples, and applicable institutional research policies and procedures. 
This protocol and any amendments will be submitted to a properly constituted Institutional 
Review Board (IRB)  in agreement with local legal prescriptions, for formal approval of the 
study conduct.  The decision of the IRB concerning the conduct of the study will be made in 
writing to the investigator and a copy of this decision will be provided to the sponsor before 
commencement of this study.  The investigator should provide a list of IRB members and their 
affiliate to the sponsor. 
All subjects for this study will be provided a consent form describing this study and will be 
provided sufficient information to make an informed decision about their participation in this 
study.  This consent form will be submitted with the protocol for review and approval by the 
IRB for the study.  The formal consent of a subject, using the IRB-approved consent form, 
must be obtained before that subject undergoes any study procedure.  The consent form must 
be signed by the subject or legally acceptable surrogate, and the investigator-designated 
research professional obtaining the consent. The consenting process and documentation will 
follow Standard Operating Procedures of the NYU PCC CTO. 
 
Treating investigators will obtain informed consent after explaining the study and answering 
all questions the subject or subject’s legally authorized representative may have. Individuals 
who are authorized to obtain consent will be listed on the FDA form 1572, and may also be 
listed in the protocol and consent form document. If necessary, a translator and consent form 
in the subject’s native language will be provided.  
An IRB must approve the final study protocol, including the final version of the Informed 
Consent Form and any other written information to be provided to the subjects. The 


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investigator will ensure the distribution of these documents to the applicable IRB, and to the 
study site staff. 
The opinion of the IRB must be given in writing. The investigator must submit the written 
approval to the NYU CTO before enrollment of any subject into the study. 
The IRB must approve all advertising used to recruit subjects for the study. 
The NYU CTO must approve any modifications to the Informed Consent Form that are needed 
to meet local requirements. 
The NYU CTO will provide Principal Investigators with safety updates/reports according to 
local requirements. 
Progress reports and notifications of serious and unexpected adverse drug reactions will be 
provided to the IRB according to local regulations and guidelines. 
 
10.4 Compliance with Trial Registration and Results Posting Requirements 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the Sponsor of the trial is solely 
responsible for determining whether the trial and its results are subject to the requirements for 
submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov.  Information posted 
will allow subjects to identify potentially appropriate trials for their disease conditions and 
pursue participation by calling a central contact number for further information on appropriate 
trial locations and trial site contact information.     
10.5 Quality Management System 
Weekly registration reports will be generated to monitor subject accruals and completeness of 
registration data. Routine data quality reports will be generated to assess missing data and 
inconsistencies. Accrual rates and extent and accuracy of evaluations and follow-up will be 
monitored periodically throughout the study period, and potential problems will be brought to 
the attention of the study team for discussion and action.  Random-sample data quality and 
protocol compliance audits will be conducted by the study team, at a minimum of two times 
per year, and more frequently if indicated. 
 
The site will be monitored as outlined in the study Monitoring Plan. The study Monitoring 
Plan outlines the description of monitoring approaches, frequency of monitoring, 
communication, documentation, and management of non-compliance.  
All subjects who sign and informed consent document and are screened for entry into the study 
must be documented. Subjects who fail to meet eligibility criteria must have the reason(s) 
recorded in the subject’s source documents.  


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10.6 Data Management 
Data management support for this study will be provided by DataCore, a core resource at 
NYULMC that will provide comprehensive data management to facilitate efficient data 
collection, query management, data monitoring and cleaning, and database lock.  DataCore 
will create electronic Case Report Forms (eCRF) using an electronic data capture (EDC) 
system, and will provide and maintain the Data Management Plan and Date Entry Guidelines 
for site staff in concert with the study biostatistic staff. 
Clinical data during the subject visit will be entered directly into the EPIC Electronic Health 
Record system at NYU sites and at Bellevue sites, then transcribed by site staff (e.g., Clinical 
Research Associates) into the eCRF pages for the clinical study in the Data Management 
system. The DataCore Clinical Data Manager will monitor study data entry for completeness 
and validity, query site staff for data clarification of invalid or missing entries, and oversee 
data entry, data cleaning and database lock timelines. The DataCore SAS programmer will 
provide routine data quality reports to the study team including the Clinical Data Manager; 
standard and ad-hoc reports for the clinical study team; and provide the required datasets to 
Biostatistics for DSMC reports, interim and final analyses in an ongoing and ad-hoc basis. 
10.6.1 Source Documents 
Source documentation refers to original records of observations, clinical findings and 
evaluations that are subsequently recorded as data.  Source documentation should be 
consistent with data entered into the electronic data capture system.  Relevant source 
documentation to be reviewed by the DSMC throughout the study includes: 
1.  Baseline measures to assess eligibility and disease status 
2.  Subject demographics 
3.  Concurrent medications 
4.  Treatment records 
5.   Adverse events 
 
10.6.2 Data and Source Documentation 
An electronic database capture system will be created to record the data for this trial.  Research 
coordinators will input clinical trial data into the database.  This database is password protected 
and only the PI, assigned research coordinator, and CTO quality assurance specialists will have 
access to the database.  The electronic database capture system is the primary data collection 
instrument for the study.  All data requested in this system must be reported.  All missing data 
must be explained.  The quality assurance specialists will monitor this trial every 4-6 weeks 
for data entry accuracy. 
10.6.3 Case Report Forms 
 


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 All data requested on the CRF must be recorded.  All missing data must be explained.  If a 
space on the CRF is left blank because the procedure was not done or the question was not 
asked, write “N/D”.  If the item is not applicable to the individual case, write “N/A”.  All 
entries should be printed legibly in black ink.  If any entry error has been made, to correct such 
an error, draw a single straight line through the incorrect entry and enter the correct data above 
it.  All such changes must be initialed and dated.  DO NOT ERASE OR WHITE OUT 
ERRORS.  For clarification of illegible or uncertain entries, print the clarification above the 
item, then initial and date it. 
10.6.4 Records Retention 
The CTO’s protocol for records retention will be followed. It is the investigator’s 
responsibility to retain study essential documents for at least 3 years after the formal closure 
of the study.  
 
10.7 Monitoring of the study, Auditing and Inspecting 
This investigator-initiated study will be monitored by the Data Safety Monitoring Committee 
(DSMC) of the New York University Cancer Center. The DSMC operates based on the  
National Cancer Institute approved Charter. It is a multidisciplinary committee, consisting of 
clinical investigators/oncologists, biostatisticians, nurses and research administration staff 
knowledgeable of research methodology and design and in proper conduct of clinical trials, 
that is responsible for monitoring safety, conduct, and compliance in accordance with protocol 
data monitoring plans for clinical trials conducted in the NYU Perlmutter Cancer Center that 
are not monitored by another institution or agency.  The DSMC reports to the Director of the 
NYU Perlmutter Cancer Center. 
This phase II trial will be monitored by DSMC quarterly (from the date the first patient is 
enrolled), at times of pre-specified response assessment, and at the completion of the study, 
prior to study closure. This review includes accrual data, subject demographics and adverse 
events. Principal Investigators are required to attend the review of their studies. Additional 
interim reviews can be scheduled based on SAE reports, investigator identified issues, external 
information, etc. 
At the NYU Perlmutter Cancer Center, all investigator-initiated protocols are subject to a 
standardized data and safety monitoring, which includes scientific peer review, IRB review, 
Phase I/II committee review and DSMC review as well as internal auditing.  
The review of AEs and trial conduct for this trial occurs at several levels: 
1. 
Principal Investigator: Adverse events are evaluated monthly by the principal 
investigator in conjunction with the research nurses, data manager and research team.  
  


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2. 
DSMC, quarterly 
3. 
IRB: An annual report to the IRB is submitted by the trial PI for continuation 
of the protocol. It includes a summary of all AEs, total enrollment with demographics, 
protocol violations, and current status of subjects as well as available research data. 
4. 
In addition, the quality assurance unit will monitor this trial extensively, 
including real-time review of all eCRFs to ensure completeness and compliance with 
the protocol,accuracy and consistency of the data, and adherence to ICH Guidelines for 
Good Clinical Practice (GCP).  In addition, a first subject audit will be conducted 
within four weeks of enrollment. 
Study Monitoring Plan 
This study will be monitored according to the above monitoring plan.  The investigator will 
allocate adequate time for such monitoring activities.  The Investigator will also ensure that 
the monitor or other compliance or quality assurance reviewer is given access to all pertinent 
study-related documents and study related facilities (e.g. pharmacy, diagnostic laboratory, 
etc.), and has adequate space to conduct the monitoring visit. 
Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the IRB/IEC, 
the sponsor, government regulatory bodies, and university compliance and quality assurance 
groups of all study related documents (e.g. source documents, regulatory documents, data 
collection instruments, study data etc.).  The investigator will ensure the capability for 
inspections of applicable study-related facilities (e.g. pharmacy, diagnostic laboratory, etc.). 
Participation as an investigator in this study implies acceptance of potential inspection by 
government regulatory authorities and applicable University compliance and quality assurance 
offices.    The investigator will contact the PCC CTO immediately if contacted by a regulatory 
agency about an inspection at the center. 
 
11.0  STUDY FINANCES 
11.1 Funding Source 
This protocol will be funded in part by Eisai.  Drug will be provided by Eisai and Merck 
Pharmaceuticals. 
11.2 Subject Stipends or Payments 
There are no subject/patient payments or stipends for participation in this research study.   
 
12.0   PUBLICATION PLAN 
The study PI holds the primary responsibility for publication of the results of the study. 


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13.0 APPENDICES 
13.1 Table 16: ECOG Performance Status 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, but 
unable to carry out any work activities. Up and about more than 50% 
of waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. 
Totally confined to bed or chair. 
5 
Dead. 
* As published in Am. J. Clin. Oncol.:  Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., 
McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology 
Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative Oncology Group, Robert Comis 
M.D., Group Chair. 
 
13.2 Common Terminology Criteria for Adverse Events V4.03 (CTCAE) 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.03 will be utilized for adverse event reporting. 
(http://ctep.cancer.gov/reporting/ctc.html) 
13.3 Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for 
Evaluating Response in Solid Tumors 
RECIST version 1.1* will be used in this study for assessment of tumor response. While either 
CT or MRI may be utilized, as per RECIST 1.1, CT is the preferred imaging technique in this 
study. 
* As published in the European Journal of Cancer: 
 
E.A. Eisenhauer, P. Therasse, J. Bogaerts, L.H. Schwartz, D. Sargent, R. Ford, J. 
Dancey, S. Arbuck, S. Gwyther, M. Mooney, L. Rubinstein, L. Shankar, L. Dodd, R. Kaplan, 


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D. Lacombe, J. Verweij. New response evaluation criteria in solid tumors: Revised RECIST 
guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47. 
In addition, volumetric analysis will be explored by central review for response assessment. 
 
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