Conditions: Renal Cell Carcinoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 11
Healthy volunteers: no

Brief summary:
This is a single-arm, multicenter, phase 2 study of lenvatinib in combination with pembrolizumab (lenvatinib 20 mg/day + pembrolizumab 200mg q3weeks) in subjects with unresectable advanced or metastatic non-clear cell renal carcinoma who have not received any chemotherapy for advanced disease.

Detailed description:

Arms:
arm 1: * Lenvatinib 20 mg/day will be administered orally on a daily basis and pembrolizumab 200 mg will be infused once every 3 weeks.
* Subjects may be treated with pembrolizumab for a maximum of 35 cycles or approximately 2 years, but treatment with lenvatinib can continue beyond 2 years if the subject does not meet other treatment discontinuation criteria.

Interventions: intervention 1: Lenvatinib intervention 2: Pembrolizumab intervention 3: Research blood collection
Intervention descriptions: intervention 1: Lenvatinib will be provided by Merck. intervention 2: Merck will provide pembrolizumab intervention 3: -Within 2 weeks prior to first dose of study drug, cycle 4 day 1, and at the off-treatment assessment

Protocol document:
Prot_SAP_000.pdf: 
 
Version 10 March 2022 
 
page 1 of 83 
 
 
 
A single arm, multicenter, phase 2 trial to evaluate the efficacy of lenvatinib (LEN) in 
combination with pembrolizumab (KEYtruda) in subjects with locally advanced or 
metastatic Non-clear cell renal cell carcinoma (The LENKYN Trial) 
 
Washington University School of Medicine 
Division of Oncology 
660 South Euclid Avenue, Campus Box 8056 
St. Louis, MO  63110 
 
Protocol #: 202003148 
Version Date: 10 March 2022 
 
Coordinating Center: 
Washington University School of Medicine 
 
Principal Investigator: 
Joel Picus, M.D. 
Phone: (314) 362-5740 
E-mail:  jpicus@wustl.edu  
 
Sub-Investigators 
 
Institution 
 
 
Modality 
Eric Knoche, M.D. 
 
Washington University 
Medical Oncology 
Melissa Reimers, M.D. 
Washington University 
Medical Oncology 
Peter Oppelt, M.D. 
 
Washington University 
Medical Oncology 
Russell Pachynski, M.D. 
Washington University 
Medical Oncology 
Bruce Roth, M.D. 
 
Washington University 
Medical Oncology 
Jingqin (Rosy) Luo, Ph.D. 
Washington University 
Biostatistics 
 
Study Drugs:  
 
Lenvatinib 
Pembrolizumab (MK-3475, Keytruda) 
 
IND#:  
 
148556 EXEMPT 
IND Sponsor: 
N/A 
NCT#: 
 
NCT04267120  
Funded by: 
 
Merck  
 
CONFIDENTIAL 
The information contained in this document is regarded as confidential and, except to the extent necessary 
to obtain informed consent, may not be disclosed to another party unless law or regulations require such 
disclosure.  Persons to whom the information is disclosed must be informed that the information is 
confidential and may not be further disclosed by them 
A single arm, multicenter, phase 2 trial to evaluate the efficacy of lenvatinib (LEN) in 
combination with pembrolizumab (KEYtruda) in subjects with locally advanced or 
metastatic Non-clear cell renal cell carcinoma (The LENKYN Trial) 
 


 
Version 10 March 2022 
 
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Protocol Revision History 
 
Initial Approval Version 
 
 
 
 
 
 
24-Mar-2020 
Amendment #1 Version 
 
 
 
 
 
 
31-Aug-2021 
Amendment #2 Version 
 
 
 
 
 
 
10-Mar-2022 
 
 
 


 
Version 10 March 2022 
 
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A single arm, multicenter, phase 2 trial to evaluate the efficacy of lenvatinib (LEN) in 
combination with pembrolizumab (KEYtruda) in subjects with locally advanced or 
metastatic Non-clear cell renal cell carcinoma (The LENKYN Trial) 
 
Principal Investigator Signature Page 
 
 
Principal Investigator 
(printed): 
      
Name of Institution:       
  
 PI Signature 
 
 
 
 
 
Date 
 
By my signature, I agree to personally supervise the conduct of this study 
and to ensure its conduct in compliance with the protocol, informed 
consent, IRB/HRPO procedures, the Declaration of Helsinki, ICH Good 
Clinical Practices guidelines, and the applicable parts of the United 
States Code of Federal Regulations or local regulations governing the 
conduct of clinical studies. 
 
 
 
 


 
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STATEMENT OF COMPLIANCE 
The trial will be carried out in accordance with International Conference on Harmonisation Good 
Clinical Practice (ICH GCP) and the following:  
 
 United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 
CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812)  
 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Subjects Protection and ICH GCP Training. 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the Institutional Review Board (IRB) for review and approval.  Approval of both 
the protocol and the consent form must be obtained before any participant is enrolled.  Any 
amendment to the protocol will require review and approval by the IRB before the changes are 
implemented to the study.  In addition, all changes to the consent form will be IRB-approved; a 
determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent, using a previously approved consent form. 
 
 
 
 
 
 
 
 


 
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Glossary of Abbreviations 
 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT  
Alanine transaminase (serum glutamic pyruvic transaminase) 
ANC 
Absolute neutrophil count 
ASCO 
American Society of Clinical Oncology 
AST  
Aspartate transaminase 
BCG 
Bacillus Calmette-Guérin 
BOR 
Best overall response  
BP 
Blood pressure  
BUN 
Blood urea nitrogen  
CBC 
Complete blood count 
CBR 
Clinical benefit rate  
ccRCC 
Clear cell RCC 
CFR 
Code of Federal Regulations 
chRCC 
Chromophobe RCC  
CL  
Clearance  
CONSORT 
Consolidated standards of reporting trials 
CR 
Complete response 
CTFG 
Clinical trial facilitation group  
CRF 
Case report form 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTEP 
Cancer Therapy Evaluation Program 
DCR 
Disease control rate  
DLT 
Dose limiting toxicity 
DNA 
Deoxyribonucleic acid 
DOB 
Date of birth 
DSMB 
Data Safety Monitoring Board 
DVT 
Deep vein thrombosis 
EBRT 
External beam radiotherapy 
ECG (or EKG) 
Electrocardiogram 
ECI 
Events of Clinical Interest  
EDTA 
Ethylenediaminetetraacetic acid 
EU 
European Union 
FDA 
Food and Drug Administration 
FDG-PET 
Fluorodeoxyglucose - positron emission tomography 
FFPE 
Formalin-fixed paraffin-embedded 
FGFR1–3 
Fibroblast growth factor receptor 1 
FSH 
Follicle stimulating hormone 
FWA 
Federal wide assurance 


 
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GCP 
Good Clinical Practice 
GI 
Gastrointestinal  
H&P 
History & Physical  
HDPE 
High-density polyethylene  
HHS 
Department of Health and Human Services 
HIV 
Human Immunodeficiency Virus 
HRPO 
Human Research Protection Office (IRB) 
HRT 
Hormonal replacement therapy 
KEY 
KM 
IND 
Keytruda (Pembrolizumab) 
Kaplan-Meier 
Investigational New Drug 
IgG4 
Immunoglobulin G4 
INR 
International normalized ratio  
irAE 
Immune-related adverse event  
IRB 
Institutional Review Board 
IV 
Intravenous  
LEN 
mAb 
mTOR 
MRI 
Lenvatinib 
monoclonal antibody 
mammalian target of rapamycin 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 
NCCN 
National Cancer Center Network 
nccRCC 
NCI 
Non-clear cell renal cell carcinoma 
National Cancer Institute 
NIH 
National Institutes of Health 
OHRP 
Office of Human Research Protections  
ORR 
Overall response rate 
OS 
Overall survival 
OTC 
Over-the-counter  
PBMC 
Peripheral blood mononuclear cell 
PD 
Progressive disease 
PD-1 
Programmed cell death 1 
PDGF 
Platelet-derived growth factor 
PDGFRα 
Platelet-derived growth factor receptor α 
PD-L1 
Programmed cell death ligand 1 
PD-L2  
Programmed cell death ligand 2 
PEM 
PFS 
PI 
Pembrolizumab 
Progression-free survival  
Principal investigator 
PMDA 
Pharmaceutical and Medical Devices agency 
PR 
Partial response 


 
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PRES 
Posterior reversible encephalopathy syndrome 
PS 
Performance status  
PSA 
Prostate-specific antigen 
QASMC 
Quality Assurance and Safety Monitoring Committee 
RCC 
RECIST 
Renal Cell Carcinoma 
Response Evaluation Criteria in Solid Tumors (Committee) 
RET 
Rearranged during transfection 
RF 
Radiofrequency 
RFS 
Relapse free survival 
RNA 
Ribonucleic acid 
RR 
Response rate 
RTK 
Receptor tyrosine kinase 
SAE 
Serious adverse event 
SCC 
Siteman Cancer Center 
SD 
Stable disease 
T1DM 
Type 1 diabetes mellitus 
TSH 
Thyroid stimulating hormone 
ULN 
Upper limit of normal  
UPN 
Unique patient number 
uRCC 
Unclassified RCC 
US 
Ultrasound 
VEGF 
Vascular endothelial growth factor 
VEGFR 
Vascular endothelial growth factor receptor 
WBC 
White blood cell (count) 
WOCBP 
Women of childbearing potential  
 
 


 
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Table of Contents 
PROTOCOL SUMMARY ........................................................................................................... 10 
Synopsis ................................................................................................................................... 10 
SCHEMA ..................................................................................................................................... 11 
1.0 
SCHEDULE OF ACTIVITIES......................................................................................... 12 
2.0 
BACKGROUND AND RATIONALE ............................................................................. 13 
2.1 
Renal Cell Carcinoma ................................................................................................... 13 
2.2 
Non-Clear Cell Renal Cell Carcinoma (nccRCC)......................................................... 13 
2.3 
Pembrolizumab.............................................................................................................. 13 
2.4 
Lenvatinib...................................................................................................................... 14 
2.5 
Lenvatinib and Pembrolizumab .................................................................................... 14 
2.6 
Study Design ................................................................................................................. 14 
3.0 
OBJECTIVES AND ENDPOINTS .................................................................................. 15 
4.0 
STUDY POPULATION ................................................................................................... 17 
4.1 
Inclusion Criteria ........................................................................................................... 17 
4.2 
Exclusion Criteria .......................................................................................................... 19 
4.3 
Inclusion of Women and Minorities.............................................................................. 21 
5.0 
REGISTRATION PROCEDURES .................................................................................. 21 
5.1 
Confirmation of Patient Eligibility ................................................................................ 21 
5.2 
Patient Registration in the Siteman Cancer Center OnCore Database .......................... 21 
5.3 
Assignment of UPN ...................................................................................................... 22 
5.4 
Screen Failures .............................................................................................................. 22 
6.0 
TREATMENT PLAN ....................................................................................................... 22 
6.1 
Study Intervention Administration ................................................................................ 22 
6.2 
Definitions of Evaluability ............................................................................................ 22 
6.3 
Concomitant Medications/Vaccinations ....................................................................... 23 
6.4 
Women of Childbearing Potential (WOCBP) ............................................................... 25 
6.5 
Contraception Requirements ......................................................................................... 25 
6.6 
Pregnancy Testing ......................................................................................................... 27 
6.7 
Duration of Therapy ...................................................................................................... 27 
6.8 
Duration of Follow-up ................................................................................................... 27 
6.9 
Lost to Follow-Up ......................................................................................................... 27 
7.0 
DOSE DELAYS/DOSE MODIFICATIONS ................................................................... 28 
7.1 
Lenvatinib...................................................................................................................... 28 
7.2 
Pembrolizumab.............................................................................................................. 32 
8.0 
REGULATORY AND REPORTING REQUIREMENTS .............................................. 38 
8.1 
Washington University PI Reporting Requirements ..................................................... 38 
8.2 
Secondary Site Reporting Requirements....................................................................... 42 
8.3 
Exceptions to Expedited Reporting ............................................................................... 42 
9.0 
PHARMACEUTICAL INFORMATION ......................................................................... 43 
9.1 
Lenvatinib...................................................................................................................... 43 
9.2 
Pembrolizumab.............................................................................................................. 44 
10.0 CORRELATIVE STUDIES ............................................................................................. 47 
10.1 Blood Collection ........................................................................................................... 47 
10.2 Tumor Tissue................................................................................................................. 48 
11.0 DATA SUBMISSION SCHEDULE ................................................................................ 49 


 
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11.1 Adverse Event Collection in the Case Report Forms .................................................... 49 
12.0 MEASUREMENT OF EFFECT....................................................................................... 49 
12.1 Antitumor Effect – Immune-Related RECIST (iRECIST) Criteria .............................. 49 
12.2 Response Criteria .......................................................................................................... 51 
13.0 DATA AND SAFETY MONITORING ........................................................................... 58 
14.0 AUDITING ....................................................................................................................... 60 
15.0 STATISTICAL CONSIDERATIONS.............................................................................. 60 
15.1 Study design .................................................................................................................. 60 
15.2 Endpoints ....................................................................................................................... 60 
15.3 Statistical Hypotheses ................................................................................................... 61 
15.4 Sample Size Determination ........................................................................................... 61 
15.5 Population for Analyses ................................................................................................ 62 
15.6 Statistical Analyses ....................................................................................................... 62 
15.7 Continuous monitoring for toxicity using a Pocock-type boundary ............................. 64 
16.0 MULTICENTER REGULATORY REQUIREMENTS .................................................. 65 
17.0 REFERENCES ................................................................................................................. 66 
APPENDIX A: Karnofsky Performance Status Scale ................................................................. 68 
APPENDIX B: PATIENT’S MEDICATION DIARY ................................................................ 69 
APPENDIX C: Definitions for Adverse Event Reporting ........................................................... 70 
APPENDIX D: Reporting Timelines ........................................................................................... 73 
APPENDIX E: Washington University Unanticipated Problem Reporting Cover Sheet ........... 76 
APPENDIX F: TUMOR TISSUE SUBMISSION FORM .......................................................... 77 
APPENDIX G: PBMC & PLASMA CORRELATIVE BLOOD SUBMISSION FORM .......... 78 
 
 


 
Version 10 March 2022 
 
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PROTOCOL SUMMARY 
 
Synopsis 
 
Title: 
A single arm, multicenter, phase 2 trial to evaluate the efficacy of 
lenvatinib (LEN) in combination with pembrolizumab (KEYtruda) 
in subjects with locally advanced or metastatic Non-clear cell renal 
cell carcinoma (The LENKYN Trial) 
Study Description: 
This is a single-arm, multicenter, phase 2 study of lenvatinib 20 mg 
QD in combination with pembrolizumab 200mg q3weeks in 
subjects with locally advanced or metastatic nccRCC who have not 
received any systemic therapy for advanced disease. 
Objectives: 
Primary Objective: To evaluate objective response rate (ORR) of 
lenvatinib in combination with pembrolizumab in subjects with 
locally advanced or metastatic nccRCC. 
 
Secondary Objectives 
 To assess safety and tolerability of lenvatinib in 
combination with pembrolizumab in nccRCC patients 
 To evaluate progression-free survival (PFS) 
 To evaluate overall survival (OS) 
Endpoints: 
Primary Endpoint: The primary efficacy endpoint is ORR defined 
as the proportion of subjects who have a best overall response 
(BOR) of CR or PR. 
 
Secondary Endpoints:  
 Safety and tolerability – by CTCAE v 5.0 
 Progression-Free Survival (PFS) – defined as the time from 
date of first dose of study drug to date of first documentation 
of disease progression or death, whichever occurs first. 
 Overall Survival (OS) – defined as the time from the date of 
first dose of study drug until date of death from any cause. 
Study Population: 
The study population includes patients 18 years or older with locally 
advanced or metastatic histologically confirmed nccRCC who have 
not received any systemic therapy for advanced disease. 
Phase: 
Phase II 
Description of Sites / 
Facilities Enrolling: 
This is a multicenter trial with the intention of activating a total of 
four sites within the US. 
Description 
of 
Study 
Intervention: 
Lenvatinib (20 mg/day) administered orally in combination with 
pembrolizumab (200mg) infused every 3 weeks 
Study Duration: 
36 months  
Participant Duration: 
24 months  
 
 
 
 
 
 
 
 
 


 
Version 10 March 2022 
 
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SCHEMA 
 
 
 
 
 
#
#
Lenvatinib 20mg PO QD, 21 Day Cycle
Pembrolizumab IV 200mg Q3week
Clinic Visit
CT Chest and CT/MRI Abdomen & Pelvis
# Blood Sample Collection
Screening, Enrollment
Tumor Tissue Collection
#
End of Treatment


 
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1.0 
SCHEDULE OF ACTIVITIES 
 
Screening tests may take place no more than 21 days prior to the first day of study treatment.  
Window for study visits during treatment is +/- 7 days. 
1. Women of childbearing potential only 
2. Lenvatinib is to be self-administered daily on each day of every 21-day cycle 
3. Within 72 hours prior to first dose 
4. After coming off treatment, patients will be followed every 12 weeks +/- 1 week until death for survival. If 
patients discontinue treatment prior to progression, patients will continue to be followed by scans 
approximately every 9 weeks until progression or the start of another anti-cancer therapy. 
5. To be drawn at screening or C1D1 (up to 14 days prior to the start of treatment) 
6. C4D1 only 
7. Archival from within 3 months (preferred), up to 6 months acceptable; if no biopsy has been performed in the 
6 months prior to treatment start then an SOC biopsy should take place after a patient has been determined to 
be eligible for the trial, if safe and feasible. See section 10.0 for more details. 
8. Scans should continue every 9 weeks regardless of cycle length. See Section 12 for further instructions of 
timelines for obtaining confirmatory scans. For responses, or progression, a confirmatory scan should be 
performed at least 4 weeks after the initial scan showing progression or response. 
9. Albumin, alkaline phosphatase, total bilirubin (and direct bilirubin if total bilirubin is above ULN), 
bicarbonate, BUN, calcium, chloride, creatinine, glucose, phosphorus, potassium, total protein, AST, ALT, 
sodium 
 
 
 
 
  
Screening  
C1D1 
D1 of each 
subsequent cycle  
Q9 
wks 
EOT 
FU4 
Informed consent 
X 
  
  
 
  
  
H&P, PS 
X 
  
  
 
  
  
Vital signs 
X 
  
X 
 
  
  
CBC 
X 
X 
X 
 
X 
 
Blood chemistry9  
X 
  
X 
 
  
  
Pregnancy test1 
X3 
  
  
 
  
  
TSH 
X 
 
X 
 
 
 
INR 
X 
 
X 
 
 
 
Urinalysis 
X 
 
 
 
 
 
UPCR 
 
X 
X 
 
 
 
ECG 
X 
 
 
 
 
 
CT or MRI8 
X 
 
 
X 
X  
  
Pembrolizumab 
  
X 
X 
 
  
  
Lenvatinib2 
  
X----------------------X2 
 
  
  
Research tissue collection7 
 X 
 
  
 
  
  
Research blood collection  
 X5 
X5  
X6 
 
X 
  
Adverse events 
X--------------------------------------------------------- X 
Progression and survival 
 
 
 
 
 
X 


 
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2.0 
BACKGROUND AND RATIONALE 
 
2.1 
Renal Cell Carcinoma 
 
Kidney cancer accounts for approximately 2% of all cancer diagnoses and cancer deaths 
worldwide, with incidence rates generally higher in developed countries. Annually, 
approximately 295,000 new kidney cancer cases are diagnosed and approximately 
134,000 deaths are recorded worldwide (1). Men are more affected than women (a 2:1 
ratio of new diagnoses). Renal cell carcinoma (RCC) denotes cancer originated from renal 
epithelium and accounts for more than 90% of cancers in the kidney (2). The disease 
encompasses more than 10 histological and molecular subtypes, of which clear cell RCC 
(ccRCC) is most common and accounts for the most (~80%) kidney cancer-related deaths.  
 
Localized ccRCC can be successfully managed with surgery, whereas metastatic ccRCC 
is refractory to conventional chemotherapy (1). However, over the past two decades, 
marked advances in treatment of metastatic ccRCC have been made, with targeted agents 
(including sorafenib, sunitinib, bevacizumab, pazopanib and axitinib that inhibit vascular 
endothelial growth factor (VEGF) and its receptor (VEGFR)) and everolimus and 
temsirolimus, which inhibit mTOR complex 1, being approved (3). Since 2015, agents 
with additional targets aside from VEGFR have been approved, such as cabozantinib and 
lenvatinib; immunotherapies such as nivolumab, avelumab, pembrolizumab, and 
ipilimumab have also been added to the armamentarium for metastatic ccRCC (1, 4-6).  
 
2.2 
Non-Clear Cell Renal Cell Carcinoma (nccRCC) 
 
Patients with non-clear cell renal cell carcinoma (nccRCC) constitute 25-30% of RCC 
patients. nccRCC includes papillary RCC (pRCC, ∼15%), chromophobe RCC (chRCC, 
∼5%), rare molecular subtypes (<1%, e.g. TFE3 fusion kidney cancer), and unclassified 
RCC (uRCC, ~4%)(2, 7, 8). Due to rarity, advanced nccRCC patients have generally been 
excluded from most RCC clinical trials that focus on ccRCC (9). Hence, there is no first-
line standard of care for RCC patients with non-clear cell histology (9, 10). Accordingly, 
the choice of therapy in this patient population is challenging and is often extrapolated 
from the ccRCC patients and from retrospective studies. The National Comprehensive 
Cancer Network (NCCN) guidelines recommend sunitinib as the preferred regimen, with 
everolimus and cabozantinib being the alternative regimens (10). Sunitinib and 
everolimus offers first line PFS of 8.1 and 5.6 months respectively (11, 12), while PFS on 
any line of cabozantinib is 6.7 months (13). Similarly, ORR on first line sunitinib and 
everolimus as well as any line cabozantinib are 18%, 9% and 27%, respectively (3, 11, 
13). Hence, it is crucial to develop more effective therapies in the patient population. Of 
note, a recent 2019 GU ASCO meeting abstract of KEYNOTE Arm B reported 25% 
response rate of nccRCC treated with single agent Keytruda (14). 
 
2.3 
Pembrolizumab 
 
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody 
(mAb) with high specificity of binding to the programmed cell death 1 (PD-1) receptor, 


 
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thus inhibiting its interaction with programmed cell death ligand 1 (PD-L1) and 
programmed cell death ligand 2 (PD-L2). Based on preclinical in vitro data, 
pembrolizumab has high affinity and potent receptor blocking activity for PD-1. 
Pembrolizumab has an acceptable preclinical safety profile and is in clinical development 
as an intravenous (IV) immunotherapy for advanced malignancies. Keytruda™ 
(pembrolizumab) is indicated for the treatment of patients across a number of indications 
(15). 
 
2.4 
Lenvatinib 
 
Lenvatinib is an oral, multi–tyrosine kinase inhibitor active against RET, VEGFR1–3, 
FGFR1–3, KIT, and PDGFRα (16, 17). It is approved in the US in combination with 
everolimus for patients with advanced renal cell carcinoma following 1 prior 
antiangiogenic therapy (18).  
 
2.5 
Lenvatinib and Pembrolizumab 
 
The effect of combining lenvatinib with pembrolizumab has been evaluated in a 
multicenter, open-label phase Ib/II trial in patients with metastatic tumors, including clear 
cell renal cell carcinoma (ccRCC) (NCT02501096). Patients received oral lenvatinib 20 
mg daily in combination with pembrolizumab 200 mg IV every 3 weeks. Out of the 30 
patients enrolled, 12 (40%) were treatment-naive and 18 (60%) had at least one prior 
anticancer therapy. Objective response rate (ORR) at week 24 was 63.3% (95% CI, 43.9–
80.1) by investigator review, per immune related RECIST. ORR by IRR using RECIST 
1.1 was 66.7% (95% CI, 47.2–82.7), and median PFS was 17.7 mos (95% CI, 9.6–NE). 
Grade 3 or 4 adverse events (AEs) occurred in 21 (70%) pts; however, 4 (13%) 
discontinued treatment due to AE. The most common AEs were diarrhea (83%), fatigue 
(70%), hypothyroidism (67%), stomatitis (63%), and nausea (60%). The current treatment 
paradigm in RCC is shifting towards combination therapies, as they are more promising 
in overcoming the different mechanisms of resistance implicated. Lenvatinib and 
pembrolizumab have shown promising efficacy results in a phase Ib/IIb study of patients 
with metastatic ccRCC (19). Therefore, we propose a consortium-based phase II trial of 
lenvatinib and pembrolizumab in patients with locally advanced or metastatic nccRCC. 
The LENKYN trial is the first to test this combination in advanced nccRCC patients. 
 
2.6 
Study Design 
 
2.6.1 Overall Design 
 
This is a single-arm, multicenter, phase 2 study of lenvatinib in combination with 
pembrolizumab (lenvatinib 20 mg/day + pembrolizumab 200mg q3weeks) in 
subjects with unresectable advanced or metastatic nccRCC who have not received 
any chemotherapy for advanced disease.  
 
A Simon’s Two-Stage Design will be implemented in approximately 34 enrolled 
subjects. Nine subjects will be enrolled in Stage 1. If there are at least 2 responders 


 
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as assessed by ORR, the study will proceed to Stage 2 in which 25 more subjects 
may be enrolled. Otherwise, the study will stop early for futility. In the final 
analysis of 34 subjects, at least 9 responders are required to show a statistically 
significant improvement of ORR over historical control in the same patient 
population (one-sided type I error of 5% and targeting for 80% power). 
 
This study consists of 3 phases:  
1. Pre-treatment phase (Screening Periods) 
2. Treatment phase (starting Cycle 1 Day 1)  
3. Post-treatment phase (End of Treatment Visit and survival follow-up) 
 
The pre-treatment phase is planned to last no longer than 21 days and will include 
a screening period to establish protocol eligibility. 
 
The treatment phase will begin at the time of study drug administration on Day 1 
of Cycle 1 and continue in 21-day (3-week) cycles until completion of the off-
treatment assessments (within 30 days after the last study drug administration). 
Lenvatinib 20 mg/day will be administered orally on a daily basis and 
pembrolizumab 200 mg will be infused once every 3 weeks.  Subjects will undergo 
safety and efficacy assessments. Toxicity will be managed by treatment 
interruption, dose reduction and/or treatment discontinuation. Subjects who 
discontinue one of the study drugs due to its toxicities may continue to receive the 
other study drug as long as they demonstrate clinical benefit. Subjects will 
discontinue both study drugs at the time of confirmed disease progression, 
development of unacceptable toxicity, withdrawal of consent, or study 
termination. Subjects may be treated with pembrolizumab for a maximum of 35 
cycles or approximately 2 years, but treatment with lenvatinib can continue 
beyond 2 years if the subject does not meet other treatment discontinuation criteria. 
 
The post-treatment phase will start at the End of Treatment Visit and will continue 
as long as the subject is alive or until the study subject withdraws consent. Subjects 
who discontinue study treatment before disease progression will continue to 
undergo tumor assessment every 9 weeks ±1 week until documentation of disease 
progression or start of another anticancer therapy. Follow-up assessment for 
survival will be performed every 12 weeks ±1 week until death. 
 
A total of approximately 34 subjects will be enrolled. 
 
 
3.0 
OBJECTIVES AND ENDPOINTS 
 
Objectives 
Endpoints 
Justification for Endpoints 
Primary 
To evaluate objective 
response rate (ORR) of 
lenvatinib in combination 
The primary efficacy 
endpoint is ORR defined as 
the proportion of subjects 
There is no standard of care for 
locally advanced unresectable or 
metastatic nccRCC. This trial 


 
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with pembrolizumab in 
subjects with locally 
advanced or metastatic 
nccRCC.  
who have a best 
overall response (BOR) of 
CR or PR. 
 
wishes to establish effective 
treatment regimen for nccRCC at 
the first line setting. Hence, 
BOR of CR or PR is chosen as 
the primary endpoint. 
Secondary 
To assess safety and 
tolerability of lenvatinib in 
combination with 
pembrolizumab 
CTCAE v 5.0 
Although the safety profile of 
combining lenvatinib at 20mg 
daily and pembrolizumab 200mg 
Q3weeks was reported to be 
tolerable and is currently being 
investigated in a large phase III 
first-line trial for ccRCC, there is 
no safety and tolerability data of 
this combination in nccRCC. 
To evaluate progression-
free survival (PFS) 
Progression-Free Survival 
(PFS) – defined as the time 
from date of first dose of 
study drug to date of first 
documentation of disease 
progression or death, 
whichever occurs first. 
Progression free survival has 
been shown to be a good 
surrogate endpoint for survival 
benefit demonstrated in RCC. 
To evaluate overall 
survival (OS) 
 
Overall Survival (OS) – 
defined as the time from the 
date of first dose of study 
drug until date of death 
from any cause. 
Although the overall survival 
data takes a long time to mature 
and is with many confounding 
factors, it remains as the final 
proof of cancer treatment 
benefit. 
Tertiary/Exploratory 
To explore clinical benefit 
rate (CBR) 
Clinical benefit rate (CBR) 
is the proportion of subjects 
who have a BOR of CR or 
PR or durable stable disease 
(SD). Stable disease must be 
achieved at ≥ 23 weeks after 
first lenvatinib 
administration to be 
considered durable SD. 
 
There is no standard of care for 
nccRCC and no established 
biomarkers to predict treatment 
response of nccRCC to 
combined targeted and immune 
therapies. Blood and tissue 
biomarkers correlated with 
treatment outcome of nccRCC 
will be explored in this trial. 
 
 
 
 
To explore disease control 
rate (DCR) 
Disease control rate (DCR) 
is the proportion of subjects 
who have a BOR of CR, PR 
or SD. 
To explore duration of 
response (DOR) 
 
Duration of response (DOR) 
is defined as the time from 
the date that the criteria are 


 
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met for CR or PR 
(whichever is recorded first) 
to the date that progressive 
disease (PD) is objectively 
documented or death, 
whichever occurs first. 
To identify and explore 
tumor and blood 
biomarkers that correlate 
with clinical outcomes, 
including efficacy 
Blood immune cell CyTOF 
panel, plasma ProcartaPlex 
cytokine/chemokine/growth 
factor panel, and tissue 
MxIF tumor-immune 
interface panel will be 
performed on respective 
enrolled patient specimens. 
To explore the relationship 
of biomarkers, safety, and 
efficacy data using a 
model-based approach 
Potential biomarkers 
derived from this study will 
include DNA, RNA, 
protein, immune profiles, 
and tumor-immune 
interactions.  
 
 
4.0 
STUDY POPULATION 
 
4.1 
Inclusion Criteria 
 
1. Locally advanced or metastatic histologically confirmed nccRCC (2, 7).  Must have 
one of the following subtypes of nccRCC: 
a. papillary RCC 
b. chromophobe RCC 
c. TFE-3/B translocation RCC 
d. SDHB-loss RCC 
e. TSC1-loss RCC 
f. sarcomatoid RCC without clear cell component 
g. unclassified RCC 
 
2. Has not received any prior lines of systemic therapy except adjuvant or neoadjuvant 
treatments. 
 
3. Radiologically measurable disease meeting the following criteria: 
a. At least 1 lesion of ≥ 10 mm in the longest diameter for a non-lymph node or ≥ 15 
mm in the short axis diameter for a lymph node which is serially measurable 
according to iRECIST (Section 12) using computerized tomography (CT) or 
magnetic resonance imaging (MRI). 
b. Lesions that have had external beam radiotherapy (EBRT) or locoregional 
therapies such as radiofrequency (RF) ablation must show evidence of subsequent 


 
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progressive disease (substantial size increase of ≥20%) to be deemed a target 
lesion.  Patients who received EBRT must be at least 2 weeks out from last RT 
treatment. 
 
4. At least 18 years of age. 
 
5. Karnofsky performance status ≥ 70% (see Appendix A) 
 
6. Blood pressure (BP) ≤ 150/90 mmHg at screening with or without antihypertensive 
medications and no change in antihypertensive medications within 1 week prior to 
Cycle 1 Day 1. 
 
7. Adequate renal function defined as creatinine 1.5 x ULN or calculated creatinine 
clearance ≥40 mL/min per the Cockcroft and Gault formula with creatinine levels >1.5 
x ULN. 
 
8. Adequate bone marrow function: 
a. Absolute neutrophil count (ANC) ≥1500/mm3 (≥1.5 x 103/L) 
b. Platelets ≥100,000/mm3 (≥100 x 109/L) 
c. Hemoglobin ≥9.0 g/dL 
 
9. Adequate blood coagulation function as evidenced by an International Normalized 
Ratio (INR) ≤1.5 
 
10. Adequate liver function as evidenced by: 
a. bilirubin ≤1.5 times the upper limit of normal (ULN) 
b. alkaline phosphatase (ALP) ≤3×ULN (in the case of liver metastases ≤5×ULN) 
c. alanine aminotransferase (ALT) ≤3×ULN (in the case of liver metastases 
≤5×ULN) 
d. aspartate aminotransferase (AST) ≤3×ULN (in the case of liver metastases 
≤5×ULN). 
In case ALP is >3×ULN (in the absence of liver metastases) or >5×ULN (in the 
presence of liver metastases) AND the subject also is known to have bone metastases, 
the liver specific ALP isoenzyme must be separated from the total and used to assess 
the liver function instead of the total ALP. 
 
11. Subjects with known brain metastases will be eligible if they have completed the 
primary brain therapy (such as whole brain radiotherapy, stereotactic radiosurgery, or 
complete surgical resection) and if they have remained clinically stable, 
asymptomatic, and off steroids for at least 2 months before starting study treatment. 
 
12. All females of childbearing potential (please refer to Section 6.4) must have a negative 
serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of 
beta-human chorionic gonadotropin [β-hCG]) at the screening visit. Females of 
childbearing potential* must agree to use a highly effective method of contraception 
(please refer to Section 6.5) for the entire study period and for 120 days after study 


 
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discontinuation 
 
13. Male subjects who are partners of women of childbearing potential must follow one 
of the methods of contraception described in Section 6.5 beginning at least 1 menstrual 
cycle prior to starting study drugs, throughout the entire study period, and for 120 days 
after the last dose of study drug, unless the male subjects are totally sexually abstinent 
or have undergone a successful vasectomy with confirmed azoospermia or unless the 
female partners have been sterilized surgically or are otherwise proven sterile. 
 
14. Archival tumor tissue from within 3 months (preferred) or up to 6 months 
(acceptable)must be available prior to the first dose of study drug for biomarker 
analysis. If no biopsy has been performed in the prior 6 months, an SOC biopsy is 
requested if safe and feasible. In the case tissue cannot be provided, patients can be 
enrolled upon consultation and agreement by the trial PI. 
 
Note: In case of submitting unstained cut slides, freshly cut slides should be submitted 
to the testing laboratory within 14 days from when the slides are cut. 
 
15. Ability to understand and willingness to sign an IRB approved written informed 
consent document (or that of legally authorized representative, if applicable). 
 
4.2 
Exclusion Criteria 
 
1. Predominant clear cell renal cell carcinoma (RCC) 
 
2. Uncontrolled or untreated brain metastasis  
 
3. Major surgery performed within 4 weeks prior to the first dose of study drugs or 
scheduled for major surgery during the study. Subjects must have recovered 
adequately from any toxicity and/or complications from major surgery prior to starting 
therapy. 
 
4. Subjects having >1+ proteinuria on urinalysis will undergo 24-h urine collection for 
quantitative assessment of proteinuria. Subjects with urine protein ≥1 g/24-hour will 
be ineligible. 
 
5. Gastrointestinal malabsorption, gastrointestinal anastomosis, or any other condition 
that might affect the absorption of lenvatinib. 
 
6. New York Heart Association congestive heart failure of grade II or above, unstable 
angina, myocardial infarction within the past 6 months, or serious cardiac arrhythmia 
associated with significant cardiovascular impairment within the past 6 months. 
 
7. Prolongation of QTc interval to >480 msec. 
 
8. Active hemoptysis (bright red blood of at least 0.5 teaspoon) within 3 weeks prior to 


 
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the first dose of study drug. 
 
9. Clinically significant active infection (any infection requiring systemic treatment).  
 
10. Subject is known to be positive for Human Immunodeficiency Virus (HIV), Hepatitis 
B, or Hepatitis C  
 
11. Serious nonhealing wound, ulcer, or bone fracture.  
 
12. Known intolerance to either of the study drugs (or any of the excipients).  
 
13. History of organ allograft (subject has had an allogenic tissue/solid organ transplant), 
or allogeneic stem cell transplant (subject has received blood-forming stem cells from 
a donor). 
 
14. Biologic response modifiers (e.g., granulocyte colony-stimulating factor) within 4 
weeks before study entry. Chronic erythropoietin therapy is permitted provided that 
no dose adjustments were made within 2 months before first dose of study treatment. 
 
15. Any medical or other condition which, in the opinion of the investigator, would 
preclude participation in a clinical trial. 
 
16. Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the trial, starting with the pre-screening or screening visit 
through 120 days after the last dose of trial treatment.  If the required urine pregnancy 
test is positive (or cannot be confirmed as negative) within 72 hours prior to the start 
of treatment, a serum pregnancy test will be required. 
 
17. Excluding the primary tumor leading to enrollment in this study, any other active 
malignancy (except for definitively treated melanoma in-situ, basal or squamous cell 
carcinoma of the skin, or carcinoma in-situ of the bladder or cervix) within the past 36 
months. 
 
18. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any 
other form of immunosuppressive therapy within 7 days prior to the first dose of study 
treatment. The use of up to 10 mg/day of prednisone or equivalent is approved and 
does not exclude the patient from the trial. 
 
19. Active autoimmune disease that has required systemic treatment in past 2 years (i.e., 
with use of disease modifying agents, > 10 mg of prednisone per day, 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. The use of up to 10 mg/day of 
prednisone or equivalent is approved and does not exclude the patient from the trial. 
 
20. Has a history of (non-infectious) pneumonitis/interstitial lung disease that required 


 
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maintenance steroids (>10 mg of prednisone) or current pneumonitis/interstitial lung 
disease. 
 
21. Has received a live-virus vaccination or live-attenuated vaccine within 30 days of 
planned treatment start. Administration of killed vaccines is allowed. 
 
4.3 
Inclusion of Women and Minorities 
 
Both men and women and members of all races and ethnic groups are eligible for this trial.   
 
 
5.0 
REGISTRATION PROCEDURES 
 
Patients must not start any protocol intervention prior to registration through the Siteman 
Cancer Center. 
 
The following steps must be taken before registering patients to this study: 
 
1. Confirmation of patient eligibility by Washington University 
2. Registration of patient in the Siteman Cancer Center database 
3. Assignment of unique patient number (UPN) 
 
Once the patient has been entered in the Siteman Cancer Center OnCore database, the WUSM 
coordinator will forward verification of enrollment and the UPN via email. 
 
5.1 
Confirmation of Patient Eligibility 
 
Confirm patient eligibility by collecting the information listed below and scanning and 
emailing it to the research coordinator listed in the Siteman Cancer Center Clinical Trials 
Core Protocol Procedures for Secondary Sites packet at least two business days prior to 
registering patient: 
 
1. Your name and contact information (telephone number, fax number, and email 
address) 
2. Your site PI’s name, the registering MD’s name, and your institution name 
3. Patient’s race, sex, and DOB 
4. Three letters (or two letters and a dash) for the patient’s initials 
5. Currently approved protocol version date 
6. Copy of signed consent form (patient name may be blacked out) 
7. Planned date of enrollment 
8. Completed eligibility checklist, signed and dated by a member of the study team 
9. Copy of appropriate source documentation confirming patient eligibility 
 
5.2 
Patient Registration in the Siteman Cancer Center OnCore Database 
 
Registrations may be submitted Monday through Friday between 8am and 5pm CT. 


 
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Urgent late afternoon or early morning enrollments should be planned in advance and 
coordinated with the Washington University research coordinator.  Registration will be 
confirmed by the research coordinator or his/her delegate by email within two business 
days. Verification of eligibility and registration should be kept in the patient chart. 
 
All patients at all sites must be registered through the Siteman Cancer Center OnCore 
database at Washington University. 
 
5.3 
Assignment of UPN 
 
Each patient will be identified with a unique patient number (UPN) for this study.  Patients 
will also be identified by first, middle, and last initials.  If the patient has no middle initial, 
a dash will be used on the case report forms (CRFs).  All data will be recorded with this 
identification number on the appropriate CRFs. 
 
5.4 
Screen Failures 
 
Screen failures are defined as participants who consent to participate in the clinical trial 
but are not subsequently entered in the study.  A minimal set of screen failure information 
is required to ensure transparent reporting of screen failure participants, to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities.  Minimal information includes 
demography, screen failure details, eligibility criteria, and any serious adverse event (if 
applicable).   
 
 
6.0 
TREATMENT PLAN 
 
6.1 
Study Intervention Administration 
 
Lenvatinib 20 mg will be administered with water orally once a day (with or without food) 
in 21-day cycles at approximately the same time each day. Treatment cycles will be 
counted continuously regardless of dose interruptions (meaning that cycles will not last 
for more than 21 days regardless of the number of lenvatinib doses a patient receives 
during that cycle). On Day 1 (D1) of each cycle, it will be administered approximately 
within 1 hour after completion of pembrolizumab administration.  
 
Pembrolizumab will be administered as a dose of 200 mg as a 30-minute IV infusion, 
Q3W (25 minutes to 40 minutes are acceptable), for a maximum of 35 cycles.  
 
6.2 
Definitions of Evaluability 
 
All patients who receive any study treatment are evaluable for toxicity.  Patients are 
evaluated from first receiving study treatment until a 30-day follow up after the conclusion 
of treatment or death. 
 


 
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All patients who have received at least one cycle of therapy and have their disease re-
evaluated will be considered evaluable for response (exceptions will be those who exhibit 
objective disease progression prior to the end of Cycle 1 who will also be considered 
evaluable).   
 
6.3 
Concomitant Medications/Vaccinations 
 
Medications or vaccinations specifically prohibited in the exclusion criteria are not 
allowed during the ongoing trial.  If there is a clinical indication for one of these or other 
medications or vaccinations specifically prohibited during the trial, discontinuation from 
trial therapy or vaccination may be required.  The final decision on any supportive therapy 
or vaccination rests with the investigator and/or the subject's primary physician.  
 
6.3.1 Acceptable Concomitant Medications  
 
All treatments that the investigator considers necessary for a participant’s welfare 
may be administered at the discretion of the investigator in keeping with the 
community standards of medical care.  All concomitant medication will be 
recorded on the case report form (CRF) including all prescription, over-the-
counter (OTC), herbal supplements, and IV medications and fluids.  If changes 
occur during the trial period, documentation of drug dosage, frequency, route, and 
date may also be included on the CRF. 
All concomitant medications received within 28 days before the first dose of trial 
treatment and 30 days after the last dose of trial treatment should be recorded.  
Concomitant medications administered after 30 days after the last dose of trial 
treatment should be recorded for SAEs and ECIs. 
6.3.2 Prohibited Concomitant Medications 
 
Participants 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 lenvatinib and pembrolizumab 
 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 study treatment and 
while participating in the study.  Examples of live vaccines include, but are 
not limited to, the following: measles, mumps, rubella, varicella/zoster, 
yellow fever, rabies, BCG, and typhoid vaccine. Seasonal influenza 
vaccines for injection are generally killed virus vaccines and are allowed; 


 
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however, intranasal influenza vaccines (eg, FluMist®) are live attenuated 
vaccines and are not allowed.  
 Systemic glucocorticoids for any purpose other than to modulate 
symptoms from an event of clinical interest of suspected immunologic 
etiology.  The use of physiologic doses of corticosteroids may be approved 
after consultation with the PI. 
 
Participants who, in the assessment by the investigator, require the use of any of 
the aforementioned treatments for clinical management should be removed from 
the study.  All treatments that the Investigator considers necessary for a 
participant’s welfare may be administered at the discretion of the Investigator in 
keeping with the community standards of medical care.   
 
Lenvatinib can prolong the QT interval, so providers must use caution with 
coadministration of QT-prolonging agents. 
 
Medications or vaccinations specifically prohibited in the exclusion criteria are not 
allowed during the ongoing study.  If there is a clinical indication for any 
medication or vaccination specifically prohibited during the study, discontinuation 
from study therapy or vaccination may be required.  The final decision on any 
supportive therapy or vaccination rests with the investigator and/or the 
participant's primary physician.  However, the decision to continue the participant 
on study treatment requires the mutual agreement of the investigator and the 
participant. 
 
There are no prohibited therapies during the post-treatment follow-up phase. 
 
6.3.3 Rescue Medications and Supportive Care 
 
Participants should receive appropriate supportive care measures as deemed 
necessary by the treating investigator.  Suggested supportive care measures for the 
management of AEs with potential immunologic etiology are outlined along with 
the dose modification guidelines in Section 7.0.  Where appropriate, these 
guidelines include the use of oral or IV treatment with corticosteroids, as well as 
additional anti-inflammatory agents if symptoms do not improve with 
administration of corticosteroids.  Note that several courses of steroid tapering 
may be necessary as symptoms may worsen when the steroid dose is decreased.  
For each disorder, attempts should be made to rule out other causes such as 
metastatic disease or bacterial or viral infection, which might require additional 
supportive care.  The treatment guidelines are intended to be applied when the 
Investigator determines the events to be related to pembrolizumab.  
 
Note: If after the evaluation of the event, it is determined not to be related to 
pembrolizumab, the Investigator does not need to follow the treatment guidance.  
Refer to Section 7.0 for guidelines regarding dose modification and supportive 
care.  


 
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It may be necessary to perform conditional procedures such as bronchoscopy, 
endoscopy, or skin photography as part of evaluation of the event. 
 
6.4 
Women of Childbearing Potential (WOCBP) 
 
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below).  
 
Women in the following categories are not considered WOCBP: 
 Premenarchal 
 Premenopausal female with 1 of the following: 
o Documented hysterectomy 
o Documented bilateral salpingectomy 
o Documented bilateral oophorectomy 
Note:  Documentation can come from the site personnel’s review of the 
participant’s medical records, medical examination, or medical history 
interview. 
 Postmenopausal female 
o A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause.  
 A high follicle stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not 
using hormonal contraception or hormonal replacement therapy 
(HRT). However, in the absence of 12 months of amenorrhea, 
confirmation with two FSH measurements in the postmenopausal 
range is required.  
o Females on HRT and whose menopausal status is in doubt will be required 
to use one of the non-hormonal highly effective contraception methods if 
they wish to continue their HRT during the study. Otherwise, they must 
discontinue HRT to allow confirmation of postmenopausal status before 
study enrollment. 
 
6.5 
Contraception Requirements  
 
Male Participants 
Male participants with female partners of childbearing potential are eligible to participate 
if they agree to one of the following during the protocol defined time frame:  
 
 Be abstinent from penile-vaginal intercourse as their usual and preferred lifestyle 
(abstinent on a long term and persistent basis) and agree to remain abstinent 
 Use a male condom plus partner use of a contraceptive method with a failure rate 
of <1% per year as described in the table below when having penile-vaginal 
intercourse with a woman of childbearing potential who is not currently pregnant. 


 
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 Note: Men with a pregnant or breastfeeding partner must agree to remain abstinent 
from penile-vaginal intercourse or use a male condom during each episode of 
penile penetration. 
 
Female Participants 
Female participants of childbearing potential are eligible to participate if they agree to use 
a highly effective method of contraception consistently and correctly as described in the 
table below during the protocol-defined time frame.  
 
Highly Effective Contraceptive Methods That Are User Dependent a  
Failure rate of <1% per year when used consistently and correctly. 
● Combined (estrogen- and progestogen- containing ) hormonal contraception b, c 
○ Oral  
○ Intravaginal  
○ Transdermal  
○ Injectable 
● Progestogen-only hormonal contraception b, c 
○ Oral  
○ Injectable  
Highly Effective Methods That Have Low User Dependency  
Failure rate of <1% per year when used consistently and correctly. 
● Progestogen- only contraceptive implant b, c  
● Intrauterine hormone-releasing system (IUS) b  
● Intrauterine device (IUD) 
● Bilateral tubal occlusion 
● Vasectomized partner  
A vasectomized partner is a highly effective contraception method provided that the 
partner is the sole male sexual partner of the WOCBP and the absence of sperm has 
been confirmed. If not, an additional highly effective method of contraception should 
be used.  
● Sexual abstinence  
Sexual abstinence is considered a highly effective method only if defined as refraining 
from heterosexual intercourse during the entire period of risk associated with the study 
treatment. The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the study and the preferred and usual lifestyle of the participant.)  
Notes:  
Use should be consistent with local regulations regarding the use of contraceptive 
methods for participants of clinical studies.  
 
a) Typical use failure rates are lower than perfect-use failure rates (i.e. when used 
consistently and correctly).  
b) If hormonal contraception efficacy is potentially decreased due to interaction with 
study treatment, condoms must be used in addition to the hormonal contraception 
during the treatment period and for at least 120 days after the last dose of study 
treatment . 
c) If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) 
guidelines, acceptable hormonal contraceptives are limited to those which inhibit 
ovulation.  
 


 
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6.6 
Pregnancy Testing  
 
WOCBP should only be included after a negative highly sensitive urine or serum 
pregnancy test.  
 
Following initiation of treatment, pregnancy testing will be performed whenever an 
expected menstrual cycle is missed or when pregnancy is otherwise suspected; at the time 
points specified in the study calendar, and as required locally. 
 
6.7 
Duration of Therapy 
 
If at any time the constraints of this protocol are considered to be detrimental to the 
patient’s health and/or the patient no longer wishes to continue protocol therapy, the 
protocol therapy should be discontinued and the reason(s) for discontinuation documented 
in the case report forms. 
 
In the absence of treatment delays due to adverse events, treatment with pembrolizumab 
may continue for a maximum of 35 cycles (approximately 2 years) and treatment with 
lenvatinib may continue indefinitely or until one of the following criteria applies: 
 
 Documented and iRECIST confirmed disease progression 
 Death 
 Adverse event(s) that, in the judgment of the investigator, may cause severe or 
permanent harm or which rule out continuation of study drug 
 General or specific changes in the patient’s condition render the patient unable to 
receive further treatment in the judgment of the investigator 
 Suspected pregnancy 
 Serious noncompliance with the study protocol 
 Lost to follow-up 
 Patient withdraws consent 
 Investigator removes the patient from study 
 The Siteman Cancer Center decides to close the study 
 
Patients who prematurely discontinue treatment for any reason will still be followed as 
indicated in the study calendar. 
 
6.8 
Duration of Follow-up 
 
After coming off treatment, patients will be followed approximately every 12 weeks until 
death for survival. Patients who discontinue prior to progression will continue scans 
approximately every 9 weeks until progression or the start of another anti-cancer therapy.  
Patients removed from study for unacceptable adverse events will be followed until 
resolution or stabilization of the adverse event. 
 
6.9 
Lost to Follow-Up 
 


 
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A participant will be considered lost to follow-up if he or she fails to return for 2 scheduled 
visits and is unable to be contacted by the study team. 
 
The following actions must be taken if the participant fails to return to clinic for a required 
study visit: 
o The study team will attempt to contact the participant and reschedule the missed 
visit within 2 weeks and counsel the participant on the importance of maintaining 
the assigned visit schedule and ascertain if the participant wishes to and/or should 
continue in the study. 
o Before a participant is deemed lost to follow-up, the investigator or designee will 
make every effort to regain contact with the participant (where possible, 3 
telephone calls and, if necessary, a certified letter to the participant’s last known 
mailing address).  These contact attempts should be documented in the 
participant’s medical record or study file. 
o Should the participant continue to be unreachable, he or she will be considered to 
have withdrawn from the study with a primary reason of lost to follow-up. 
 
 
7.0 
DOSE DELAYS/DOSE MODIFICATIONS 
 
Other holds and modifications beyond those described below may be made at the discretion of 
the PI. Dose holds of modifications for lenvatinib and pembrolizumab can occur independently 
of each other provided the toxicity is clearly attributable to the individual therapy, with the 
exception of toxicities that fall under the guidance in Section 7.2. 
 
7.1 
Lenvatinib 
 
Lenvatinib dose reduction and interruption for subjects who experience lenvatinib-related 
toxicity will be in accordance with the dose reduction instructions shown in the tables 
below. Any dose reduction below 4 mg/day must be discussed with the trial PI. Once the 
dose has been reduced, it cannot be increased at a later date.  
 
Dose Reduction Recommendations for Lenvatinib Treatment-Related Toxicity 
Initial 
Lenvatinib Dose 
Adjusted Dose To Be Administered 
Reduction 1 
Reduction 2 
Reduction 3 
Reduction 4 
20 mg QD 
14 mg QD 
10 mg QD 
8 mg QD 
4a mg QD 
a. Consult trial PI for further dose reduction recommendations. 
 
Occurrence of Lenvatinib 
Treatment-related 
Toxicitya,b 
During Therapy 
Adjusted Dosef 
Grade 1, Tolerable Grade 2 
Any occurrence 
Continue treatment 
No change 
Intolerable Grade 2c,d and Grade 3g 
First occurrence 
Interrupt lenvatinib until resolved 
to tolerable Grade 2, or Grade 0-1 
Reduce lenvatinib by 1 
dose level 


 
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Second occurrence 
(same toxicity or new toxicity) 
Interrupt lenvatinib until resolved 
to tolerable Grade 2, or Grade 0-1 
Reduce lenvatinib by 1 
more dose level 
Third occurrence 
(same toxicity or new toxicity) 
Interrupt lenvatinib until resolved 
to tolerable Grade 2, or Grade 0-1 
Reduce lenvatinib by 1 
more dose level 
Fourth occurrence 
(same toxicity or new toxicity) 
Interrupt lenvatinib until resolved 
to tolerable Grade 2, or Grade 0-1 
Reduce lenvatinib by 1 
more dose level 
Grade 4e,g 
Any occurrence 
Discontinue lenvatinib 
a. An interruption of lenvatinib treatment for more than 21 days (due to lenvatinib treatment-related 
toxicities) will require a discussion with the Sponsor before treatment can be resumed. 
b. Excluding alopecia. Initiate optimal medical management for nausea, vomiting, hypothyroidism, 
hypertension, and/or diarrhea prior to any lenvatinib interruption or dose reduction.  
c. Applicable only to Grade 2 toxicities judged by subject and/or physician to be intolerable. 
d. Obese subjects with weight loss do not need to return to the baseline weight or 10% of baseline 
weight (i.e. grade 1 weight loss).  These subjects will restart the study drugs at a lower dose once their 
weight remains stable for at least 1 week and they reached the normal BMI (if the weight loss occurred 
but it is still above normal BMI, they can restart the study treatment at a lower dose once the weight 
has been stable for at least 1 week).  Normal BMI should be used as the new baseline for further dose 
reductions. 
e. Excluding laboratory abnormalities judged to be non-life-threatening, in which case manage as 
Grade 3. 
f. Refer to table above for adjusted dose. 
g. For asymptomatic Grade ≥3 elevations of amylase and lipase, the trial PI should be consulted to 
obtain permission to continue treatment. 
 
7.1.1 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 of ≤150/90 mm Hg at the time of study entry 
and, if known to be hypertensive, have been on a stable dose of antihypertensive 
therapy for at least 1 week before Cycle 1/Day 1. 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 elevated BP (systolic BP 
≥140 mm Hg or diastolic BP ≥90 mm Hg) is confirmed on 2 assessments a 
minimum of 1 hour apart. One BP assessment is defined as the mean value of 3 
measurements at least 5 minutes apart. The choice of antihypertensive treatment 
should be individualized to the subject’s clinical circumstances and follow 
standard medical practice. For previously normotensive subjects, appropriate 
antihypertensive therapy should be started when systolic BP ≥140 mm Hg or 
diastolic BP ≥90 mm Hg is first observed on 2 assessments a minimum of 1 hour 
apart. For those subjects already on antihypertensive medication, treatment 
modification may be necessary if hypertension persists. For subjects with 
hypertension and proteinuria, appropriate therapy, eg, angiotensin-converting 
enzyme inhibitor or angiotensin-II receptor antagonist, is preferred (Kilfoy, et al., 
2009). 


 
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Lenvatinib should be withheld in any instance where a subject is at imminent risk 
to develop a hypertensive crisis or has significant risk factors for severe 
complications of uncontrolled hypertension (eg, BP ≥160/100 mm Hg, significant 
risk factors for cardiac disease, intracerebral hemorrhage, or other significant co-
morbidities). Once the subject has been on the same hypertensive medications for 
at least 48 hours and the BP is controlled, lenvatinib should be resumed as 
described below. 
 
During the Treatment Period, subjects with systolic BP ≥160 mm Hg or diastolic 
BP ≥100 mm Hg must have their BP monitored on Day 15 or more frequently as 
clinical indicated until systolic BP has been ≤150 mm Hg and diastolic BP has 
been ≤95 mm Hg for 3 consecutive months. If a repeat event of systolic BP ≥160 
mm Hg or diastolic BP ≥100 mm Hg occurs, the subject must resume the Day 15 
evaluation until systolic BP has been ≤150 mm Hg and diastolic BP has been ≤95 
mm Hg for 3 consecutive months. 
 
The following guidelines should be followed for the management of systolic BP 
≥160 mm Hg or diastolic BP ≥100 mm Hg confirmed on repeat measurements 
after 1 hour: 
 
1. Continue lenvatinib and institute antihypertensive therapy for subjects not 
already receiving antihypertensive medication 
2. For those subjects already on antihypertensive medication, dose of the current 
agent may be increased, if appropriate, or 1 or more agents of a different class 
of antihypertensive should be added. 
3. If systolic BP ≥160 mm Hg or diastolic BP ≥100 mm Hg persists despite 
maximal antihypertensive therapy, then lenvatinib administration should be 
interrupted. It should be restarted at one lower dose level as specified in Table 
3 only when systolic BP ≤150 mm Hg and diastolic BP ≤95 mm Hg and the 
subject has been on a stable dose of antihypertensive medication for at least 48 
hours 
- 
If systolic BP ≥160 mmHg or diastolic BP ≥100 mmHg recurs on the first 
dose reduction despite optimal management of hypertension with 
antihypertensive medications (either by dose increase or the addition of a 
different class of restarted at an additional dose reduction as specified in 
Table 3 only when systolic BP ≤150 mmHg and diastolic BP ≤95 mmHg 
and the subject has been on a stable dose of antihypertensive medication 
for at least 48 hours. 
- 
If systolic BP ≥160 mmHg or diastolic BP ≥100 mmHg recurs on the 
second dose reduction 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. It should be restarted at a third dose reduction as specified 
in Table 3 only when systolic BP ≤150 mmHg and diastolic BP ≤95 mmHg 


 
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and the subject has been on a stable dose of antihypertensive medication 
for at least 48 hours. 
 
The following guidelines should be followed for the management of Grade 4 
hypertension (life-threatening consequences): 
 Institute appropriate medical management 
 Discontinue study drug 
 
7.1.2 Management of Proteinuria 
 
Regular assessment of proteinuria should be conducted as detailed in the study 
calendar. Guidelines for assessment and management of proteinuria: 
1. Grading will be based on the 24-hour urinary protein result. Management 
of lenvatinib administration will be based on the grade of proteinuria 
according to instructions contained the table above, “Dose Modifications 
for Lenvatinib Treatment-Related Toxicity.” 
2. A 24-hour urine collection (within 72 hours) to verify the grade of 
proteinuria for protein quantitation is required in the following situations: 
a. The first (initial) occurrence of ≥2+ proteinuria on urine dipstick 
while on study drug 
b. A subsequent increase in severity of urine dipstick proteinuria 
occurring on the same lenvatinib dose level 
c. When there has been a lenvatinib dose reduction and at the new 
dose level the urine protein dipstick result is 2+, 3+, or 4+ 
3. Urine dipstick testing for subjects with proteinuria ≥2+ should be 
performed on Day 15 (or more frequently as clinically indicated) until the 
results have been 1+ or negative for 3 consecutive months. 
 
Grading of proteinuria should be performed according to CTCAE v 5 but will be 
based on the 24-hour urine collection for total protein result, if a 24-hour urine was 
performed at that time point. 
 
For subjects with lenvatinib-related toxicity, the dose reduction and/or interruption 
instructions provided in the table above, “Dose Modifications for Lenvatinib 
Treatment-Related Toxicity,” should be followed. 
 
7.1.3 Management of Hepatotoxicity 
 
Regular monitoring of liver function tests (eg, alanine transaminase [ALT], 
aspartate transaminase [AST], bilirubin levels) should be conducted as detailed in 
the study calendar and as clinically indicated. If signs occur indicating a decrease 
in liver function by 1 grade or more from baseline, the instructions contained in 
the table above, “Dose Modifications for Lenvatinib Treatment-Related Toxicity,” 
should be followed. Appropriate supportive care should be provided together with 
close monitoring. If hepatic failure occurs the study drug must be discontinued. 
 


 
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7.1.4 Management of Thromboembolic Events 
 
Subjects should be advised to pay attention to the symptoms suggestive of venous 
thromboembolic events, which include acute onset of dyspnea, chest pain, cough, 
hemoptysis, tachypnea, tachycardia, cyanosis, DVT signs including lower-
extremity swelling, redness and warmth to touch or tenderness. In case any of these 
signs or symptoms appear, subjects should be instructed to report such signs and 
symptoms promptly to the treating physician. If a thromboembolic event is 
confirmed, instructions contained in the table above, “Dose Modifications for 
Lenvatinib Treatment-Related Toxicity,” should be followed. Appropriate 
supportive care should be provided together with close monitoring. If a subject 
experiences life-threatening (Grade 4) thromboembolic reactions, including 
pulmonary embolism, the study drug must be discontinued. 
 
7.1.5 Management of Posterior Reversible Encephalopathy Syndrome 
(PRES) 
 
In clinical studies with lenvatinib, events of posterior reversible encephalopathy 
syndrome (PRES) were reported in less than 1% of lenvatinib-treated subjects. 
PRES is a neurological disorder that can present with headache, seizure, lethargy, 
confusion, altered mental function, blindness, and other visual or neurological 
disturbances. Mild to severe hypertension may be present. MRI is necessary to 
confirm the diagnosis of PRES. Appropriate measures should be taken to control 
blood pressure. In subjects with signs or symptoms of PRES, dose interruptions, 
reductions, or discontinuation may be required per instructions included in the 
table above, “Dose Modifications for Lenvatinib Treatment-Related Toxicity.” 
Please refer to Section 7 of the Investigator's Brochure for further information on 
lenvatinib, including the full set of special warnings and precautions for use 
(Section 7.4.4). 
 
7.1.6 Management of Hypocalcemia 
 
Serum calcium should be monitored every 3 weeks per the study calendar. 
Hypocalcemia should be treated per institutional guidelines (e.g., using, as 
appropriate, calcium, magnesium, and Vitamin D supplementation) until 
resolution. 
 
7.2 
Pembrolizumab 
 
Pembrolizumab dose interruption for subjects who experience pembrolizumab-related 
toxicity will be in accordance with the table below. Adverse events (both nonserious and 
serious) associated with pembrolizumab exposure, including coadministration with 
additional compounds, may represent an immunologic etiology. These AEs 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 the table below.  


 
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Dose Modification and Toxicity Management Guidelines for Immune-related Adverse Events Associated with Pembrolizumab 
and Combination Therapy 
 
General instructions: 
1. Corticosteroid taper should be initiated upon AE improving to Grade 0 or 1 and continue to taper over at least 4 weeks. 
2. For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has improved to Grade 0 or 1 and corticosteroid has been 
tapered. Pembrolizumab should be permanently discontinued if AE does not resolve within 12 weeks of last dose or corticosteroids cannot be reduced to ≤10 
mg prednisone or equivalent per day within 12 weeks. 
*For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other immunosuppressive treatment should be initiated 
irAEs cannot be controlled by corticosteroids. 
Immune-
related 
Adverse Event 
Toxicity Grade or 
Conditions 
(CTCAE V5.0) 
Action Taken with 
Pembrolizumab 
irAE Management with 
Corticosteroids and 
Other Therapies 
Monitor and 
Follow-up 
Pneumonitis 
Grade 2 
Withhold 
Administer corticosteroids (initial 
dose of 1-2 mg/kg 
prednisone or equivalent) followed by 
taper.  
Add prophylactic antibiotics for 
opportunistic infections. 
Monitor subjects for signs and 
symptoms of pneumonitis. 
Evaluate subjects with 
suspected pneumonitis 
with radiographic imaging and 
initiate corticosteroid treatment. 
Grade 3 or 4, 
or recurrent 
Grade 2 
Permanently 
discontinue 
Diarrhea / 
Colitis 
Grade 2 or 3 
Withhold 
Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper. Subjects 
with diarrhea/ colitis should be advised 
to drink liberal quantities of clear 
fluids. If sufficient oral fluid intake is 
not feasible, fluid and electrolytes 
should be substituted via IV infusion. 
Monitor subjects for signs and 
symptoms of enterocolitis (i.e., 
diarrhea, abdominal pain, blood 
or mucus in stool with or 
without fever) and of bowel 
perforation (i.e., 
peritoneal signs and ileus). 
Subjects with Grade ≥2 diarrhea 
suspecting colitis should 
consider GI consultation and 
performing endoscopy to rule 
out colitis 
Grade 4 or recurrent 
Grade 3 
Permanently 
discontinue 
AST / ALT 
elevation or 
Increased 
bilirubin 
Grade 2a 
Withhold 
Administer corticosteroids (initial dose 
of 0.5 - 1 mg/kg prednisone or 
equivalent) followed by taper. 
Monitor with liver function tests 
(consider weekly or more 
frequently until liver enzyme 
value returned to baseline or is 
stable) 
Grade 3b or 4c 
 
Permanently 
discontinue 
Administer corticosteroids (initial dose 
of 1-2 mg/kg prednisone or equivalent) 
followed by taper. 


 
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Type 1 diabetes 
mellitus 
(T1DM) 
or 
Hyperglycemia 
Newly onset 
T1DM or 
Grade 3 or 4 
hyperglycem 
ia associated 
with 
evidence of 
β-cell failure 
Withholdd 
Initiate insulin replacement therapy for 
subjects with T1DM. Administer 
antihyperglycemic in subjects with 
hyperglycemia. 
Monitor subjects for 
hyperglycemia or other signs 
and symptoms of 
diabetes. 
Hypophysitis 
Grade 2 
Withhold 
Administer corticosteroids and initiate 
hormonal replacements as clinically 
indicated. 
Monitor for signs and 
symptoms of hypophysitis 
(including hypopituitarism and 
adrenal insufficiency). 
Grade 3 or 4 
Withhold or 
permanently 
discontinued 
Hyperthyroidism 
Grade 2 
Continue 
Treat with nonselective 
beta-blockers (eg, propranolol) or 
thionamides as appropriate. 
Monitor for signs and 
symptoms of thyroid disorders. 
Grade 3 or 4 
Withhold or 
permanently 
discontinued 
Hypothyroidism 
Grade 2-4 
Continue 
Initiate thyroid replacement hormones 
(eg, levothyroxine or liothyroinine) per 
standard of care. 
Monitor for signs and 
symptoms of thyroid 
disorders. 
Nephritis: 
grading 
according to 
increased 
creatinine or 
acute kidney 
injury 
Grade 2 
Withhold 
Administer corticosteroids (prednisone 
1-2 mg/kg or equivalent) followed by 
taper. 
Monitor changes of renal 
function. 
Grade 3 or 4 
Permanently 
discontinue 
Neurological 
Toxicities 
Grade 2 
 
Withhold 
 
Based on severity of AE administer 
corticosteroids 
Ensure adequate evaluation to 
confirm etiology and/or exclude 
other causes 
Grade 3 or 4 
Permanently discontinue 
Myocarditis 
Grade 1 
Withhold 
Based on severity of AE administer 
corticosteroids. 
Ensure adequate evaluation to 
confirm etiology and/or exclude 
other causes 
Grade 2, 3 or 4 
Permanently 
discontinue 


 
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Exfoliative 
Dermatologic 
Conditions 
Suspected SJS, TEN, or 
DRESS 
Withhold 
Based on severity of AE administer 
corticosteroids 
Ensure adequate evaluation to 
confirm etiology or exclude 
other causes 
Confirmed SJS, TEN, or 
DRESS 
Permanently discontinue 
All other irAEs 
Persistent 
Grade 2 
Withhold 
Based on type and severity of AE 
administer corticosteroids. 
Ensure adequate evaluation to 
confirm etiology and/or exclude 
other causes. 
Grade 3 
Withhold or 
discontinue based on the type 
of evente 
Grade 4 or 
recurrent 
Grade 3 
Permanently 
discontinue 
AE(s)=adverse event(s); ALT= alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common Terminology Criteria for Adverse Events; DRESS=Drug Rash with 
Eosinophilia and Systemic Symptom; GI=gastrointestinal; IO=immuno-oncology; ir=immune related; IV=intravenous; SJS=Stevens-Johnson Syndrome; T1DM=type 1 diabetes 
mellitus; TEN=Toxic Epidermal Necrolysis; ULN=upper limit of normal. 
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations. 
 
a AST/ALT: >3.0 to 5.0 x ULN if baseline normal; >3.0 to 5.0 x baseline, if baseline abnormal; bilirubin:>1.5 to 3.0 x ULN if baseline normal; >1.5 to 3.0 x baseline if baseline 
abnormal 
b AST/ALT: >5.0 to 20.0 x ULN, if baseline normal; >5.0 to 20.0 x baseline, if baseline abnormal; bilirubin:>3.0 to 10.0 x ULN if baseline normal; >3.0 to 10.0 x baseline if baseline 
abnormal 
c AST/ALT: >20.0 x ULN, if baseline normal; >20.0 x baseline, if baseline abnormal; bilirubin: >10.0 x ULN if baseline normal; >10.0 x baseline if baseline abnormal 
d The decision to withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician. If control achieved or ≤ Grade 2, pembrolizumab 
may be resumed. 
e Events that require discontinuation include but are not limited to: encephalitis, and other clinically important irAEs (eg, vasculitis and sclerosing cholangitis) 
 
Dosing interruptions are permitted in the case of medical / surgical events or logistical reasons not related to study therapy (eg, elective surgery, 
unrelated medical events, subject vacation, and/or holidays). Subjects should be placed back on study treatment within 3 weeks of the scheduled 
interruption, unless otherwise discussed with the Sponsor. The reason for interruption should be documented in the subject's study record. 
 
 
 


 
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7.2.1 Supportive Care Guidelines for Infusion Reactions 
 
Pembrolizumab may cause severe or life-threatening reactions including severe 
hypersensitivity or anaphylaxis.  Signs and symptoms usually develop during or 
shortly after drug infusion and generally resolve completely within 24 hours of 
completion of infusion. Dose modification and toxicity management guidelines on 
pembrolizumab associated infusion reaction are provided in the table below. 
 
 
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 
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 with: 
 
Diphenhydramine 
50 mg po (or 
equivalent dose of 
antihistamine). 
 
Acetaminophen 
500-1000 mg po (or 
equivalent dose of 
analgesic). 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly responsive to 
symptomatic medication and/or brief 
interruption of infusion); recurrence of 
symptoms following initial improvement; 
hospitalization indicated for other clinical 
sequelae (e.g., renal impairment, pulmonary 
infiltrates) 
 
Grade 4: 
Life-threatening; pressor or ventilatory 
support indicated 
Stop Infusion. 
Additional appropriate medical therapy may include but is not 
limited to: epinephrine**, IV fluids, antihistamines, NSAIDS, 
acetaminophen, narcotics, oxygen, pressors, corticosteroids. 
 
Increase monitoring of vital signs as medically indicated until 
the subject is deemed medically stable in the opinion of the 
investigator. 
 
Hospitalization may be indicated. 
 
** In cases of anaphylaxis, epinephrine should be used 
immediately. 
 
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. 
 
For further information, please refer to the Common Terminology Criteria for Adverse Events v5.0 (CTCAE) 
at http://ctep.cancer.gov 
 
 
 
 


 
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7.2.2 Combination Therapy with Pembrolizumab 
 
Attribution of Toxicity: When study interventions are administered in 
combination, attribution of an adverse event to a single component is likely to be 
difficult.  Therefore, while the investigator may attribute a toxicity event to the 
combination, to lenvatinib alone or to pembrolizumab alone, for adverse events 
listed in the table in Section 7.2 above, both interventions must be held. 
. 
 
Restarting Study Interventions: 
 Participants may not have any dose modifications (no change in dose or schedule) 
of pembrolizumab in this study, as described in the table in sSection 7.2 above. If 
pembrolizumab is to be held for a related toxicity, the dose will be skipped and 
restarted at the next cycle if resolved. 
 If the toxicity does not resolve or the criteria for resuming treatment are not 
met, the participant must be discontinued from all study interventions, 
unless the toxicity can be clearly attributed to only one of the study 
therapies. 
 If the toxicities do resolve and conditions are aligned with what is defined 
in the table in Section 7.2 above, the combination of lenvatinib and 
pembrolizumab may be restarted at the discretion of the investigator. In 
these cases where the toxicity is attributed to the combination or to 
lenvatinib alone, re-initiation of pembrolizumab as a monotherapy may be 
considered at the principal investigator’s discretion. 
 
 
8.0 
REGULATORY AND REPORTING REQUIREMENTS 
 
The entities providing oversight of safety and compliance with the protocol require reporting as 
outlined below. Please refer to Appendix C for definitions and Appendix D for a grid of reporting 
timelines. 
 
Adverse events will be tracked from start of treatment through 120 days after last day of study 
treatment.  All adverse events must be recorded on the toxicity tracking case report form (CRF) 
with the exception of: 
 Baseline adverse events, which shall be recorded on the medical history CRF 
 
Refer to the data submission schedule in Section 11 for instructions on the collection of AEs in the 
EDC. 
 
Reporting requirements for Washington University study team may be found in Section 8.1.  
Reporting requirements for secondary site study teams participating in Washington University-
coordinated research may be found in Section 8.2. 
 
8.1 
Washington University PI Reporting Requirements 


 
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8.1.1 Reporting to the Human Research Protection Office (HRPO) at 
Washington University 
 
Reporting will be conducted in accordance with Washington University IRB 
Policies. 
 
Pre-approval of all protocol exceptions must be obtained prior to implementing the 
change. 
 
8.1.2 Reporting to the Quality Assurance and Safety Monitoring 
Committee (QASMC) at Washington University 
 
The Washington University PI (or designee) is required to notify the QASMC of 
any unanticipated problems involving risks to participants or others occurring at 
WU or any BJH or SLCH institution that has been reported to and acknowledged 
by HRPO.  (Unanticipated problems reported to HRPO and withdrawn during the 
review process need not be reported to QASMC.) 
 
QASMC must be notified within 10 days of receipt of IRB acknowledgment via 
email to qasmc@wustl.edu. Submission to QASMC must include the myIRB form 
and any supporting documentation sent with the form. 
 
For events that occur at secondary sites, the Washington University PI (or designee) 
is required to notify the QASMC within 10 days of Washington University 
notification via email to qasmc@wustl.edu.  Submission to QASMC must include 
either the myIRB form and supporting documentation or (if not submitted to 
myIRB) the date of occurrence, description of the event, whether the event is 
described in the currently IRB approved materials, the event outcome, 
determination of relatedness, whether currently enrolled participants will be 
notified, and whether the informed consent document and/or any study procedures 
will be modified as a result of this event. 
 
8.1.3 Reporting to Merck  
 
8.1.3.1 Overdose 
 
If an adverse event(s) is associated with (“results from”) the overdose of a 
Merck product (either pembrolizumab or lenvatinib), 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 


 
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(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 Washington University PI and within 2 working days 
hours to Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 
661-6229) 
 
8.1.3.2 Pregnancy and Lactation 
 
Although pregnancy and infant exposure during breastfeeding 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 study. 
 
Pregnancies and infant exposures during breastfeeding that occur after the 
consent form is signed but before treatment allocation/randomization must 
be reported by the investigator if they cause the participant to be excluded 
from the trial, or are the result of a protocol-specified intervention, including 
but not limited to washout or discontinuation of usual therapy, diet, placebo 
treatment or a procedure.   
 
Pregnancies and infant exposures during breastfeeding that occur from the 
time of treatment allocation/randomization through 120 days following 
cessation of Sponsor’s product, or 30 days following cessation of treatment 
if the participant initiates new anticancer therapy, whichever is earlier, must 
be reported by the investigator.  All reported pregnancies must be followed 
to the completion/termination of the pregnancy. Pregnancy outcomes of 
spontaneous abortion, missed abortion, benign hydatidiform mole, blighted 
ovum, fetal death, intrauterine death, miscarriage and stillbirth must be 
reported as serious events (Important Medical Events).  If the pregnancy 
continues to term, the outcome (health of infant) must also be reported. 
 
Such events must be reported within 24 hours to the Washington University 
PI and within 2 working days to Merck Global Safety. (Attn: Worldwide 
Product Safety; FAX 215 661-6229) 
 
8.1.3.3 Serious Adverse Events 
 
For the time period beginning when the consent form is signed until 
treatment allocation/randomization, any serious adverse event, or follow up 
to a serious adverse event, including death due to any cause that occurs to 
any participant must be reported within 24 hours to the Washington 
University PI and within 2 working days to Merck Global Safety if it causes 
the participant to be excluded from the trial, or is the result of a protocol-
specified intervention, including but not limited to washout or 


 
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discontinuation of usual therapy, diet, placebo treatment or a procedure. 
 
For the time period beginning at treatment allocation/randomization 
through 90 days following cessation of treatment, or 30 days following 
cessation of treatment if the participant initiates new anticancer therapy, 
whichever is earlier, any serious adverse event, or follow up to a serious 
adverse event, including death due to any cause whether or not related to 
the Merck product, must be reported within 24 hours to the Washington 
University PI and within 2 working days to Merck Global Safety. 
 
Additionally, any serious adverse event, considered by an investigator who 
is a qualified physician to be related to Merck product that is brought to the 
attention of the investigator at any time following consent through the end 
of the specified safety follow-up period specified in the paragraph above, or 
at any time outside of the time period specified in the previous paragraph 
also must be reported immediately to Merck Global Safety. 
 
SAE reports and any other relevant safety information are to be 
forwarded to the Merck Global Safety facsimile number:  +1-215-661-
6229 
 
A copy of all 15 Day Reports and Annual Progress Reports is submitted as 
required by FDA, European Union (EU), Pharmaceutical and Medical 
Devices agency (PMDA) or other local regulators. Investigators will cross 
reference this submission according to local regulations to the Merck 
Investigational Compound Number (IND, CSA, etc.) at the time of 
submission.  Additionally investigators will submit a copy of these reports 
to Merck & Co., Inc. (Attn: Worldwide Product Safety; FAX 215 661-6229) 
at the time of submission to FDA. 
 
8.1.3.4 Events of Clinical Interest (ECI) 
 
Selected non-serious and serious adverse events are also known as Events 
of Clinical Interest (ECI) and must be reported within 2 working days to 
Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 661-
6229). 
 
For the time period beginning when the consent form is signed until 
treatment allocation/randomization, any ECI, or follow up to an ECI, that 
occurs to any participant must be reported within 2 working days to Merck 
Global Safety if it causes the participant to 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. 
 


 
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For the time period beginning at treatment allocation/randomization 
through 90 days following cessation of treatment, or 30 days following 
cessation of treatment if the participant initiates new anticancer therapy, 
whichever is earlier, any ECI, or follow up to an ECI, whether or not related 
to Merck product, must be reported within 2 working days to Merck Global 
Safety. 
 
8.1.4 Reporting to Secondary Sites 
 
The Washington University PI (or designee) will notify the research team at each 
secondary site of all unanticipated problems involving risks to participants or others 
that have occurred at other sites within 10 working days of the occurrence of the 
event or notification of the PI of the event.  This includes events that take place 
both at Washington University and at other secondary sites, if applicable.  Refer to 
Section 16.0 (Multicenter Management) for more information. 
 
8.2 
Secondary Site Reporting Requirements 
 
The research team at each secondary site is required to promptly notify the Washington 
University PI and designee of all serious adverse events (refer to Appendix C, Section D) 
within 1 working day of the occurrence of the event or notification of the secondary site’s 
PI of the event.  This notification may take place via email if there is not yet enough 
information for a formal written report (using an FDA Form 3500a (MedWatch) and 
Washington University’s cover sheet (Appendix E)).  A formal written report must be sent 
to the Washington University PI and designee within 4 calendar days (for fatal or life-
threatening suspected adverse reactions) or 11 calendar days (for serious unexpected 
adverse reactions) of the occurrence of the event or notification of the secondary site’s PI 
of the event. 
 
The research team at a secondary site is responsible for following its site’s guidelines for 
reporting applicable events to its site’s IRB according to its own institutional guidelines.  
The research team at Washington University is responsible for reporting all applicable 
events to Merck as needed. 
 
Washington University pre-approval of all protocol exceptions must be obtained prior to 
implementing the change.  Local IRB approval must be obtained as per local guidelines.  
Washington University IRB approval is not required for protocol exceptions occurring at 
secondary sites. 
 
8.3 
Exceptions to Expedited Reporting 
 
Events that do not require expedited reporting as described in Section 8.1 include: 
 planned hospitalizations 
 hospitalizations < 24 hours 
 respite care 
 events related to disease progression 


 
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Events that do not require expedited reporting must still be captured in the EDC. 
 
 
9.0 
PHARMACEUTICAL INFORMATION 
 
9.1 
Lenvatinib 
 
9.1.1 Lenvatinib Description 
 
Lenvatinib 4-[3-Chloro-4-(N’-cyclopropylureido)phenoxyl]- 7-methoxyquinoline- 
6-carboxamide methanesulfonate (lenvatinib mesilate) is an oral, potent multiple 
receptor tyrosine kinase (RTK) inhibitor that selectively inhibits vascular 
endothelial growth factor (VEGF) receptors, VEGFR1 (FLT1), VEGFR2 (KDR), 
and VEGFR3 (FLT4), in addition to other pro-angiogenic and oncogenic pathway-
related RTKs including fibroblast growth factor (FGF) receptor FGFR1-4, platelet-
derived growth factor (PDGF) receptor PDGFRα, KIT, and RET. Nonclinical 
studies showed lenvatinib to be a potent antiangiogenesis agent with antitumor 
activity versus various human cancer xenograft models in athymic mice. Lenvatinib 
drug substance is a white to pale yellow powder that is being used in the 
capsuleformulation for the clinical studies evaluating lenvatinib. It is slightly 
soluble in water and has a molecular weight of 522.96 and a pKa of 5.27 (mesilate 
salt). 
 
9.1.2 Clinical Pharmacology 
 
Please refer to Section 2.2.1 of the Lenvatinib IB.  
 
9.1.3 Pharmacokinetics and Drug Metabolism 
 
Please refer to Section 2.2.1 of the Lenvatinib IB. 
 
9.1.4 Supplier(s) 
 
Lenvatinib will be provided by Merck.  
 
 
9.1.5 Dosage Form and Preparation 
 
E7080 drug products used in clinical studies are hard capsules containing 1, 4, or 
10 mg E7080 as anhydrous free base. The size of the capsules is No. 4 for all 
strengths with an average length of 14.3 mm. The color of the cap is yellowish-red 
for all strengths. The colors of the body are white, yellowish-red, and yellow for 
the 1-mg, 4-mg, and 10-mg strengths, respectively (capsules with or without 
markings in black ink might be used). 
 
9.1.6 Storage and Stability 


 
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E7080 capsules are packaged in cold form blisters or high-density polyethylene 
(HDPE) bottles with a polypropylene cap and desiccant. The blisters and bottles 
should be stored under room temperature. 
 
9.1.7 Administration 
 
Lenvatinib will be given at a dose of 20 mg (two 10 mg capsules) once daily. The 
daily dose of lenvatinib is to be modified as needed according to the dose/toxicity 
management plan.  
 
Lenvatinib is to be taken at the same time each day with or without food.  
 
9.1.8 Special Handling Instructions 
 
Any unused medicinal product or waste material should be disposed of in 
accordance with local requirements. Do not open the capsule. Avoid repeat 
exposure to contents of the capsule.  
 
9.2 
Pembrolizumab 
 
Pembrolizumab may be provided as a sterile, preservative-free, clear to slightly opalescent, 
colorless to slightly yellow solution that requires dilution for IV infusion. Each vial 
contains 100 mg of pembrolizumab in 4 mL of solution. Each 1 mL of solution contains 
25 mg of pembrolizumab. 
 
9.2.1 Investigational Product – Pembrolizumab  
 
The investigator shall take responsibility for and shall take all steps to maintain 
appropriate records and ensure appropriate supply, storage, handling, distribution 
and usage of investigational product in accordance with the protocol and any 
applicable laws and regulations. 
 
Pembrolizumab will be provided by Merck as summarized in the table below: 
Product Name & Potency 
Dosage Form 
Pembrolizumab 100 mg/ 4mL 
Solution for Injection 
 
9.2.2 Clinical Pharmacology 
 
The PK 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 
200 mg). Furthermore, pembrolizumab has a low potential of eliciting the formation 
of ADAs.  
 
9.2.3 Pharmacokinetics and Drug Metabolism 


 
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Pembrolizumab is administered intravenously and is therefore immediately and 
completely bioavailable. 
 
Consistent with a limited extravascular distribution, the volume of distribution of 
pembrolizumab at steady state is small (6.0 L; CV%: 20%). As expected for an 
antibody, pembrolizumab does not bind to plasma proteins in a specific manner. 
 
Pembrolizumab is catabolized through nonspecific pathways; metabolism does not 
contribute to its CL. 
 
Pembrolizumab CL is approximately 23% lower (geometric mean, 195 mL/day 
[CV%: 40%]) after achieving maximal change at steady state compared with the 
first dose (252 mL/day [CV%: 37%]); this decrease in CL with time is not 
considered clinically meaningful. The geometric mean value (CV%) for the 
terminal half-life is 22 days (32%) at steady-state. 
 
9.2.4 Packaging and Labeling Information 
 
Supplies will be labeled in accordance with regulatory requirements.  
 
9.2.5 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. 
 
9.2.6 Supplier 
 
Merck will provide pembrolizumab as a liquid drug product. 
 
9.2.7 Dosage Form and Preparation 
 
Merck will provide pembrolizumab as a 100 mg/vial liquid drug product. 
 
The liquid drug product is clear to opalescent, essentially free of visible particles. 
The liquid product is intended for IV administration. The liquid drug product can 
be further diluted with normal saline or 5% dextrose in the concentration range of 
1 to 10 mg/mL in IV containers made of PVC or non-PVC material. The infusion 
solution should be administered immediately. 
 
9.2.8 Administration 
 
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 


 
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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). 
 
9.2.9 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. 
 
9.2.10 Storage and Stability 
 
Pembrolizumab (MK-3475) solutions may be stored at room temperature for a 
cumulative time of up to 6 hours. The 6-hour countdown begins when the vial is 
pierced and includes room temperature storage of reconstituted drug product 
solution in vials, room temperature storage of admixture solutions in the IV bags 
and the duration of infusion. (Please note this 6-hour timeframe is to provide a 
microbial control strategy. The microbial clock only starts when the product stopper 
is pierced and not when the vial is removed from the refrigerator.) 
 
In addition, reconstituted vials and/or IV bags may be stored under refrigeration at 
2 °C to 8 °C (36 °F to 46 °F), total cumulative storage time at room temperature 
and refrigeration should not exceed 24 hours.  
 
If refrigerated, allow the IV bags to come to room temperature prior to use.   
 
9.2.11 Returns and Reconciliation  
 
The investigator is responsible for keeping accurate records of the clinical supplies 
received from Merck or designee, the amount dispensed to and returned by the 
subjects and the amount remaining at the conclusion of the trial.  
 
Upon completion or termination of the study, all unused and/or partially used 
investigational product will be destroyed at the site per institutional policy. It is the 
Investigator’s responsibility to arrange for disposal of all empty containers, 
provided that procedures for proper disposal have been established according to 
applicable federal, state, local and institutional guidelines and procedures, and 
provided that appropriate records of disposal are kept. 
 
 


 
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10.0 
CORRELATIVE STUDIES 
 
Biomarker discovery and/or validation will be performed to identify blood or tumor biomarkers 
that may be useful to predict subject response to lenvatinib and/or pembrolizumab, as determined 
by evaluation of response-related and/or safety-related outcomes as well as for potential use in 
diagnostic development. Blood samples from subjects receiving lenvatinib and pembrolizumab 
may be analyzed using global proteomic methods, enzyme-linked immunosorbent assay (ELISA), 
multiplex bead-based immunoassay, or other assays/methods or new technology. The decision to 
perform exploratory biomarker analysis may be based on the clinical outcome of this study and/or 
the signals observed in other clinical studies or other information available at that time. 
 
Data obtained will be used for research, to assist in developing safer and more effective treatments 
and will not be used to change the diagnosis of the subject or alter the therapy of the subject. The 
DNA will not be used to determine or predict risks for diseases that an individual subject does not 
currently have. Any sample or derivatives (DNA, RNA, and protein) may be stored for up to 15 
years to assist in any research scientific questions related to lenvatinib, pembrolizumab, cancer 
and/or for potential diagnostic development. 
 
10.1 
Blood Collection  
 
10.1.1 Collection of Specimen 
 
Blood samples for the development of exploratory predictive biomarkers will be 
collected within 2 weeks prior to the first dose of study drug, on Cycle 4 Day 1, and 
at the Off-Tx assessment. A blood sample for peripheral blood mononuclear cells 
(PBMC) and plasma isolation will be collected from consented subjects for 
potential analysis. Plasma will be used for protein biomarkers analysis. PBMCs will 
be used for immune cell profiling (e.g. tumor infiltrating lymphocytes, T-cell 
repertoire, and immune cell types). At each blood collection time point, two 10ml 
EDTA tubes (purple preferred, pink acceptable) will be filled and transferred to the 
Tissue Procurement Core (TPC) at Washington University (coordinating site) or 
processed according to the instructions in Appendix H (secondary sites). 
 
10.1.2 Handling and Shipping of Specimen(s) 
 
Blood tubes collected will be either taken to the TPC immediately following draw 
for processing (coordinating site) or processed according to instructions in 
Appendix H (secondary sites). Secondary sites must bulk ship frozen samples at a 
minimum of every 2 months to the address provided below in protected shipment 
container. 
Hannah Black, Washington University School of Medicine 
660 South Euclid CB 8056-29-10200 
St. Louis, MO 63110, USA 
Phone: 314-747-2089, 314-362-9913 or 314-273-2696  
 


 
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Samples should only be shipped Monday through Wednesday. If Thursday 
shipping is required, please contact the study team at LENKYN@wustl.edu to 
assess availability or recommended storage conditions. Blood cannot be shipped on 
a Friday. See Appendix G for further shipping instructions. 
 
10.2 
Tumor Tissue 
 
10.2.1 Collection of Specimen(s) 
 
Subjects will be required to provide an archival tumor tissue sample before 
treatment for biomarker analyses (patients without archival tissue can be enrolled 
upon consultation and agreement by the trial PI). Archived, formalin-fixed paraffin-
embedded (FFPE) tissue or an OCT embedded frozen tissue block will be collected 
from all subjects for potential assessment of protein biomarkers which may be 
important in the development and progression of cancer as well as for potential use 
in diagnostic development. Appropriate technology/methodologies will be used 
based on the amount of tumor tissue available. 
 
10.2.2 Handling of Specimens 
 
Sufficient tumor tissue specimens, preferably collected within 3 months but no 
more than 24 months prior to enrollment with an associated pathology report, will 
be required in the form of an OCT embedded frozen tissue block (preferred), 
formalin-fixed paraffin-embedded block or 20 unstained slides. A minimum of 10 
slides will be acceptable if tumor tissue is limited. In these situations, it is 
recommended to consult with the protocol team to discuss the specifics of the case.  
 
10.2.3 Shipping of Specimens 
 
Tumor samples will be either taken to the TPC upon obtaining tissue slides/block 
(coordinating site), or shipped on the same day the samples are obtained to the 
address provided below in protected shipment container (secondary sites). 
Hannah Black, Washington University School of Medicine 
660 South Euclid CB 8056-29-10200 
St. Louis, MO 63110, USA 
Phone: 314-747-2089, 314-362-9913 or 314-273-2696  
 
Samples should only be shipped Monday through Wednesday. If Thursday 
shipping is required, please contact the study team at LENKYN@wustl.edu to 
assess availability or recommended storage conditions. Tissue cannot be shipped 
on a Friday. See Appendix F for further shipping instructions. 
 
 


 
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11.0 
DATA SUBMISSION SCHEDULE 
 
Case report forms with appropriate source documentation will be completed according to the 
schedule listed in this section. 
 
Case Report Form 
Submission Schedule 
Original Consent Form 
Prior to registration 
On-Study Form 
Medical History Form 
Prior to starting treatment 
Treatment Form 
Every cycle 
Toxicity Form 
Continuous 
Treatment Summary Form 
Completion of treatment 
Follow Up Form 
Every 12 weeks until death 
iRECIST Form 
Baseline, every 9 weeks, end of treatment 
Blood Form 
Baseline, C4D1, end of treatment  
Tissue Form  
Baseline  
Progression Form 
Time of progression 
Death Form 
Time of death 
MedWatch Form 
See Section 7.0 for reporting requirements 
 
Any queries generated by Washington University must be responded to within 28 days of receipt 
by the participating site.  The Washington University research team will conduct a regular review 
of data status at all secondary sites, with appropriate corrective action to be requested as needed. 
 
11.1 
Adverse Event Collection in the Case Report Forms 
 
All adverse events that occur beginning with start of treatment (minus exceptions defined 
in Section 8.0) must be captured in the Toxicity Form.  Baseline AEs should be captured 
on the Medical History Form. 
 
Participant death due to disease progression should be reported on the Toxicity Form as 
grade 5 disease progression.  If death is due to an AE (e.g. cardiac disorders: cardiac arrest), 
report as a grade 5 event under that AE.  Participant death must also be recorded on the 
Death Form. 
 
 
12.0 
MEASUREMENT OF EFFECT 
 
For the purposes of this study, patients should be re-evaluated for response every 9 weeks. In 
addition to a baseline scan, confirmatory scans may also be obtained in accordance with the 
guidance below following either initial documentation of objective response or initial 
documentation of progression. 
 
 
12.1 
Antitumor Effect – Immune-Related RECIST (iRECIST) Criteria 
 


 
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12.1.1 Definitions 
 
Evaluable for Adverse Events.  All patients will be evaluable for adverse event 
evaluation from the time of their first treatment. 
 
Evaluable for Response.  All patients who have received at least one cycle of 
therapy and have their disease re-evaluated will be considered evaluable for 
response (exceptions will be those who exhibit objective disease progression prior 
to the end of Cycle 1 who will also be considered evaluable).  Patients on therapy 
for at least this period and who meet the other listed criteria will have their response 
classified according to the definitions set out below. 
 
Response and progression will be evaluated in this study using the revised 
international criteria (RECIST version 1.1) proposed by the RECIST committee as 
well as the modified iRECIST guidelines.  Investigators should note the different 
requirements for confirmatory scans as well as follow up for the two criteria. 
 
Until radiographic progression based on RECIST 1.1, there is no distinct iRECIST 
assessment. In participants who show evidence of radiological PD by RECIST 1.1 
the Investigator will decide whether to continue a participant on study treatment 
until repeat imaging 4 to 8 weeks later is obtained using iRECIST for participant 
management.  This decision by the Investigator should be based on the participant’s 
overall clinical condition. 
 
Clinical stability is defined as the following:  
 Absence of symptoms and signs indicating clinically significant progression 
of disease 
 No decline in ECOG performance status  
 No requirements for intensified management, including increased 
analgesia, radiation, or other palliative care 
 
Any participant deemed clinically unstable should be discontinued from study 
treatment at site-assessed first radiologic evidence of PD and is not required to have 
repeat tumor imaging for confirmation of PD by iRECIST. 
 
If the Investigator decides to continue treatment, the participant may continue to 
receive study treatment and the tumor assessment should be repeated 4 to 8 weeks 
later to confirm PD by iRECIST, per Investigator assessment. 
 
12.1.2 RECIST 1.1 Response and Evaluation Endpoints 
 
Measurable Disease.  Measurable tumor lesions (nodal, subcutaneous, lung 
parenchyma, solid organ metastases) are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as ≥20 mm 
with chest X-ray and as ≥10 mm with CT scan or clinical examination.  Bone 
lesions are considered measurable only if assessed by CT scan and have an 


 
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identifiable soft tissue component that meets these requirements (soft tissue 
component ≥10 mm by CT scan).  Malignant lymph nodes must be ≥15 mm in the 
short axis to be considered measurable; only the short axis will be measured and 
followed.  All tumor measurements must be recorded in millimeters (or decimal 
fractions of centimeters).  Previously irradiated lesions are not considered 
measurable unless progression has been documented in the lesion. 
 
Non-Measurable Disease.  All other lesions (or sites of disease), including small 
lesions are considered non-measurable disease.  Bone lesions without a measurable 
soft tissue component, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonis, inflammatory breast disease, lymphangitic 
involvement of lung or skin and abdominal masses followed by clinical 
examination are all non-measurable.  Lesions in previously irradiated areas are non-
measurable, unless progression has been demonstrated. 
 
Target Lesions.  When more than one measurable tumor lesion is present at baseline 
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 
and will be recorded and measured at baseline.  Target lesions should be selected 
on the basis of their size (lesions with the longest diameter), be representative of all 
involved organs, and be those that lend themselves to reproducible repeated 
measurements.  Note that pathological nodes must meet the criterion of a short axis 
of ≥15 mm by CT scan and only the short axis of these nodes will contribute to the 
baseline sum.  All other pathological nodes (those with short axis ≥10 mm but <15 
mm) should be considered non-target lesions.  Nodes that have a short axis <10 mm 
are considered non-pathological and should not be recorded or followed.  At 
baseline, the sum of the target lesions (longest diameter of tumor lesions plus short 
axis of lymph nodes: overall maximum of 5) is to be recorded. 
 
After baseline, a value should be provided on the CRF for all identified target 
lesions for each assessment, even if very small.  If extremely small and faint lesions 
cannot be accurately measured but are deemed to be present, a default value of 5 
mm may be used.  If lesions are too small to measure and indeed are believed to be 
absent, a default value of 0 mm may be used. 
 
Non-Target Lesions.  All non-measurable lesions (or sites of disease) plus any 
measurable lesions over and above those listed as target lesions are considered non-
target lesions.  Measurements are not required but these lesions should be noted at 
baseline and should be followed as "present" or "absent." 
 
12.1.3 Response Criteria   
 
All patients will have their best response from the start of study treatment until the 
end of treatment classified as outlined below: 
 


 
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Complete Response (CR):  Disappearance of target and non-target lesions and 
normalization of tumor markers.  Pathological lymph nodes must have short axis 
measures <10 mm (Note:  continue to record the measurement even if <10 mm and 
considered CR).  Residual lesions (other than nodes <10 mm) thought to be non-
malignant should be further investigated (by cytology specialized imaging or other 
techniques as appropriate for individual cases [Eur J Ca 45:228-247, 2009]) before 
CR can be accepted.  Confirmation of response is only required in non-randomized 
studies. 
 
Partial Response (PR):  At least a 30% decrease in the sum of measures (longest 
diameter for tumor lesions and short axis measure for nodes) of target lesions, 
taking as reference the baseline sum of diameters.  Non target lesions must be non-
PD.  Confirmation of response is only required in non-randomized studies. 
 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD taking as reference the smallest sum of diameters on 
study. 
 
Progressive Disease (PD):  At least a 20% increase in the sum of diameters of 
measured lesions taking as references the smallest sum of diameters recorded on 
study (including baseline) AND an absolute increase of ≥5 mm.  Appearance of 
new lesions will also constitute PD (including lesions in previously unassessed 
areas).  In exceptional circumstances, unequivocal progression of non-target 
disease may be accepted as evidence of disease progression, where the overall 
tumor burden has increased sufficiently to merit discontinuation of treatment or 
where the tumor burden appears to have increased by at least 73% in volume.  
Modest increases in the size of one or more non-target lesions are NOT considered 
unequivocal progression.  If the evidence of PD is equivocal (target or non-target), 
treatment may continue until the next assessment, but if confirmed, the earlier date 
must be used. 
 
Integration of target, non-target, and new lesions into response assessment 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Response For This 
Category Also Requires 
Target lesions ± non target lesions  
CR 
CR 
No 
CR 
Normalization of tumor 
markers, tumor nodes <10 mm 
CR 
Non-CR/non-PD 
No 
PR 
Normalization of tumor 
markers, tumor nodes <10 mm 
CR 
Not all evaluated 
No 
PR 
  
PR 
Non-PD/not all 
evaluated 
No 
PR 
  
SD 
Non-PD/not all 
evaluated 
No 
SD 
Documented at least once ≥4 
weeks from baseline 


 
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Integration of target, non-target, and new lesions into response assessment 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Response For This 
Category Also Requires 
Not all 
evaluated 
Non-PD 
No 
NE 
  
PD 
Any 
Any 
PD 
  
Any 
PD 
Any 
PD 
  
Any 
Any 
Yes 
PD 
  
Non target lesions ONLY 
No Target 
CR 
No 
CR 
Normalization of tumor 
markers, tumor nodes <10 mm 
No Target 
Non-CR/non-PD 
No 
Non-CR/ 
non-PD 
  
No Target 
Not all evaluated 
No 
NE 
  
No Target 
Unequivocal PD 
Any 
PD 
  
No Target 
Any 
Yes* 
PD 
  
Note: Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be reported as 
"symptomatic deterioration." This is a reason for stopping therapy, but is NOT objective PD. 
Every effort should be made to document the objective progression even after discontinuation 
of treatment. 
 
*Investigators should record all new lesions.  If the new lesion is felt to be equivocal, 
treatment may be continued pending further assessments. 
 
12.1.4 iRECIST Response Assessment 
 
Overall response will also be assessed using iRECIST.  Immunotherapeutics may 
result in infiltration of immune cells leading to transient increase in the size in 
malignant lesions, or undetectable lesions becoming detectable.  The criteria are 
identical to those of RECIST 1.1 in many respects but have been adapted to account 
for instances where an increase in tumor burden, or the appearance of new lesions, 
does not reflect true tumor progression. 
 
Key differences are described below.  All responses defined using iRECIST criteria 
are designated with a prefix.  iRECIST time-point and best overall responses will 
be recorded separately. 
 
Confirming progression:  Unlike RECIST 1.1, iRECIST requires the confirmation 
of progression and uses the terms iUPD (unconfirmed progression) and iCPD 
(confirmed progression).  Confirmatory scans should be performed at least 4 weeks, 
but no longer than 8 weeks, after iUPD. 
 


 
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iCPD is confirmed if further increase in tumor burden, compared to the last 
assessment, is seen as evidenced by one or more of the following: 
 Continued increase in tumor burden (from iUPD) where RECIST 1.1 
definitions of progression had been met (from nadir) in target, non-target 
disease, or new lesions. 
o Progression in target disease worsens with an increase of at least 5 mm in 
the absolute value of the sum. 
o Continued unequivocal progression in non-target disease with an increase 
in tumor burden. 
o Increase in size of previously identified new lesion(s) (an increase of at least 
5 mm in the absolute value of the sum of those considered to be target new 
lesions) or additional new lesions. 
 RECIST 1.1 criteria are met in lesions types (target or non-target or new 
lesions) where progression was not previously identified, including the 
appearance of additional new lesions. 
 
If iUPD is not confirmed at the next assessment, then the appropriate response will 
be assigned (iUPD if the criteria are still met, but no worsening, or iSD, iPR, or 
iCR if those criteria are met compared to baseline).  The prior documentation of 
iUPD does not preclude assigning iCR, iPR, or iSD in subsequent time-point 
assessments or as best overall response (BOR) providing that iCPD is not 
documented at the next assessment after iUPD (Lancet Oncol 18:e143-e152, 2017 
- Table 2). 
 
New lesions:   
New lesions should be assessed and measured as they appear using RECIST 1.1 
criteria (maximum of 5 lesions, no more than 2 per site, at least 10 mm in long axis 
[or 15 mm in short axis for nodal lesions]), and recorded as New Lesions - Target 
(NLT) and New Lesion - Non-Target (NLNT) to allow clear differentiation from 
baseline target and non-target lesions. 
 
New lesions may either meet the criteria of NLT or NLNT to drive iUPD (or iCPD).  
However, the measurements of target lesions should NOT be included in the sum 
of measures of original target lesions identified at baseline.  Rather, these 
measurements will be collected on a separate table in the case record form. 
 
PD is confirmed in the New Lesion category if the next imaging assessment, 
conducted at least 4 weeks (but not more than 8 weeks) after iUPD confirms further 
progression from iUPD with either an increase of at least 5 mm in the absolute 
value of the sum of NLT OR an increase (but not necessarily unequivocal increase) 
in the size of NLNT lesions OR the appearance of additional new lesions. 
 


 
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Time-point (TP) iResponse 
Target 
Lesions* 
Non-Target 
Lesions* 
New 
Lesions* 
Time Point Response 
No prior 
iUPD** 
Prior iUPD**, *** 
iCR 
iCR 
No 
iCR 
iCR 
iCR 
Non-iCR/Non- 
iUPD 
No 
iPR 
iPR 
iPR 
Non-iCR/Non- 
iUPD 
No 
iPR 
iPR 
iSD 
Non-iCR/Non- 
iUPD 
No 
iSD 
iSD 
iUPD with 
no change 
OR decrease 
from last TP 
iUPD with no 
change OR 
decrease from 
last TP 
Yes 
NA 
NLs confirms iCPD if NLs 
were previously identified and 
increase in size (≥5 mm in SOM 
for NLT or any increase for 
NLNT) or number. If no change 
in NLs (size or number) from 
last TP, remains iUPD. 
iSD 
iUPD 
No 
iUPD 
Remains iUPD unless iCPD 
confirmed based in further 
increase in size of NT disease 
(need not meet RECIST 1.1 
criteria for unequivocal PD). 
iUPD 
Non-iCR/Non-
iUPD 
No 
iUPD 
Remains iUPD unless iCPD 
confirmed based on further 
increase in SOM of at least 5 
mm, otherwise remains iUPD. 
iUPD 
iUPD 
No 
iUPD 
Remains iUPD unless iCPD 
confirmed based on further 
increase in: 
 previously identified T 
lesion iUPD SOM ≥5 mm 
and/or 
 NT lesion iUPD (prior 
assessment - need not be 
unequivocal PD) 
iUPD 
iUPD 
Yes 
iUPD 
Remains iUPD unless iCPD 
confirmed based on further 
increase in: 
 previously identified T 
lesion iUPD ≥5 mm and/or 


 
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Time-point (TP) iResponse 
Target 
Lesions* 
Non-Target 
Lesions* 
New 
Lesions* 
Time Point Response 
No prior 
iUPD** 
Prior iUPD**, *** 
 previously identified NT 
lesion iUPD (need not be 
unequivocal) and/or 
 size or number of new 
lesions previously identified 
Non-
iUPD/PD 
Non-iUPD/PD 
Yes 
iUPD 
Remains iUPD unless iCPD 
confirmed based on increase in 
size or number of new lesions 
previously identified. 
* Using RECIST 1.1 principles.  If no PSPD occurs, RECIST 1.1 and iRECIST categories for 
CR, PR, and SD would be the same.  
** in any lesion category.  
*** previously identified in assessment immediately prior to this TP. 
 
All patients will have their iBOR from the start of study treatment until the end of treatment 
classified as outlined below. 
 
iRECIST best overall response (iBOR) 
TPR 1 
TPR 2 
TPR 3 
TPR 4 
TPR 5 
iBOR 
iCR 
iCR, iPR, 
iUPD, NE 
iCR, iPR, 
iUPD, NE 
iUPD 
iCPD 
iCR 
iUPD 
iPR, iSD, 
NE 
iCR 
iCR, iPR, 
iSD, iUPD, 
NE 
iCR, iPR, 
iSD, iUPD, 
iCPD, NE 
iCR 
iUPD 
iPR 
iPR, iSD, 
iUPD, NE 
iPR, iSD, 
iUPD, NE, 
iCPD 
iPR, iSD, 
iUPD, NE, 
iCPD 
iPR 
iUPD 
iSD, NE 
PR 
iPR, iSD, 
iUPD, NE 
iPR, iSD, 
iUPD, 
iCPD, NE 
iPR 
iUPD 
iSD 
iSD, iUPD, 
NE 
iSD, iUPD, 
iCPD, NE 
iSD, iUPD, 
ICPD, NE 
iSD 
iUPD 
iCPD 
Anything 
Anything 
Anything 
iCPD 
iUPD 
iUPD 
iCPD 
Anything 
Anything 
iCPD 
iUPD 
NE 
NE 
NE 
NE 
iUPD 


 
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iRECIST best overall response (iBOR) 
TPR 1 
TPR 2 
TPR 3 
TPR 4 
TPR 5 
iBOR 
Table assumes a randomized study where confirmation of CR or PR is not required. 
 NE = not evaluable that cycle. 
 Designation "I" for BOR can be used to indicate prior iUPD to aid in data 
interpretation. 
 For patients with non-target disease only at baseline, only CR or non-CR/non-PD 
can be assigned at each TPR but is not shown in the table for ease of presentation. 
 
12.1.5 Response and Stable Disease Duration (RECIST 1.1 and iRECIST) 
 
Response duration will be measured from the time measurement criteria for CR/PR 
or iCR/iPR (whichever is first recorded) are first met until the first date that 
recurrent or PD is objectively documented, taking as reference the smallest 
measurements recorded on study (including baseline).  
 
Stable disease duration will be measured from the time of start of treatment until 
the criteria for progression are met, taking as reference the smallest sum on study 
(including baseline). 
 
12.1.6 Methods of Measurement 
 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-up.  
Assessments should be identified on a calendar schedule and should not be affected 
by delays in therapy.  While on study, all lesions recorded at baseline should have 
their actual measurements recorded at each subsequent evaluation, even when very 
small (e.g., 2 mm).  If it is the opinion of the radiologist that the lesion has likely 
disappeared, the measurement should be recorded as 0 mm.  If the lesion is believed 
to be present and is faintly seen but too small to measure, a default value of 5 mm 
should be assigned.  For lesions which fragment/split add together the longest 
diameters of the fragmented portions; for lesions which coalesce, measure the 
maximal longest diameter for the "merged lesion." 
 
Clinical Lesions.  Clinical lesions will only be considered measurable when they 
are superficial and ≥10 mm as assessed using calipers (e.g., skin nodules).  For the 
case of skin lesions, documentation by color photography including a ruler to 
estimate the size of the lesion is recommended.  If feasible, imaging is preferred. 
  
Chest X-Ray.  Chest CT is preferred over chest X-ray, particularly when 
progression is an important endpoint, since CT is more sensitive than X-ray, 
particularly in identifying new lesions.  However, lesions ≥20 mm on chest X-ray 
may be considered measurable if they are clearly defined and surrounded by aerated 
lung. 
 


 
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CT, MRI.  CT is the best currently available and reproducible method to measure 
lesions selected for response assessment.  This guideline has defined measurability 
of lesions on CT scan based on the assumption that CT slice thickness is 5 mm or 
less.  When CT scans have slice thickness greater than 5 mm, the minimum size for 
a measurable lesion should be twice the slice thickness.  MRI is also acceptable in 
certain situations (e.g., for body scans).  Other specialized imaging or other 
techniques may also be appropriate for individual case (Eur J Ca 45:228-247, 
2009).  For example, while PET scans are not considered adequate to measure 
lesions, PET-CT scans may be used providing that the measures are obtained from 
the CT scan and the CT scan is of identical diagnostic quality to a diagnostic CT 
(with IV and oral contrast). 
 
Ultrasound.  Ultrasound is not useful in assessment of lesion size and should not be 
used as a method of measurement.  If new lesions are identified by ultrasound in 
the course of the study, confirmation by CT is advised. 
 
Endoscopy, Laparoscopy.  The utilization of these techniques for objective tumor 
evaluation is not advised.  However, they can be useful to confirm complete 
pathological response when biopsies are obtained or to determine relapse in trials 
where recurrence following complete response or surgical resection is an endpoint. 
 
Tumor Markers.  Tumor markers alone cannot be used to assess objective tumor 
response.  If markers are initially above the upper normal limit, however, they must 
normalize for a patient to be considered in CR. 
 
Cytology, Histology.  These techniques can be used to differentiate between PR 
and CR in rare cases if required by protocol (for example, residual lesions in tumor 
types such as germ cell tumors, where known residual benign tumors can remain).  
When effusions are known to be a potential adverse effect of treatment (e.g., with 
certain taxane compounds or angiogenesis inhibitors), the cytological confirmation 
of the neoplastic origin of any effusion that appears or worsens during treatment 
when the measurable tumor has met criteria for response or stable disease is advised 
to differentiate between response or SD and PD. 
 
 
13.0 
DATA AND SAFETY MONITORING 
 
In compliance with the Washington University Institutional Data and Safety Monitoring Plan, an 
independent Data and Safety Monitoring Board (DSMB) will be specifically convened for this 
trial to review toxicity data.  A DSMB will consist of no fewer than 3 members including 2 clinical 
investigators and a biostatistician.  DSMB members must be employed by Washington University, 
Barnes-Jewish Hospital, or St. Louis Children’s Hospital.  Like investigators, DSMB members are 
subject to the Washington University School of Medicine policies regarding standards of conduct. 
Individuals invited to serve on the DSMB will disclose any potential conflicts of interest to the 
trial principal investigator and/or appropriate university officials, in accordance with institution 
policies. Potential conflicts that develop during a trial or a member’s tenure on a DSMB must also 


 
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be disclosed.  
 
Until such a time as the first secondary site enrolls its first patient, a semi-annual DSM report to 
be prepared by the study team will be submitted to the Quality Assurance and Safety Monitoring 
Committee (QASMC) semi-annually beginning six months after study activation at Washington 
University (if at least one patient has been enrolled) or one year after study activation (if no patients 
have been enrolled at the six-month mark). 
 
The DSM report for the DSMB will be prepared by the study team with assistance from the study 
statistician, will be reviewed by the DSMB, and will be submitted to the QASM Committee.  The 
DSMB must meet at least every six months beginning six months after enrollment of the first 
patient at a secondary site, no more than one month prior to the due date of the DSM report to 
QASMC.  This report will include: 
 
 HRPO protocol number, protocol title, Principal Investigator name, data coordinator 
name, regulatory coordinator name, and statistician 
 Date of initial HRPO approval, date of most recent consent HRPO approval/revision, 
date of HRPO expiration, date of most recent QA audit, study status, and phase of study 
 History of study including summary of substantive amendments; summary of accrual 
suspensions including start/stop dates and reason; and summary of protocol exceptions, 
error, or breach of confidentiality including start/stop dates and reason 
 Study-wide target accrual and study-wide actual accrual including numbers from 
participating sites 
 Protocol activation date at each participating site 
 Average rate of accrual observed in year 1, year 2, and subsequent years at each 
participating site 
 Expected accrual end date, accrual by site 
 Objectives of protocol with supporting data and list the number of participants who 
have met each objective 
 Early stopping rules with supporting data and list the number of participants who have 
met the early stopping rules 
 Summary of toxicities at all participating sites  
 Abstract submissions/publications 
 Summary of any recent literature that may affect the safety or ethics of the study 
 
Further DSMB responsibilities are described in the DSMB charter. 
 
The study principal investigator and coordinator will monitor for serious toxicities on an ongoing 
basis. Once the principal investigator or coordinator becomes aware of an adverse event, the AE 
will be reported to the HRPO and QASMC according to institutional guidelines (please refer to 
Section 8.0). 
 
Refer to the Washington University Quality Assurance and Data Safety Monitoring Committee 
Policies and Procedures for full details on the responsibilities of the DSMB.  This is located on the 
QASMC website at https://siteman.wustl.edu/research/clinical-research-resources/protocol-
office-prmcqasmc/. 


 
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14.0 
AUDITING 
 
As coordinating center of this trial, Washington University (via the Quality Assurance and Safety 
Monitoring Committee (QASMC) will monitor each participating site to ensure that all protocol 
requirements are being met; that applicable federal regulations are being followed; and that best 
practices for patient safety and data collection are being followed per protocol.  Participating sites 
will be asked to send copies of all audit materials, including source documentation.  The audit 
notification will be sent to the Washington University Research Patient Coordinator, who will 
obtain the audit materials from the participating institution. 
 
Notification of an upcoming audit will be sent to the research team one month ahead of the audit. 
Once accrual numbers are confirmed, and approximately 30 days prior to the audit, a list of the 
cases selected for review (up to 10 for each site) will be sent to the research team. However, if 
during the audit the need arises to review cases not initially selected, the research team will be 
asked to provide the additional charts within two working days. 
 
Items to be evaluated include: 
 Subject screening and enrollment 
 Reporting of adverse events 
 Maintenance of HIPAA compliance 
 Completeness of regulatory documentation 
 Completeness of participant documentation 
 Acquisition of informed consent 
 IRB documentation 
 Issues of protocol adherence 
 
Additional details regarding the auditing policies and procedures can be found at 
https://siteman.wustl.edu/research/clinical-research-resources/protocol-office-prmcqasmc/. 
 
 
15.0 
STATISTICAL CONSIDERATIONS 
 
15.1 
Study design 
 
This is a single arm, multicenter, phase II study of of lenvatinib in combination with 
pembrolizumab (lenvatinib 20 mg/day + pembrolizumab 200mg q3weeks) in subjects with 
locally advanced or metastatic nccRCC who have not received any systemic therapy for 
stage IV RCC.  
 
15.2 
Endpoints 
 
The primary endpoint is ORR, defined as the proportion of response-evaluable patients 
who have a best overall response (BOR) of either CR or PR, as graded by RECIST V1.1. 
 


 
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The secondary endpoints include:  
1) Toxicity profiles and adverse events. The severity of AEs will be graded according to 
NCI Common Terminology Criteria for Adverse Events (CTCAE) v5.0.   
2) Progression-Free Survival (PFS): defined as the time from date of first dose of study 
drugs to date of first documented disease progression or death to any cause or latest 
follow up, whichever occurs first.  
 
If the disease recurrence/progression assessment involves more than one date, the earliest 
date will be used as the event date.  A patient will be censored at the date of the last 
radiographic disease assessment indicating a lack of recurrence, if any of the following 
occurs before documented disease progression: 
 Patient is alive and progression free at the time of analysis data cut-off. 
 Disease progression or death occurs right after missing data for a scheduled 
radiographic disease assessment (including missing the assessment or assessment 
results in an in-evaluable status for overall response per RECIST 1.1). 
 Patient receives non-protocol systemic anticancer treatment. 
 Patients missing baseline disease assessment will be censored at date of receiving 
first drugs. 
 For equivocal findings of progression (e.g., very small and uncertain new lesions; 
cystic changes or necrosis in existing lesions), treatment may continue until the next 
scheduled assessment.  If progression is confirmed at the next scheduled 
assessment, the date of progression should be the earlier date when progression was 
suspected.  
 
3) Overall Survival (OS), defined as the time from the date of first dose of study drugs 
until date of death from any cause or latest follow up. 
 
15.3 
Statistical Hypotheses 
 
In this population, ORR in first line treatment in locally advanced or metastatic non-clear 
cell RCC (nccRCC) is assumed to be 15%. Most published ORR prior to 2019 was at ~8%. 
However, the most recently reported data in Feb, 2019, on Keynote 427 cohort B nccRCC, 
a phase II study, was 24.8% Hence, the ORR in this study is estimated  35%, which is 
deemed a clinical meaningful improvement. Hence, the null and alternative hypotheses are 
set as follows: 
H0: ORR≤15% versus Ha: ORR ≥35% 
 
15.4 
Sample Size Determination 
 
The Simon’s Two-Stage optimal design was adopted to design the study with a one-sided 
type I error rate of 5% and targeting for 80% power. Approximately 34 efficacy evaluable 
subjects will be enrolled. During the 1st stage, 9 subjects will be enrolled and if there are 
≥2 responders as assessed by ORR, the study will proceed to Stage 2 in which 25 new 
subjects will be enrolled; otherwise, the study will stop early for futility. In the final 
analysis of 34 efficacy evaluable subjects, ≥9 responders are required to claim preliminary 
efficacy of the treatment combination over historical control in the same patient population. 


 
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The actual alpha level was 0.047 and the actual power was 0.811. The early termination 
probability is estimated at 0.5995 if null is true and the average sample size is around 19. 
 
15.5 
Population for Analyses 
 
 Safety Analysis set: refers to the set of participants who take at least one dose of 
the study interventions and will be used for safety analysis. 
 Efficacy Analysis set: refers to the participants who take at least two cycles of the 
combined study interventions and have baseline and at least one tumor assessment 
after receiving treatments unless discontinued due to disease progression, death or 
toxicity. Subjects received less than 2 cycles of combination treatments will be 
replaced with additional participants. Efficacy analysis set will be used as the 
primary set for ORR and other efficacy endpoints.  
 Per-Protocol Analysis set: refers to the participants who follows the protocol 
without major violation and have received at least 80% of the targeted dosage. This 
set will be used for sensitivity analyses of the efficacy endpoints. 
 
15.6 
Statistical Analyses 
 
15.6.1 General Approach 
 
Descriptive statistics will be used to summarize all data including mean, median, 
standard deviation, inter-quartile range etc. for continuous data and count and 
percentages for categorical data. Data will be analyzed as observed and no data 
imputation will be performed. Statistical significance is set at 5% level. 
 
15.6.2 Analysis of the Primary Endpoint(s) 
 
The primary endpoint ORR assessed by investigator review will be analyzed using 
the efficacy analysis set. ORR will be calculated as the proportion of patients who 
achieves the BOR of either CR or PR per RECISIST v1.1 and the 95% Clopper-
Pearson exact CI will be derived.  
 
The right-side one-sample binomial exact test will be conducted to test the 
hypothesis testing as follows: 
H0: ORR≤15% vs. Ha: ORR ≥35%. 
 
15.6.3 Analysis of Secondary Endpoint(s) 
 
PFS and OS will be analyzed using Kaplan–Meier product-limit estimates. Median 
PFS and OS and the cumulative probability of PFS at 3, 6, and 12 months and 
cumulative probability of OS at 6, 12, and 18 months will be presented with two-
sided 95% confidence interval (CI) if estimable. PFS censoring rules will follow 
Food and Drug Administration (FDA) Guidance for Industry, Clinical Trial 
Endpoints for the Approval of Cancer Drugs and Biologics (2007). The KM 


 
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estimates of cumulative PFS and OS will be plotted over time with 95% CI if 
estimable. 
 
15.6.4 Safety Analyses 
 
Safety analyses will be performed using the Safety Analysis set. Safety data include 
adverse events and lab data will be summarized using descriptive statistics. AE and 
Severe AE will be summarized by count and percentages by relationship to study 
drugs, by grade and by patient characteristics. Categorical lab data will be 
summarized by number and percentage. Continuous lab  data will be summarized 
using n (number of subjects with available data), mean, standard deviation (SD), 
median, and range (minimum and maximum) unless otherwise specified. General 
safety will be assessed by the monitoring and recording of all AEs and serious 
adverse events (SAEs), regular monitoring of hematology and blood chemistry, 
regular measurement of vital signs, ECG, and the performance of physical 
examinations (PE) and other safety assessments in line with local regulations 
governing a study of this nature. Laboratory test results will be summarized using 
3 categories, hematology, liver and renal, and other clinical chemistry. Hematology 
and clinical chemistry parameters that are graded by CTCAE v 4.03 will be 
summarized by CTCAE grade. Shifts from baseline to the worst CTCAE grade will 
be tabulated. 
 
Progression of nccRCC and signs and symptoms clearly related to the disease 
progression should not be captured as an AE. Disease progression is a study 
endpoint and should be captured in the CRF as per the guidelines for reporting 
disease progression.  
 
In case of life-threatening bleeding, the investigator should discontinue lenvatinib 
per Synopsis Table for Grade 4 toxicity and treat the subject based on the 
institution’s standard practice. Clinically significant bleeding will be considered as 
study-specific events and should always be considered as serious important medical 
events, which will be entered on the adverse event CRF and reported using the 
procedures for reporting SAEs, even if the study-specific event does not meet other 
serious criteria. 
 
15.6.5 Planned Interim Analysis 
 
An interim analysis for futility will be performed based on the Simon’s 2-stage 
optimal design when 9 efficacy evaluable patients are evaluable for ORR. The study 
will stop early if 2 or fewer responders are observed. If 3 or more responders are 
confirmed before the planned interim analysis and the safety profiles of both drugs 
are acceptable, the study will continue to Stage 2 and a normal interim analysis may 
be waived. There will be no enrollment gap for the interim analysis. 
 
At the final analysis with 34 efficacy evaluable patients, the study will claim 
preliminary efficacy to warrant further study if 9 or more responders are observed. 


 
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Threshold 
Interim Analysis 
Continue to enroll if ≥2 responders among the 
first  9 efficacy evaluable patients 
Final Analysis 
Reject H0 if ≥9 responders among n=34 patients 
 
15.6.6 Planned subset Analyses 
 
Exploratory subset analysis on efficacy endpoints may be performed, for example, 
by race, by sex, by histological subtype. 
 
15.6.7  Exploratory endpoint Analyses 
 
A 2-sided 95% Clopper–Pearson CI will be constructed for CBR and DCR. DOR 
will be analyzed using the KM method described above. 
 
15.7 
Continuous monitoring for toxicity using a Pocock-type boundary  
 
We will monitor the occurrence of intolerable toxicities (as defined below) in the 34 
efficacy evaluable patients using a Pocock-type boundary for repeated testing for toxicity 
(20). This boundary is equivalent to testing the null hypothesis, after each patient, that the 
event rate is equal to 0.25, using a one-sided alpha level 0.016 test.  The accrual will be 
halted if excessive numbers of intolerable toxicities are seen, that is, if the number of 
intolerable toxicities is equal to or exceeds boundary (bn) out of a total of n patients treated 
and with full follow-up (see table below).  This is a Pocock-type stopping boundary that 
yields the probability of crossing the boundary ≤0.05 when the rate of intolerable toxicities 
is equal to the acceptable rate of 0.25. 
 
Number of Patients, n 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 
Boundary, bn 
- 
- 
- 
4 5 5 5 6 6 7 7 7 8 8 9 9 9 10 10 10 
Number of Patients, n 21 22 23 24 25 26 27 28 29 30 31 32 33 34  
 
 
 
 
 
Boundary, bn 
11 11 11 12 12 12 13 13 14 14 14 15 15 15  
 
 
 
 
 
 
Intolerable toxicities include severe treatment-emergent adverse events which can’t be 
resolved within 7 days, including 
 Death  
 Life-threatening adverse drug experience 
 Inpatient hospitalization or prolongation of existing hospitalization 
 A persistent or significant disability/incapacity (i.e., a substantial disruption of a 
person’s ability to conduct normal life functions)  
 Any other experience which, based upon appropriate medical judgment, may 
jeopardize the subject and may require medical or surgical intervention to prevent 
one of the outcomes listed above  
 
 


 
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16.0 
MULTICENTER REGULATORY REQUIREMENTS 
 
Washington University requires that each participating site sends its informed consent document 
to be reviewed and approved by the Washington University Regulatory Coordinator (or designee) 
prior to IRB/IEC submission.    
 
Site activation is defined as when the secondary site has received official written documentation 
from the coordinating center that the site has been approved to begin enrollment.  At a minimum, 
each participating institution must have the following documents on file at Washington University 
prior to study activation: 
 Documentation of IRB approval of the study in the form of a letter or other official 
document from the participating institution’s IRB.  This documentation must show which 
version of the protocol was approved by the IRB. 
 Documentation of IRB approval of an informed consent form. The consent must include a 
statement that data will be shared with Washington University, including the Quality 
Assurance and Safety Monitoring Committee (QASMC), the DSMC (if applicable), and 
the Washington University study team. 
 Documentation of FWA, signed FDA Form 1572 (if applicable), and the CVs of all 
participating investigators. 
 Protocol signature page signed and dated by the investigator at each participating site. 
 
The coordinating center Principal Investigator (or designee) is responsible for disseminating to the 
participating sites all study updates, amendments, reportable adverse events, etc.  Protocol/consent 
modifications and IB updates will be forwarded electronically to the secondary sites within 4 
weeks of obtaining Washington University IRB approval.  Activated secondary sites are expected 
to submit protocol/consent/IB modifications to their local IRBs within 4 weeks of receipt unless 
otherwise noted.  Upon the secondary sites obtaining local IRB approval, documentation of such 
shall be sent to the Washington University study team within 2 weeks of receipt of approval. 
 
Documentation of participating sites’ IRB approval of annual continuing reviews, protocol 
amendments or revisions, all SAE reports, and all protocol violations/deviations/exceptions must 
be kept on file at Washington University. 
 
The investigator or a designee from each institution must participate in a regular conference call 
to update and inform regarding the progress of the trial. 
 
 


 
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17.0 
REFERENCES 
 
1. 
Hsieh JJ, Purdue MP, Signoretti S, Swanton C, Albiges L, Schmidinger M, et al. Renal 
cell carcinoma. Nat Rev Dis Primers. 2017;3:17009. 
2. 
Moch H, Humphrey PA, Ulbright TM. Who classification of tumours of the urinaryt 
system and male genital organs.  Who classification of tumours of the urinaryt system and male 
genital organs2016. 
3. 
Choueiri TK, Motzer RJ. Systemic Therapy for Metastatic Renal-Cell Carcinoma. N Engl 
J Med. 2017;376(4):354-66. 
4. 
Powles T, Rini B. Novel Agents and Drug Development Needs in Advanced Clear Cell 
Renal Cancer. J Clin Oncol. 2018:JCO2018792655. 
5. 
Rini BI, Plimack ER, Stus V, Gafanov R, Hawkins R, Nosov D, et al. Pembrolizumab 
plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med. 2019. 
6. 
Motzer RJ, Penkov K, Haanen J, Rini B, Albiges L, Campbell MT, et al. Avelumab plus 
Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med. 2019. 
7. 
Albiges L, Flippot R, Rioux-Leclercq N, Choueiri TK. Non-Clear Cell Renal Cell 
Carcinomas: From Shadow to Light. J Clin Oncol. 2018:JCO2018792531. 
8. 
Hsieh JJ, Le V, Cao D, Cheng EH, Creighton CJ. Genomic classifications of renal cell 
carcinoma: a critical step towards the future application of personalized kidney cancer care with 
pan-omics precision. J Pathol. 2018;244(5):525-37. 
9. 
Giles RH, Choueiri TK, Heng DY, Albiges L, Hsieh JJ, Linehan WM, et al. 
Recommendations for the Management of Rare Kidney Cancers. Eur Urol. 2017;72(6):974-83. 
10. 
Jonasch E. NCCN Guidelines Updates: Management of Metastatic Kidney Cancer. J Natl 
Compr Canc Netw. 2019;17(5.5):587-9. 
11. 
Armstrong AJ, Halabi S, Eisen T, Broderick S, Stadler WM, Jones RJ, et al. Everolimus 
versus sunitinib for patients with metastatic non-clear cell renal cell carcinoma (ASPEN): a 
multicentre, open-label, randomised phase 2 trial. Lancet Oncol. 2016;17(3):378-88. 
12. 
Tannir NM, Jonasch E, Albiges L, Altinmakas E, Ng CS, Matin SF, et al. Everolimus 
Versus Sunitinib Prospective Evaluation in Metastatic Non-Clear Cell Renal Cell Carcinoma 
(ESPN): A Randomized Multicenter Phase 2 Trial. Eur Urol. 2016;69(5):866-74. 
13. 
Martinez Chanza N, Xie W, Asim Bilen M, Dzimitrowicz H, Burkart J, Geynisman DM, 
et al. Cabozantinib in advanced non-clear-cell renal cell carcinoma: a multicentre, retrospective, 
cohort study. Lancet Oncol. 2019;20(4):581-90. 
14. 
Lee J-L, Ziobro M, Gafanov R, Matveev VB, Suarez C, Donskov F, et al. KEYNOTE-
427 cohort B: First-line pembrolizumab (pembro) monotherapy for advanced non‒clear cell 
renal cell carcinoma (NCC-RCC). Journal of Clinical Oncology. 2019;37(15_suppl):4569-. 
15. 
Drake CG, Stein MN. The Immunobiology of Kidney Cancer. J Clin Oncol. 
2018:JCO2018792648. 
16. 
Matsui J, Funahashi Y, Uenaka T, Watanabe T, Tsuruoka A, Asada M. Multi-kinase 
inhibitor E7080 suppresses lymph node and lung metastases of human mammary breast tumor 
MDA-MB-231 via inhibition of vascular endothelial growth factor-receptor (VEGF-R) 2 and 
VEGF-R3 kinase. Clin Cancer Res. 2008;14(17):5459-65. 
17. 
Yamamoto Y, Matsui J, Matsushima T, Obaishi H, Miyazaki K, Nakamura K, et al. 
Lenvatinib, an angiogenesis inhibitor targeting VEGFR/FGFR, shows broad antitumor activity in 
human tumor xenograft models associated with microvessel density and pericyte coverage. Vasc 
Cell. 2014;6:18. 


 
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18. 
Motzer RJ, Hutson TE, Glen H, Michaelson MD, Molina A, Eisen T, et al. Lenvatinib, 
everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, 
phase 2, open-label, multicentre trial. Lancet Oncol. 2015;16(15):1473-82. 
19. 
Lee C-H, Makker V, Rasco DW, Taylor MH, Stepan DE, Shumaker RC, et al. 
Lenvatinib+ pembrolizumab in patients with renal cell carcinoma: Updated results. American 
Society of Clinical Oncology; 2018. 
20. 
Ivanova A, Qaqish BF, Schell MJ. Continuous toxicity monitoring in phase II trials in 
oncology. Biometrics. 2005;61(2):540-5. 
 
We would like to thank the Alvin J. Siteman Cancer Center at Washington University School of 
Medicine and Barnes-Jewish Hospital in St. Louis, Missouri, for the use of the Clinical Trials Core 
which provided protocol development services. The Siteman Cancer Center is supported in part 
by an NCI Cancer Center Support Grant #P30 CA91842. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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APPENDIX A: Karnofsky Performance Status Scale 
 
 
 


 
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APPENDIX B: PATIENT’S MEDICATION DIARY 
 
Today’s Date:    
 
 
 
 
 
 
Agent:    
 
 
 
 
Cycle:    
 
 
 
 
 
 
 
 
 
Patient Name:    
 
 
 
 
 
 
Study ID#:   
 
 
 
 
INSTRUCTIONS TO THE PATIENT: 
1. Complete one form for each month.  Take 20 mg (2 capsules) of lenvatinib daily at approximately 
the same time each day.  Take the lenvatinib with a glass of water and drink the glass of water in 
as little time as possible.  Swallow the capsules whole and do not chew the capsules.   
2. Record the date, the number of capsules taken, and when you took them. 
3. If you forgot to take your lenvatinib dose and it cannot be taken within 12 hours of the normal 
dosing time within the same day, then do not take a dose that day.  Restart taking the lenvatinib 
the next day. 
4. If you have any questions or notice any side effects, please record them in the comments section.  
Record the time if you should vomit. 
5. Please return the forms to your physician or your study coordinator when you go to your next 
appointment.  Please bring your unused study medications and/or empty bottles with you to each 
clinic visit so that a pill count can be done. 
6. Avoid St. John’s Wort, Seville oranges, grapefruit, grapefruit juice, grapefruit hybrids, pummelos, 
and exotic citrus fruits from 7 days before you start taking lenvatinib and throughout the entire 
study.   
Day 
Date 
What time was 
dose taken? 
# of tablets 
taken 
 
Comments 
1 
 
 
 
 
2 
 
 
 
 
3 
 
 
 
 
4 
 
 
 
 
5 
 
 
 
 
6 
 
 
 
 
7 
 
 
 
 
8 
 
 
 
 
9 
 
 
 
 
10 
 
 
 
 
11 
 
 
 
 
12 
 
 
 
 
13 
 
 
 
 
14 
 
 
 
 
15 
 
 
 
 
16 
 
 
 
 
17 
 
 
 
 
18 
 
 
 
 
19 
 
 
 
 
20 
 
 
 
 
21 
 
 
 
 
 


 
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APPENDIX C: Definitions for Adverse Event Reporting 
 
A. Adverse Events (AEs) 
 
As defined in 21 CFR 312.32: 
 
Definition: any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug-related. 
 
Grading: the descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for all toxicity reporting.  A 
copy of the CTCAE version 5.0 can be downloaded from the CTEP website. 
 
Attribution (relatedness), Expectedness, and Seriousness: the definitions for the terms 
listed that should be used are those provided by the Department of Health and Human Services’ 
Office for Human Research Protections (OHRP).  A copy of this guidance can be found on 
OHRP’s website: 
http://www.hhs.gov/ohrp/policy/advevntguid.html 
 
B. Suspected Adverse Reaction (SAR) 
 
As defined in 21 CFR 312.32: 
 
Definition: any adverse event for which there is a reasonable possibility that the drug caused 
the adverse event.  “Reasonable possibility” means there is evidence to suggest a causal 
relationship between the drug and the adverse event.  “Suspected adverse reaction” implies a 
lesser degree of certainty about causality than adverse reaction, which means any adverse event 
caused by a drug. 
 
C. Life-Threatening Adverse Event / Life Threatening Suspected Adverse Reaction  
 
As defined in 21 CFR 312.32: 
 
Definition: any adverse drug event or suspected adverse reaction is considered “life-
threatening” if, in the view of the investigator, its occurrence places the patient at immediate 
risk of death. It does not include an adverse event or suspected adverse reaction that, had it 
occurred in a more severe form, might have caused death. 
 
D.  Serious Adverse Event (SAE) or Serious Suspected Adverse Reaction 
 
As defined in 21 CFR 312.32: 
 
Definition:  an adverse event or suspected adverse reaction is considered “serious” if, in the 
view of the investigator, it results in any of the following outcomes: 
o Death 
o A life-threatening adverse event 


 
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o Inpatient hospitalization or prolongation of existing hospitalization 
o A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
o A congenital anomaly/birth defect 
o A new cancer (that is not a condition of the study 
o Associated with an overdose 
o Any other important medical event that does not fit the criteria above but, based upon 
appropriate medical judgment, may jeopardize the subject and may require medical or 
surgical intervention to prevent one of the outcomes listed above 
 
E. Protocol Exceptions 
 
Definition: A planned change in the conduct of the research for one participant. 
 
F. Deviation 
 
Definition: Any alteration or modification to the IRB-approved research without prospective 
IRB approval.  The term “research” encompasses all IRB-approved materials and documents 
including the detailed protocol, IRB application, consent form, recruitment materials, 
questionnaires/data collection forms, and any other information relating to the research study. 
 
A minor or administrative deviation is one that does not have the potential to negatively impact 
the rights, safety, or welfare of participants or others or the scientific validity of the study. 
 
A major deviation is one that does have the potential to negatively impact the rights, safety, or 
welfare of participants or others or the scientific validity of the study. 
 
G. Overdose 
 
Definition: 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. In the event of overdose, the subject should 
be observed closely for signs of toxicity.  Appropriate supportive treatment should be provided 
if clinically indicated. 
 
An overdose of lenvatinib will be defined as any dose of 120 mg or greater (≥ 6 times the 
indicated dose).  There is no specific antidote for overdose with lenvatinib.  In case of suspected 
overdose, lenvatinib should be withheld and supportive care initiated. 
 
H. Events of Clinical Interest  
 
Events of clinical interest for this trial include: 
 
1. an overdose of Merck product (either pembrolizumab or lenvatinib), as defined in 
Section 8.6.1 - Definition of an Overdose for This Protocol and Reporting of Overdose 
to the Sponsor, that is not associated with clinical symptoms or abnormal laboratory 


 
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results.  
2. an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the 
upper limit of normal and, at the same time, an alkaline phosphatase lab value that is 
less than 2X the upper limit of normal, as determined by way of protocol-specified 
laboratory testing or unscheduled laboratory testing.* 
 
*Note:  These criteria are based upon available regulatory guidance documents. The purpose 
of the criteria is to specify a threshold of abnormal hepatic tests that may require an additional 
evaluation for an underlying etiology.   
 
 


 
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APPENDIX D: Reporting Timelines 
 
Expedited Reporting Timelines 
Event 
HRPO 
QASMC 
Merck 
Serious adverse event 
 
 
Report within 2 working 
days. 
Unanticipated 
problem involving risk 
to participants or 
others 
Report within 10 working 
days.  If the event results 
in the death of a 
participant enrolled at 
WU/BJH/SLCH, report 
within 1 working day. 
Report via email 
after IRB 
acknowledgment 
 
Overdose 
 
 
If an AE is associated with 
overdose of either 
pembrolizumab or 
lenvatinib, report as a 
serious adverse event within 
2 working days. 
 
If an overdose is taken 
without any associated AE, 
report as a non-serious 
Event of Clinical Interest to 
Merck within 2 working 
days. 
Pregnancy and infant 
exposure during 
breastfeeding 
 
 
Report within 2 working 
days. 
Event of Clinical 
Interest 
 
 
Report within 2 working 
days. 
Major deviation 
Report within 10 working 
days.  If the event results 
in the death of a 
participant enrolled at 
WU/BJH/SLCH, report 
within 1 working day. 
 
 
A series of minor 
deviations that are 
being reported as a 
continuing 
noncompliance 
Report within 10 working 
days.   
 
 
Protocol exception 
Approval must be 
obtained prior to 
implementing the change 
 
 
Complaints 
If the complaint reveals an 
unanticipated problem 
involving risks to 
participants or others OR 
noncompliance, report 
within 10 working days.  
 
 


 
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Expedited Reporting Timelines 
Event 
HRPO 
QASMC 
Merck 
If the event results in the 
death of a participant 
enrolled at 
WU/BJH/SLCH, report 
within 1 working day.  
Otherwise, report at the 
time of continuing review. 
Breach of 
confidentiality 
Within 10 working days. 
 
 
Incarceration 
If withdrawing the 
participant poses a safety 
issue, report within 10 
working days.   
 
If withdrawing the 
participant does not 
represent a safety issue 
and the patient will be 
withdrawn, report at 
continuing review. 
 
 
 
Routine Reporting Timelines 
Event 
HRPO 
QASMC 
Merck 
Adverse event or SAE 
that does not require 
expedited reporting 
If they do not meet the definition of an 
unanticipated problem involving risks 
to participants or others, report 
summary information at the time of 
continuing review 
Adverse events will be 
reported in the toxicity 
table in the DSM report 
which is typically due 
every 6 months. 
 
Minor deviation 
Report summary information at the 
time of continuing review. 
 
 
Complaints 
If the complaint reveals an 
unanticipated problem involving risks 
to participants or others OR 
noncompliance, report within 10 
working days.  If the event results in 
the death of a participant enrolled at 
WU/BJH/SLCH, report within 1 
working day.  Otherwise, report at the 
time of continuing review. 
 
 
Incarceration 
If withdrawing the participant poses a 
safety issue, report within 10 working 
days.   
 
If withdrawing the participant does not 
represent a safety issue and the patient 
will be withdrawn, report at continuing 
review. 
 
 
 


 
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Expedited Reporting Timelines for Secondary Sites 
Event 
WU (Coordinating Center) 
Local IRB 
Merck 
Serious AND 
unexpected suspected 
adverse reaction 
Report no later than 11 calendar days 
after it is determined that the 
information qualifies for reporting. 
Report all 
applicable 
events to local 
IRB according 
to local 
institutional 
guidelines. 
The research team 
at Washington 
University is 
responsible for 
reporting all 
applicable events 
to Merck as 
needed. 
Unexpected fatal or 
life-threatening 
suspected adverse 
reaction 
Report no later than 4 calendar days 
after initial receipt of the information. 
Unanticipated 
problem involving risk 
to participants or 
others 
Report no later than 4 calendar days 
after initial receipt of the information. 
Overdose 
Report within 24 hours. 
Event of Clinical 
Interest 
Report within 24 hours. 
Pregnancy and infant 
exposure during 
breastfeeding 
Report within 24 hours. 
Adverse event or SAE 
that does not require 
expedited reporting 
As per routine data entry expectations 
Protocol exception 
Approval must be obtained prior to 
implementing the change. 
 
 
 


 
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APPENDIX E: Washington University Unanticipated Problem Reporting Cover Sheet 
 
SAE COVER SHEET- Secondary Site Assessment 
 
Washington University HRPO#:  
Washington University PI:  
Subject Initials:   
Subject ID:  
Treating MD:  
Treating Site:  
EVENT TERM:  
Admission Date:  
EVENT GRADE: 
Date of site’s first notification: 
 
Treating MD Event Assessment:  
 
 
Is this event possibly, probably, or definitely related study treatment? 
 
 yes  
 
 no 
 
If yes, please list which drug (if more than one)______________________________ 
 
       
Explain ______________________________________________________________________ 
 
______________________________________________________________________________ 
 
 
 
_________________________           ___________________________      _________________  
Physician’s Name 
 
 
Physician’s Signature 
 
Date 
 
 


 
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APPENDIX F: TUMOR TISSUE SUBMISSION FORM 
 
Submitter Name:  ______________                      Submitter’s Phone #:   
 
 
 
 
 
STUDY ID#:   202003148 
 
 
Subject ID:   
 
 
 
 
 
Participant Initials: (first, middle, last) _____________________  DOB:                        
 
 
Collection Site (select one):      
☐ Washington University School of Med       
 
☐ Cornell University 
  
☐ Stanford University  
 
 
 
☐ Tulane University 
 
Specimen(s) Submitted:  Please label tissue block or slides with Study ID, Subject ID, Date of 
Collection, and type of sample (ie, FFPE or OCT block).  
 
Specimen Type 
Timepoint 
Date Collected 
(MM/DD/YY) 
Number of 
Slides/Specimens 
Site of Tissue 
☐Fixed tissue 
block 
☐tissue slides 
☐OCT embedded 
frozen tissue 
Pre-treatment 
 
 
 
 
Shipping directions: Samples should only be shipped Monday through Wednesday. If Thursday shipping 
is required, please contact the study team at LENKYN@wustl.edu to assess availability or recommended 
storage conditions. Tissue cannot be shipped on a Friday. Samples to be shipped same day obtained when 
possible in protected shipment container for overnight delivery by FEDEX. In case of submitting 
unstained cut slides, freshly cut slides should be shipped within 14 days from when the slides are 
cut. FFPE samples can be sent at room temperature, on cool packs if ambient temperature requires. 
OCT tissue should be shipped on dry ice. 
 
Pathology Report: redact PHI and include with tumor specimen shipment (required) 
 
Shipment Address: 
 
 
 
 
 
Hannah Black, Washington University School of Medicine 
660 South Euclid Campus Box 8056-29-10200  
St. Louis, MO 63110, USA  
Phone: 314-747-2089, 314-362-9913 or 314-273-2696 
 
Sample tracking number: _____________________ 
Please send the original requisition with the samples. Retain a copy for the research chart. 
 
Please send email notification of shipment, along with a copy of this submission form and 
the FedEx tracking number to: LENKYN@wustl.edu 
 
 
 
 
 
 


 
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APPENDIX G: PBMC & PLASMA CORRELATIVE BLOOD SUBMISSION FORM 
 
Submitter Name: ________                      Submitter’s Phone #:   
 
 
 
 
 
STUDY ID#:   202003148 
 
 
Subject ID:   
 
 
 
 
 
Participant Initials: (first, middle, last) _____________________  DOB:                        
 
 
Collection Site (select one):      
☐ Washington University School of Med       
 
☐ Cornell University 
  
☐ Stanford University  
 
 
 
☐ Tulane University 
 
Specimen(s) Submitted:  Please label tubes with Study ID, Subject ID, Date of Collection, and type of 
specimen (ie, plasma or PBMC). Requisition can be used for multiple timepoints but only one patient.  
   
Shipping directions: Samples should only be shipped Monday through Wednesday. If Thursday shipping 
is required, please contact the study team at LENKYN@wustl.edu to assess availability or recommended 
storage conditions. Blood cannot be shipped on a Friday. Samples to be bulk shipped frozen at a 
minimum of every 2 months in protected shipment container for overnight delivery by FEDEX.  
 
Shipment Address: 
 
 
 
 
 
Hannah Black, Washington University School of Medicine 
660 South Euclid Campus Box 8056-29-10200  
St. Louis, MO 63110, USA  
Phone: 314-747-2089, 314-362-9913 or 314-273-2696 
 
Sample tracking number: _____________________ 
Please send the original requisition with the samples. Retain a copy for the research chart. 
 
Please send email notification of shipment, along with a copy of this submission form and 
the FedEx tracking number to: LENKYN@wustl.edu 
 
 
 
Specimen Type 
Timepoint 
Number of 
Cryovials 
Date Collected 
(MM/DD/YY) 
Time collected 
(__:__) 
☐ PBMCs 
☐ double spun 
plasma   
☐ Pre-treatment 
☐ Cycle 4    
☐ Off treatment 
 
 
 
☐ PBMCs 
☐ double spun 
plasma   
☐ Pre-treatment 
☐ Cycle 4    
☐ Off treatment 
 
 
 
☐ PBMCs 
☐ double spun 
plasma   
☐ Pre-treatment 
☐ Cycle 4    
☐ Off treatment 
 
 
 
☐ PBMCs 
☐ double spun 
plasma   
☐ Pre-treatment 
☐ Cycle 4    
☐ Off treatment 
 
 
 


 
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APPENDIX H: RECOMMENDED BLOOD PROCESSING INSTRUCTIONS 
 
 
It is requested that secondary sites process two 10mL tubes of EDTA blood (purple top 
preferred, pink acceptable) to double spun plasma and PBMCs prior to shipping in order to 
ensure samples are viable for analyses. If the secondary site is unable to process according to the 
instructions below or if the processing SOPs differ, contact LENKYN@wustl.edu for alternate 
arrangements or approval of the SOP.  
 
ISOLATION OF PLASMA FROM PERIPHERAL BLOOD 
(adopted from SOP-200 from TPC, v3.1, dated 7/20/2020) 
Safety 
Use universal safety precautions and don appropriate personal protective equipment when 
handling human samples. 
Materials 
 Clinical centrifuge with swinging bucket rotor 
 Microcentrifuge (4℃) 
 Cryovials (2.0mL) 
 Microcentrifuge tubes (5.0mL) 
 Transfer pipette 
 Dry ice and container 
Procedure 
Platelet Poor Plasma (PPP) Isolation (also known as Double Spun Plasma): Whole Blood EDTA 
BCTs 
1. Centrifuge two 10mL EDTA BCTs at 1,600 × g for 10 minutes at room temperature. 
2. The specimen will separate into three layers: plasma, buffy coat and RBCs 
3. Carefully transfer plasma into 5 mL flip-top microcentrifuge tube. 
3.1. Do not disturb white blood cell/platelet or red blood cell layers. 
4. Pellet residual cells/platelets via centrifugation at 13,000 rpm (16,000 × g) for 10 minutes at 
4°C. 
5. Aliquot 1.5 mL plasma into labeled cryovials (up to 6 cryos) and immediately store at -80°C. 
 
ISOLATING PBMCS FROM PERIPHERAL BLOOD USING Ficoll-Paque™ Plus 
REAGENT  
(adopted from SOP-203 from TPC, v2.2, dated 5/21/2021) 
Safety 
Use universal safety precautions and don appropriate personal protective equipment when 
handling human samples. 
Materials 
 Clinical Centrifuge with swinging bucket rotor 
 Microcentrifuge (4℃) 
 Cryovials (2 mL) 
 Microcentrifuge Tubes with O-ring lid (1.5 mL) 
 15 mL Conical Tubes 
 50 mL Conical Tubes 
 RBC Lyse Solution, Qiagen or equivalent 
 Phosphate Buffered Saline (PBS) 


 
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 Ficoll-Paque PlusTM (Ficoll) 
 Leucosep™ or SepMate™ Tubes 
 Freezing Medium (90% FBS + 10% DMSO) 
 Rocker (Gyro Mini Nutating Mixer) 
 Control-rate freezing container 
 Cool Box™ insert, Cool Box™ and frozen ice pack 
 Serological pipette 
 Serological pipettes 
 Transfer pipette (5.8 mL) 
 Fine-tip transfer pipette (1.5 mL) 
 Blood Bloc absorbent wipes, or equivalent 
 Wet ice and container 
 Dry ice and container 
 
For preparation of cryopreserved cells the following materials are required: 
 Prepare Freezing Media by adding 55.5 mL of DMSO to a 500 mL thawed FBS 
container, mix thoroughly and pour into eleven 50 mL conical tubes. 
 
Procedure 
1. Plasma Collection 
1.1. Perform plasma isolation as described above. Once complete, combine the fractionated 
sample (erythrocytes, granulocytes and lymphocytes, platelets) with the remaining whole 
blood or whole bone marrow into a 50 mL conical tube. 
2. Preparation of Whole Blood 
2.1. Dilute one 10mL EDTA BCT of whole blood 1:1 with PBS in a labeled 50 mL conical 
tube depending on starting volume of whole blood. 
Example: if processing 20 mL whole blood, combine 20 mL whole blood and 20 mL 
PBS in a 50 mL conical tube. 
3. Isolation of Mononuclear Cells from Whole Blood using LeucosepTM Tubes 
3.1. Leucosep tubes cannot be used if granulocyte isolation is required. If the processing 
ntoes requires the collection of granulocytes, proceed to Step 6. 
3.2. Prepare the Leucosep tubes by filling the 50 mL Luecosep tube with 15 mL of room 
temperature Ficoll and centrifuge at 1000 x g for 2 minutes at room temperature. 
3.2.1. The Ficoll is now located below the porous barrier of the Leucosep tube. 
3.2.2. Leucosep tubes can be prepped in advance of use and stored for 3 months. 
Prepped Leucosep tubes must be stored at room temperature and away from direct 
exposure to light. 
3.3. Transfer 15-30 mL of diluted blood directly into the Leucosep tube and centrifuge at 800 
x g for 15 minutes at room temperature. Set rotor brake to 6 and allow the centrifuge to 
come to a complete stop before removing the tubes. 
3.4. Aspirate the Plasma/PBS layer fraction with a serological or transfer pipette and discard. 
Leave behind 5 to 10 mm of Plasma/PBS above the Mononuclear Cell layer in order to 
reduce presence of platelets in the cell isolate. 
3.4.1. Alternatively, this step can be skipped if there is a small amount of original 
suspension and the MC layer is indistinct. 


 
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3.5. Harvest the supernatant containing the Mononuclear Cells by pouring the supernatant 
directly into 50 mL conical tubes. 
3.5.1. The Mononuclear Cell isolate from two Leucosep™ Tubes can be pooled into a 
single 50 mL conical tube. 
3.6. Bring the volume in the conical tube to 50 mL using PBS and mix 5 times by gentle 
inversion. 
3.7. Pellet the Mononuclear Cells using centrifugation at 400 x g for 10 minutes at room 
temperature. 
3.8. Remove the supernatant and turn the tube upside down and briefly place on a Blood bloc 
to allow the remaining supernatant to drain. 
3.9. Suspend the pellet in 1-5 mL of PBS; gently pipette up and down. 
3.10. 
Proceed to Step 6--Cell Suspension Quantitation. 
4. Isolation of Mononuclear Cells from Whole Blood or Bone Marrow using SepMate™ Tubes 
4.1. SepMate tubes cannot be used if granulocyte isolation is required. If the processing notes 
requires the collection of granulocytes, proceed to Step 6. 
4.2. SepMate tubes can be prepared in advance and stored for 3 months. Pipet 15 mL of room 
temperature Ficoll onto the SepMate insert. 
4.2.1. Centrifuge at 1000 x g for 2 minutes at room temperature. 
4.2.2. The top of the density gradient medium will be above the insert. 
4.2.3. Prepped SepMate tubes must be stored vertically at room temperature and away 
from direct exposure to light. 
4.3. Keeping the tube vertical, add the diluted whole blood sample by pouring down the side 
of the tube. Take care not to pour the diluted sample directly through the central hole. 
4.4. Centrifuge at 1200 x g for 10 minutes, with the brake on. 
4.4.1. If it appears that separation did not occur (sample appears dark red), centrifuge at 
1200 x g for an additional 10 minutes. 
4.5. Pour off the top layer into a new 50 mL conical tube. Do not invert tube for longer 
than 2 seconds. 
4.5.1. If samples from two or more tubes will be pooled, carefully aspirate the 
Plasma/PBS layer without disturbing the MC layer before pouring into a new 50 
mL conical tube. 
4.6. Bring the volume in the conical tube to 50 mL using PBS and mix 5 times by gentle 
inversion. 
4.7. Pellet the Mononuclear Cells using centrifugation at 400 x g for 10 minutes at room 
temperature. 
4.8. Remove the supernatant and turn the tube upside down and briefly place on a Blood bloc 
to allow the remaining supernatant to drain. 
4.9. Suspend the pellet in 1-5 mL of PBS; gently pipette up and down. 
4.10. 
Proceed to Step 6--Cell Suspension Quantitation. 
5. Isolation of Mononuclear Cells and Granulocytes using Ficoll Layering in Conical Tubes 
5.1. This procedure must be used if Mononuclear Cell and Granulocyte isolation is required 
from peripheral whole blood. 
5.2. Prepare the Ficoll reagent. 
5.2.1. Ensure the Ficoll reagent is at room temperature. 
5.2.2. To an empty 15 mL, add 4 mL of Ficoll reagent for every 10 mL of diluted whole 
blood sample intended for processing. 


 
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5.2.3. Carefully layer the diluted whole blood sample onto the Ficoll reagent using a 
serological or transfer pipette. 
5.2.3.1. 
Tilt the conical tube and touch the pipette tip to the inside of the tube and 
allow the sample to slowly slide down the side of the tube. Do not 
submerge the pipette tip below the Ficoll reagent layer. 
5.2.4. Disengage the rotor break and centrifuge the tubes at 400 × g for 25 minutes at 
room temperature. Allow the centrifuge to come to a complete stop before 
removing the tubes. 
5.2.5. Centrifugation will separate the sample into 4 distinct layers (top to bottom): 
plasma/PBS layer, Mononuclear cells, Ficoll, Granulocytes and Erythrocytes. 
5.3. Isolation of Mononuclear Cells 
5.3.1. Remove and discard the upper Plasma/PBS layer. 
5.3.1.1. 
Alternatively, pierce through the upper Plasma/PBS layer to reach the 
white interface layer using a transfer pipette. 
5.3.2. Transfer the white interface layer containing the Mononuclear Cells to a new 50 
mL conical tube. Prolonged contact with Ficoll is toxic to cells. Remove and wash 
cells as quickly as possible. 
5.3.3. Pellet the Mononuclear Cells with centrifugation at 400 × g for 10 minutes at 
room temperature. 
5.3.4. Remove supernatant and discard. 
5.3.5. Add 1 to 5 mL of PBS to the cell pellet and gently pipette up and down to avoid 
aerosolizing the solution while resuspending the cells. 
5.3.6. Proceed to Step 6--Cell Suspension Quantitation. 
5.4. Isolation of Granulocytes 
5.4.1. Insert a transfer pipette through the Ficoll layer to the granulocyte and erythrocyte 
layer. Transfer the layer into a new 50 mL conical tube. 
5.4.1.1. 
The granulocyte and erythrocyte layers from multiple tubes, with total layer 
volume not exceeding 10ml, may be pooled together in a single 50 mL 
conical tube. 
5.4.2. Add enough RBC Lyse Solution to bring the total volume to 40 mL, mix 5 times 
with gentle inversion and place on the rocker for 10 minutes at room temperature. 
5.4.3. Pellet the Granulocytes with centrifugation at 400 × g for 10 minutes at room 
temperature. 
5.4.4. Pour off the supernatant. Turn the tube upside down and briefly place on a Blood 
bloc to allow the remaining supernatant to drain. 
5.4.5. Add 1 – 5 mL of PBS to the cell pellet and gently pipette up and down to 
resuspend the cells. 
5.4.6. Proceed to Step 6--Cell Suspension Quantitation. 
6. Cell Suspension Quantitation 
6.1. To establish total cell count, concentration and viability of cell suspensions, analyze the 
samples and record cell count. 
7. Frozen Cell Pellet Derivative 
7.1. Based on the measured total cell count, add enough PBS to the cell suspension to 
achieve 1×107 cells/mL; gently mix the cell suspension by pipetting up and down and 
transfer 1 mL (1×107 cells/mL) into separate, labeled 1.5 mL microcentrifuge tubes. 


 
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7.1.1. If quantitation measures less than 1×107 isolated cells, pellet the cell suspension 
via centrifugation at 400 × g for 10 minutes at room temperature. Pour off the 
PBS, turn the tube upside down and briefly place on a Blood Bloc to drain. 
Suspend the pellet in 1 mL of PBS and transfer the entire cell suspension to a 
single 1.5 mL microcentrifuge tube. 
7.1.2. If quantitation measures more than what is required by the collection protocol, the 
cell suspension is aliquoted to 5 microcentrifuge tubes, and the excess is 
discarded. 
7.1.3. If quantitation was not required by the collection protocol, but a pre-determined 
number of cell pellets will be generated, suspend the cell pellet in a total volume 
of PBS equal to the volume needed to deliver 1 mL of cell suspension into each 
1.5 mL microcentrifuge tube equal to the number of desired cell pellets. 
7.2. Centrifuge the cells at 1500 × g for 5 minutes at 4°C; remove supernatant using a fine-tip 
transfer pipette and discard. 
7.3. Specimen is snap frozen in LN2, EtOH/dry ice bath, or crushed dry ice. 
8. Cryopreserved Cell Derivative 
8.1. Pre-chill labeled cryovials in a Cool Box™. 
8.2. Centrifuge counted cell suspension at 400 × g for 10 minutes at room temperature to 
pellet the sample. Pour off the PBS, turn the tube upside down and briefly place on a 
Blood Bloc to drain. 
8.2.1. Alternatively, using a fine tip pipette, pull off the supernatant while being careful 
not to disturb the cell pellet and discard pipette. 
8.3. Based on the measured total cell count, add enough Freezing Medium to the cell pellet to 
achieve 1×107 cells/mL or as indicated on BSF; gently mix the cell suspension by 
pipetting up and down and transfer 1mL into separate, labeled cryovials. 
8.3.1. If quantitation measures less than 1×107 isolated cells or amount specified on 
BSF, suspend the pellet in 1mL of freezing medium and transfer the entire cell 
suspension to a single cryovial. 
8.3.2. If quantitation measures more than what is required by the collection protocol, the 
cell suspension is aliquoted to 5 cryovials at 1x107 /mL and the excess is 
discarded. 
8.3.3. If quantitation was not required by the collection protocol, or a pre-determined 
number of aliquots will be generated at an unspecified cell count, suspend the cell 
pellet in a total volume of Freezing Medium equal to the volume needed to deliver 
1 mL of cell suspension to each cryovial aliquot needed. 
8.4. Transfer the aliquots from the Cool Box™ into a controlled-rate freezing container and 
immediately store the container at -80°C. Allow the aliquots to freeze at -80°C for a 
minimum of 8 hours before transferring to long-term storage.