Clinical trial NCT04447755
Conditions: Relapsed or Refractory Solid Tumors
Sponsor: Merck Sharp & Dohme LLC
Start date: 2020-07-30; Completion date: 2025-02-13
Enrollment: 127 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The main purpose of this study is to evaluate the antitumor activity and safety of Lenvatinib (MK-7902/E7080) in children, adolescents, and young adults with relapsed or refractory solid malignancies after administration. Participants will be enrolled into initial tumor-specific cohorts which will be expanded based on observed response.

Detailed description:

Arms: arm 1: Participants with Ewing sarcoma will receive lenvatinib 14 mg/m\^2 once daily (QD) orally until progressive disease or unacceptable toxicity. arm 2: Participants with rhabdomyosarcoma will receive lenvatinib 14 mg/m\^2 QD orally until progressive disease or unacceptable toxicity. arm 3: Participants with high grade glioma will receive lenvatinib 14 mg/m\^2 QD orally until progressive disease or unacceptable toxicity. arm 4: Participants with diffuse midline glioma will receive lenvatinib 14 mg/m\^2 QD orally until progressive disease or unacceptable toxicity. arm 5: Participants with medulloblastoma will receive lenvatinib 14 mg/m\^2 QD orally until progressive disease or unacceptable toxicity. arm 6: Participants with ependymoma will receive lenvatinib 14 mg/m\^2 QD orally until progressive disease or unacceptable toxicity. arm 7: Participants with other solid tumors will receive lenvatinib 14 mg/m\^2 QD orally until progressive disease or unacceptable toxicity.
Interventions: intervention 1: Lenvatinib
Intervention descriptions: intervention 1: Lenvatinib capsules administered orally at 14 mg/m\^2 QD

Protocol documents:
Prot_SAP_000.pdf: 
Official Protocol Title:
NCT number:
Document Date:
An Open-Label, Multicenter Phase 2 Basket
Study to Evaluate the Antitumor Activity and
Safety of Lenvatinib in Children, Adolescents,
and Young Adults with Relapsed or Refractory
Solid Malignancies
NCT04447755
08 JUN 2022


PRODUCT: MK 7902  
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Title Page
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME LLC, RAHWAY, NJ, USA (MSD).
Protocol Title: An Open-Label, Multicenter Phase 2 Basket Study to Evaluate the Antitumor 
Activity and Safety of Lenvatinib in Children, Adolescents, and Young Adults with Relapsed 
or Refractory Solid Malignancies
Protocol Number: 013-04 (E7080-G000-231)
Compound Number: MK-7902 (E7080/lenvatinib)
Sponsor Name:
Merck Sharp & Dohme LLC
(hereafter referred to as the Sponsor or MSD)
This study is co-funded by MSD and Eisai.
Legal Registered Address:
126 East Lincoln Avenue
P.O. Box 2000
Rahway, NJ 07065 USA
Regulatory Agency Identifying Number(s):
IND
147052
EudraCT
2019-004441-33
NCT
NCT04447755
Approval Date: 08 June 2022
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Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor contact information can be found in the Investigator Study
File Binder (or equivalent).
Investigator Signatory
I agree to conduct this clinical study in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol.
Typed Name:
Title:
Date
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Amendment 4
08-JUN-2022
Further enrollment of participants into the other solid tumors’ cohort was 
discontinued due to insufficient antitumor activity of lenvatinib in this patient 
population, with FDA and EMA agreement obtained.
Amendment 3
11-AUG-2021
Global amendment to modify the futility rules for the three target tumor cohorts 
based on results from the futility analyses completed for the corresponding cohorts 
in Study E7080-A001-216 (Study of Lenvatinib in Combination With Everolimus in 
Recurrent and Refractory Pediatric Solid Tumors, Including Central Nervous System 
Tumors). Changed the definition of evaluable participants for consistency with 
Study E7080-A001-216 and to accommodate a health authority request.
Amendment 2
14-OCT-2020
The study protocol has been revised to require (1) A minimum of 6 participants less 
than 17 years of age for each of the HGG, RMS, and EWS/pPNET target tumor
cohorts, (2) Reduced PK sampling in children weighing <13 kg (3) Reduced PD 
sampling for children <16 kg (4) Medications known to prolong the QT interval are 
to be initiated cautiously; and (5) Added a requirement to normalize electrolytes 
prior to starting treatment per the lenvatinib SmPC and to also specify on study that 
electrolytes should be replenished as appropriate. Dose modification guidelines for 
QT interval prolongation to align with lenvatinib development program was also 
added.
Amendment 
1/Czech Republic-
specific 
amendment
18-AUG-2020
To address feedback from Czech Republic regulatory authorities.
Original Protocol
26-FEB-2020
Not applicable
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 04
Overall Rationale for the Amendments:
Further enrollment of participants into the other solid tumors’ cohort was discontinued due to insufficient antitumor activity with 
lenvatinib for this patient population, with FDA and EMA agreement obtained.
Summary of Changes Table:
Section # and Name
Description of Change 
Brief Rationale 
1.1 Synopsis
4.4 Beginning and End of 
Study Definition
9.7.2 Efficacy Interim 
Analysis
Added text indicating that enrollment into 
the other solid tumors cohort was 
discontinued
Insufficient antitumor activity of lenvatinib in 
participants in the other solid tumors’ cohort; FDA and 
EMA agreement obtained.
10.7.3 Italy
1.3 Schedule of Activities
8 Study Assessments and 
Procedures
8.3 Safety Assessments
Included details regarding maximum blood 
volumes and a reference to “Ethical 
Considerations for Clinical Trials on 
Medicinal Products Conducted With 
Minors” [European Commission 2017]
Added references to Appendix 7 (Country-
specific Requirements) where needed
To address the Italian Health Authority’s 
recommendation to stipulate maximum blood volumes to 
be taken from participants in Italy
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Section # and Name
Description of Change 
Brief Rationale 
1.3 Schedule of Activities
8.3.6.1 Hematology and 
Clinical Chemistry
Updated text to clarify that hematology, 
blood chemistry, and urinalysis samples 
are to be obtained and assessed, and the 
results are to be reviewed, prior to study 
drug administration on C1D1 and within 
72 hours prior to the visit for all 
subsequent cycles
To clarify timing of study assessments
1.1 Synopsis
Added a statement acknowledging that the 
EWS and HGG cohorts were not 
expanded.
For completeness; futility was concluded in the 
corresponding cohorts in Study E7080-A001-216.
5 Study Population
Added text regarding the collection and 
use of demographic data
To clarify the collection, use, and confidentiality of 
demographic data provided by the participants.
Title Page
Section 10.1.1 Code of 
Conduct for Clinical Trials
Sponsor entity name and address change
Merck Sharp & Dohme Corp. underwent an entity name 
and address change to Merck Sharp and Dohme LLC, 
Rahway, NJ, USA. This conversion resulted only in an 
entity name change and update to the address.
8.4.7 Events of Clinical 
Interest
Added text to indicate that lenvatinib 
overdose is not considered an ECI
To clarify the reporting of lenvatinib overdose
10.3.2 Definition of AE
Formerly Section 10.3.1
Revised text to clarify that lenvatinib 
overdose without an associated AE is not 
reportable as an AE
Added a reference to Section 8.5 
(Treatment of Overdose)
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Section # and Name
Description of Change 
Brief Rationale 
8.4.5 Pregnancy and 
Exposure During 
Breastfeeding
Added text to ensure that any pregnancy 
complications, as well as the medical 
reason for elective termination of a 
pregnancy, are reported as AEs or SAEs
Added ‘ectopic pregnancy’ to the list of 
pregnancy outcomes to be reported as 
serious events (Important Medical Events)
To ensure that all pregnancy complications, outcomes, 
and medical reasons for elective termination of a 
pregnancy are properly reported
1.1 Synopsis
4.4 Beginning and End of 
Study Definition
Replaced withdraws ‘from the study’ with 
withdraws ‘consent’
To clarify the intent regarding the end of the study
8 Study Assessments and 
Procedures
Added text “or dental”
“All study-related medical or dental 
decisions must be made by an investigator 
who is a qualified physician.”
To correct a previous omission
1.1 Synopsis
6.1 Study Intervention(s) 
Administered
In the ‘Use’ column, replaced 
‘Experimental’ with ‘Test Product’
To align with EU CTR
4.4 Beginning and End of 
Study Definition
Added definition of end of study for 
analysis and reporting purposes
Added definition of local start of the study 
for countries in the EEA
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Section # and Name
Description of Change 
Brief Rationale 
6.1 Study Intervention(s) 
Administered
Replaced ‘IMP/NIMP’ column header 
with ‘IMP or NIMP/AxMP’
Updated the abbreviations and added text 
to describe the use of IMP and 
NIMP/AxMP classifications 
To align with EU CTR
8.4 Adverse Events, Serious 
Adverse Events, and Other 
Reportable Safety Events
Added text stating that investigators need 
to document if an SAE was associated 
with a medication error, misuse, or abuse
10.3.1 Definitions of 
Medication Error, Misuse, 
and Abuse
New section added
8.2.1.2 Tumor Imaging 
During the Study
Added “pregnancy” to the list of reasons to 
discontinue imaging
For consistency with the reasons to discontinue imaging 
in Section 8.2.1.3
8.11.4 Discontinued 
Participants Continuing to be 
Monitored in the Study
Revised section title to “Participants 
Discontinued From Study Intervention but 
Continuing to be Monitored in the Study”
To clarify the information that is included within this 
section
Title Page
Added NCT number
To include the ClinicalTrials.gov Identifier
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Section # and Name
Description of Change 
Brief Rationale 
6.6.7 Management of 
Hepatotoxicity
Deleted redundant sentence
“If hepatic failure occurs, the study drug 
must be discontinued.”
To remove redundancy
8.10 Health Economics 
Medical Resource 
Utilization and Health 
Economics
Revised section title to “Medical Resource 
Utilization and Health Economics”
Throughout document
Minor administrative, formatting, 
grammatical, and/or typographical changes 
were made throughout the document.
To ensure clarity and accurate interpretation of the intent 
of the protocol
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Table of Contents
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1
PROTOCOL SUMMARY ............................................................................................18
1.1
Synopsis.................................................................................................................18
1.2
Schema ..................................................................................................................22
1.3
Schedule of Activities...........................................................................................23
2
INTRODUCTION..........................................................................................................40
2.1
Study Rationale....................................................................................................40
2.2
Background ..........................................................................................................40
2.2.1
Pharmaceutical and Therapeutic Background .............................................41
2.2.1.1
Epidemiology and Current Therapeutic Options...............................42
2.2.1.1.1
High-grade Glioma ..................................................................42
2.2.1.1.2
Rhabdomyosarcoma.................................................................43
2.2.1.1.3
Ewing’s Sarcoma/pPNET........................................................43
2.2.1.2
Clinical Data on Lenvatinib in Children and Adolescent Patients ....44
2.2.2
Preclinical and Clinical Studies ...................................................................45
2.3
Benefit/Risk Assessment......................................................................................45
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................45
4
STUDY DESIGN............................................................................................................47
4.1
Overall Design......................................................................................................47
4.2
Scientific Rationale for Study Design.................................................................49
4.2.1
Rationale for Endpoints ...............................................................................49
4.2.1.1
Efficacy Endpoints.............................................................................49
4.2.1.1.1
RECIST 1.1..............................................................................50
4.2.1.1.2
RANO ......................................................................................50
4.2.1.2
Safety Endpoints................................................................................50
4.2.1.3
Pharmacokinetic Endpoints ...............................................................50
4.2.1.4
Pharmacodynamic Endpoints.............................................................50
4.2.1.5
Planned Exploratory Biomarker Research.........................................51
4.3
Justification for Dose...........................................................................................52
4.4
Beginning and End of Study Definition .............................................................53
4.4.1
Clinical Criteria for Early Study Termination .............................................53
5
STUDY POPULATION ................................................................................................54
5.1
Inclusion Criteria.................................................................................................54
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5.2
Exclusion Criteria................................................................................................60
5.3
Lifestyle Considerations......................................................................................61
5.3.1
Meals and Dietary Restrictions....................................................................61
5.3.2
Contraception...............................................................................................61
5.3.3
Pregnancy.....................................................................................................62
5.3.4
Use in Nursing Women................................................................................62
5.4
Screen Failures.....................................................................................................62
5.5
Participant Replacement Strategy......................................................................62
6
STUDY INTERVENTION............................................................................................63
6.1
Study Intervention(s) Administered...................................................................63
6.2
Preparation/Handling/Storage/Accountability .................................................65
6.2.1
Dose Preparation..........................................................................................65
6.2.2
Handling, Storage, and Accountability........................................................65
6.3
Measures to Minimize Bias: Randomization and Blinding..............................66
6.3.1
Intervention Assignment..............................................................................66
6.3.2
Stratification.................................................................................................66
6.3.3
Blinding........................................................................................................66
6.4
Study Intervention Compliance..........................................................................66
6.5
Concomitant Therapy..........................................................................................66
6.5.1
Prohibited Concomitant Medications ..........................................................67
6.5.2
Rescue Medications and Supportive Care ...................................................67
6.6
Dose Modification ................................................................................................67
6.6.1
Blood Pressure .............................................................................................69
6.6.2
Management of Hypertension......................................................................69
6.6.3
Management of Proteinuria..........................................................................72
6.6.4
Management of Gastrointestinal Symptoms and Acute Abdominal Pain ...73
6.6.5
Management of Thromboembolic Events....................................................74
6.6.6
Management of Posterior Reversible Encephalopathy Syndrome 
(PRES)/Reversible Posterior Leukoencephalopathy Syndrome (RPLS).....74
6.6.7
Management of Hepatotoxicity....................................................................74
6.6.8
Management of Hypocalcemia ....................................................................75
6.6.9
Management of Hemorrhage .......................................................................75
6.6.10
Management of Fistula Formation and Gastrointestinal Perforation...........75
6.6.11
Management of QT Prolongation ................................................................75
6.6.12
Management of Osteonecrosis of the Jaw ...................................................75
6.7
Other Allowed Dose Interruptions for Lenvatinib ...........................................76
6.8
Intervention After the End of the Study............................................................76
6.9
Clinical Supplies Disclosure................................................................................76
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6.10
Standard Policies..................................................................................................76
6.10.1
Study Site Retention Samples......................................................................76
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................76
7.1
Discontinuation of Study Intervention...............................................................76
7.2
Participant Withdrawal From the Study...........................................................77
7.3
Lost to Follow-up .................................................................................................78
8
STUDY ASSESSMENTS AND PROCEDURES........................................................78
8.1
Administrative and General Procedures ...........................................................79
8.1.1
Informed Consent/Assent.............................................................................79
8.1.1.1
General Informed Consent/Assent.....................................................79
8.1.2
Inclusion/Exclusion Criteria ........................................................................80
8.1.3
Participant Identification Card.....................................................................80
8.1.4
Medical History ...........................................................................................80
8.1.5
Prior and Concomitant Medications Review...............................................80
8.1.5.1
Prior Medications...............................................................................80
8.1.5.2
Concomitant Medications..................................................................80
8.1.6
Assignment of Screening Number...............................................................81
8.1.7
Assignment of Treatment/Allocation Number.............................................81
8.1.8
Study Intervention Administration ..............................................................81
8.1.8.1
Timing of Dose Administration.........................................................81
8.1.8.2
Compliance ........................................................................................82
8.1.9
Discontinuation and Withdrawal .................................................................82
8.1.10
Participant Blinding/Unblinding..................................................................82
8.1.11
Calibration of Equipment.............................................................................82
8.1.12
Demography.................................................................................................82
8.2
Efficacy/Immunogenicity Assessments ..............................................................83
8.2.1
Tumor Imaging and Assessment of Disease................................................83
8.2.1.1
Initial Tumor Imaging........................................................................83
8.2.1.2
Tumor Imaging During the Study......................................................84
8.2.1.3
End-of-Treatment and Follow-up Tumor Imaging............................84
8.2.1.4
RECIST 1.1 Assessment of Disease..................................................84
8.2.1.5
RANO Assessment of Disease...........................................................85
8.2.2
Palatability and Acceptability of Lenvatinib Suspension Formulation .......85
8.3
Safety Assessments...............................................................................................85
8.3.1
Physical Examinations.................................................................................85
8.3.2
Dental Examination .....................................................................................86
8.3.3
Vital Signs....................................................................................................86
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8.3.4
Electrocardiograms ......................................................................................87
8.3.5
Echocardiograms or Multigated Acquisition Scans.....................................87
8.3.6
Clinical Safety Laboratory Assessments .....................................................88
8.3.6.1
Hematology and Clinical Chemistry..................................................88
8.3.6.2
Urine Dipstick/Urinalysis ..................................................................89
8.3.6.3
Thyroid Function Testing ..................................................................89
8.3.6.4
Lansky Play Score or Karnofsky Performance Status.......................90
8.3.6.5
Proximal Tibial Growth Plate Measurement .....................................90
8.3.6.6
Pregnancy Test...................................................................................90
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety 
Events....................................................................................................................90
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................91
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......92
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...93
8.4.4
Regulatory Reporting Requirements for SAE .............................................93
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................93
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................94
8.4.7
Events of Clinical Interest............................................................................94
8.5
Treatment of Overdose........................................................................................94
8.6
Pharmacokinetics.................................................................................................95
8.7
Pharmacodynamics..............................................................................................95
8.8
Biomarkers ...........................................................................................................95
8.8.1
Planned Genetic Analysis Sample Collection..............................................95
8.9
Future Biomedical Research Sample Collection...............................................95
8.10
Medical Resource Utilization and Health Economics.......................................96
8.11
Visit Requirements...............................................................................................96
8.11.1
Screening......................................................................................................96
8.11.2
Treatment Period..........................................................................................96
8.11.3
Telephone Contact or Visit..........................................................................97
8.11.4
Participants Discontinued From Study Intervention but Continuing to be 
Monitored in the Study ................................................................................97
8.11.5
Post-treatment Visits....................................................................................97
8.11.5.1
Safety Follow-up Visit.......................................................................97
8.11.5.2
Efficacy Follow-up Visits..................................................................97
8.11.5.3
Survival Follow-up Assessments.......................................................97
8.11.6
Survival Status .............................................................................................98
9
STATISTICAL ANALYSIS PLAN .............................................................................98
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9.1
Statistical Analysis Plan Summary.....................................................................99
9.2
Responsibility for Analyses/In-house Blinding ...............................................100
9.3
Hypotheses/Estimation ......................................................................................100
9.4
Analysis Endpoints.............................................................................................100
9.4.1
Efficacy Endpoints.....................................................................................101
9.4.2
Safety Endpoints........................................................................................101
9.4.3
Pharmacokinetic Endpoints .......................................................................102
9.4.4
Palatability and Acceptability Questionnaire.............................................102
9.5
Analysis Populations..........................................................................................102
9.5.1
Efficacy Analysis Population.....................................................................102
9.5.2
Safety Analysis Population........................................................................102
9.5.3
Pharmacokinetic Analysis Population .......................................................102
9.6
Statistical Methods.............................................................................................103
9.6.1
Statistical Methods for Efficacy Analyses.................................................103
9.6.2
Statistical Methods for Safety Analyses ....................................................104
9.6.3
Summary of Baseline Characteristics, Demographics, and Other 
Analyses.....................................................................................................105
9.6.4
Statistical Methods for Pharmacokinetic, Pharmacodynamic, and Other 
Biomarker Analyses...................................................................................105
9.7
Interim Analyses ................................................................................................105
9.7.1
Safety Interim Analyses.............................................................................105
9.7.2
Efficacy Interim Analysis ..........................................................................105
9.8
Multiplicity .........................................................................................................107
9.9
Sample Size and Power Calculations ...............................................................107
9.10
Subgroup Analyses.............................................................................................108
9.11
Compliance (Medication Adherence)...............................................................108
9.12
Extent of Exposure.............................................................................................108
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS...................................................................................................109
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations......109
10.1.1
Code of Conduct for Clinical Trials...........................................................109
10.1.2
Financial Disclosure...................................................................................111
10.1.3
Data Protection...........................................................................................112
10.1.3.1
Confidentiality of Data ....................................................................112
10.1.3.2
Confidentiality of Participant Records.............................................112
10.1.3.3
Confidentiality of IRB/IEC Information..........................................112
10.1.4
Committees Structure.................................................................................113
10.1.4.1
External Data Monitoring Committee .............................................113
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10.1.5
Publication Policy......................................................................................113
10.1.6
Compliance with Study Registration and Results Posting Requirements .113
10.1.7
Compliance with Law, Audit, and Debarment ..........................................114
10.1.8
Data Quality Assurance .............................................................................115
10.1.9
Source Documents .....................................................................................116
10.1.10
Study and Site Closure...............................................................................116
10.2
Appendix 2: Clinical Laboratory Tests............................................................117
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.............................................................119
10.3.1
Definitions of Medication Error, Misuse, and Abuse................................119
10.3.2
Definition of AE ........................................................................................119
10.3.3
Definition of SAE ......................................................................................120
10.3.4
Additional Events Reported in the Same Manner as SAE.........................121
10.3.5
Recording AE and SAE .............................................................................122
10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ......................................................................................................123
10.4
Appendix 4: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation..................................124
10.5
Appendix 5: Contraceptive Guidance..............................................................125
10.5.1
Definitions..................................................................................................125
10.5.2
Contraception Requirements......................................................................126
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................127
10.7
Appendix 7: Country-specific Requirements..................................................128
10.7.1
Sweden.......................................................................................................128
10.7.2
Czech Republic..........................................................................................128
10.7.3
Italy ............................................................................................................129
10.8
Appendix 8: Response Assessment in Neuro-Oncology (RANO) Response 
Criteria................................................................................................................130
10.9
Appendix 9: Lansky Play Score........................................................................135
10.10 Appendix 10: Karnofsky Performance Status Scale Definitions Rating 
(%) Criteria ........................................................................................................136
10.11 Appendix 11 Blood Pressure Levels for Boys by Age and Height 
Percentile ............................................................................................................137
10.12 Appendix 12: Blood Pressure Levels for Girls by Age and Height 
Percentile ............................................................................................................139
10.13 Appendix 13: Body Mass Index-For-Age Percentiles.....................................141
10.14 Appendix 14: Monoclonal Antibodies Half-Lives...........................................143
10.15 Appendix 15: Abbreviations .............................................................................144
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REFERENCES.............................................................................................................147
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LIST OF TABLES
Table 1
Schedule of Activities................................................................................23
Table 2
Study Interventions....................................................................................64
Table 3
Criteria for Temporary Discontinuation of Study Drug, Dose 
Reduction, and Resumption of Treatment .................................................68
Table 4
Reporting Time Periods and Time Frames for Adverse Events and 
Other Reportable Safety Events.................................................................92
Table 5
Table Analysis Strategy for Key Efficacy Variables...............................104
Table 6
Response Rate and Confidence Intervals for Potential Efficacy Results 106
Table 7
Protocol-required Safety Laboratory Assessments..................................118
Table 8
Target Lesion Response...........................................................................131
Table 9
Lesion Response for Enhancing Nontarget Lesions................................131
Table 10
Radiographic Response............................................................................132
Table 11
Overall Response .....................................................................................134
08BFHY


PRODUCT: MK 7902  
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PROTOCOL/AMENDMENT NO.: 013 04 (E7080 G000 231)
MK 7902 013 04 FINAL  PROTOCOL
08 JUN 2022
LIST OF FIGURES
Figure 1
Study Design..............................................................................................22
Figure 2
Procedures Associated with Management of Hypertension ......................72
Figure 3
Sequential Monitoring Rules for Efficacy and Futility............................107
08BFHY


PRODUCT: MK 7902  
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PROTOCOL/AMENDMENT NO.: 013 04 (E7080 G000 231)
MK 7902 013 04 FINAL  PROTOCOL
08 JUN 2022
1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: An Open-Label, Multicenter Phase 2 Basket Study to Evaluate the Antitumor 
Activity and Safety of Lenvatinib in Children, Adolescents, and Young Adults with Relapsed 
or Refractory Solid Malignancies
Short Title: Lenvatinib for Pediatric Patients with Relapsed/Refractory Solid Tumors
Acronym: Protocol 013 (E7080-G000-231)
Hypotheses, Objectives, and Endpoints:
In children, adolescents, and young adults with relapsed or refractory solid malignancies 
treated with lenvatinib:
Primary Objectives
Primary Endpoints
- To determine the ORR at Week 16, by each 
tumor type, per RECIST 1.1 or RANO (for 
HGG only) as assessed by the investigator.
- Objective Response, defined as a confirmed 
(≥4 weeks after initial response) CR or PR.
Secondary Objectives
Secondary Endpoints
- To evaluate ORR, by each tumor type, per 
RECIST 1.1 or RANO (for HGG only) as 
assessed by the investigator.
- Objective Response, defined as a confirmed 
(≥4 weeks after initial response) CR or PR. 
- To evaluate PFS per RECIST 1.1 or RANO 
(for HGG only), by each tumor type.
- PFS defined as the time from the date of the 
first administration of lenvatinib until the 
date of first documentation of PD or death 
(whichever occurs first).
- To evaluate the BOR, DOR, DCR, and 
CBR, by each tumor type.
- BOR defined as the participant’s best 
confirmed response (CR or PR) over the 
treatment period.
- DOR defined as the time from the date of 
the first documented CR or PR to the date 
first documentation of progressive disease or 
death (whichever occurs first).
- Disease control defined as a BOR of CR or 
PR, or SD. To be assigned a BOR of SD, the 
time from the first administration of study 
drug until the date of documented SD should 
be ≥7 weeks.
- Clinical benefit defined as a BOR of CR or 
PR, or durable SD (SD duration ≥23 weeks 
since the first dose of the study treatment).
08BFHY


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- To evaluate the safety of lenvatinib.
- AEs, SAEs, clinical laboratory values, vital 
signs, 12-lead ECGs, urine dipstick, Lansky 
play scores or Karnofsky performance status 
scores, physical examination findings, dental 
examination findings, height, and closure of 
proximal tibial plates.
- To assess the palatability and acceptability 
of the suspension formulation of lenvatinib.
- Palatability questionnaire using a facial 
hedonic scale.
- To characterize the PK of lenvatinib.
- Assessment of population-based PK 
parameters of lenvatinib.
Overall Design:
Study Phase
Phase 2
Primary Purpose
Treatment
Indication
Treatment of relapsed/refractory pediatric solid tumors 
including: HGG, RMS, or EWS/pPNET and other solid 
tumors, excluding osteosarcoma.
Population
Children, adolescents, and young adults with 
relapsed/refractory HGG, RMS, or EWS/pPNET, or other 
solid tumors, excluding osteosarcoma.
Participants with HGG, RMS and EWS/pPNET may only be 
enrolled in the tumor-specific cohorts and may not be 
enrolled in the other solid tumors’ cohort. Participants with 
CNS tumors other than HGG are eligible for enrollment into 
the other solid tumors’ cohort.
Study Type
Interventional
Intervention Model
Single Group
This is a multi-site study.
Type of Control
None
Study Blinding
Unblinded Open-label
Blinding Roles
No Blinding
Estimated Duration of Study
The Sponsor estimates that the study will require 
approximately 42 months from the time the first participant 
(or their legally acceptable representative) provides 
documented informed consent/assent until the last 
participant’s last study-related contact.
08BFHY


PRODUCT: MK 7902  
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PROTOCOL/AMENDMENT NO.: 013 04 (E7080 G000 231)
MK 7902 013 04 FINAL  PROTOCOL
08 JUN 2022
Number of Participants:
A minimum of 36 participants will be enrolled, 9 evaluable participants in each of 4 cohorts: 
HGG, RMS, EWS/pPNET, and other solid tumors. The final sample size of participants will 
depend on the number of tumor types that meet the futility bar and the antitumor activity in 
evaluable participants observed in the corresponding tumor cohort in Study E7080-A001-
216. The enrollment in the HGG, RMS, and EWS/pPNET cohorts is capped at a maximum of 
17 evaluable participants each. The enrollment for each tumor type expanded based on 
response in the other solid tumors’ cohort is also capped at a maximum of 17 evaluable 
participants. Based on these factors and the projected enrollment period, it is estimated that 
up to approximately 150 participants could be enrolled. Participants will meet the criteria for 
being evaluable for an objective response if they have measurable disease present at baseline 
and at least 1 postbaseline efficacy assessment, unless they have discontinued prior to the 
first efficacy assessment due to progressive disease. Participants who are not evaluable for 
objective response will be replaced.
Intervention Groups and Duration:
Intervention 
Groups
Intervention 
Group Name
Drug
Dose 
Strength
Dose 
Frequency
Route of 
Admin.
Regimen/ 
Treatment 
Period
Use
Lenvatinib
14 mg/m2
(maximum 
daily dose 
of 24 mg)
Once Daily
Orally
Daily
Test 
Product
Total 
Number
1 arm
Duration of 
Participation
Each participant will participate in the study from the time the participant 
provides documented informed consent/assent through the final contact.
After a Screening phase of up to 28 days, each participant will be assigned to 
receive study intervention with lenvatinib. Participants will continue to 
receive lenvatinib until disease progression is verified by the investigator
using RECIST 1.1 or RANO (for participants with HGG) criteria, initiation of 
another anticancer therapy, development of unacceptable toxicity, or 
withdrawal of consent, whichever occurs first. Estimated time of lenvatinib 
treatment is 1 year. However, participants can continue on treatment with 
lenvatinib until a treatment discontinuation criterion is met.
At the end of treatment, each participant will be followed for 30 days for the 
occurrence of AEs/SAEs and for spontaneously reported pregnancy as 
described in Section 8.4.
08BFHY


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Participants who discontinue lenvatinib treatment for reasons other than 
radiographic disease progression or initiation of new anticancer therapy will 
have post-treatment follow-up imaging for disease status every 8 weeks for up 
to 24 weeks, then every 12 weeks thereafter until documentation of disease 
progression or start of a new anticancer agent, whichever occurs first, unless 
the participant withdraws consent, becomes lost to follow-up, or the study is 
terminated. Participants who discontinue lenvatinib treatment due to 
documented radiographic disease progression or initiation of new anticancer 
therapy will move to survival follow-up.
Participants will be followed by telephone every 12 weeks for survival status 
until death unless the participant withdraws consent, becomes lost to follow-
up, or the study is terminated.
A database lock for the primary analysis will occur when all participants in all 
cohorts have discontinued the study or if the last evaluable participant has 
completed the Week 16 imaging assessment, whichever comes first.
Enrollment will be stopped for a specific cohort/tumor type if no objective 
responses occur in the first 9 evaluable participants (i.e., the futility boundary 
is crossed), or a lack of antitumor activity is concluded for the corresponding 
tumor cohort in Study E7080-A001-216.
EWS and HGG cohorts were not expanded because futility was concluded for 
the corresponding cohorts in Study E7080-A001-216. Further enrollment of 
participants into the other solid tumors’ cohort was discontinued due to 
insufficient antitumor activity of lenvatinib in this patient population.
The overall study ends when the last evaluable participant completes the last 
study-related telephone call or visit, withdraws consent, or is lost to follow-up 
(ie, the participant is unable to be contacted by the investigator).
Additional details are in Section 4.1.
Study Governance Committees:
Steering Committee
No
Executive Oversight Committee
No
Data Monitoring Committee
Yes
Clinical Adjudication Committee
No
Study governance considerations are outlined in Appendix 1.
Study Accepts Healthy Volunteers: No
A list of abbreviations used in this document can be found in Appendix 15.
08BFHY


PRODUCT: MK 7902  
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PROTOCOL/AMENDMENT NO.: 013 04 (E7080 G000 231)
MK 7902 013 04 FINAL  PROTOCOL
08 JUN 2022
1.2
Schema
The study design is depicted in Figure 1.
Figure 1
Study Design
1.
The enrollment period may last up to approximately 30 months from the time of enrollment of the first 
participant. Additionally, data cutoff may occur when the last evaluable participant (see Section 1.1 for 
definition of evaluable) enrolled in the study has completed the Week 16 imaging assessment or 
discontinues prior to Week 16 imaging assessment, whichever occurs first.
2.
If no objective responses are observed at the time of enrollment of the ninth evaluable participant in a 
specific cohort or other tumor type, enrollment will be paused in said cohort or other tumor type until 
the IA for these 9 evaluable participants is completed. If at least 1 objective response is observed at 
the time of enrollment of the ninth evaluable participant in a specific cohort or other tumor type, 
enrollment may continue in said cohort or other tumor type.
3.
In addition to the futility rules above, the enrollment of 3 target tumor cohorts will stop if a lack of
antitumor activity is concluded for the corresponding tumor cohort in Study E7080-A001-216.
08BFHY


PRODUCT: MK 7902  
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MK 7902 013 04 FINAL  PROTOCOL
08 JUN 2022
1.3
Schedule of Activities
Table 1
Schedule of Activities
Study 
Period
Screening
Intervention
Cycle = 28 Days
EOT
Post-treatment Visits
NOTES
Visit 
Timing/ 
Cycle No.
1
2
3
4
5 –
last
Safety 
FU
Efficacy 
(Imaging)
FU Visits
Sur-
vival
FU
Cycle Day
1
8
15
1
15
1
1
1
At DC
30 days 
after last 
dose
Q8W for 24 
weeks, then 
Q12W
Q12
W
Scheduling 
Window
-28 to -1
±2
±2
±2
±2
±2
±2
±2
±7
±7
±7
Administrative Procedures
Informed 
Consent/
Assent
X
Documented informed 
consent/assent may be obtained 
up to 4 weeks prior to C1D1 and 
must be obtained prior to
performing any protocol-
specified procedure. Results of a 
test performed as part of routine 
clinical management are 
acceptable in lieu of a screening 
test if performed within the 
specified time frame for 
screening.
Inclusion/
Exclusion 
Criteria
X
See Appendix 7 for country-
specific requirements.
Participant 
Identifi-
cation Card
X
At the time of allocation, site 
personnel will add the allocation 
number to the identification card.
Demograph-
ics
X
08BFHY


PRODUCT: MK 7902  
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MK 7902 013 04 FINAL  PROTOCOL
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Study 
Period
Screening
Intervention
Cycle = 28 Days
EOT
Post-treatment Visits
NOTES
Visit 
Timing/ 
Cycle No.
1
2
3
4
5 –
last
Safety 
FU
Efficacy 
(Imaging)
FU Visits
Sur-
vival
FU
Cycle Day
1
8
15
1
15
1
1
1
At DC
30 days 
after last 
dose
Q8W for 24 
weeks, then 
Q12W
Q12
W
Scheduling 
Window
-28 to -1
±2
±2
±2
±2
±2
±2
±2
±7
±7
±7
Medical/
surgical 
history
X
Prior 
anticancer 
medication/
procedures
X
Prior/ 
Concomitant 
medication 
review
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications will be 
recorded throughout the study 
and for 30 days after last dose. 
Off-study anticancer therapy will 
be recorded from study treatment 
discontinuation until time of 
death or until withdrawal from 
survival FU.
Cancer 
staging as 
appropriate 
for pediatric 
tumor type
X
08BFHY


PRODUCT: MK 7902  
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MK 7902 013 04 FINAL  PROTOCOL
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Study 
Period
Screening
Intervention
Cycle = 28 Days
EOT
Post-treatment Visits
NOTES
Visit 
Timing/ 
Cycle No.
1
2
3
4
5 –
last
Safety 
FU
Efficacy 
(Imaging)
FU Visits
Sur-
vival
FU
Cycle Day
1
8
15
1
15
1
1
1
At DC
30 days 
after last 
dose
Q8W for 24 
weeks, then 
Q12W
Q12
W
Scheduling 
Window
-28 to -1
±2
±2
±2
±2
±2
±2
±2
±7
±7
±7
Tanner 
Staging
X
X
X
X
X
Tanner Stage will be assessed for 
all participants aged ≥8 years
(females) or ≥9 years (males) 
during screening or C1D1, at 
EOT, and during efficacy and 
survival FU. During efficacy and 
survival FU, perform annually 
until puberty has completed or 
through survival FU, whichever 
comes first. Assessment can be
performed by a local healthcare 
provider and reported by 
telephone contact if clinic visits 
are not possible for post-
treatment visits after the 30-day
safety FU.
Allocation
X
08BFHY


PRODUCT: MK 7902  
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PROTOCOL/AMENDMENT NO.: 013 04 (E7080 G000 231)
MK 7902 013 04 FINAL  PROTOCOL
08 JUN 2022
Study 
Period
Screening
Intervention
Cycle = 28 Days
EOT
Post-treatment Visits
NOTES
Visit 
Timing/ 
Cycle No.
1
2
3
4
5 –
last
Safety 
FU
Efficacy 
(Imaging)
FU Visits
Sur-
vival
FU
Cycle Day
1
8
15
1
15
1
1
1
At DC
30 days 
after last 
dose
Q8W for 24 
weeks, then 
Q12W
Q12
W
Scheduling 
Window
-28 to -1
±2
±2
±2
±2
±2
±2
±2
±7
±7
±7
Survival 
status
Updated survival status may be 
requested at any time during the 
course of the study. Participants 
will be offered survival FU for at 
least 1 year.
During survival FU, participants 
will be followed every 12 weeks 
until death, unless the participant 
becomes lost to FU, withdraws 
consent, or the study is 
terminated.
Study Intervention Administration
Lenvatinib 
dispensing
Lenvatinib dose based on BSA 
calculation at D1 of each cycle.
Lenvatinib 
administrat-
ion (orally, 
once daily)
X
X
X
X
X
X
X
X
Lenvatinib may be taken at home 
except on C1D1, C1D15, and 
C2D1; on these days lenvatinib 
will be taken in the clinic.
Participants will receive 
lenvatinib treatment until disease 
progression (by investigator 
assessment), intolerable toxicity, 
initiation of another anticancer 
therapy, or voluntary 
discontinuation by the participant 
at any time, whichever occurs 
first. 
08BFHY


PRODUCT: MK 7902  
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MK 7902 013 04 FINAL  PROTOCOL
08 JUN 2022
Study 
Period
Screening
Intervention
Cycle = 28 Days
EOT
Post-treatment Visits
NOTES
Visit 
Timing/ 
Cycle No.
1
2
3
4
5 –
last
Safety 
FU
Efficacy 
(Imaging)
FU Visits
Sur-
vival
FU
Cycle Day
1
8
15
1
15
1
1
1
At DC
30 days 
after last 
dose
Q8W for 24 
weeks, then 
Q12W
Q12
W
Scheduling 
Window
-28 to -1
±2
±2
±2
±2
±2
±2
±2
±7
±7
±7
Efficacy Procedures
Palatability 
Question-
naire
X
To be completed once on C1D1
by all participants who receive 
suspension formulation, with the 
exception of participants using a 
nasogastric or gastrostomy tube. 
If the questionnaire is not 
completed on C1D1, it should be 
completed at the earliest next site 
visit. If the participant is unable 
to complete the questionnaire,
this must be done by their parents 
or legal guardian.
Tumor 
Imaging 
(CT/MRI) 
and Tumor 
Assessment 
by 
investigator 
via RECIST 
1.1 or 
RANO 
(HGG only)
X
X
Imaging is performed at 
Screening, every 8 W (±7 days) 
from the date of lenvatinib
initiation until Week 24, then 
every 12 W thereafter (±7 days) 
or sooner if there is evidence of 
PD). Imaging for participants 
who discontinue lenvatinib 
without documented PD will be 
performed every 8 W (±7 days) 
until Week 24, then every 12 W 
thereafter (±7 days) or until the 
start of a new anticancer agent, 
whichever occurs first.
08BFHY


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Study 
Period
Screening
Intervention
Cycle = 28 Days
EOT
Post-treatment Visits
NOTES
Visit 
Timing/ 
Cycle No.
1
2
3
4
5 –
last
Safety 
FU
Efficacy 
(Imaging)
FU Visits
Sur-
vival
FU
Cycle Day
1
8
15
1
15
1
1
1
At DC
30 days 
after last 
dose
Q8W for 24 
weeks, then 
Q12W
Q12
W
Scheduling 
Window
-28 to -1
±2
±2
±2
±2
±2
±2
±2
±7
±7
±7
Brain 
CT/MRI
(If clinically 
indicated)
X
X
Participants with HGG and 
participants with protocol-eligible 
treated brain metastases require 
brain scans at all tumor 
assessment timepoints. 
Safety Procedures
AEs/SAEs
X
X
AEs will be recorded from the 
date of documented informed 
consent, throughout the study, 
and for 30 days after last dose. 
SAEs irrespective of relationship 
to study treatment must be 
reported as soon as possible, but
not later than 24 hours.
Physical 
examination
X
X
X
X
X
X
X
X
X
A comprehensive physical and 
oral examination (including a 
neurological examination) at 
Screening and at C1D1 and at 
visits indicated in the SoA. Only 
perform at C1D1 if the screening 
physical examination was 
performed >7 days prior to C1D1.
A symptom-directed physical and 
oral examination will be 
performed on C1D1 and at any 
time during the study, as 
clinically indicated.
08BFHY


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Study 
Period
Screening
Intervention
Cycle = 28 Days
EOT
Post-treatment Visits
NOTES
Visit 
Timing/ 
Cycle No.
1
2
3
4
5 –
last
Safety 
FU
Efficacy 
(Imaging)
FU Visits
Sur-
vival
FU
Cycle Day
1
8
15
1
15
1
1
1
At DC
30 days 
after last 
dose
Q8W for 24 
weeks, then 
Q12W
Q12
W
Scheduling 
Window
-28 to -1
±2
±2
±2
±2
±2
±2
±2
±7
±7
±7
Dental 
Evaluation
X
Per local standard of care, but no less than 
annually.
X
Dental examination by a dentist 
or qualified dental professional 
should be conducted per local 
institutional guidelines during 
screening (can occur up to 4 
weeks after first dose). Dental 
examination after screening 
should occur per local standard of 
care, but no less than annually, 
and at EOT unless the most 
recent dental examination was
done within the last 6 months,
then the dental examination is not 
required.
Postbaseline dental examinations 
are not required for participants 
for whom permanent teeth 
(excluding third molars) are 
evaluated to be fully erupted at 
screening.
08BFHY


PRODUCT: MK 7902  
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MK 7902 013 04 FINAL  PROTOCOL
08 JUN 2022
Study 
Period
Screening
Intervention
Cycle = 28 Days
EOT
Post-treatment Visits
NOTES
Visit 
Timing/ 
Cycle No.
1
2
3
4
5 –
last
Safety 
FU
Efficacy 
(Imaging)
FU Visits
Sur-
vival
FU
Cycle Day
1
8
15
1
15
1
1
1
At DC
30 days 
after last 
dose
Q8W for 24 
weeks, then 
Q12W
Q12
W
Scheduling 
Window
-28 to -1
±2
±2
±2
±2
±2
±2
±2
±7
±7
±7
Telephone 
Contact or 
Visit
X
On C1D8, participants will have a 
telephone or clinic visit to assess
for early toxicity and BP can be
measured at home or at a local 
pharmacy for reporting at this 
visit. An unscheduled visit can 
occur prior to C1D15 if necessary 
for safety.
08BFHY


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Study 
Period
Screening
Intervention
Cycle = 28 Days
EOT
Post-treatment Visits
NOTES
Visit 
Timing/ 
Cycle No.
1
2
3
4
5 –
last
Safety 
FU
Efficacy 
(Imaging)
FU Visits
Sur-
vival
FU
Cycle Day
1
8
15
1
15
1
1
1
At DC
30 days 
after last 
dose
Q8W for 24 
weeks, then 
Q12W
Q12
W
Scheduling 
Window
-28 to -1
±2
±2
±2
±2
±2
±2
±2
±7
±7
±7
Vital Signs 
(BP, HR, 
RR, body 
temp, 
height, and 
weight)
X
X
X
X
X
X
X
X
X
X
X*
X*
Vital signs may be performed 
more frequently as clinically 
indicated. BP that is consistently 
above the 95th percentile for sex, 
age, and height/length requires 
further evaluation. Refer to 
hypertension guidelines in 
Section 6.6.2.
BP monitoring will occur once 
every 2 weeks during the first 2 
cycles, or more frequently if 
clinically indicated.
Height and weight measurement 
will be obtained at C1D1 and 
thereafter at D1 of every cycle, 
and at EOT. *Height will also be 
monitored every 3 months in 
efficacy and survival follow-up
until puberty has completed.
Telephone contact is acceptable 
for height assessment if clinic 
visits are not possible at post-
treatment visits after the 30-day
safety FU.
08BFHY


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Study 
Period
Screening
Intervention
Cycle = 28 Days
EOT
Post-treatment Visits
NOTES
Visit 
Timing/ 
Cycle No.
1
2
3
4
5 –
last
Safety 
FU
Efficacy 
(Imaging)
FU Visits
Sur-
vival
FU
Cycle Day
1
8
15
1
15
1
1
1
At DC
30 days 
after last 
dose
Q8W for 24 
weeks, then 
Q12W
Q12
W
Scheduling 
Window
-28 to -1
±2
±2
±2
±2
±2
±2
±2
±7
±7
±7
12-Lead 
ECG
X
X
X
Xa
X
X
Single 12-lead ECG. If possible, 
participants must be in the 
recumbent position for a period of 
5 minutes prior to the ECG. ECG 
should be conducted at Screening, 
C1D1, C2D1, and aD1 of every 
4th cycle (ie, C6, C10, C14, etc.), 
EOT, and Safety FU. 
ECG at C1D1 and C2D1 should 
be conducted approximately 2 
hours after lenvatinib dose. For 
high-risk participants (as defined 
in Section 8.3.4), conduct ECG 
monitoring in every cycle.
Echocardio-
gram or 
MUGA scan
X
Performed every 16 ± 2 Weeks after the first 
dose of study drug or sooner, if clinically 
indicated.
X
Lansky Play 
Score/ 
Karnofsky 
Performance 
Score
X
X
X
X
X
X
X
X
Scores obtained on C1D1 prior to
allocation may also be used as the 
screening value to determine 
eligibility. Lansky Play Score will 
be used for participants up to and 
including 16 years of age.
Karnofsky Performance Score 
will be used for participants 
>16 years of age.
08BFHY


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Study 
Period
Screening
Intervention
Cycle = 28 Days
EOT
Post-treatment Visits
NOTES
Visit 
Timing/ 
Cycle No.
1
2
3
4
5 –
last
Safety 
FU
Efficacy 
(Imaging)
FU Visits
Sur-
vival
FU
Cycle Day
1
8
15
1
15
1
1
1
At DC
30 days 
after last 
dose
Q8W for 24 
weeks, then 
Q12W
Q12
W
Scheduling 
Window
-28 to -1
±2
±2
±2
±2
±2
±2
±2
±7
±7
±7
Proximal 
Tibial 
growth 
plates x-ray
X
Xa
For participants 2 to 17 years 
(≥18 years not required). X-ray of 
only 1 leg is required.
aX-ray at EOT is required only
for participants with open growth 
plates at screening and must be 
performed on the same leg as 
screening x-ray.
Laboratory Assessments
Pregnancy 
Test
X
X
X
X
X
X
X
X
In WOCBP, a serum or urine 
pregnancy test (Appendix 2) will 
be performed at screening and at 
C1D1 prior to allocation (within 
24 hours prior to the first dose of 
study drug), prior to D1 of every 
subsequent cycle, at EOT, and at 
the Safety FU visit.
Results must be reviewed prior to
administration of study drug on 
C1D1 and within 24 hours prior 
to dispensing study drug for all 
subsequent cycles.
Clinical 
Chemistry/ 
Hematology
X
X
X
X
X
X
X
X
X
X
Hematology and clinical 
chemistry can be performed 
within 7 days prior to the first 
dose of lenvatinib (C1D1) as part 
of the screening visit and do not 
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Study 
Period
Screening
Intervention
Cycle = 28 Days
EOT
Post-treatment Visits
NOTES
Visit 
Timing/ 
Cycle No.
1
2
3
4
5 –
last
Safety 
FU
Efficacy 
(Imaging)
FU Visits
Sur-
vival
FU
Cycle Day
1
8
15
1
15
1
1
1
At DC
30 days 
after last 
dose
Q8W for 24 
weeks, then 
Q12W
Q12
W
Scheduling 
Window
-28 to -1
±2
±2
±2
±2
±2
±2
±2
±7
±7
±7
need to be repeated at C1D1, 
unless clinically indicated.
Samples are to be obtained and 
assessed and the results reviewed 
prior to study drug administration 
on C1D1 and within 72 hours 
prior to the visit for all 
subsequent cycles.
If ≥Grade 3 hematologic or 
clinical chemistry toxicity, repeat 
laboratory test and AEs 
assessment at least every 3 days 
(until improvement to <Grade 3).
Results obtained on C1D1 prior 
to allocation may also be used as 
screening values to determine 
eligibility if assessed prior to 
allocation.
Electrolytes such as potassium, 
calcium, and magnesium should 
be monitored and abnormalities, 
when considered clinically 
significant, should be corrected in 
all participants before starting 
treatment.
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Study 
Period
Screening
Intervention
Cycle = 28 Days
EOT
Post-treatment Visits
NOTES
Visit 
Timing/ 
Cycle No.
1
2
3
4
5 –
last
Safety 
FU
Efficacy 
(Imaging)
FU Visits
Sur-
vival
FU
Cycle Day
1
8
15
1
15
1
1
1
At DC
30 days 
after last 
dose
Q8W for 24 
weeks, then 
Q12W
Q12
W
Scheduling 
Window
-28 to -1
±2
±2
±2
±2
±2
±2
±2
±7
±7
±7
INR or PT
X
INR or PT should only be 
performed as part of the screening 
assessment and as clinically 
indicated.
Urine 
Dipstick (or 
urinalysis)
Testing
X
X
X
X
X
X
X
X
X
X
Dipstick is the preferred method 
for urinalysis.
Urine dipstick/urinalysis testing 
can be performed within 7 days 
prior to the first dose of 
lenvatinib (C1D1) as part of the 
screening visit and does not need 
to be repeated at C1D1 (unless 
clinically indicated) and within 
72 hours prior to the visit at 
subsequent cycles. 
Urine dipstick/urinalysis testing 
will be performed during
screening, at C1D1, C1D15, 
C2D1, C2D15, and D1 of every 
subsequent cycle, or more 
frequently as clinically indicated, 
at the EOT and at the Safety FU 
visit.
For participants with proteinuria 
≥2+ (≥100 mg/dL), urine 
dipstick/urinalysis testing should 
be performed on D15 (or more 
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Study 
Period
Screening
Intervention
Cycle = 28 Days
EOT
Post-treatment Visits
NOTES
Visit 
Timing/ 
Cycle No.
1
2
3
4
5 –
last
Safety 
FU
Efficacy 
(Imaging)
FU Visits
Sur-
vival
FU
Cycle Day
1
8
15
1
15
1
1
1
At DC
30 days 
after last 
dose
Q8W for 24 
weeks, then 
Q12W
Q12
W
Scheduling 
Window
-28 to -1
±2
±2
±2
±2
±2
±2
±2
±7
±7
±7
frequently as clinically indicated) 
until the results have been 1+ or 
negative for 2 treatment cycles. If 
a new event of proteinuria ≥2+ 
(≥100 mg/dL) occurs, refer to 
Section 6.6.3 for further 
management guidelines.
Urine glucose should be 
performed as part of the urine 
dipstick/urinalysis.
TSH, Free 
T4
X
X
X
Xa
X
X
The screening blood sample for 
thyroid function testing can be 
obtained within 7 days prior to
the first dose of lenvatinib 
(C1D1) as part of the screening 
visit and does not need to be 
repeated at C1D1 (unless 
clinically indicated) and within 
72 hours prior to the visit at 
subsequent cycles. TSH and free 
T4 should be assessed for all 
participants. Assessment should 
be obtained at screening C2D1, 
aevery 2 cycles thereafter, at EOT 
and at the Safety FU visit.
If not done locally, can be done at 
a central laboratory.
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Study 
Period
Screening
Intervention
Cycle = 28 Days
EOT
Post-treatment Visits
NOTES
Visit 
Timing/ 
Cycle No.
1
2
3
4
5 –
last
Safety 
FU
Efficacy 
(Imaging)
FU Visits
Sur-
vival
FU
Cycle Day
1
8
15
1
15
1
1
1
At DC
30 days 
after last 
dose
Q8W for 24 
weeks, then 
Q12W
Q12
W
Scheduling 
Window
-28 to -1
±2
±2
±2
±2
±2
±2
±2
±7
±7
±7
Pharmacokinetics/Pharmacodynamics/Biomarkers
PK blood 
samples, 
participants 
≥13 kg body 
weight
X
X
X
PK blood samples drawn:
C1D1: 0.5-4 hours and 6-10 
hours postdose (no predose 
required)
C1D15: predose, 0.5-4 hours 
and 6-10 hours postdose
C2D1: predose and 2-12 hours 
postdose.
Postdose samples are not needed 
if the lenvatinib administration is 
skipped. If dose interruption is 
necessary at these time points, 
contact the Sponsor. See 
Appendix 7 for country-specific 
requirement.
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Study 
Period
Screening
Intervention
Cycle = 28 Days
EOT
Post-treatment Visits
NOTES
Visit 
Timing/ 
Cycle No.
1
2
3
4
5 –
last
Safety 
FU
Efficacy 
(Imaging)
FU Visits
Sur-
vival
FU
Cycle Day
1
8
15
1
15
1
1
1
At DC
30 days 
after last 
dose
Q8W for 24 
weeks, then 
Q12W
Q12
W
Scheduling 
Window
-28 to -1
±2
±2
±2
±2
±2
±2
±2
±7
±7
±7
PK blood 
samples, 
participants 
<13 kg body 
weight
X
X
X
PK blood samples drawn:
C1D1: 0.5-4 hours postdose
(no predose required)
C1D15: 6-10 hours postdose
(no predose required)
C2D1: predose and 2-12 hours 
postdose.
Postdose samples are not needed 
if the lenvatinib administration is 
skipped. If dose interruption is 
necessary at these time points, 
contact the Sponsor.
See Appendix 7 for 
country-specific requirement.
Buccal swab 
(DNA) for 
Genetic 
Analysis
X
Collection of buccal swabs to 
obtain genomic DNA will be 
performed at C1D1 prior to 
allocation. If sampling is not 
performed predose, sampling may 
occur at any subsequent visit.
Blood for 
serum 
biomarkers, 
participants 
≥16 kg body 
weight
X
X
X
X
X
X
Collect predose: C1D1, C1D15, 
C2D1, C3D1, C5D1, and at EOT.
See Appendix 7 for 
country-specific requirement.
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Study 
Period
Screening
Intervention
Cycle = 28 Days
EOT
Post-treatment Visits
NOTES
Visit 
Timing/ 
Cycle No.
1
2
3
4
5 –
last
Safety 
FU
Efficacy 
(Imaging)
FU Visits
Sur-
vival
FU
Cycle Day
1
8
15
1
15
1
1
1
At DC
30 days 
after last 
dose
Q8W for 24 
weeks, then 
Q12W
Q12
W
Scheduling 
Window
-28 to -1
±2
±2
±2
±2
±2
±2
±2
±7
±7
±7
Blood for 
serum 
biomarkers, 
participants 
<16 kg body 
weight
X
X
X
Collect predose: C1D1, C2D1, 
and C3D1.
See Appendix 7 for 
country-specific requirement.
Archival 
Tumor 
Blocks or 
Slides
Providing archival tumor tissue is 
not required for participation in 
the study and is an optional
collection. If an archival tumor 
tissue is available from a biopsy
performed as standard of care 
prior to study treatment, it can be 
submitted to the central 
laboratory anytime during the
study.
AE  adverse event; BP  blood pressure; BSA  body surface area; C  Cycle; CT  computerized tomography; D  Day; DC  discontinuation; ECG  electrocardiogram; EOT 
 end of treatment visit; h
 hour, HR  heart rate; INR  International normalized ratio; MRI  magnetic resonance imaging; P/C ratio  urine protein to creatinine ratio; PK  
pharmacokinetics; PS  performance score; PT  prothrombin time; RANO  Response Assessment in Neuro Oncology. RECIST 1.1  Response Evaluation Criteria in Solid 
Tumors, version 1.1; RR  respiratory rate; SAE  serious adverse event; T4  thyroxine; TSH  thyroid stimulating hormone; W  weeks; WOCBP  women of childbearing
potential.
Note:
All procedures and assessments are to be performed prior to administration of lenvatinib unless otherwise indicated. Refer to Section 8.
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2
INTRODUCTION
2.1
Study Rationale
Currently, treatment of solid tumors in pediatric patients includes supportive care, surgery, 
radiation therapy, immunotherapy, targeted therapy, stem cell transplant, and/or
chemotherapy. Treatment of relapsed/refractory/progressive disease depends on factors such 
as age, performance status, initial response to therapy, time since original diagnosis/prior 
relapse, and whether tumor recurrence is local or diffuse.
The disease burden caused by several relapsed/refractory pediatric solid tumors is significant 
and represents an area of unmet need. For the majority of pediatric solid tumors, there is no 
accepted treatment regimen for relapsed/refractory disease and efficacy outcomes have 
plateaued with traditional cytotoxic chemotherapy. Five-year survival rates for many 
pediatric solid tumors other than neuroblastoma have not changed since the 1990s [Smith, M. 
A., et al 2010].
Pediatric solid tumors typically originate in rapidly growing normal tissue. The use of 
anticancer therapy on the developing body and subsequent cancer risk is of concern. Studies 
have shown that the risk of subsequent cancer increases with age, female gender, treatment 
era, increased age at diagnosis, and radiotherapy [Friedman, D. L., et al 2010]. For patients 
with solid tumors, the highest risk is for survivors of EWS/pPNET, followed by CNS and 
solid organ cancers.
There is a clear, unmet need for improved and targeted therapies, particularly in the 
relapsed/refractory setting.
The antitumor activity of lenvatinib in vivo has been shown in several xenograft models of 
pediatric solid tumors, namely EWS/pPNET, RMS, and osteosarcoma (lenvatinib IB). In the 
pediatric clinical study E7080-G000-207 (Study 207), lenvatinib monotherapy demonstrated 
antitumor activity in patients with relapsed/refractory osteosarcoma (Section 2.2.1.2). The 
data suggest that lenvatinib may have activity in the treatment of pediatric solid tumors when 
administered alone in patients with relapsed/refractory malignancies where no available 
therapeutic options exist. It is therefore warranted to further assess the activity of lenvatinib 
in pediatric solid tumors, aside from osteosarcoma, that are relapsed/refractory to standard 
therapy. The primary efficacy goal of this Phase 2 basket study is to assess the antitumor 
activity of lenvatinib monotherapy in children, adolescents, and young adults (≤21 years with 
relapsed/refractory solid tumors (excluding osteosarcoma, which is being evaluated in 
Study 207).
2.2
Background
Lenvatinib (also known as E7080 or MK-7902) is a potent multiple RTK inhibitor that 
selectively inhibits VEGF receptors, VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 
(FLT4), in addition to other pro-angiogenic and oncogenic pathway-related RTKs, including 
FGFR 1-4, PDGFRα, KIT, and RET.
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Studies have also demonstrated that lenvatinib’s mechanism of action includes 
immunomodulation in the TME. This includes decreases in immunosuppressive TAMs, 
activated cytotoxic T-cell increases, and activation of IFN-γ signaling, which contribute to 
lenvatinib’s antitumor activity [Kato, Y., et al 2019] [Kimura, T., et al 2018].
Refer to the IB/approved labeling for detailed background information on lenvatinib.
2.2.1
Pharmaceutical and Therapeutic Background
Angiogenesis, the formation of new blood vessels from a preexisting vascular network, is 
essential for tumor growth and metastasis. VEGF and its family of receptors (VEGFRs 1-3) 
play a major role in tumor angiogenesis [Ferrara, N., et al 2003] [Ellis, L. M. 2008] 
[Tammela, T. 2010]. Accumulated evidence suggests that FGF and its receptor tyrosine 
kinase, FGFR, also play important roles for tumor angiogenesis [Cross, M. J. 2001] [Lieu, C., 
et al 2011] [Limaverde-Sousa, G., et al 2014].
Lenvatinib is a potent multiple RTK inhibitor that selectively inhibits VEGF receptors, 
VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4), FGFR1-4, PDGFRα, KIT, and 
RET. Among known kinase inhibitors in clinical use, lenvatinib is one of the only inhibitors 
currently labeled with a mechanism of action as an inhibitor of not only VEGFRs, but also 
FGFRs, both of which are currently believed to be very important for tumor angiogenesis.
Pediatric tumors are highly vascularized. Serum VEGF was shown to be elevated in several 
pediatric solid tumors including pPNET and EWS [Pavlakovic, H., et al 2001] [El-Houseini, 
M. E., et al 2004]. High serum VEGF levels [El-Houseini, M. E., et al 2004] [DuBois, S. 
2007] [Taylor, M., et al 2009] as well as soluble VEGFR2 plasma levels and circulating 
endothelial cells correlated with metastatic disease status in several pediatric tumor types 
[Taylor, M., et al 2009] and outcome in osteosarcoma [Taylor, J. G. 6th., et al 2009].
FGF2 is a critical signaling molecule for primitive neural crest cells. FGF2/FGFR1 activation 
induced growth inhibition, neuronal differentiation, and apoptosis in EWS/pPNET [Sturla, L. 
M., et al 2000] [Kim, M. S., et al 2004]. Basic fibroblast growth factor (bFGF)/FGFR1 
strongly induced the motility and invasion of EWS/pPNET cells [Kamura, S., et al 2010]. 
Embryonal RMS patient biopsy specimens were found to overexpress FGFR3 [Hirotsu, M., 
et al 2009] and FGFR4 has been implicated in RMS [Cao, L., et al 2010] [Taylor, J. G. 6th., 
et al 2009].
High expression of PDGF and its receptors (PDGFRα) highlight the role of the PDGF 
pathway in several pediatric tumors (eg, osteosarcoma [Kubo, T., et al 2008], glioma [Mauro, 
A., et al 1991], diffuse pontine glioma [Zarghooni, M., et al 2010], nephroblastoma 
[Ghanem, M., et al 2010], and EWS/pPNET [Schaefer, K. L., et al 2008]). PDGFR
expression is associated with clinical stage (nephroblastoma [Ghanem, M., et al 2010]) and 
metastases (EWS [Schaefer, K. L., et al 2008], medulloblastoma [MacDonald, T. J., et al 
2001]), and correlates with event-free survival (eg, osteosarcoma [Kubo, T., et al 2008]).
Strong, diffuse staining for c-kit was seen in a proportion of synovial sarcomas, 
osteosarcomas, and EWS/pPNET, though to a lesser extent in neuroblastomas, Wilms’
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tumors, and RMS, and was negative in alveolar soft part sarcomas and desmoplastic small 
round cell tumors [Smithey, B. E., et al 2002].
2.2.1.1
Epidemiology and Current Therapeutic Options
Cancer in children has a low overall incidence (18.6 cases per 100,000 children [National 
Cancer Institute 2018]), however, it is the leading cause of death in this population. Solid 
tumors constitute approximately 60% of childhood malignancies, with leukemia, lymphoma, 
and reticuloendothelial neoplasms accounting for the remaining 40% (SEER Cancer 
Statistics Review, 1975-2016, National Cancer Institute, posted April 2019).
Age affects the incidence of pediatric solid tumors. Across all age groups, CNS neoplasms 
constitute the majority; however, between 10 and 14 years of age, malignant bone tumors, 
soft tissue and other extraosseous sarcomas, other malignant epithelial, and neoplasms and 
melanomas are more common. Up to the age of 14 years, the most common solid tumor types
are neuroblastoma and other peripheral nervous cell tumor and renal tumors, whereas 
between 15 and 19 years, germ cell and trophoblastic tumors neoplasms of the gonads, 
melanomas and other malignant epithelial neoplasms increase in frequency [Ries, L. A. G., et 
al 1999].
Some of the most common types of solid tumors found in children are brain tumors, RMS, 
and EWS/pPNET. Unfortunately, 5-year survival rates for pediatric solid tumors other than 
neuroblastoma have remained largely unchanged since the 1990s, and there is little evidence 
that more effective use of available cytotoxic agents will be sufficient for substantial 
progress[Smith, M. A., et al 2010].
2.2.1.1.1
High-grade Glioma
Brain and other CNS tumors are the most common form of solid tumors in children and 
account for the majority of cancer deaths in patients 19 years and younger. According to 
CBTRUS (2016), the overall incidence is 5.70 per 100,000 children younger than 19 years, 
which is approximately 6% of all brain tumors among affected individuals of any age 
[Ostrom, Q. T., et al 2016]. The incidence of HGG (including anaplastic astrocytoma, 
anaplastic oligodendrioglioma, glioblastoma, mixed glioma, and malignant glioma) 
according to CBTRUS (2016) is approximately 0.96 per 100,000 and is similar between the 
sexes [Ostrom, Q. T., et al 2016].
Pediatric HGG is a highly vascularized, very aggressive tumor type. Despite improvements 
in neurosurgery, radiotherapy, and chemotherapy, the outcome for children with HGG 
remains poor. The median duration of survival for newly diagnosed HGG is approximately 
18 to 24 months [Qaddoumi, I., et al 2009]. Although numerous treatment approaches have 
been tested, outcomes have remained dismal, with 2-year survival rates in most trials ranging 
from 10% to 30% [MacDonald, T. J., et al 2011].
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2.2.1.1.2
Rhabdomyosarcoma
Rhabdomyosarcoma is a malignant tumor of mesenchymal origin and is the most common 
soft tissue sarcoma in children. The incidence of RMS is 4.5 cases per 1 million children; 
approximately two-thirds of cases are diagnosed in children younger than 10 years of age and 
there is a slight male predominance. The 2 most common histological types of RMS are 
embryonal (57% of patients) and alveolar (23% of patients) [Dasgupta, R. 2012] 
[Ognjanovic, S., et al 2009]. Embryonal RMS occurs mainly in the 0- to 4-year age group 
(~4 cases per 1 million children, with a lower rate in adolescents, ~1.5 cases per 1 million 
adolescents), while the incidence of alveolar RMS is constant from ages 0 to 19 years, with 
approximately 1 case per 1 million children and adolescents. The reported median time to 
first relapse is approximately 1.5 years and has not changed in the past 2 decades 
[Dantonello, T. M., et al 2013] [Mazzoleni, S., et al 2005].
Current multimodality treatments for RMS, including chemotherapy, surgery, and 
radiotherapy, result in long-term survival of approximately 85% of patients with localized 
disease at presentation. However, up to one-third of these patients experience local or 
metastatic relapse, and survival after recurrence is usually poor, with little meaningful 
improvement of survival over the past 30 years [Winter, S., et al 2015].
2.2.1.1.3
Ewing’s Sarcoma/pPNET
The EWS family of tumors encompasses a number of aggressive malignant tumors, including 
EWS/pPNET, Askin tumor, and neuroepithelioma. These tumors can occur in bone or soft 
tissue and are characterized by a nonrandom chromosomal rearrangement, the most frequent 
of which is EWS/FLI t(11;22)(q24;q12) translocation [Burchill, S. A. 2003].
Ewing sarcoma/pPNET is rare, with an overall age-adjusted incidence in children, 
adolescents, and young adults of approximately 3 per 1 million, per year, and has remained 
unchanged for more than 30 years [Esiashvili, N., et al 2008] [National Cancer Institute 
2017]. It is the second most common primary bone cancer in the pediatric population after 
osteosarcoma and occurs most frequently in adolescents and young adults; the median age at 
initial diagnosis is 15 years [Esiashvili, N., et al 2008] [National Cancer Institute 2017] 
[Skubitz, K. M. 2007]. Ewing sarcoma is rare among individuals over the age of 30 years and 
under the age of 5 years [Bernstein, M., et al 2006]. The median time to first relapse after
initial diagnosis is 17 to 18 months [Barker, L. M., et al 2005] [Stahl, M., et al 2011].
The presence of metastases is the most prominent adverse prognostic factor in EWS/pPNET. 
Metastases are detected in 15% to 33% of patients at the time of initial diagnosis [Ladenstein, 
R., et al 2010]. Additionally, 30% to 40% of patients with initially localized EWS/pPNET
develop recurrent disease and 80% to 90% of patients have widespread disease [Stahl, M., et 
al 2011]. When systemic therapy is combined with adequate local control measures, applied 
to both primary and metastatic sites, the overall cure rate is 20% [National Cancer Institute 
2017]. For patients with recurrent EWS/pPNET, the current 5-year OS rate is only 10% to 
15% [Huang, M. 2011] [National Cancer Institute 2017].
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2.2.1.2
Clinical Data on Lenvatinib in Children and Adolescent Patients
The safety, tolerability, and antitumor activity of lenvatinib in the pediatric population is 
being evaluated in Phase 1/2 Study 207. In the Phase 1 portion (Cohort 1), the recommended 
Phase 2 dose for lenvatinib as monotherapy in pediatric patients with solid tumors was 
determined to be 14 mg/m2 (Section 4.3).
The Phase 2 portion of Study 207 assessed lenvatinib as a single agent in children, 
adolescents, and young adults with relapsed/refractory osteosarcoma (Cohort 2B; n 31). As 
of the data cutoff date of 02-AUG-2018, 9 of 28 evaluable participants (32.1%) achieved PFS 
at 4 months; median PFS was 3.0 months (95% CI: 1.8, 5.4) [Gaspar, N., et al 2018].
The safety profile of single-agent lenvatinib in pediatric patients is consistent with the known 
lenvatinib toxicities in adults, and PK data from Study 207 showed that exposure to 
lenvatinib in pediatric patients dosed by BSA is similar to adults receiving a fixed daily dose 
of lenvatinib [Gaspar, N., et al 2018] [Gaspar, N., et al 2017]. The recommended pediatric 
dose for single-agent lenvatinib is 14 mg/m2 daily, which in terms of exposure, is equivalent 
to the adult daily dosage of 24 mg [Gaspar, N., et al 2017].
In the single-agent expansion cohort of patients with osteosarcoma treated at the RP2D of 
lenvatinib (n 31), TEAEs occurred in 29 patients (93.5%). The most frequently reported 
TEAEs (occurring in 40% or more of subjects), in descending order of frequency were 
decreased appetite, headache, vomiting, hypothyroidism, and proteinuria. Grade ≥3 TEAEs 
were reported in 20 subjects (64.5%), and such events in >2 subjects were back pain and 
tumor pain. Twenty-eight subjects (90.3%) had TEAEs reported by the investigator to be 
treatment-related, which were Grade ≥3 in 7 subjects (22.6%). The most frequently reported 
treatment-related TEAEs, occurring in 30% or more of subjects, were decreased appetite, 
hypertension, and hypothyroidism. Four subjects (12.9%) had Grade 5 AEs during treatment: 
cardio-respiratory arrest (n 2) and respiratory failure or respiratory distress (1 each). All 
were considered by the investigator to be secondary to disease progression and not related to 
study drug. Non-fatal SAEs occurred in 20 subjects (64.5%). Events that occurred in >1 
participant each were: back pain (n 4), pneumothorax (n 4), dyspnea (n 3), tumor pain 
(n 3), and platelet count decreased (n 2). Additionally, there were no treatment-related fatal 
TEAEs.
In the single-agent expansion cohort of 31 patients with osteosarcoma, PFS at 4 months 
(PFS-4m) was 37.8% (95% CI: 20.0, 55.4) and median PFS was 3 months (95% CI: 1.8, 5.4). 
The median follow-up time for PFS was 16.6 months (95% CI: 5.5, 16.6). Thirty of the 31 
patients enrolled in this cohort had measurable disease per RECIST 1.1. Two subjects had a 
BOR of PR (6.7%; 95% CI: 0.8, 22.1), and an additional 13 subjects had SD ≥7 weeks 
(43.3%). The median duration of objective response was 4.6 months (95% CI: NE, NE). 
Additionally, one participant had evaluable disease with a BOR of non-CR/non-PD.
Overall, the toxicity profile observed for single-agent lenvatinib in pediatric patients with 
refractory/relapsed solid tumors in the dose-finding cohort is consistent with the lenvatinib 
toxicity profile observed in adults.
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2.2.2
Preclinical and Clinical Studies
Refer to the lenvatinib IB for preclinical and clinical study data for lenvatinib.
2.3
Benefit/Risk Assessment
As discussed in Sections 2.1 and 2.2.1.1, there is an unmet need for expanding treatment 
options for pediatric patients with relapsed/refractory solid tumors. Data from Study 207 
indicate that pediatric patients with osteosarcoma may benefit from treatment with 
single-agent lenvatinib, and safety data suggest that toxicity is manageable in these patients. 
Therefore, it is planned to investigate the use of single-agent lenvatinib in other highly 
vascularized pediatric solid tumors that exhibit upregulation of VEGF/FGF/PDGF.
It cannot be guaranteed that participants in clinical studies will directly benefit from 
treatment during participation, as clinical studies are designed to provide information about 
the safety and effectiveness of an investigational medicine.
Additional details regarding specific benefits and risks for participants participating in this 
clinical study may be found in the accompanying IB and informed consent documents.
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
In children, adolescents, and young adults with relapsed or refractory solid malignancies
treated with lenvatinib:
Objectives
Endpoints
Primary
•
To determine the ORR at Week 16, by 
each tumor type, per RECIST 1.1 or 
RANO (for HGG only) as assessed by the 
investigator.
•
Objective Response, defined as a 
confirmed (≥4 weeks after initial 
response) CR or PR.
Secondary
•
To evaluate ORR, by each tumor type,
per RECIST 1.1 or RANO (for HGG 
only) as assessed by the investigator.
•
Objective Response, defined as a 
confirmed (≥4 weeks after initial 
response) CR or PR.
•
To evaluate PFS per RECIST 1.1 or 
RANO (for HGG only), by each tumor 
type.
•
PFS defined as the time from the date of 
the first administration of lenvatinib until 
the date of first documentation of PD or 
death (whichever occurs first).
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Objectives
Endpoints
•
To evaluate the BOR, DOR, DCR, and 
CBR, by each tumor type.
•
BOR defined as the participant’s best 
confirmed response (CR or PR) over the 
treatment period.
•
DOR defined as the time from the date of 
the first documented CR or PR to the 
date first documentation of progressive 
disease or death (whichever occurs first).
•
Disease control defined as a BOR of CR
or PR, or SD. To be assigned a BOR of 
SD, the time from the first administration 
of study drug until the date of 
documented SD should be ≥7 weeks.
•
Clinical benefit defined as a BOR of CR 
or PR, or durable SD (SD duration 
≥23 weeks since the first dose of the 
study treatment).
•
To evaluate the safety of lenvatinib.
•
AEs, SAEs, clinical laboratory values, 
vital signs, 12-lead ECGs, urine dipstick, 
Lansky play scores or Karnofsky 
performance status scores, physical 
examination findings, dental examination 
findings, height, and closure of proximal 
tibial plates.
•
To assess the palatability and 
acceptability of the suspension 
formulation of lenvatinib.
•
Palatability questionnaire using a facial 
hedonic scale.
•
To characterize the PK of lenvatinib.
•
Assessment of population-based PK 
parameters of lenvatinib.
Tertiary/Exploratory
•
To explore relationships between 
exposure and AE and efficacy.
•
Plasma lenvatinib exposure parameters 
and assessment of AEs associated with 
lenvatinib treatment.
•
To explore OS, by each tumor type.
•
OS defined as the time from the date of 
the first administration of study drug 
until the date of death from any cause. 
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Objectives
Endpoints
•
To identify molecular (genomic, 
metabolic, and/or proteomic) biomarkers 
that may be indicative of clinical 
response/resistance, safety, and/or the 
mechanism of action of lenvatinib.
•
Molecular (genomic, metabolic, and/or 
proteomic) determinants of response or 
resistance to treatments, using blood 
and/or tumor tissue.
4
STUDY DESIGN
4.1
Overall Design
This is an open-label, multicenter, Phase 2 basket study to evaluate the antitumor activity and 
safety of lenvatinib in children, adolescents, and young adults between 2 to ≤21 years of age 
with relapsed or refractory malignant solid tumors. Four cohorts will be evaluated: HGG, 
RMS, EWS/pPNET, and any other solid tumors (aside from osteosarcoma).
A minimum of 36 participants will be enrolled, 9 evaluable participants in each of 4 cohorts: 
HGG, RMS, EWS/pPNET, and other solid tumors, as follows:

HGG: at least 9 evaluable participants (a minimum of 6 participants <17 years of age)

RMS: at least 9 evaluable participants (a minimum of 6 participants <17 years of age)

EWS/pPNET: at least 9 evaluable participants (a minimum of 6 participants <17 
years of age)

Other solid tumor types: at least 9 evaluable participants (with any number of 
pediatric participants across all other tumor types).
The final sample size of patients will depend on the number of tumor types that meet the 
futility bar and the antitumor activity observed in evaluable participants in the corresponding 
tumor cohort in Study E7080-A001-216. The enrollment in the HGG, RMS, and 
EWS/pPNET cohorts is capped at a maximum of 17 evaluable participants each. The 
enrollment for each tumor type expanded based on response in the other solid tumors’ cohort 
is also capped at a maximum of 17 evaluable participants. Based on these factors and the 
projected enrollment period, it is estimated that up to approximately 150 participants could 
be enrolled. Participants will meet the criteria for being evaluable for an objective response if 
they have measurable disease present at baseline and at least 1 postbaseline efficacy 
assessment, unless they have discontinued prior to the first efficacy assessment due to 
progressive disease. Participants who are not evaluable for objective response will be 
replaced.
Expansion portion of the study: This study uses a sequential monitoring procedure to 
evaluate for futility and to evaluate efficacy of lenvatinib by assessing antitumor activity. IAs 
will be performed after 9 evaluable participants are enrolled in each of the 3 target tumor 
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cohorts to assess ORR at Week 16. Separate IAs will be performed for each specific tumor 
type within the other solid tumors’ cohort if 9 evaluable participants are enrolled for that 
tumor type. Assessment of ORR will be based on tumor response as assessed by the 
investigator using RECIST 1.1 for all tumor types except for HGG, which will be assessed 
by the investigator using RANO criteria. Enrollment within a cohort will be stopped for 
futility if no response is observed among the first 9 evaluable participants (i.e. if the futility 
boundary is crossed), or a lack of antitumor activity is concluded for the corresponding tumor 
cohort in Study E7080-A001-216. The results of the IAs will be reviewed by the Sponsor and 
recommendations will be given for expanding a cohort or a specific tumor type within the 
other solid tumors’ cohort, to up to 17 evaluable participants, which will include the initial 
9 evaluable participants from the cohort.
The enrollment period may last up to approximately 30 months from the time of enrollment 
of the first participant. Additionally, data cutoff may occur when the last evaluable
participant (see Section 1.1 for definition of evaluable) enrolled in the study has completed 
the Week 16 imaging assessment or discontinues prior to the Week 16 imaging assessment, 
whichever occurs first.
If no objective responses are observed at the time of enrollment of the ninth evaluable 
participant in a specific cohort or other tumor type, enrollment will be paused in said cohort 
or other tumor type until the IA for these 9 evaluable participants is completed. If at least 1 
objective response is observed at the time of enrollment of the ninth evaluable participant in 
a specific cohort or other tumor type, enrollment may continue in said cohort or other tumor 
type.
Participants will receive lenvatinib treatment until disease progression as assessed by the 
investigator per RECIST 1.1 or per RANO for participants with HGG, initiation of another 
anticancer therapy, development of unacceptable toxicity, or withdrawal of consent,
whichever occurs first. The estimated time of treatment is 1 year (12 cycles). However, 
participants can continue on treatment with lenvatinib until a treatment discontinuation 
criterion is met.
The primary objective of the study is to evaluate ORR at Week 16 for each cohort separately
as assessed per RECIST 1.1 or RANO (for HGG) by the investigator. On-study imaging 
assessments will be performed at screening, every 8 weeks from the date of lenvatinib
initiation until Week 24, then every 12 weeks thereafter, or as clinically indicated (±7 days).
All responses will be confirmed at a follow-up examination ≥28 days after the initial 
response. Images will be collected by a central imaging vendor for possible independent 
review of response; site assessment (RECIST 1.1 or RANO for HGG) will be considered for 
purposes of satisfying the primary efficacy endpoint.
Safety and tolerability will be assessed by clinical review of all relevant safety parameters 
including AEs, physical examinations, laboratory tests, vital signs, ECGs, Lansky Play Score 
and KPS, dental examination findings, height, and proximal tibial growth plate.
At the end of treatment, each participant will be followed 30 days for the occurrence of 
AEs/SAEs.
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Participants who discontinue lenvatinib treatment for reasons other than radiographic disease 
progression or initiation of new anticancer therapy will have post-treatment tumor 
assessments performed every 8 weeks for 24 weeks, then every 12 weeks thereafter until 
documentation of disease progression or start of a new anticancer agent, whichever occurs 
first, unless the participant withdraws consent, becomes lost to follow-up, or the study is 
terminated.
Participants will be followed by telephone every 12 weeks for survival status until death 
unless the participant withdraws consent, becomes lost to follow-up, or the study is 
terminated.
Specific procedures to be performed during the study, as well as their prescribed times and 
associated visit windows, are outlined in the SoA in Section 1.3. Details of each procedure 
are provided in Section 8.
4.2
Scientific Rationale for Study Design
This Phase 2 basket study uses a sequential monitoring procedure to assess the antitumor 
activity of lenvatinib in children, adolescents, and young adults with relapsed/refractory 
malignancies for which there are no standard therapy regimens. The sequential monitoring
design allows enrollment of a limited number of participants to determine drug activity,
thereby preventing exposure of participants to a drug that is inactive for the specific tumor 
type. The safety of lenvatinib will be evaluated at the RP2D of single-agent lenvatinib 
(14 mg/m2), as determined in Study 207.
4.2.1
Rationale for Endpoints
4.2.1.1
Efficacy Endpoints
This study will use ORR, defined as the proportion of participants with confirmed objective 
response (an objective response of CR or PR at Week 16, based on RECIST 1.1 or RANO 
for HGG as assessed by the investigator) as the primary endpoint. For single-arm studies, 
ORR is commonly used to assess clinical activity of therapies in the treatment of pediatric 
solid tumors. The use of RECIST 1.1 and the use of RANO for HGG to assess ORR is 
typically considered acceptable by regulatory authorities.
Antitumor activity for participants with neuroblastoma enrolled in the other solid tumors’
cohort will be determined by the following criteria and combined with RECIST-based 
efficacy for assessment of the study endpoints.

CR: Complete resolution of all MIBG-positive lesions.

PR: Resolution of at least 1 MIBG-positive lesion, with persistence of other 
MIBG-positive lesions.

SD: No changes in MIBG scan in number of positive lesions.
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
PD: Development of new MIBG-positive lesions.
DOR, BOR over the treatment period, DCR, CBR, and PFS are secondary endpoints that will 
serve as additional measures of efficacy and are commonly accepted endpoints by both 
regulatory authorities and the oncology community.
Overall survival, defined as the time from the first day of study intervention to death due to 
any cause, will be an exploratory endpoint.
4.2.1.1.1
RECIST 1.1
RECIST 1.1 will be used by the investigator when assessing images for determining 
eligibility and for efficacy measures using a maximum of 5 target lesions in total and 2 per 
organ (Section 8.2.1.4).
4.2.1.1.2
RANO
RANO criteria will be used by the investigator when assessing images for determining 
eligibility and for efficacy measures for HGG. A standard MRI-imaging protocol will be 
performed for use in the assessments, based on a published consensus [Ellingson, B. 
M.,Bendszus, M., et al 2015].
4.2.1.2
Safety Endpoints
Safety parameters commonly used for evaluating investigational systemic cancer treatments 
are included as safety endpoints. These endpoints include, but are not limited to, the 
incidence, causality, and outcome of AEs/SAEs, changes in clinical laboratory values, vital 
signs, 12-lead ECGs, Lansky Play Score or KPS, results of physical examination findings, 
dental examination findings, height, and closure of proximal tibial plates.
4.2.1.3
Pharmacokinetic Endpoints
Based on lenvatinib PK data obtained in this study and from other studies, a population PK 
analysis will be performed.
4.2.1.4
Pharmacodynamic Endpoints
Blood samples for serum markers will be collected for participants as specified in the SoA 
(Section 1.3).
Biomarker discovery and/or validation will be performed to identify blood or tumor 
biomarkers that may be useful to predict participant response to study drug as well as for 
potential use in diagnostic development. Blood samples may undergo global proteomic 
and/or single-analyte ELISA or multiplex immunoassays based on the amount of sample 
available. Potential blood biomarkers to be explored include FGF ligands (eg, FGF2/bFGF, 
FGF19, FGF21, FGF23) and angiogenesis-related markers (eg, VEGF, Ang 1/2, sTie 2, 
HGF, PlGF). In addition, biomarkers identified in other lenvatinib clinical studies may also 
be assessed in samples collected from participants enrolled in this study. The decision to 
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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.
4.2.1.5
Planned Exploratory Biomarker Research
Much remains to be learned regarding how best to leverage lenvatinib in treating pediatric 
patients. Thus, to aid future patients, it is important to investigate the determinants of 
response or resistance, as well as determinants of AEs in the course of our clinical studies. 
These efforts may identify novel predictive/PD biomarkers and generate information that 
may better guide single-agent and combination therapies. To identify novel biomarkers, 
biospecimens (ie, blood components, tumor material) will be collected to support analyses of 
cellular components (eg, protein, DNA, RNA, metabolites) and other circulating molecules. 
Investigations may include but are not limited to:
Germline (blood) genetic analyses (eg, SNP analyses, whole exome sequencing, whole 
genome sequencing)
This research may evaluate whether genetic variation within a clinical study population 
correlates with response to the treatment(s) under evaluation. If genetic variation is found to 
predict anti-tumor activity or AEs, the data might inform optimal use of therapies in the 
patient population. Furthermore, it is important to evaluate germline DNA variation across 
the genome in order to interpret tumor-specific DNA mutations.
Genetic (DNA) analyses from tumor
The application of new technologies, such as next generation sequencing, has provided 
scientists the opportunity to identify tumor-specific DNA changes (ie, mutations, methylation 
status, microsatellite instability) contributing towards the development/progression of cancer 
and/or driving response to therapy. To conduct this type of research, it is important to 
identify tumor-specific mutations that occur across all genes in the tumor genome. 
Evaluation of molecular targets and signaling pathways including angiogenesis and/or 
growth factor related signaling pathways related to lenvatinib may also be explored. Thus, 
genome-wide approaches may be used for this effort. Note that in order to understand tumor-
specific mutations, it is necessary to compare the tumor genome with the germline genome.
Circulating tumor DNA and/or RNA may also be evaluated from blood samples.
Tumor and blood RNA analyses
Both genome-wide and targeted messenger RNA (mRNA) expression profiling and 
sequencing in tumor tissue and in blood may be performed to define gene signatures that 
correlate to clinical response to treatment. Known gene signatures may be evaluated, and 
new signatures identified. Individual genes related to growth factor signaling pathways (eg, 
VEGF and FGF) may also be evaluated. MicroRNA profiling may also be pursued as well as 
exosomal profiling.
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Proteomics and IHC using blood or tumor
Tumor and blood samples from this study may undergo proteomic analyses. Tumor or blood-
derived proteins may be found to correlate with response to lenvatinib therapy. Therefore, 
tumor tissue may be subjected to proteomic analyses using a variety of platforms that could 
include but are not limited to immunoassays and liquid chromatography/mass spectrometry. 
This approach could identify novel protein biomarkers that could aid in patient selection for 
lenvatinib therapy.
Other blood-derived biomarkers
In addition to expression on the tumor tissue, circulating cytokines and angiogenic factors,
and other tumor derived proteins can be shed from tumor and released into the blood. Assays 
such as enzyme-linked immunosorbent assay (ELISA) measure such proteins in serum. 
Correlation of expression with response to lenvatinib therapy may identify new approaches 
for predictive biomarkers in blood, representing a major advance from today’s reliance on 
assessing tumor biomarkers. This research would serve to develop such assays for future 
clinical use.
The T-cell repertoire from tumor tissue and blood components may be evaluated.
4.3
Justification for Dose
The recommended dose for lenvatinib as a single agent in pediatric patients (2 to <18 years) 
with relapsed or refractory solid malignant tumors was determined in the Phase 1 portion of 
Study 207, using TiTE CRM. The recommended dose was defined as the dose with dose-
limiting toxicity rate closest to the targeted 20% rate [Gaspar, N., et al 2017].
A total of 23 participants were enrolled in 3 dose levels: 11 mg/m2 (n 5), 14 mg/m2 (n 11), 
and 17 mg/m2 (n 17). The most frequent tumor types were rhabdomyosarcoma (n
5), 
Ewing sarcoma (n  4), and neuroblastoma (n  3). BOR was stable disease (n
12).
Dose-limiting toxicities were reported in 3 participants at the 14 mg/m2 dose during Cycle 1. 
All were considered related to lenvatinib. Dose-limiting toxicities were: 1 report each of 
Grade 3 ALT level increased, Grade 3 hypertension, and Grade 4 hypertension. All 
participants recovered after either interruption (ALT increase), reduction (Grade 3
hypertension) or discontinuation (Grade 4) of lenvatinib therapy. Based on these results, the 
recommended Phase 2 dose of lenvatinib in children, adolescents, and young adults was 
determined to be 14 mg/m2, which is equivalent to the recommended daily dose of 24 mg/day 
of lenvatinib in adults with radioiodine-refractory DTC.
In this study, the lenvatinib daily dose will be calculated based on BSA, and the actual daily 
dose will not exceed 24 mg/day. Participants may receive lenvatinib until disease progression 
is radiographically documented by the investigator per RECIST 1.1 or per RANO criteria for 
participants with HGG, initiation of another anticancer therapy, development of unacceptable 
toxicity, or withdrawal of consent, whichever occurs first. The estimated time of lenvatinib 
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treatment is 1 year. However, participants continuing to derive benefit from lenvatinib 
treatment can continue to receive lenvatinib until a treatment discontinuation criterion is met.
4.4
Beginning and End of Study Definition
The study begins when the first participant (or their legally acceptable representative) 
provides documented informed consent/assent. The overall study ends when the last 
participant completes the last study-related contact, withdraws consent, or is lost to follow-up 
(ie, the participant is unable to be contacted by the investigator).
For purposes of analysis and reporting, the overall study ends when the Sponsor receives the 
last laboratory result or at the time of final contact with the last participant, whichever comes 
last.
If the study includes countries in the European Economic Area (EEA), the local start of the 
study in the EEA is defined as First Site Ready (FSR) in any Member State.
Enrollment will be stopped for a specific cohort/tumor type if no objective responses occur in 
the first 9 evaluable participants who have completed the Week 16 imaging assessment (or 
discontinued before Week 16 for progressive disease) or the futility boundary is crossed.
EWS and HGG cohorts were not expanded because futility was concluded for the 
corresponding cohorts in Study E7080-A001-216. Further enrollment of participants into the 
other solid tumors' cohort was discontinued due to insufficient antitumor activity of 
lenvatinib in this patient population.
4.4.1
Clinical Criteria for Early Study Termination
The enrollment period may last up to approximately 30 months from the time of enrollment 
of the first participant. Additionally, data cutoff may occur when the last evaluable 
participant (see Section 1.1 for definition of evaluable) enrolled in the study has completed 
the Week 16 imaging assessment or discontinues prior to the Week 16 imaging assessment, 
whichever occurs first).
If no objective responses are observed at the time of enrollment of the ninth evaluable 
participant in a specific cohort or other tumor type, enrollment will be paused in said cohort 
or other tumor type until the IA for these 9 evaluable participants is completed. If at least 1 
objective response is observed at the time of enrollment of the ninth evaluable participant in 
a specific cohort or other tumor type, enrollment can continue in said cohort or other tumor 
type.
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5
STUDY POPULATION
As stated in the Code of Conduct for Clinical Trials (Appendix 1.1), our studies include 
people of varying age, race, ethnicity, and sex. The collection and use of these demographic 
data is to follow all local laws and guidelines in keeping with the needs for participant 
confidentiality while supporting the study of the disease, its related factors, and the IMP 
under investigation.
Male/female children, adolescents, and young adult participants with relapsed or refractory 
pediatric solid tumors (excluding osteosarcoma) between the ages of 2 and 21 years inclusive
will be enrolled in this study.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
A participant will be eligible for inclusion in the study if the participant:
Type of Participant and Disease Characteristics
1. Has histologically or cytologically documented relapsed, or refractory pediatric solid 
malignancy excluding osteosarcoma.
Participants with diffuse midline glioma (formerly known as diffuse intrinsic pontine 
glioma), optic pathway glioma, or pineal tumors with elevated tumor markers (AFP, ß-
hCG, or hCG) do not require histological or cytological confirmation of diagnosis. 
Participants with diffuse midline glioma are not eligible for the HGG cohort and should 
only be enrolled in the other solid tumors’ cohort.
2. Has measurable disease as defined by RECIST 1.1 or RANO for HGG, meeting the 
criteria below:

All tumor types except HGG and neuroblastoma: At least 1 lesion measuring ≥1.0 cm 
in the longest diameter for a non-lymph node or ≥1.5 cm in the short-axis diameter 
for a lymph node that is reproducibly measurable on CT or MRI scans.

HGG: At least 1 contrast-enhancing lesion with clearly defined margins on 
T1-weighted MRI scan, measuring ≥1.0 cm in 2 perpendicular diameters, and visible 
on at least 2 axial slices (preferably no more than 5 mm apart with 0 mm gap).

Participants with neuroblastoma who do not have measurable disease per RECIST 1.1
but have MIBG-positive evaluable disease may be enrolled.

Tumor lesions situated in a previously irradiated area or in an area subjected to other 
locoregional therapy are considered measurable only if progression has been observed
in such lesions since the completion of therapy.
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3. Has a performance status as defined below:

Lansky Play Score ≥50 for participants up to and including 16 years of age.

KPS ≥50 for participants >16 years of age.

Neurologic deficits in participants with primary CNS tumors must have been stable 
for at least 7 days prior to study enrollment. Participants who are unable to walk 
because of paralysis, but who can perform ADL while wheelchair bound, will be 
considered ambulatory for the purpose of assessing the performance score.
4. Demonstrate adequate organ function as defined below:
System
Laboratory Value
Hematological
For participants without bone marrow involvement
ANC
≥1000/µL
Platelets
≥75,000/µL
Hemoglobin
≥8.0 g/dL (a hemoglobin of <8.0 g/dL is acceptable 
if it is corrected by growth factor or transfusion 
before C1D1)
For participants with known bone marrow involvement
ANC
≥800/µL and leucocyte count ≥1×109/L
Platelets
≥75,000/µL
(May receive transfusions provided they are not 
known to be refractory to platelet transfusions)
Hemoglobin
(May receive transfusions provided they are not 
known to be refractory to red cell transfusions.)
Renal
Creatinine by age/gendera
OR
Measured or calculatedb creatinine clearance
Age
Maximum Serum 
Creatinine (mg/dL)
Male
Female
2 to <6 years
0.8
0.8
6 to <10 years
1
1
10 to <13 years
1.2
1.2
13 to <16 years
1.5
1.4
≥16 years
1.7
1.4
OR
≥70 mL/min/1.73 m2
Hepatic
Total bilirubin
≤1.5 ×ULN for age, except for unconjugated 
hyperbilirubinemia of Gilbert’s syndrome
ALT and AST
ALT and AST ≤3 × ULN (in the case of liver 
metastases ≤5 × ULN)
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System
Laboratory Value
Coagulation
INR or PT
≤1.5 ×ULN (participants on anticoagulant therapy 
must remain within the therapeutic PT or INR 
range)
ALT alanine aminotransferase; ANC absolute neutrophil count; AST aspartate aminotransferase; GFR glomerular 
filtration rate; INR international normalized ratio; PT prothrombin time; ULN upper limit of normal.
a
The threshold creatinine values in this table were derived from the Schwartz formula for estimating GFR utilizing child 
length and stature data published by the CDC.
b
Creatinine clearance should be calculated per institutional standards (see Appendix 7 for country specific 
requirements).
5. Has urine dipstick <2+ for proteinuria. Participants who have ≥2+ proteinuria on dipstick 
urinalysis should undergo a spot P/C ratio that should be Grade <2 per CTCAE v5.0, and 
if possible, perform a 24-hour urine collection (children and adolescents ≤12 years of age 
must have ≤500 mg of protein/24 hours and participants >12 years of age must have ≤1 g 
of protein/24 hours).
6. Has no clinical evidence of nephrotic syndrome.
7. Has adequate BP control with or without antihypertensive medications, defined as:

BP < the 95th percentile for sex, age, and height/length (≤150/90 mm Hg for 
participants aged 18 to 21 years) at Screening (as per NHLBI guidelines; Appendix 
11 and Appendix 12) and no change in antihypertensive medications within 1 week 
prior to Cycle 1 Day 1.
8. Has adequate cardiac function:

Adequate cardiac function as evidenced by left ventricular shortening fraction of 
≥27% by echocardiogram or LVEF ≥50% at C1D1 prior to allocation as determined 
by echocardiography or MUGA scan.

QT interval corrected for heart rate using Fridericia’s formula (QTcF) ≤480 msec.
9. Has adequate neurologic function:

Participants with seizure disorder may be enrolled if on anticonvulsants and seizure 
disorder is well controlled.
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10. Has fully recovered to CTCAE v5.0 Grade ≤1 (except for alopecia, ototoxicity, and 
Grade ≤2 peripheral neuropathy) from the acute toxic effects of all prior anticancer 
therapy and must meet the following minimum duration from prior anticancer-directed 
therapy prior to enrollment. If after the required timeframe, the numerical eligibility 
criteria are met, eg, blood count criteria, the participant is considered to have recovered 
adequately.
a.
Cytotoxic chemotherapy or other chemotherapy known to be myelosuppressive: 
≥21 days after the last dose of cytotoxic or myelosuppressive chemotherapy (42 days 
if prior nitrosourea).
b. Anticancer agents not known to be myelosuppressive (eg, not associated with reduced 
platelet or absolute neutrophil counts): ≥7 days after the last dose of agent.
c.
Monoclonal antibodies: ≥21 days or 3 half-lives (whichever is shorter) of the 
antibody must have elapsed after the last dose of a monoclonal antibody (including 
checkpoint inhibitors; Appendix 14). Toxicity related to prior antibody therapy must 
be recovered to Grade ≤1.
d. Corticosteroids: If used to modify immune AEs related to prior therapy, ≥14 days 
must have elapsed since last dose of corticosteroid. For reasons other than immune 
AEs, participants receiving corticosteroids who have not been on a stable or 
decreasing dose of corticosteroid for at least 7 days prior to enrollment are not 
eligible.
e.
Hematopoietic growth factors: ≥14 days after the last dose of a long-acting growth 
factor (eg, NEULASTA®) or 7 days for short-acting growth factor. For agents that 
have known AEs occurring beyond 7 days after administration, this period must be 
extended beyond the time during which AEs are known to occur.
f.
Interleukins, interferons, and cytokines (other than hematopoietic growth factors): 
≥21 days after the completion of interleukins, interferons, or cytokines (other than 
hematopoietic growth factors).
g. Stem cell infusions (with or without total body irradiation):
o
Allogeneic (non-autologous) bone marrow or stem cell transplant, or any stem 
cell infusion including donor leukocytes infusion or boost infusion: ≥84 days after 
infusion and no evidence of graft versus host disease.
o
Autologous stem cell infusion including boost infusion: ≥42 days.
h. Cellular Therapy: ≥42 days after the completion of any type of cellular therapy (eg, 
modified T cells, natural killer cells, dendritic cells, etc).
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i.
Radiotherapy (XRT)/External Beam Irradiation including Protons: ≥14 days after 
local XRT; ≥150 days after total body irradiation, craniospinal XRT, or if radiation to 
≥50% of the pelvis; ≥42 days if other substantial bone marrow radiation.
j.
Radiopharmaceutical therapy (eg, 131I-MIBG): ≥42 days after systemically 
administered radiopharmaceutical therapy.
k. VEGF/VEGFR-targeted therapies:
o
Must not have received prior exposure to lenvatinib
o
No more than 2 prior VEGF/VEGFR-targeted therapies
Demographics
11.
Male or female ≥2 years to ≤21 years of age, on the day the main informed 
consent/assent is signed.
Male Participants
12.
Male participants are eligible to participate if they agree to the following during the 
intervention period and for at least 7 days after the last dose of study intervention:
•
Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent 
on a long term and persistent basis) and agree to remain abstinent
OR
•
Must agree to use contraception unless confirmed to be azoospermic (vasectomized or 
secondary to medical cause [Appendix 5]) as detailed below:
-
Agree to use a male condom plus partner use of an additional contraceptive method 
when having penile-vaginal intercourse with a WOCBP who is not currently 
pregnant. Note: Men with a pregnant or breastfeeding partner must agree to remain 
abstinent from penile-vaginal intercourse or use a male condom during each episode 
of penile-vaginal penetration.
-
Contraceptive use by men should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies. If the contraception 
requirements in the local label for any of the study interventions is more stringent than 
the requirements above, the local label requirements are to be followed.
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Female Participants
13. A female participant is eligible to participate if she is not pregnant or breastfeeding, and 
at least one of the following conditions applies:
•
Is not a WOCBP
OR
•
Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate 
of <1% per year), with low user dependency, or be abstinent from heterosexual 
intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent 
basis), as described in Appendix 5 during the intervention period and for at least 30 days 
post lenvatinib.
•
A WOCBP must have a negative highly sensitive pregnancy test ([urine or serum] as 
required by local regulations) within 24 hours before the first dose of study intervention.
•
If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum 
pregnancy test is required. In such cases, the participant must be excluded from 
participation if the serum pregnancy result is positive.
•
Additional requirements for pregnancy testing during and after study intervention are 
located in Appendix 2.
•
The investigator is responsible for review of medical history, menstrual history, and 
recent sexual activity to decrease the risk for inclusion of a woman with an early 
undetected pregnancy.
•
Contraceptive use by women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies. If the contraception 
requirements in the local label for any of the study interventions is more stringent than 
the requirements above, the local label requirements are to be followed.
Informed Consent/Assent
14. Is willing and able to provide (and/or their parents or legal guardians) documented 
informed consent/assent for the study. Documented informed consent is required from 
participants ≥18 years.
15. Is willing and able to comply with the protocol, scheduled follow-up, and management of 
toxicity as judged by the investigator.
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5.2
Exclusion Criteria
The participant must be excluded from the study if the participant:
Medical Conditions
1. Has had major surgery within 3 weeks prior to C1D1.
Note: Adequate wound healing after major surgery must be assessed clinically, 
independent of time elapsed for eligibility.
2. Has GI bleeding or active hemoptysis (bright red blood of at least half teaspoon) within 
21 days prior to enrollment.
3. Has CNS tumors with a history of symptomatic tumor hemorrhage.
4. Has evidence of new intracranial hemorrhage of more than punctate size on MRI 
assessment obtained within 28 days prior to study enrollment.
5. Has radiographic evidence of encasement or invasion of a major blood vessel or of 
intratumoral cavitation. 
Note: The degree of proximity to major blood vessels should be considered for exclusion 
because of the potential risk of severe hemorrhage associated with tumor 
shrinkage/necrosis after lenvatinib therapy.
6. Has evidence of untreated CNS metastases (exception: participants with primary CNS 
tumors and leptomeningeal disease).
7. Has GI malabsorption, GI anastomosis, or any other condition that in the opinion of the 
investigator might affect the absorption of lenvatinib.
8. Has preexisting ≥Grade 3 GI or non-GI fistula.
9. Has any active infection requiring systemic therapy.
10. Is known to be HIV positive. Note: HIV testing is required at screening only when 
mandated by local health authority (see Appendix 7 for country-specific requirements).
11. Has known active viral hepatitis B virus (eg, HBsAg reactive) or Hepatitis C virus (eg,
HCV RNA [qualitative] is detected) infection. Note: Testing for hepatitis B or hepatitis C 
is required at screening only when mandated by local health authority (see Appendix 7 
for country-specific requirements).
12. Has clinically significant cardiovascular disease within 6 months from first dose of study 
intervention, including New York Heart Association Class III or IV congestive heart 
failure, unstable angina, myocardial infarction, cerebral vascular accident, or cardiac 
arrhythmia associated with hemodynamic instability. Note: Medically controlled 
arrhythmia would be permitted.
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13. Has non-healing wound, tumor ulceration, unhealed or incompletely healed fracture, or a 
compound (open) bone fracture at the time of enrollment.
Prior/Concomitant Therapy
Prior/Concurrent Clinical Study Experience
14. Is currently participating and receiving study therapy or has participated in a study of an 
investigational agent and received study therapy or used an investigational device within 
4 weeks of the date of allocation.
Note: Participants who have entered the follow-up phase of an investigational study may 
participate as long as it has been 4 weeks after the last dose of the previous
investigational agent.
Diagnostic Assessments
Other Exclusions
15. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the study, interfere with the participant’s participation 
for the full duration of the study, or is not in the best interest of the participant to 
participate, in the opinion of the treating investigator.
16. Has known hypersensitivity to any component of the investigational product (lenvatinib 
or ingredients).
17. Has known psychiatric or substance abuse disorders that would interfere with cooperation 
with the requirements of the study.
5.3
Lifestyle Considerations
5.3.1
Meals and Dietary Restrictions
Participants should maintain a normal diet unless modifications are required to manage an 
AE such as diarrhea, nausea, or vomiting. Lenvatinib capsules may be administered with or 
without food.
5.3.2
Contraception
Lenvatinib may have adverse effects on a fetus in utero. Refer to Appendix 5 for approved 
methods of contraception.
Participants should be informed that taking the study intervention may involve unknown 
risks to the fetus (unborn baby) if pregnancy were to occur during the study. To participate in 
the study, WOCBP must adhere to the contraception requirement (Appendix 5) from the day 
of study intervention initiation throughout the study period up and up to 30 days post 
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lenvatinib. If there is any question that a WOCBP will not reliably comply with the 
requirements for contraception, that participant should not be entered into the study.
5.3.3
Pregnancy
If a participant inadvertently becomes pregnant while on lenvatinib, the participant will be 
immediately discontinued from study treatment. The site will contact the participant at least 
monthly and document the participant’s status until the pregnancy has been completed or 
terminated. The outcome of the pregnancy will be reported to Sponsor without delay and 
within 24 hours if the outcome is a serious adverse experience (eg, death, abortion, 
congenital anomaly, or other disabling or life-threatening complication to the mother or 
newborn). The study investigator will make every effort to obtain permission to follow the 
outcome of the pregnancy and report the condition of the fetus or newborn to the Sponsor as 
described in Section 8.4. If a male participant impregnates his female partner, the study 
personnel at the site must be informed immediately and the pregnancy must be reported to 
the Sponsor and followed as described in Section 8.4.
5.3.4
Use in Nursing Women
It is unknown whether lenvatinib is excreted in human milk. Since many drugs are excreted 
in human milk, and because of the potential for serious adverse reactions in the nursing 
infant, participants who are breastfeeding are not eligible for enrollment.
5.4
Screen Failures
Screen failures are defined as participants who consent/assent to participate in the clinical 
study, 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 CONSORT publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure details, eligibility 
criteria, and any AEs or SAEs meeting reporting requirements as outlined in the data entry 
guidelines.
5.5
Participant Replacement Strategy
A participant who is not evaluable for objective response will be replaced.
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6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
Clinical supplies will be packaged to support enrollment . Clinical supplies will be affixed 
with a clinical label in accordance with regulatory requirements.
6.1
Study Intervention(s) Administered
The study intervention to be used in this study is outlined in Table 2.
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Table 2
Study Interventions
Arm 
Name
Arm 
Type
Intervention 
Name
Intervention
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Adminis-
tration
Regimen/
Treatment
Period
Use
IMP
or
NIMP/
AxMP
Sourcing
Arm 1
Experi-
mental
Lenvatinib
Drug
Capsule
1 mg, 4 mg, 
10 mg
14 mg/m2
Oral
Once daily
Test 
Product
IMP
Central
EEA=European Economic Area; IMP=investigational medicinal product; NIMP/AxMP=noninvestigational/auxiliary medicinal product.
The classification of IMP and NIMP/AxMP in this table is based on guidance issued by the European Commission and applies to countries in the EEA. Country 
differences with respect to the definition/classification of IMP and NIMP/AxMP may exist. In these circumstances, local legislation is followed.
After adjustments for body surface area, the lenvatinib daily dose will not exceed 24 mg.
A participant who is not evaluable for objective response will be replaced. 
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All supplies indicated in Table 2 will be provided per the "Sourcing" column depending upon 
local country operational requirements. If local sourcing, every attempt should be made to 
source these supplies from a single lot/batch number.
Refer to Section 6 for details regarding administration of the study intervention.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
Lenvatinib is a capsule for oral administration and does not require preparation. For 
participants unable to swallow capsules a suspension can be prepared. See the Pharmacy 
Manual for additional information.
6.2.2
Handling, Storage, and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received, and any discrepancies are 
reported and resolved before use of the study intervention.
Only participants enrolled in the study may receive study intervention, and only authorized 
site staff may supply or administer study intervention. All study interventions must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
For all study sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return, or local discard 
and destruction if appropriate. Where local discard and destruction is appropriate, the 
investigator is responsible for ensuring that a local discard/destruction procedure is 
documented.
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) as per local guidelines unless otherwise 
instructed by the Sponsor.
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 study 
interventions in accordance with the protocol and any applicable laws and regulations.
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6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
Treatment allocation will occur centrally using an interactive response technology. 
Participants will be assigned to 1 of 4 cohorts based on their malignancy.
6.3.2
Stratification
No stratification based on age, sex, or other characteristics will be used in this study.
6.3.3
Blinding
This is an open-label study; therefore, the Sponsor, investigator, and participant will know 
the intervention administered.
6.4
Study Intervention Compliance
Interruption from the protocol-specified lenvatinib treatment ≥28 days requires consultation 
between the investigator and the Sponsor and written documentation of the collaborative 
decision on participant management.
6.5
Concomitant Therapy
Treatment (including blood products, blood transfusions, fluid transfusions, antibiotics, and 
antidiarrheal drugs, etc.) for AEs or therapy to ameliorate symptoms may be administered at 
the discretion of the investigator, unless it is expected to interfere with the evaluation of (or 
to interact with) the study medication. Prophylactic use of G-CSFs is not permitted.
Administration of systemic corticosteroids for PD is not permitted.

Administration of systemic corticosteroids will be limited to premedication or the 
short-term treatment of acute medical conditions in accordance with approved 
indications, institutional, or national guidelines.

Inhaled steroids are allowed for management of asthma.
Palliative radiotherapy of up to 2 painful preexisting, nontarget bone metastases will be 
permitted without being considered PD.
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6.5.1
Prohibited Concomitant Medications
Participants are prohibited from receiving the following therapies during screening and while 
on treatment during the study:
•
Concurrent anticancer therapies such as chemotherapy, TKIs, radiotherapy (with the 
exception of palliative radiotherapy as specified in Section 6.5), antitumor interventions 
(surgical resection, surgical debulking of tumor, etc.), or cancer immunotherapy.
•
Concurrent other investigational drugs.
For participants who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management, continuation of the study medication,
and further participation in the study must be discussed and agreed upon with the Sponsor.
If participants receive additional anticancer therapies, this will be judged to represent 
evidence of disease progression, and study medication will be discontinued. These 
participants should complete all off-treatment assessments and continue to be followed for 
survival in the Survival Follow-up Period.
Further information on the prohibited concomitant therapies for lenvatinib is included in the 
prescribing information.
6.5.2
Rescue Medications and Supportive Care
Participants should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.
6.6
Dose Modification
Lenvatinib dose reduction and interruption for participants who experience lenvatinib-related 
toxicity will be in accordance with the dose modifications described in Table 3. AEs will be 
graded using CTCAE v5.0.
Asymptomatic laboratory abnormalities, including Grade ≥3 abnormalities (eg, elevations of 
amylase and lipase) that are not considered clinically relevant by the investigator should be 
managed per institutional guidelines; continuation of treatment should be discussed with the 
Sponsor.
Dose reductions will occur in succession based on the previous dose. Each reduction is a 
20% reduction from the previous dose. Once the dose has been reduced, it cannot be 
increased at a later date, unless the dose has been mistakenly decreased; in this situation, 
Sponsor’s approval is required to increase the dose. An interruption of lenvatinib >28 days 
will require consultation between the investigator and the Sponsor and written documentation 
of the collaborative decision on participant management.
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Table 3
Criteria for Temporary Discontinuation of Study Drug, Dose Reduction, and 
Resumption of Treatment
Dose Modification Guidelines for Lenvatinib-Related Toxicity
Treatment-Related Toxicitya,b
Management
Dose Adjustment
Grade 1 or Tolerable Grade 2
Continue treatment
No change
Intolerable Grade 2c, d or Grade 3e
First occurrence
Interrupt lenvatinib until 
resolved to Grade 0-1 or 
tolerable Grade 2
11.2 mg/m2 (or 20% 
reduction of the starting 
dose) orally QD (1-level 
reduction)
Second occurrence
(same toxicity or new toxicity)
Interrupt lenvatinib until 
resolved to Grade 0-1 or 
tolerable Grade 2
9.0 mg/m2 (or 20% 
reduction of the previous 
dose) orally QD (1-level 
reduction)
Third occurrence
(same toxicity or new toxicity)
Interrupt lenvatinib until 
resolved to Grade 0-1 or 
tolerable Grade 2
7.2 mg/m2 (or 20% 
reduction of the previous 
dose) orally QD (1-level 
reduction)
Fourth occurrence
(same toxicity or new toxicity)
Interrupt lenvatinib
Discuss with Sponsor
Grade 4f: Discontinue Study Treatment
Abbreviations: BMI = body mass index; CTC = Common Toxicity Criteria; CTCAE = Common Terminology 
Criteria for Adverse Events; QD = once daily.
Note: For grading, see CTCAE version 5.0. Collect all CTC grades of adverse events, decreasing and increasing 
grade.
a
An interruption of study treatment > 28 days will require Sponsor`s approval before treatment can be 
resumed.
b
Initiate optimal medical management for nausea, vomiting, hypertension, hypothyroidism, and/or diarrhea 
prior to any study treatment interruption or dose reduction.
c
Applicable only to Grade 2 toxicities judged by the participant and/or physician to be intolerable.
d
Obese participants with weight loss do not need to return to the baseline weight or 10% of baseline weight 
(ie, Grade 1 weight loss). These participants will restart lenvatinib 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 lenvatinib 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. Refer to Appendix 13 for BMI-
for-age percentiles.
e
For asymptomatic laboratory abnormalities, such as Grade ≥3 elevations of amylase and lipase that are not 
considered clinically relevant by the investigator, continuation of treatment should be discussed with the 
Sponsor.
f
Excluding laboratory abnormalities judged to be non-life-threatening, in which case manage as Grade 3.
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6.6.1
Blood Pressure
For children, BP varies by the sex and age of the child and it is closely related to height and 
weight. BP will be assessed in terms of percentile for sex, age, and height/length. Guidelines 
to sex, age, and height/length-specific percentiles of BP are provided in Appendix 11 and 
Appendix 12. BP that is consistently above the 95th percentile based on sex, age, and 
height/length (or BP ≥140/90 mm Hg for participants 18 to 21 years old) requires further 
evaluation. A referral to a cardiologist is recommended for participants who develop 
hypertension during the study. Ideally, cardiovascular assessments and the management of 
hypertension should be supervised by a cardiologist. Exercise, excitement, coughing, crying, 
and struggling may raise the systolic pressure of children as much as 40 to 50 mm Hg greater 
than their usual level. Variability in BP in children of approximately the same age and body 
build should be expected, and serial measurements should always be obtained when 
evaluating a participant with hypertension. BP values for the management of hypertension 
for participants 18 to 21 years old are included in parentheses in Section 6.6.2.
6.6.2
Management of Hypertension
Hypertension is a recognized side-effect of treatment with drugs inhibiting VEGF signaling. 
Investigators should therefore ensure that participants enrolled to receive treatment with 
lenvatinib have BP <95th percentile (BP ≤150/90 mm Hg) for sex, age, and height/length 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.
Regular assessment of BP should be conducted as detailed in the SoA (Section 1.3). 
Hypertension will be graded using CTCAE v5.0, based on BP measurements only (and not 
on the number of antihypertensive medications).
If the participant’s first BP measurement of the current assessment is elevated (systolic BP 
≥95th percentile [BP ≥140 mm Hg] or diastolic BP ≥95th percentile [BP ≥90 mm Hg]), the 
BP measurement should be repeated approximately 5 minutes later. The mean value of 
2 measurements approximately 5 minutes apart is defined as 1 BP assessment. If the BP 
assessment (ie, the mean of the 2 BP measurements obtained at approximately 5 minutes 
apart) is elevated (systolic BP ≥95th percentile [BP ≥140 mm Hg] or diastolic BP ≥95th
percentile [BP ≥90 mm Hg]), a confirmatory assessment should be obtained at least 
30 minutes later by performing 2 measurements (at approximately 5 minutes apart) to yield a 
mean value (Figure 2).
Antihypertensive agents should be started as soon as elevated BP (systolic BP ≥95th
percentile [BP ≥140 mm Hg] or diastolic BP ≥95th percentile [BP ≥90 mm Hg]) is confirmed 
on 2 assessments obtained 30 minutes apart. The choice of antihypertensive treatment should 
be individualized to the participant’s clinical circumstances and follow standard medical 
practice. For previously normotensive participants, monotherapy with one of the classes of 
antihypertensives should be started when systolic BP ≥95th percentile (BP ≥140 mm Hg) or 
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diastolic BP ≥95th percentile (BP ≥90 mm Hg) is first observed on 2 assessments obtained 
30 minutes apart. For those participants already on antihypertensive medication, treatment 
modification may be necessary if hypertension persists.
Lenvatinib should be withheld in any instances where a participant is at imminent risk to 
develop a hypertensive crisis or has significant risk factors for severe complications of 
uncontrolled hypertension (eg, BP ≥99th percentile [BP ≥160/100 mm Hg], significant risk 
factors for cardiac disease, intracerebral hemorrhage, or other significant comorbidities). 
Once the participant has been on the same antihypertensive medications for at least 48 hours 
and the BP is controlled, lenvatinib should be resumed as described below.
During the treatment period, participants with systolic BP ≥99th percentile 
(BP ≥160 mm Hg) or diastolic BP ≥99th percentile (BP ≥100 mm Hg) must have their BP 
monitored on Day 15 (or more frequently as clinically indicated) until systolic BP has been 
<95th percentile (≤150 mm Hg) and diastolic BP has been <95th percentile (≤95 mm Hg) for 
2 consecutive treatment cycles. If a repeat event of systolic BP ≥99th percentile 
(BP ≥160 mm Hg) or diastolic BP ≥99th percentile (BP ≥100 mm Hg) occurs, the participant
must resume the Day 15 evaluation until systolic BP has been <95th percentile 
(≤150 mm Hg) and diastolic BP has been <95th percentile (≤95 mm Hg) for 2 consecutive 
treatment cycles.
The following guidelines should be followed for the management of systolic BP ≥99th
percentile (BP ≥160 mm Hg) or diastolic BP ≥99th percentile (BP ≥100 mm Hg) confirmed 
on repeat measurements after at least 30 minutes:

Continue lenvatinib and institute antihypertensive therapy for participants not already 
receiving antihypertensive medication.

For those participants already on antihypertensive medication, the dose of the current 
agent may be increased, if appropriate, or 1 or more agents of a different class of 
antihypertensive should be added.

If systolic BP ≥99th percentile (BP ≥160 mm Hg) or diastolic BP ≥99th percentile (BP 
≥100 mm Hg) persists despite maximal antihypertensive therapy, then lenvatinib 
administration should be interrupted and restarted at a lower dose QD (1 dose level 
reduction [20%] as specified in Table 3) only when systolic BP <95th percentile 
(BP ≤150 mm Hg) and diastolic BP <95th percentile (BP ≤95 mm Hg) and the participant
has been on a stable dose of antihypertensive medication for at least 48 hours.
o
If systolic BP ≥99th percentile (BP ≥160 mm Hg) or diastolic BP ≥99th percentile 
(BP ≥100 mm Hg) 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 antihypertensive), then lenvatinib administration 
should be interrupted and restarted at an additional dose reduction only when systolic 
BP <95th percentile (BP ≤150 mm Hg) and diastolic BP <95th percentile 
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(BP ≤95 mm Hg) and the participant has been on a stable dose of antihypertensive 
medication for at least 48 hours.
o
If systolic BP ≥99th percentile (BP ≥160 mm Hg) or diastolic BP ≥99th percentile 
(BP ≥100 mm Hg) 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 and restarted at a third dose reduction only when systolic 
BP <95th percentile (BP ≤150 mm Hg) and diastolic BP<95th percentile (BP ≤95 mm 
Hg) and the participant has been on a stable dose of antihypertensive medication for 
at least 48 hours.
o
Additional dose reduction should be discussed with the Sponsor.
The following guidelines should be followed for the management of Grade 4 hypertension 
(life-threatening consequences):

Institute appropriate medical management

Discontinue lenvatinib
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Figure 2
Procedures Associated with Management of Hypertension
SCREENING
BP mmHg <95th Percentile [<150/90 mmHg]
If known with HTN, no change in anti HTN meds within 1 week
On the Study (Starting Dose)
BP mmHg ≥ 95th percentile [≥140/90 mmHg] on 2 assessments 
30 mins apart
No Tx with HTN Meds
On anti HTN Meds
Start anti HTN Monotherapy
Start anti HTN Monotherapy
Increase Dose of 
Current anti-HTN AgentOR
Add 1 or more agents of 
different Class of anti-HTN Med
BP mmHg ≥ 99th percentile [≥160/100 
mmHg] on 2 assessments 30 mins apart
If not on anti HTN meds, institute 
monotherapy anti HTN meds
If on anti HTN meds, increase dose or 
add 1 more agent of different class of 
anti HTN meds 
BP mmHg ≥99th percentile [≥160/100 mmHg] persists despite 
optimal anti-HTN meds
Interrupt study drug and restart at a lower dose (20% reduction of 
starting dose) once BP (mmHg) is <95th percentile  [<150/90 mmHg]
BP mmHg ≥99th percentile [≥160/100 mmHg] recurs despite 
optimal anti-HTN meds
BP mmHg ≥99th percentile [≥160/100 mmHg] recurs despite 
optimal anti-HTN meds
Additional dose reduction should be discussed with the Sponsor
Management of Hypertension
Interrupt study drug and restart at a lower dose (20% reduction of 
starting dose) once BP (mmHg) is <95th percentile  [<150/90 mmHg]
Interrupt study drug and restart at a lower dose (20% reduction of 
starting dose) once BP (mmHg) is <95th percentile  [<150/90 mmHg]
1 BP assessment is defined as the mean value 
of 2 measurements at least 5 min apart
Abbreviations: BP  blood pressure; HTN  hypertension; Tx  treatment.
6.6.3
Management of Proteinuria
Regular assessment for proteinuria should be conducted as detailed in the SoA (Table 1). 
Guidelines for assessment and management of proteinuria are summarized as follows:
Grading of Proteinuria
•
Grading according to CTCAE v5.0 will be based on the protein-creatinine ratio or 
24-hour urinary protein result if available. For participants ≥18 years of age, if the 
participant has 4+ proteinuria by dipstick (≥1000 mg/dL by urinalysis), a 24-hour urinary 
protein result is required to confirm Grade 3 proteinuria.
Management of Proteinuria
•
Management of lenvatinib administration will be based on the grade of proteinuria 
according to Table 3.
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•
In the event of nephrotic syndrome, lenvatinib must be discontinued.
Detection and Confirmation
•
Perform urine dipstick testing per the SoA (Table 1). Urine dipstick testing is the 
preferred method for testing for urinary protein, however, urinalysis may be used if the use of 
urine dipsticks is not feasible.
•
For participants ≥18 years of age, a 24-hour urine collection (initiated as soon as possible 
and at least within 72 hours) or an immediate spot P/C test AND for participants
<18 years of age, an immediate spot P/C test, and if possible, a 24-hour urine collection 
(initiated as soon as possible and at least within 72 hours) is required in the following 
situations:
o
The first (initial) occurrence of ≥2+ (≥100 mg/dL) proteinuria on urine dipstick (or 
urinalysis) while on lenvatinib.
o
A subsequent increase in severity of urine dipstick or urinalysis proteinuria occurring 
on the same lenvatinib dose level.
o
When there has been a lenvatinib dose reduction and at the new dose level the urine 
protein dipstick result is ≥2+ (≥100 mg/dL).
Note: For participants ≥18 years of age, a 24-hour urine collection (initiated as soon 
as possible and at least within 72 hours) to verify the grade of proteinuria is required 
when P/C test is ≥2.4.
Monitoring
•
Urine dipstick or urinalysis testing for participants with proteinuria ≥2+(≥100 mg/dL)
should be performed on Day 15 (or more frequently as clinically indicated) until the 
results have been 1+(10 mg/dL) or negative for 2 consecutive 28-day treatment cycles.
•
Proteinuria monitoring can be performed at the local laboratory or investigator site but 
must be managed by the site physician.
6.6.4
Management of Gastrointestinal Symptoms and Acute Abdominal Pain
Initial management of acute abdominal pain in these study participants should be focused on 
treating the underlying cause where possible, ensuring appropriate hydration/rehydration, and 
symptomatic pain improvement consistent with participant’s age and in accordance with 
local and institutional standards of care. Appropriate supportive care should be provided 
together with close monitoring.
For AEs of abdominal pain believed related to lenvatinib or more specific AEs believed 
related to lenvatinib that result in the symptom of abdominal pain, follow instructions 
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contained in Table 3 regarding lenvatinib dose reduction and interruption. For Grade 4 AEs 
that result in abdominal pain, lenvatinib must be discontinued.
GI symptoms including diarrhea should be managed by providing symptomatic treatment. If 
the symptoms persist (eg, diarrhea for more than 10 days), guidelines in Table 3 should be 
followed. GI symptoms should be monitored closely and evaluated using CT, contrast-
enhanced MRI, ultrasound, or other diagnostic imaging if clinically indicated, at the 
investigator’s discretion.
6.6.5
Management of Thromboembolic Events
Participants should be advised to pay attention to symptoms suggestive of venous 
thromboembolic events, which include acute onset of shortness of breath, dyspnea, chest 
pain, cough, hemoptysis, tachypnea, tachycardia, cyanosis, deep vein thrombosis signs 
including lower-extremity swelling, redness, and warmth to touch or tenderness. In case any 
of these symptoms appear, participants should be instructed to report such symptoms 
promptly to the treating physician. If a thromboembolic event is confirmed, instructions 
contained in Table 3 should be followed. Appropriate supportive care should be provided 
together with close monitoring. If a participant experiences a Grade 3 or life-threatening 
(Grade 4) thromboembolic reaction, including pulmonary embolism, lenvatinib must be 
discontinued.
Arterial thromboembolic events (eg, new onset, worsening, or unstable angina, myocardial 
infarction, transient ischemic attack, and cerebrovascular accident) of any grade require 
discontinuation of lenvatinib.
6.6.6
Management of Posterior Reversible Encephalopathy Syndrome 
(PRES)/Reversible Posterior Leukoencephalopathy Syndrome (RPLS)
PRES/RPLS is a neurological disorder that can present with headache, seizure, lethargy, 
confusion, altered mental function, blindness, and other visual or neurologic disturbances. 
Mild to severe hypertension may be present. An MRI is necessary to confirm the diagnosis of 
PRES/RPLS. The key diagnostic imaging feature for PRES, which can differentiate this 
entity from disease progression secondary to CNS tumors, is based on imaging evidence of 
new, bilateral/symmetric vasogenic edema without correlation with the location of the 
tumor/surgical cavity. Appropriate measures should be taken to control BP (see 
Section 6.6.1), and neurologic consultation is advised. In participants with signs or symptoms 
of PRES/RPLS, dose modification guidelines as per Table 3 should be followed.
6.6.7
Management of Hepatotoxicity
Regular monitoring of liver function tests (ALT, AST, and bilirubin levels) should be 
conducted as detailed in the SoA (Table 1) and as clinically indicated. If signs/symptoms 
indicating liver injury occur, dose modification guidelines contained in Table 3 should be 
followed. Appropriate supportive care should be provided together with close monitoring. If 
hepatic failure (any grade per CTCAE v5) occurs, lenvatinib must be discontinued.
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6.6.8
Management of Hypocalcemia
Serum calcium should be monitored monthly per the SoA (Table 1). Corrected serum 
calcium should be used to assess the grade of hypocalcemia per CTCAE v5.0, using the 
following formula:
Corrected calcium  ([4 serum albumin in g/dL] × 0.8 + serum calcium)
The formula is not applicable when serum albumin concentration is normal (˃4 g/dL); in 
such situations, the total (uncorrected) serum calcium should be used instead.
Hypocalcemia should be treated per institutional guidelines (eg, using appropriate calcium, 
magnesium, and vitamin D supplementation) until resolution.
6.6.9
Management of Hemorrhage
Dose modification guidelines in Table 3 for lenvatinib-related AEs should be followed for 
the management of hemorrhage. Lenvatinib should either be resumed at a reduced dose or 
discontinued, depending on the severity and persistence of hemorrhage.
6.6.10
Management of Fistula Formation and Gastrointestinal Perforation
Lenvatinib should be discontinued in any participants who develop Grade 4 fistula (GI or 
non-GI), or GI perforation of any grade.
6.6.11
Management of QT Prolongation
Lenvatinib should be withheld in the event of development of QT interval prolongation 
greater than 500 msec. Lenvatinib should be resumed at a reduced dose when QTc 
prolongation is resolved to <480 msec or baseline. Monitor potassium, calcium and 
magnesium, and replenish as appropriate.
6.6.12
Management of Osteonecrosis of the Jaw
Perform an oral examination prior to treatment with lenvatinib and periodically during 
lenvatinib treatment. Advise participants regarding good oral hygiene practices. Avoid 
invasive dental procedures, if possible, while on lenvatinib treatment, particularly in 
participants at higher risk. For participants requiring invasive dental procedures, 
discontinuation of bisphosphonate treatment may reduce the risk of ONJ. Withhold 
lenvatinib if ONJ develops and restart based on clinical judgement of adequate resolution 
(See Section 6.7)
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6.7
Other Allowed Dose Interruptions for Lenvatinib
If the participant is receiving treatment with lenvatinib and requires surgery during the study, 
the stop time and restart time of lenvatinib should be as follows:

For minor procedures: stop lenvatinib at least 2 days before the procedure and restart it at 
least 2 days after, once there is evidence of adequate healing and no risk of bleeding.

For major procedures: stop lenvatinib at least 1 week (5 half-lives) prior to surgery and 
then restart it at least 2 weeks after, once there is evidence of adequate healing and no 
risk of bleeding.

For scheduled dental surgery or invasive dental procedures, stop lenvatinib for at least 1 
week before the procedure, then restart lenvatinib when deemed clinically appropriate.
6.8
Intervention After the End of the Study
There is no study-specified intervention after the end of the study.
6.9
Clinical Supplies Disclosure
This  study is open-label; therefore, the participant, the study site personnel, the Sponsor, 
and/or designee are not blinded. Study intervention (name, strength, or potency) is included 
in the label text; random code/disclosure envelopes or lists are not provided.
6.10
Standard Policies
Not applicable.
6.10.1
Study Site Retention Samples
Not applicable.
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL
7.1
Discontinuation of Study Intervention
Discontinuation of study intervention does not represent withdrawal from the study.
As certain data on clinical events beyond study intervention discontinuation may be 
important to the study, they must be collected through the participant’s last scheduled follow-
up, even if the participant has discontinued study intervention. Therefore, all participants 
who discontinue study intervention prior to completion of study treatment will still continue 
to participate in the study as specified in Section 1.3 and Section 8.11.4.
Participants may discontinue study intervention at any time for any reason or be discontinued 
from the study intervention at the discretion of the investigator should any untoward effect 
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occur. In addition, a participant may be discontinued from study intervention by the 
investigator or the Sponsor if study intervention is inappropriate, the study plan is violated, or 
for administrative and/or other safety reasons. Specific details regarding procedures to be 
performed at study intervention discontinuation are provided in Section 1.3 and 
Section 8.11.4.
A participant must be discontinued from study intervention but continue to be monitored in 
the study for any of the following reasons:
•
The participant or participant’s legally acceptable representative requests to discontinue 
study intervention.
•
The participant interrupts study intervention administration for more than 28 consecutive 
days.
Note: Exceptions can be made with Sponsor consultation.
•
The participant has a medical condition or personal circumstance, which, in the opinion 
of the investigator and/or Sponsor, placed the participant at unnecessary risk from 
continued administration of study intervention.
•
The participant has a confirmed positive serum pregnancy test.
•
The participant experiences objective progression of disease (according to RECIST 1.1 or 
RANO criteria, for HGG).
•
The participant exhibits no clinical benefit (in the opinion of the investigator).
•
The participant experiences unacceptable toxicity leading to withdrawal from the study.
•
The study is terminated by the Sponsor.
•
Administrative reasons.
For participants who are discontinued from study intervention but continue to be monitored 
in the study, all visits and procedures, as outlined in the SoA, should be completed.
Discontinuation from study intervention is “permanent.” Once a participant is discontinued
from study intervention, he/she shall not be allowed to restart study intervention.
7.2
Participant Withdrawal From the Study
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent from the study.
If a participant withdraws from the study, they will no longer receive study intervention or be 
followed at scheduled protocol visits.
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Specific details regarding procedures to be performed at the time of withdrawal from the 
study, are outlined in Section 8. The procedures to be performed should a participant 
repeatedly fail to return for scheduled visits and/or if the study site is unable to contact the 
participant are outlined in Section 7.3.
7.3
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
•
The site must attempt to contact the participant and reschedule the missed visit. If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.
•
The investigator or designee must make every effort to regain contact with the participant 
at each missed visit (eg, telephone calls and/or a certified letter to the participant’s last 
known mailing address or locally equivalent methods). These contact attempts should be 
documented in the participant’s medical record.
•
Note: A participant is not considered lost to follow-up until the last scheduled visit for the 
individual participant. The missing data for the participant will be managed via the 
prespecified statistical data handling and analysis guidelines.
8
STUDY ASSESSMENTS AND PROCEDURES
•
Study procedures and their timing are summarized in the SoA.
•
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
•
The investigator is responsible for ensuring that procedures are conducted by 
appropriately qualified (by education, training, and experience) staff. Delegation of study 
site personnel responsibilities will be documented in the Investigator Trial File Binder (or 
equivalent).
•
All study-related medical or dental decisions must be made by an investigator who is a 
qualified physician.
•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
•
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of ICF may be utilized for screening or baseline 
purposes provided the procedure met the protocol-specified criteria and were performed 
within the time frame defined in the SoA.
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•
Additional evaluations/testing may be deemed necessary by the investigator and or the 
Sponsor for reasons related to participant safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (eg, HIV, Hepatitis C), and thus local regulations 
may require that additional informed consent, and assent if applicable, be obtained from 
the participant. In these cases, such evaluations/testing will be performed in accordance 
with those regulations.
The maximum amount of blood collected from each participant over the duration of the study
will be provided in the laboratory manual. Refer to Appendix 7 for country-specific 
requirements.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.
8.1
Administrative and General Procedures
8.1.1
Informed Consent/Assent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented informed consent, and assent if applicable, from each potential 
participant or their legally acceptable representative prior to participating in this clinical 
study. If there are changes to the participant’s status during the study (eg, health or age of 
majority requirements), the investigator or medically qualified designee must ensure the 
appropriate documented informed consent/assent is in place.
8.1.1.1
General Informed Consent/Assent
Informed consent/assent given by the participant or their legally acceptable representative 
must be documented on a consent/assent form. The form must include the study protocol 
number, study protocol title, dated signature, and agreement of the participant (or his/her 
legally acceptable representative) and of the person conducting the consent discussion.
A copy of the signed and dated informed consent/assent form should be given to the 
participant (or their legally acceptable representative) before participation in the study.
The initial informed consent/assent form, any subsequent revised informed consent/assent 
form, and any written information provided to the participant must receive the IRB/IEC’s 
approval/favorable opinion in advance of use. The participant or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available 
that may be relevant to the participant’s willingness to continue participation in the study. 
The communication of this information will be provided and documented via a revised 
consent/assent form or addendum to the original consent/assent form that captures the 
participant’s or the participant’s legally acceptable representative’s dated signature.
Specifics about the study and the study population are to be included in the study informed 
consent/assent form.
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Informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, and 
Sponsor requirements. The assent, as applicable will adhere to IRB/IEC requirements, 
applicable laws and regulations and Sponsor requirements.
8.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator, who is a qualified 
physician, to ensure that the participant qualifies for the study.
8.1.3
Participant Identification Card
All participants will be given a participant identification card identifying them as participants 
in a research study. The card will contain study site contact information (including direct 
telephone numbers) to be used in the event of an emergency. The investigator or qualified 
designee will provide the participant with a participant identification card immediately after 
the participant provides documented informed consent/assent. At the time of intervention
allocation, site personnel will add the treatment/allocation number to the participant 
identification card.
The participant identification card also contains contact information for the emergency 
unblinding call center so that a healthcare provider can obtain information about study 
intervention in emergency situations where the investigator is not available.
8.1.4
Medical History
A medical and surgical history will be obtained by the investigator or qualified designee. The 
medical and surgical history will collect all active conditions and any condition that is 
considered to be clinically significant by the investigator. Details regarding the disease for 
which the participant has enrolled in this study will be recorded separately and not listed as 
medical history.
8.1.5
Prior and Concomitant Medications Review
8.1.5.1
Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the participant 
within 30 days before the first dose of study intervention. Treatment for the disease for which 
the participant has enrolled in this study will be recorded separately and will not be listed as a 
prior medication.
8.1.5.2
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study. Concomitant medications will be recorded for 30 days after the last dose of 
study intervention.
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8.1.6
Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur prior to intervention allocation. Each 
participant will be assigned only 1 screening number. Screening numbers must not be re-used 
for different participants.
Any participant who is screened multiple times will retain the original screening number 
assigned at the initial screening visit. Specific details on the screening/rescreening visit 
requirements are provided in Section 8.11.1.
8.1.7
Assignment of Treatment/Allocation Number
All eligible participants will be allocated, by nonrandom assignment, and will receive a 
treatment/allocation number. The treatment/allocation number identifies the participant for 
all procedures occurring after treatment allocation. Once a treatment/allocation number is 
assigned to a participant, it can never be re-assigned to another participant.
A single participant cannot be assigned more than 1 treatment/allocation number.
8.1.8
Study Intervention Administration
Lenvatinib may be taken at home except on C1D1, C1D15, and C2D1; on these days 
lenvatinib will be taken in the clinic. An extemporaneous suspension of lenvatinib capsules 
should be used for participants unable to swallow capsules, as detailed in the Pharmacy 
Manual. Refer to Section 8.1.8.1 for further details.
Before dose administration on Day 1 of each cycle and prior to a change in dose due to dose 
reduction, the amount of lenvatinib needed for each participant must be calculated as follows:
Scheduled dose (mg/m2) × BSA (m2)  lenvatinib dose (mg)
BSA will be calculated using the method that is accepted and customarily used by the clinical 
site. BSA must be calculated on Day 1 of each cycle based on the participant’s current height 
and body weight and should not be corrected for amputation. The dose should be rounded to 
the nearest whole number. After adjustment for BSA, the daily dose of lenvatinib should not 
exceed 24 mg daily.
8.1.8.1
Timing of Dose Administration
Lenvatinib capsules are to be taken orally once daily at approximately the same time without 
regard to food intake from C1D1 onwards. Participants should not take lenvatinib on PK 
sampling days prior to their appointment (ie, C1D1, C1D15, and C2D1). On C1D1, C1D15 
and C2D1, participants should be instructed to bring their lenvatinib to the clinic. Lenvatinib 
should be administered at the study site at approximately the same time of day to
accommodate PK sample collection timing.
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If a participant misses a dose, it may be taken within 12 hours after the usual time of the 
dose. If more than 12 hours have elapsed from the time of the usual daily dose, lenvatinib 
should be taken the next day at the usual time. In the event a participant vomits after 
lenvatinib administration, the participant should not take another dose until the next 
scheduled dose.
8.1.8.2
Compliance
Lenvatinib compliance will be calculated by the Sponsor based on the study drug 
accountability documented by the site staff and monitored by the Sponsor/designee. The 
objective is 100% compliance and investigators and their staff should evaluate compliance at 
each visit and take appropriate steps to optimize compliance.
8.1.9
Discontinuation and Withdrawal
Participants who discontinue study intervention prior to completion of the treatment period
should be encouraged to continue to be followed for all remaining study visits as outlined in 
the SoA.
Participants who withdraw from the study should be encouraged to complete all applicable 
activities scheduled for the EOT visit at the time of withdrawal. Any AEs that are present at 
the time of withdrawal should be followed in accordance with the safety requirements 
outlined in Section 8.4.
8.1.10
Participant Blinding/Unblinding
This is an open-label study; there is no blinding for this study.
8.1.11
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or anti-tumor activity parameters shall be 
suitably calibrated and/or maintained to ensure that the data obtained are reliable and/or 
reproducible. Documentation of equipment calibration must be retained as source 
documentation at the study site.
8.1.12
Demography
Participant demography information will be collected at the Screening Visit. Demography 
information includes date of birth (or age), sex, and race/ethnicity (recorded in accordance 
with prevailing regulations). Tanner staging will be collected at the Screening Visit or C1D1, 
at EOT, and during efficacy and survival FU. During efficacy and survival FU, perform 
annually until puberty has completed or through survival FU, whichever comes first.
Telephone contact is acceptable for assessment if clinic visits are not possible at post-
treatment visits after the 30-day safety FU.
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8.2
Efficacy/Immunogenicity Assessments
8.2.1
Tumor Imaging and Assessment of Disease
In addition to survival, evaluation of antitumor activity will be assessed based on imaging 
evaluation of changes in tumor burden over time, until the participant is discontinued from 
the study or goes into survival follow-up. The process for image collection can be found in 
the SIM.
For participants with non-CNS solid tumors:

CT scans of the chest, abdomen and pelvis are required.

As an alternative to CT (i.e., when iodinated contrast is contraindicated or when
mandated by local practice), MRI of the abdomen and pelvis, along with a 
noncontrast CT of the chest is an acceptable alternative.

If brain imaging is performed to document the stability of existing metastases, MRI 
should be used if possible. If MRI is medically contraindicated, CT with contrast is an 
acceptable alternative.

Any additional anatomical areas as clinically indicated.
For participants with CNS Tumors:

MRI of the brain is required for the HGG cohort. MRI of the brain is strongly 
preferred over CT for non-HGG CNS tumors.

Any additional anatomical areas as clinically indicated.
Tumor imaging will be performed at the timepoints specified in Section 1.3, or as clinically 
indicated. Tumor imaging of the chest is to be acquired by CT scan. For the abdomen and 
pelvis, contrast-enhanced MRI may be used when CT with iodinated contrast is 
contraindicated, or when mandated by local practice. MRI is the strongly preferred 
modality for imaging the brain. For HGG participants, MRI is mandatory to allow for 
RANO assessment. Refer to the SIM for mandatory acquisition parameters. The same 
imaging technique should be used in a participant throughout the study to optimize the 
reproducibility of the assessment of existing and new tumor burden and improve the 
accuracy of the response assessment based on imaging. Note: for the purposes of assessing 
tumor imaging, the term “investigator” refers to the local investigator at the site and/or the 
radiological reviewer at the site or at an offsite facility.
8.2.1.1
Initial Tumor Imaging
Initial tumor imaging at Screening must be performed within 28 days prior to the date of
allocation. Tumor imaging performed as part of routine clinical management is acceptable 
for use as screening tumor imaging if it is of diagnostic quality and performed within 28 days 
prior to the date of allocation.
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Participant eligibility will be determined based on confirmation by the investigator that the 
participant has measurable disease per RECIST 1.1 for all tumor types except for HGG, 
which will be evaluated per RANO criteria. In addition, participants with neuroblastoma who 
do not have measurable disease per RECIST 1.1 but have MIBG-positive evaluable disease 
may be enrolled (see Section 4.2.1.1).
8.2.1.2
Tumor Imaging During the Study
The first on-study imaging assessment should be performed the end of Week 8 ±7 days.
Subsequent tumor imaging should be performed every 8 weeks until Week 24, then every 
12 weeks (±7days) thereafter during treatment (or sooner if there is evidence of PD). Imaging 
timing should follow calendar days from C1D1, and should not be adjusted for delays in 
cycle starts. Imaging should continue to be performed until disease progression is identified 
by the investigator, the start of new anticancer treatment, pregnancy, withdrawal of consent, 
or death, whichever occurs first.
Objective response should be confirmed by a repeat imaging assessment. Tumor imaging to 
confirm PR or CR should be performed at least 4 weeks after the first indication of a 
response is observed. Participants will then return to regular scheduled imaging, starting with 
the next scheduled imaging time point. Participants who receive additional imaging for 
confirmation do not need to undergo the next scheduled tumor imaging if it is less than 
4 weeks later; tumor imaging may resume at the subsequent scheduled imaging time point.
8.2.1.3
End-of-Treatment and Follow-up Tumor Imaging
For participants who discontinue study intervention, tumor imaging should be performed at 
the time of treatment discontinuation (±4 week window). If previous imaging was obtained 
within 4 weeks prior to the date of discontinuation, then imaging at treatment discontinuation 
is not mandatory. For participants who discontinue study intervention due to documented 
disease progression, this is the final required tumor imaging.
For participants who discontinue study intervention without documented disease progression, 
every effort should be made to continue monitoring disease status by tumor imaging using 
the same imaging schedule used while on treatment calculated from the date of allocation
until the start of a new anticancer treatment, disease progression, pregnancy, death, 
withdrawal of consent, or the end of the study, whichever occurs first.
8.2.1.4
RECIST 1.1 Assessment of Disease
RECIST 1.1 will be used as the primary measure for assessment of tumor response (except 
for HGG), for date of disease progression, and as a basis for all protocol guidelines related to 
disease status (eg, discontinuation of study intervention). RECIST 1.1 references a maximum 
of 5 target lesions in total and 2 per organ.
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8.2.1.5
RANO Assessment of Disease
RANO criteria will be used for participants with HGG as the primary measure for assessment 
of tumor response for date of disease progression, and as a basis for all protocol guidelines 
related to disease status (eg, discontinuation of study intervention). A standard MRI-imaging 
protocol will be performed for use in the assessments. Refer to Appendix 8 for RANO 
response criteria.
8.2.2
Palatability and Acceptability of Lenvatinib Suspension Formulation
The palatability and acceptability of lenvatinib suspension formulation will be assessed using 
a palatability questionnaire. All participants who receive suspension formulation, with the 
exception of participants using a NG or G tube, must complete the questionnaire according to 
the SoA. If the participant is unable to complete the questionnaire, this must be done by a 
parent or legal guardian. Measurement of palatability will be assessed using a facial hedonic
scale [Guinard, J. X. 2001].
8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided. The total amount of blood/tissue to be drawn/collected over the course of the study 
(from prestudy to poststudy visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per participant, can be found in the laboratory 
manual. Refer to Appendix 7 for country-specific requirements.
Planned time points for all safety assessments are provided in the SoA.
8.3.1
Physical Examinations
A comprehensive physical and oral examination or symptom-directed physical and oral
examination will be performed as designated in the SoA (Section 1.3). A complete physical
and oral examination at C1D1 will be performed only if the screening physical and oral 
examination was performed >7 days prior to C1D1.
A comprehensive physical and oral examination will include evaluations of the head, eyes, 
ears, nose, mouth including maxillary and mandibular mucosa, throat, neck, chest (including 
heart and lungs), abdomen, limbs, and skin, and a complete neurological examination. A 
urogenital examination will only be required in the presence of clinical symptoms related to 
this region.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
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8.3.2
Dental Examination
Information from studies in animals suggest that there is a risk of delayed tooth formation 
and/or physical growth and development. Therefore, dental examinations are being 
performed to evaluate participants for potential anomalies in tooth formation and eruption 
schedule.
Dental examination by a dentist or qualified dental professional should be conducted per 
local institutional guidelines during screening and thereafter per local standard of care, but no 
less than annually, and at EOT. The baseline dental examination can occur up to 4 weeks 
after the first dose of study intervention. If the most recent dental examination is within 6 
months prior to the EOT visit, the dental examination is not required.
Post-screening dental examinations are not required for participants for whom permanent 
teeth (excluding third molars) are evaluated to be fully erupted at screening.
8.3.3
Vital Signs
Vital sign measurements (ie, systolic and diastolic BP [mm Hg], pulse rate [beats per 
minute], respiratory rate [per minute], body temperature [in centigrade]), weight [kg], and 
height [cm]) will be obtained at the visits designated in the SoA (Section 1.3) by a validated 
method.
•
BP and heart rate will be measured after the participant has been resting for 
approximately 5 minutes. All BP measurements should be performed on the same arm, 
preferably by the same person.
•
Only 1 BP measurement is needed for participants with systolic BP <95th percentile 
(BP <140 mm Hg) and diastolic BP <95th percentile (BP <90 mm Hg). If the 
participant’s first BP measurement of the current assessment is elevated (systolic BP 
≥95th percentile [BP ≥140 mm Hg] or diastolic BP ≥95th percentile [BP ≥90 mm Hg]), 
the BP measurement should be repeated at least 5 minutes later. The mean value of 
2 measurements at least 5 minutes apart is defined as 1 BP assessment. If the BP 
assessment (ie, the mean of the 2 BP measurements obtained at least 5 minutes apart) is 
elevated (systolic BP ≥95th percentile [BP ≥140 mm Hg] or diastolic BP ≥95th percentile
[BP ≥90 mm Hg]), a confirmatory assessment should be obtained at least 30 minutes later 
by performing 2 measurements (at least 5 minutes apart) to yield a mean value.
•
At the C1D8 contact (clinic or telephone visit), and if required between clinic visits, 
participants will have BP measured. If the participant does not return to the study site for 
this BP measurement, BP may be measured, for example, at home or at a local pharmacy, 
and the results will be reviewed with the investigator or designee. The investigator/site 
may provide a diary as a tool to aid the participant in collecting BP evaluations between 
clinic visits. The sponsor will not provide diaries to the site. If BP result raises concerns, 
the investigator may require additional follow-up, including an on-site BP re-test, or other 
clinically appropriate intervention(s).
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•
Height and weight will be assessed at C1D1 and thereafter on Day 1 of every cycle 
during treatment, and at the EOT Visit. Height will also be monitored every 3 months in 
efficacy and survival follow-up until puberty has completed. Telephone contact is 
acceptable for height assessment if clinic visits are not possible at post-treatment visits 
after the 30-day safety FU.
8.3.4
Electrocardiograms
Electrocardiograms will be obtained as designated in the SoA (Section 1.3):
•
Complete, standardized, 12-lead ECG recordings that permit all 12 leads to be displayed 
on a single page with an accompanying lead II rhythm strip below the customary 3 × 4 
lead format are to be used. In addition to a rhythm strip, a minimum of 3 full complexes 
should be recorded from each lead simultaneously. Where possible, participants must be 
in the recumbent position for a period of 5 minutes prior to the ECG. The Fridericia 
correction method for calculating QTc will be used.
•
QTc prolongation has been seen in some lenvatinib studies. Monitor ECGs every cycle 
(as specified in the SoA) in participants with congenital long QT syndrome, congestive 
heart failure, bradyarrhythmias, or those who are taking drugs known to prolong the QT 
interval, including Class Ia and III antiarrhythmics. Please refer to the lenvatinib IB.
Drugs known to prolong the QTc interval (including Class Ia and III antiarrhythmics) 
must be used cautiously. Please refer to the lenvatinib IB or lenvatinib prescribing 
information.
•
An ECG abnormality may meet the criteria of an AE as described in this protocol (see 
Appendix 3) and the Case Report Form Completion Guidelines. In these instances, the 
AE corresponding to the ECG abnormality will be recorded on the appropriate CRF.
8.3.5
Echocardiograms or Multigated Acquisition Scans
A MUGA scan (using a technetium-based tracer) or an ECHO will be performed to further 
assess LVEF as designated in the SoA (Section 1.3). MUGA or ECHO scans should be 
performed locally in accordance with the institution’s standard practice. MUGA scans are the 
preferred modality. However, whichever modality is used for the initial assessment should be 
repeated for all subsequent LVEF assessments for that participant. LVEFs as assessed by the 
institution will be entered on the eCRF. Investigator assessment will be based on institutional 
reports.
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8.3.6
Clinical Safety Laboratory Assessments
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the SoA for 
the timing and frequency.
•
The investigator or medically qualified designee (consistent with local requirements) 
must review the laboratory report, document this review, and record any clinically 
relevant changes occurring during the study in the AE section of the CRF. The laboratory 
reports must be filed with the source documents. Clinically significant abnormal 
laboratory findings are those which are not associated with the underlying disease, unless 
judged by the investigator to be more severe than expected for the participant's condition.
•
All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA.
•
If laboratory values from nonprotocol-specified laboratory assessments performed at the 
institution’s local laboratory require a change in study participant management or are 
considered clinically significant by the investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the appropriate CRF (eg, SLAB).
•
For any laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 30 days for all AEs and all SAEs (or 30 days 
following cessation of treatment if the participant initiates new anticancer therapy, 
whichever occurs first) after the last dose of study intervention, every attempt should be 
made to perform repeat assessments until the values return to normal or baseline or if a 
new baseline is established as determined by the investigator.
Details regarding specific laboratory procedures/assessments to be performed in this study 
are provided below. The total amount of blood/tissue to be drawn/collected over the course 
of the study (from prestudy to poststudy visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per participant, can be found in the laboratory
manual. Refer to the SoA for the timing of laboratory assessments.
See Appendix 7 for country-specific requirement.
8.3.6.1
Hematology and Clinical Chemistry
Hematology (complete blood count with differential) and clinical chemistry will be 
performed within 7 days prior to the first dose of study intervention and do not need to be 
repeated at C1D1 (unless clinically indicated) and within 72 hours prior to all subsequent 
visits (Appendix 2). All clinical laboratory tests during the study will be performed by local 
laboratories. All hematology, blood chemistry (including pregnancy test, as applicable), and 
urinalysis samples are to be obtained prior to study drug administration and sent to the local 
laboratory on the day of collection, unless otherwise instructed.
All hematology, blood chemistry (including pregnancy test, as applicable), and urinalysis 
samples are to be obtained and assessed and the results reviewed prior to study drug 
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administration on C1D1 and within 72 hours prior to the visit for all subsequent cycles. If 
≥Grade 3 hematologic or clinical chemistry toxicity, repeat laboratory test and AEs 
assessment at least every 3 days (until improvement to <Grade 3). Refer to Table 3 for the 
management of lenvatinib-related toxicity.
Electrolytes such as potassium, calcium, and magnesium should be monitored and 
abnormalities, when considered clinically significant, should be corrected in all participants 
before starting treatment.
8.3.6.2
Urine Dipstick/Urinalysis
Urine dipstick (preferred method)/urinalysis testing during screening can be performed 
within 7 days prior to the first dose of lenvatinib (C1D1) as part of the screening visit and 
does not need to be repeated at C1D1 (unless clinically indicated) and within 72 hours prior 
to the visit at subsequent cycles.
Urine dipstick/urinalysis testing will be performed during screening and on Days 1 and 15 of 
Cycles 1 and 2, on Day 1 of every cycle thereafter or more frequently as clinically indicated,
at EOT and at the Safety Follow-up visit (Section 1.3). For participants with proteinuria 
≥2+(≥100 mg/dL), urine dipstick/urinalysis testing should be performed on Day 15 (or more 
frequently as clinically indicated) until the results have been 1+ or negative for 2 consecutive 
months. If a new event of proteinuria ≥2+(≥100 mg/dL) occurs, the participant must resume 
the Day 15 urine dipstick/urinalysis testing for evaluation of proteinuria until results are 
1+(≥10 mg/dL) or negative for 2 consecutive months. Participants who have ≥2+(≥100 
mg/dL) proteinuria on dipstick urinalysis should perform a spot P/C test and if possible,
undergo a 24-hour urine collection. Urine glucose should be performed as part of urine 
dipstick/urinalysis.
For participants with proteinuria ≥2+(≥100 mg/dL), see Section 6.6.3 for management of 
proteinuria.
8.3.6.3
Thyroid Function Testing
The screening blood sample for thyroid function testing can be obtained within 7 days prior
to the first dose of lenvatinib (C1D1) as part of the screening visit and does not need to be 
repeated at C1D1 (unless clinically indicated) and within 72 hours prior to all subsequent 
visits.
Thyroid function tests (TSH and free T4) should be assessed at Screening, C2D1, every 2 
cycles thereafter, at EOT, and at the Safety Follow-up visit. Participants may be dosed while 
thyroid function test results are pending; however, the results must be reviewed by the 
investigator when available.
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8.3.6.4
Lansky Play Score or Karnofsky Performance Status
A Lansky play score or KPS score will be obtained at Screening, at C1D1 prior to allocation, 
on Day 1 of all subsequent cycles, at the EOT, and at the Safety Follow-up Visit. Scores 
obtained on C1D1 prior to allocation may also be used as the screening value to determine 
eligibility. Lansky Play Score will be used for participants up to and including 16 years of 
age; refer to Appendix 9. KPS will be used for participants >16 years of age; refer to 
Appendix 10.
8.3.6.5
Proximal Tibial Growth Plate Measurement
Proximal tibial growth plates x-rays will be taken during Screening for participants 2 to 
17 years (≥18 years not required). X-ray of only 1 leg is required. X-ray at EOT is only 
required for participants with open growth plates at screening and must be performed on the 
same leg as the screening x-ray.
8.3.6.6
Pregnancy Test
Pregnancy tests will be performed at screening and at C1D1 prior to allocation (within 24 
hours prior to the first dose of study drug), and repeated on Day 1 of each cycle, from 
Cycle 2 onward, at the EOT, and at the Safety Follow-up visit.
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety Events
The definitions of an AE or SAE, as well as the method of recording, evaluating, and 
assessing causality of AE and SAE and the procedures for completing and transmitting AE, 
SAE, and other reportable safety event reports can be found in Appendix 3.
Adverse events, SAEs, and other reportable safety events will be reported by the participant 
(or, when appropriate, by a caregiver, surrogate, or the participant's legally authorized 
representative).
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE as well as other reportable safety events. 
Investigators need to document if an SAE was associated with a medication error, misuse, or 
abuse. Investigators remain responsible for following up AEs, SAEs, and other reportable 
safety events for outcome according to Section 8.4.3.
The investigator, who is a qualified physician, will assess events that meet the definition of 
an AE or SAE as well as other reportable safety events with respect to seriousness, 
intensity/toxicity and causality.
Progression of the cancer under study is not considered an AE as described in Section 8.4.6
and Appendix 3.
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8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information
All AEs, SAEs, and other reportable safety events that occur after the participant provides 
documented informed consent but before intervention allocation must be reported by the 
investigator if the participant is receiving placebo run-in or other run-in treatment, if the 
event cause the participant to be excluded from the study, or is the result of a protocol-
specified intervention, including but not limited to washout or discontinuation of usual 
therapy, diet, or a procedure.
•
All AEs from the time of intervention allocation through 30 days following cessation of 
study intervention must be reported by the investigator.
•
All AEs meeting serious criteria, from the time of intervention allocation through 30 days 
following cessation of study intervention.
•
All pregnancies and exposure during breastfeeding, from the time of intervention 
allocation through 30 days following cessation of study intervention.
•
Additionally, any SAE brought to the attention of an investigator at any time outside of 
the time period specified above must be reported immediately to the Sponsor if the event 
is considered related to study intervention.
Investigators are not obligated to actively seek AEs or SAEs or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study intervention or study participation, 
the investigator must promptly notify the Sponsor.
All initial and follow-up AEs, SAEs, and other reportable safety events will be recorded and 
reported to the Sponsor or designee within the time frames as indicated in Table 4.
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Table 4
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events
Type of Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation 
through 
Protocol-
specified Follow-
up Period
Reporting Time Period:
After the Protocol-
specified Follow-up 
Period
Time Frame to 
Report Event 
and Follow-up 
Information to 
Sponsor:
Nonserious Adverse 
Event (NSAE) 
Report if:
- due to protocol-
specified 
intervention
- causes exclusion
- participant is 
receiving placebo 
run-in or other 
run-in treatment
Report all
Not required
Per data entry 
guidelines
Serious Adverse 
Event (SAE) 
including Cancer and 
Overdose
Report if:
- due to protocol-
specified 
intervention
- causes exclusion
- participant is 
receiving placebo 
run-in or other 
run-in treatment
Report all
Report if:
- drug/vaccine related.
(Follow ongoing to 
outcome)
Within 24 hours 
of learning of 
event
Pregnancy/Lactation 
Exposure
Report if:
- due to 
intervention
- causes exclusion
Report all
Previously reported –
Follow to 
completion/termination; 
report outcome
Within 24 hours 
of learning of 
event
Event of Clinical 
Interest (require 
regulatory reporting)
Report if:
- due to 
intervention
- causes exclusion
Report
- potential drug-
induced liver 
injury (DILI)
- require 
regulatory 
reporting
Not required
Within 24 hours 
of learning of 
event
Event of Clinical 
Interest (do not 
require regulatory 
reporting)
Report if:
- due to 
intervention
- causes exclusion
Report
- non-DILI ECIs 
and those not 
requiring 
regulatory 
reporting
Not required
Within 5 
calendar days of 
learning of 
event
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs and other 
reportable safety events. Open-ended and nonleading verbal questioning of the participant is 
the preferred method to inquire about AE occurrence.
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8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AEs, SAEs, and other reportable safety events,
including pregnancy and exposure during breastfeeding, ECIs, cancer, and overdose will be 
followed until resolution, stabilization, until the event is otherwise explained, or the 
participant is lost to follow-up (as defined in Section 7.3). In addition, the investigator will 
make every attempt to follow all nonserious AEs that occur in allocated participants for 
outcome. Further information on follow-up procedures is given in Appendix 3.
8.4.4
Regulatory Reporting Requirements for SAE
Prompt notification (within 24 hours) by the investigator to the Sponsor of SAE is essential 
so that legal obligations and ethical responsibilities towards the safety of participants and the 
safety of a study intervention under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements and global laws and 
regulations relating to safety reporting to regulatory authorities, IRB/IECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and Sponsor policy and forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAE) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
8.4.5
Pregnancy and Exposure During Breastfeeding
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any 
pregnancy or infant exposure during breastfeeding in a participant (spontaneously reported to 
the investigator or their designee) that occurs during the study are reportable to the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy.
Any pregnancy complication will be reported as an AE or SAE. 
The medical reason (example: maternal health or fetal disease) for an elective termination of 
a pregnancy will be reported as an AE or SAE. Prenatal testing showing fetus will be born 
with severe abnormalities/congenital anomalies that leads to an elective termination of a 
pregnancy will be reported as an SAE for the fetus.
Pregnancy outcomes of ectopic pregnancy, 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.
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8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
Efficacy endpoints will not be reported to the Sponsor as described in Section 8.4.1.
Specifically, the suspected/actual events covered in this exception include any event that is 
disease progression of the cancer under study.
The Sponsor will monitor unblinded aggregated efficacy endpoint events and safety data to 
ensure the safety of the participants in the study. Any suspected endpoint that upon review is 
not progression of the cancer under study will be forwarded to Global Pharmacovigilance as 
an SAE within 24 hours of determination that the event is not progression of the cancer under 
study.
8.4.7
Events of Clinical Interest
Selected nonserious and SAEs are also known as ECIs and must be reported to the Sponsor. 
Events of clinical interest for this study include: 
An elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the upper 
limit of normal and, at the same time, an alkaline phosphatase lab value that is less than 2X 
the upper limit of normal, as determined by way of protocol-specified laboratory testing or 
unscheduled laboratory testing.* 
*Note: These criteria are based upon available regulatory guidance documents. The purpose 
of the criteria is to specify a threshold of abnormal hepatic tests that may require an 
additional evaluation for an underlying etiology. The study site guidance for assessment and 
follow up of these criteria can be found in the Investigator Study File Binder (or equivalent).
Lenvatinib overdose is not considered an ECI.
8.5
Treatment of Overdose
For the purposes of this study, an overdose will be defined as any lenvatinib dose above the 
protocol-prescribed dose if associated with an AE.
There is no specific antidote for an overdose of lenvatinib. Due to its high degree of plasma 
protein binding, lenvatinib is not expected to be dialyzable. Adverse reactions in patients 
receiving single doses of lenvatinib as high as 40 mg were similar to those in clinical studies 
at the recommended dose for DTC, renal cell carcinoma, and hepatocellular carcinoma.
No specific information is available on the treatment of overdose of lenvatinib.
All reports of lenvatinib overdose with an AE must be reported by the investigator within 
24 hours to the Sponsor either by electronic media or paper.
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8.6
Pharmacokinetics
PK blood samples will be collected as specified in the SoA (Section 1.3). Study sites must 
have appropriately trained staff and adequate equipment for procuring and processing 
specimens. Instructions for the collection, handling, and shipping procedures of PK samples 
will be provided in the laboratory manual.
Plasma concentrations of lenvatinib will be measured. Lenvatinib will be analyzed using a 
population PK approach.
Lenvatinib will be quantified by the use of validated High-Performance Liquid 
Chromatography-tandem mass spectroscopy methods.
If at some point prospective PK blood sample collection is no longer required, sites will be 
notified.
8.7
Pharmacodynamics
PD blood samples will be collected as specified in the SoA (Section 1.3). Sample collection, 
storage, and shipment instructions for PD samples will be provided in the laboratory manual.
8.8
Biomarkers
To identify novel biomarkers, the following biospecimens to support exploratory analyses of 
cellular components (eg, protein, RNA, DNA, metabolites) and other circulating molecules 
will be collected from all participants as specified in the SoA:
•
Buccal swab (DNA) for Genetic Analysis
•
Blood for Serum Biomarkers
•
Archival Tumor Blocks or Slides (optional)
Sample collection, storage, and shipment instructions for the exploratory biomarker 
specimens will be provided in the operations/laboratory manual.
8.8.1
Planned Genetic Analysis Sample Collection
The planned genetic analysis sample should be collected for planned analysis of the 
association between genetic variants in DNA and drug response. This sample will not be 
collected at the site if there is either a local law or regulation prohibiting collection, or if the 
IRB/IEC does not approve the collection of the sample for these purposes.
8.9
Future Biomedical Research Sample Collection
Not applicable.
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8.10
Medical Resource Utilization and Health Economics
Not applicable.
8.11
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
8.11.1
Screening
Documented consent/assent must be obtained prior to performing any protocol-specific 
procedure. Results of a test performed prior to the participant signing consent as part of 
routine clinical management are acceptable in lieu of a screening test if performed within the 
specified time frame. Screening procedures are to be completed within 28 days prior to the 
first dose of study intervention except for the following:
•
Laboratory tests are to be performed within 7 days prior to the first dose of study 
intervention. Exceptions are hepatitis testing and HIV testing which may be performed up 
to 28 days prior to the first dose of study intervention, if mandated by local health 
authority (see Appendix 7 for country-specific requirements).
•
Evaluation of Lansky play score or KPS is to be performed within 7 days prior to the first 
dose of study intervention.
•
For women of reproductive potential, a urine or serum pregnancy test will be performed 
within 24 hours prior to the first dose of study intervention. If urine pregnancy results 
cannot be confirmed as negative, a serum pregnancy test will be required (performed by 
the local study site laboratory).
•
Providing archival tumor tissue is not required for participation in the study and is an 
optional collection. If an archival tumor tissue is available from a biopsy performed as 
standard of care prior to study treatment, it can be submitted to the central laboratory
anytime during the study.
Participants may be rescreened after initially failing to meet the inclusion/exclusion criteria. 
Results from assessments during the initial screening period are acceptable in lieu of a repeat 
screening test if performed within the specified time frame and the corresponding 
inclusion/exclusion criteria is met. Participants who are rescreened will retain their original 
screening number.
8.11.2
Treatment Period
The estimated duration of lenvatinib treatment is 1 year. However, participants receiving 
clinical benefit from lenvatinib treatment can continue treatment with lenvatinib until a 
treatment discontinuation criterion is met.
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8.11.3
Telephone Contact or Visit
A telephone contact or visit will be scheduled to report BP and record AEs. Blood pressure 
can be taken, for example, at home or at a local pharmacy, and will be reviewed with the 
investigator or medically qualified designee (consistent with local requirements) on C1D8 to 
assess participants for development of early toxicity, as outlined in the SoA (Section 1.3). An 
unscheduled visit can occur prior to C1D15 if deemed necessary for safety by the 
investigator.
8.11.4
Participants Discontinued From Study Intervention but Continuing to be 
Monitored in the Study
The EOT visit will take place at the time lenvatinib is discontinued for any reason.
If the EOT visit takes place approximately 30 days from the last dose of lenvatinib, a 
separate Safety Follow-up visit is not required. All procedures required at the EOT and at the 
Safety Follow-up visit will be performed as a single visit.
8.11.5
Post-treatment Visits
8.11.5.1
Safety Follow-up Visit
The mandatory Safety Follow-up Visit should be conducted approximately 30 days after the 
last dose of study intervention or before the initiation of a new anticancer treatment, 
whichever comes first.
8.11.5.2
Efficacy Follow-up Visits
Participants who discontinue lenvatinib for a reason other than disease progression and/or
initiation of new anticancer therapy will move into the Efficacy Follow-up Phase and will be 
assessed as outlined in the SoA (Section 1.3) to monitor disease status. Every effort should 
be made to collect information regarding disease status until the start of new anticancer 
therapy, disease progression, death, end of study, whichever occurs first. Information 
regarding poststudy anticancer treatment will be collected if new treatment is initiated.
Participants who completed all efficacy assessments and/or will not have further efficacy 
assessments must enter the Survival Follow-up Phase.
8.11.5.3
Survival Follow-up Assessments
Participants will be offered survival follow-up for at least 1 year. Participant survival 
follow-up status will be assessed approximately every 12 weeks until death, withdrawal of 
consent, or the end of the study, whichever occurs first.
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The first survival follow-up assessment should be scheduled as described below:

For participants who discontinue treatment intervention and who will not enter the 
efficacy follow-up phase, the first survival follow-up assessment will be scheduled 
12 weeks after the discontinuation visit and/or safety follow-up visit (whichever is 
last).

For participants who completed assessments in the efficacy follow-up phase, the first 
survival follow-up assessment will be scheduled 12 weeks after the last efficacy 
assessment follow-up visit has been performed.
8.11.6
Survival Status
To ensure current and complete survival data is available at the time of database locks, 
updated survival status may be requested during the course of the study by the Sponsor. 
Upon Sponsor notification, all participants who do not/will not have a scheduled study visit 
or study contact during the Sponsor defined time period will be contacted for their survival 
status (excluding participants that have a previously recorded death event in the collection 
tool).
9
STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study. If, after the 
study has begun, changes are made to primary and/or key secondary hypotheses, or the
statistical methods related to those hypotheses, then the protocol will be amended (consistent
with ICH Guideline E9). Changes to exploratory or other non-confirmatory analyses made
after the protocol has been finalized, along with an explanation as to when and why they
occurred, will be documented in an sSAP and referenced in the CSR for the study. Post hoc
exploratory analyses will be clearly identified in the CSR. A separate molecular profiling 
analysis plan will be developed to explicitly address exploratory biomarker objectives.
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9.1
Statistical Analysis Plan Summary
Key elements of the SAP are summarized below; the comprehensive plan is provided in 
Sections 9.1-9.12.
Study Design Overview
An Open-Label, Multicenter Phase 2 Basket Study to Evaluate the 
antitumor activity and Safety of Lenvatinib in Children, Adolescents, 
and Young Adults with Relapsed or Refractory Solid Malignancies
Treatment Assignment
A minimum of 36 evaluable participants will be enrolled: 9 evaluable 
participants in each of the tumor types. The final sample size of 
participants will depend on the number of tumor types that meet the 
futility bar and the antitumor activity in evaluable participants observed 
in the corresponding tumor cohort in Study E7080-A001-216. The 
enrollment in the HGG, RMS, and EWS/pPNET cohorts is capped at a 
maximum of 17 evaluable participants each. The enrollment for each 
tumor type expanded based on response in the other solid tumors’ cohort 
is also capped at a maximum of 17 evaluable participants. Based on 
these factors and the projected enrollment period, it is estimated that up 
to approximately 150 participants could be enrolled.
The participants will receive lenvatinib 14 mg/m2 orally once daily 
(equivalent to 24 mg QD, the adult daily dose).
Analysis Populations
Antitumor activity: Evaluable Analysis Set (EAS), defined as all 
evaluable participants, who have measurable disease present at baseline 
and at least 1 postbaseline efficacy assessment, unless they have 
discontinued prior to the first efficacy assessment due to progressive 
disease.
Safety: Safety Analysis Set, defined as all participants who received at 
least 1 dose of the study drug.
Pharmacokinetic (PK): PK Analysis Set, defined as participants in Safety 
Analysis Set who had at least 1 measurable postdose plasma
concentration with an adequately documented dosing history.
Primary Endpoint(s)
The Primary Endpoint will be assessed for each tumor type:
ORR, defined as the proportion of participants with a confirmed (≥4 
weeks after initial response) CR or PR per RECIST 1.1 or RANO for
HGG as assessed by investigator, at Week 16.
Key Secondary Endpoints

ORR

BOR

DOR

DCR

CBR

PFS per RECIST 1.1 or RANO for HGG

AEs, SAEs, clinical laboratory values, vital signs, 12-lead ECGs, 
urine dipstick, Lansky play scores or Karnofsky performance 
status scores, physical examination findings, dental examination 
findings, height, and closure of proximal tibial plates.

Palatability questionnaire using a facial hedonic scale.
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Statistical Methods for Key 
Efficacy Analyses
To evaluate for efficacy of lenvatinib, data on antitumor activity will be 
analyzed by each tumor type. Objective responses will count only 
confirmed CR and PR at Week 16. Estimated ORR and its exact 95% CI 
using the method of Clopper and Pearson will be presented. The ORR, 
DCR, and CBR will be provided with exact 95% CIs using the method of 
Clopper and Pearson, and the DOR will be analyzed for responders using 
Kaplan-Meier approach. PFS will be analyzed using Kaplan-Meier 
product-limit estimates. The cumulative PFS probabilities will be plotted 
over time as appropriate.
Statistical Methods for Key 
Safety Analyses
The incidence of treatment-emergent adverse events (TEAEs) and SAEs
will be summarized by system organ class and preferred term. 
Continuous measures such as changes from baseline in laboratory test 
data, vital signs, 12-lead ECGs, cardiac function by echocardiography or 
MUGA scan, urine dipstick, and Lansky play scores or KPS scores will 
be summarized using descriptive statistics (mean, standard deviation, 
etc.) for baseline, on-treatment, and change-from-baseline values.
Interim Analyses
Multiple interim analyses may be performed in this study due to the 
sequential monitoring procedure. Results will be reviewed by the study 
team. Within each tumor type, the study will enroll a minimum of 
9 evaluable participants.
Multiplicity
No additional multiplicity adjustment is required for this study.
Sample Size and Power
9.2
Responsibility for Analyses/In-house Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the
Clinical Biostatistics department of the Sponsor.
This study is being conducted as an open-label study (ie, participants, investigators, and
Sponsor personnel will be aware of participant treatment assignments after each participant is
enrolled and treatment is assigned).
The Clinical Biostatistics department will generate the allocation schedule(s) for study
treatment assignment. Allocation will be implemented in an IVRS. Participants will be 
allocated by nonrandom assignment.
9.3
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3.
9.4
Analysis Endpoints
Efficacy and safety endpoints that will be evaluated are listed below, followed by the 
descriptions of the derivations of selected endpoints.
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9.4.1
Efficacy Endpoints
Primary Endpoints

ORR: defined as the proportion of participants with a confirmed (≥4 weeks after initial 
response) CR or PR per RECIST 1.1 or RANO for HGG as assessed by investigator, at
Week 16.
Secondary Endpoints

ORR.

BOR: defined as the participant’s best confirmed response (CR or PR) over the treatment
period.

DOR: defined as the time from the date of the first documented CR or PR to the date of 
the disease progression objectively documented or death (whichever occurs first).

DCR: defined as the percentage of participants who have a BOR of CR, PR, or SD. To 
be assigned a best overall response of SD, the time from the first administration of study 
drug until the date of documented SD should be ≥7 weeks.

CBR: defined as the percentage of participants who have a BOR of CR, PR, or durable 
SD (SD duration ≥23 weeks since the first dose of the study treatment).

PFS: defined as the time from the date of the first administration of study drug until the 
date of first documentation of PD per RECIST 1.1 or RANO for HGG or death 
(whichever occurs first).
Tertiary/Exploratory Endpoints

OS: defined as the time from the date of the first administration of study drug until the 
date of death from any cause.
9.4.2
Safety Endpoints
Safety and tolerability will be assessed by clinical review of all relevant parameters, 
including AEs, SAEs, clinical laboratory values, vital signs, 12-lead ECGs, urine dipstick, 
Lansky play scores or KPS scores, physical examination findings, dental examination
findings, height, and closure of proximal tibial plates.
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9.4.3
Pharmacokinetic Endpoints
PK blood samples will be collected as outlined in the SoA (Section 1.3). Lenvatinib 
concentration versus time data will be tabulated, summarized, and graphically presented.
Lenvatinib data will be pooled with available data from other studies and subjected to 
population PK analysis. The PK model will be parameterized in terms of clearance and 
volume of distribution. Details of the population PK analysis, if performed, will be provided 
in a separate analysis plan.
9.4.4
Palatability and Acceptability Questionnaire
Measurement of palatability will be assessed using a facial hedonic scale [Guinard, J. X. 
2001] in participants receiving the suspension formulation in the study.
9.5
Analysis Populations
9.5.1
Efficacy Analysis Population
The EAS population will serve as the primary population for the analysis of antitumor 
activity data within each tumor type in this study. EAS is defined as all evaluable 
participants, who have measurable disease present at baseline and at least 1 postbaseline
efficacy assessment, unless they have discontinued prior to the first efficacy assessment due 
to progressive disease Details on the approach to handling missing data are provided in Table 
5.
9.5.2
Safety Analysis Population
The Safety Analysis Set population will be used for the analysis of safety data in this study. 
The safety analysis set population is defined as all participants who received at least 1 dose 
of the study drug.
At least 1 laboratory or vital sign measurement obtained after at least 1 dose of study 
treatment is required for inclusion in the analysis of each specific parameter. To assess 
change from baseline, a baseline measurement at C1D1 prior to allocation is also required.
9.5.3
Pharmacokinetic Analysis Population
The population for PK analysis includes participants in safety analysis set who had at least 
1 measurable post dose plasma concentration with an adequately documented dosing history.
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9.6
Statistical Methods
9.6.1
Statistical Methods for Efficacy Analyses
This section describes the statistical methods that address the primary and secondary efficacy 
objectives. Methods related to exploratory objectives will be described in the sSAP.
Antitumor activity data will be analyzed by each tumor type. The data cutoff for the primary 
study analysis for a given tumor type will be determined by the study team, based on the 
review of data at each interim analysis and predetermined futility guidance.
Only those participants who have measurable disease present at baseline and have their 
disease re-evaluated at postbaseline visits will be considered evaluable for ORR. These 
participants will have their response classified according to RECIST 1.1 or RANO for 
participants with HGG.
Primary Efficacy Analysis
ORR: Objective responses will count only confirmed CR and PR at Week 16. Estimated 
ORR and its exact 95% CI using the method of Clopper and Pearson will be presented.
Secondary Efficacy Analyses
The BOR will be provided with the descriptive statistics. The ORR, DCR, and CBR will be 
provided with exact 95% CIs using the method of Clopper and Pearson, and the DOR will be 
analyzed for responders using Kaplan-Meier approach.
The secondary endpoint of PFS will be analyzed using Kaplan-Meier product-limit estimates. 
Median PFS and the cumulative probability of PFS at 4, 6, 12, and 24 months will be 
presented with 2-sided, 95% CIs when an adequate number of at-risk participants at those 
time points warrant the estimate. The cumulative PFS probabilities will be plotted over time 
as appropriate.
A summary of the primary analysis strategy for the key efficacy endpoints is provided in 
Table 5.
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Table 5
Table Analysis Strategy for Key Efficacy Variables
Endpoint/Variable
Statistical Method
Analysis 
Population
Missing Data Approach
Primary Analyses – Within tumor type
ORR (RECIST 1.1 
or RANO for HGG)
at Week 16
Summary statistics using 
Clopper and Pearson method
EAS
Participants in EAS with missing 
data are considered nonresponders.
Secondary Analyses – Within tumor type
ORR
Summary statistics using 
Clopper and Pearson method
EAS
Participants in EAS with missing 
data are considered nonresponders.
BOR
Summary statistics using 
Clopper and Pearson method
EAS
Missing observation in EAS 
population are counted as 
nonresponders.
DCR
Summary statistics using 
Clopper and Pearson method
EAS
Missing observation in EAS 
population are counted as 
nonresponders.
CBR
Summary statistics using 
Clopper and Pearson method
EAS
Missing observation in EAS 
population are counted as 
nonresponders.
DOR
Summary statistics using 
Kaplan-Meier method
All 
responders 
in EAS
Nonresponders are excluded in 
analysis.
PFS (RECIST 1.1 
or RANO for HGG)
Summary statistics using 
Kaplan-Meier method
EAS
Censored at last assessment.
Abbreviations: BOR=best overall response; CBR=clinical benefit rate; DCR = disease control rate;
DOR = duration of response; EAS = evaluable analysis set; ORR=overall response rate; PFS = progression-free 
survival; RANO= Response Assessment in Neuro-Oncology; RECIST 1.1 = Response Evaluation Criteria in 
Solid Tumors Version 1.1.
9.6.2
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters,
including AEs, laboratory tests, and vital signs. Safety summaries will be pooled across all 
indications. The additional safety analyses for each tumor type might be conducted if desired 
and will be documented in the sSAP. The safety analysis population will be used for the 
analysis of safety data. TEAE is defined as all AEs from the treatment start date until 30 days 
after last dose (30 days for SAE). The incidence of TEAEs and SAEs will be summarized by 
system organ class and preferred term. Continuous measures such as changes from baseline 
in laboratory test data, vital signs, 12-lead ECGs, cardiac function by echocardiography or 
MUGA scan, urine dipstick, and Lansky play scores or KPS scores will be summarized using 
descriptive statistics (mean, standard deviation, etc.) for baseline, on-treatment, and 
change-from-baseline values.
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9.6.3
Summary of Baseline Characteristics, Demographics, and Other Analyses
Baseline characteristics will be assessed by the use of tables and/or graphs for each tumor 
type with at least 9 evaluable participants enrolled. No statistical hypothesis tests will be 
performed on these characteristics. The number and percentage of participants screened, 
allocated, the primary reasons for screening failure, and the primary reason for 
discontinuation will be displayed. Demographic variables (eg, age, gender), baseline 
characteristics, and prior and concomitant medications, medical/surgical history will be 
summarized by descriptive statistics or categorical tables.
9.6.4
Statistical Methods for Pharmacokinetic, Pharmacodynamic, and Other 
Biomarker Analyses
Plasma concentrations of lenvatinib versus time data will be tabulated with descriptive 
statistics and the individual data graphed. Plasma concentrations of lenvatinib versus time 
data will be analyzed using a population PK approach to estimate population PK parameters. 
The analysis will be detailed in an analysis plan at a later date.
Pharmacokinetic data will be summarized using n, mean, standard deviation, percent 
coefficient of variation, geometric mean, median, minimum, and maximum.
9.7
Interim Analyses
9.7.1
Safety Interim Analyses
The DMC will review accumulating safety data periodically to provide an opportunity to 
terminate the study early if there are safety concerns. The timing of the safety monitoring 
will be specified in the DMC charter.
9.7.2
Efficacy Interim Analysis
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CCI
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9.8
Multiplicity
No multiplicity adjustment is required because each disease indication will be evaluated 
independently.
9.9
Sample Size and Power Calculations
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9.10
Subgroup Analyses
No subgroup analysis is planned.
9.11
Compliance (Medication Adherence)
Drug accountability data for study treatment will be collected during the study. Any 
deviation from protocol-directed administration will be reported.
9.12
Extent of Exposure
Extent of exposure for a participant will be measured by number of cycles and number of 
days in which the participant receives the study medication. Summary statistics will be 
provided on extent of exposure for the safety analysis population.
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10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1
Code of Conduct for Clinical Trials
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD)
Code of Conduct for Interventional Clinical Trials
I. Introduction
A. Purpose
MSD, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing, and reporting these trials 
in compliance with the highest ethical and scientific standards. Protection of participants in clinical trials is the 
overriding concern in the design and conduct of clinical trials. In all cases, MSD clinical trials will be conducted 
in compliance with local and/or national regulations (including all applicable data protection regulations), and 
International Council for Harmonisation Good Clinical Practice (ICH GCP), and also in accordance with the 
ethical principles that have their origin in the Declaration of Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical interventional investigations sponsored by 
MSD irrespective of the party (parties) employed for their execution (e.g., contract research organizations, 
collaborative research efforts). This Code is not intended to apply to trials that are observational in nature, or 
which are retrospective. Further, this Code does not apply to investigator initiated trials, which are not under the 
full control of MSD.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of MSD or comparator products. Alternatively, MSD 
may conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to 
determine patient preferences, etc.
The design (i.e., participant population, duration, statistical power) must be adequate to address the specific 
purpose of the trial. Participants must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
MSD selects investigative sites based on medical expertise, access to appropriate participants, adequacy of 
facilities and staff, previous performance in clinical trials, as well as budgetary considerations. Prior to trial 
initiation, sites are evaluated by MSD personnel (or individuals acting on behalf of MSD) to assess the ability 
to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol and Good Clinical Practice 
(GCP). MSD reviews clinical data for accuracy, completeness, and consistency. Data are verified versus 
source documentation according to standard operating procedures. Per MSD policies and procedures, if fraud, 
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scientific/research misconduct or serious GCP non compliance is suspected, the issues are investigated. 
When necessary, the clinical site will be closed, the responsible regulatory authorities and ethics review 
committees notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish the primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the pre specified plans for data analysis. To the 
extent scientifically appropriate, MSD seeks to publish the results of other analyses it conducts that are important 
to patients, physicians, and payers. Some early phase or pilot trials are intended to be hypothesis generating rather 
than hypothesis testing; in such cases, publication of results may not be appropriate since the trial may be 
underpowered and the analyses complicated by statistical issues such as multiplicity.
MSD’s policy on authorship is consistent with the recommendations published by the International Committee of 
Medical Journal Editors (ICMJE). In summary, authorship should reflect significant contribution to the design and 
conduct of the trial, performance or interpretation of the analysis, and/or writing of the manuscript. All named 
authors must be able to defend the trial results and conclusions. MSD funding of a trial will be acknowledged in 
publications.
III. Participant Protection
A. Regulatory Authority and Ethics Committee Review (Institutional Review Board [IRB]/Independent Ethics 
Committee [IEC])
All protocols and protocol amendments will be submitted by MSD for regulatory authority 
acceptance/authorization prior to implementation of the trial or amendment, in compliance with local and/or 
national regulations.
The protocol, protocol amendment(s), informed consent form, investigator’s brochure, and other relevant trial 
documents must be reviewed and approved by an IRB/IEC before being implemented at each site, in compliance 
with local and/or national regulations. Changes to the protocol that are required urgently to eliminate an 
immediate hazard and to protect participant safety may be enacted in anticipation of ethics committee approval.  
MSD will inform regulatory authorities of such new measures to protect participant safety, in compliance with 
local and/or national regulations.
B. Safety
The guiding principle in decision making in clinical trials is that participant welfare is of primary importance. 
Potential participants will be informed of the risks and benefits of, as well as alternatives to, trial participation. At 
a minimum, trial designs will take into account the local standard of care.
All participation in MSD clinical trials is voluntary. Participants enter the trial only after informed consent is 
obtained. Participants may withdraw from an MSD trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent possible. Unless required by 
law, only the investigator, Sponsor (or individuals acting on behalf of MSD), ethics committee, and/or regulatory 
authorities will have access to confidential medical records that might identify the participant by name.
D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed consent authorized by an 
ethics committee.
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IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time and labor intensive. It is MSD’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of MSD trials. MSD does not pay incentives to 
enroll participants in its trials. However, when enrollment is particularly challenging, additional payments may be 
made to compensate for the time spent in extra recruiting efforts.
MSD does not pay for participant referrals. However, MSD may compensate referring physicians for time spent 
on chart review and medical evaluation to identify potentially eligible participants.
B. Clinical Research Funding
Informed consent forms will disclose that the trial is sponsored by MSD, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial. However, the local ethics committee may 
wish to alter the wording of the disclosure statement to be consistent with financial practices at that institution. As 
noted above, all publications resulting from MSD trials will indicate MSD as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the trial protocol, and in signing the 
protocol, agree to support these ethical and scientific standards.
10.1.2
Financial Disclosure
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required. It is the investigator's/subinvestigator's 
responsibility to comply with any such request.
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements. 
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes. This may involve the 
transmission of information to countries that do not have laws protecting personal data.
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10.1.3
Data Protection
The Sponsor will conduct this study in compliance with all applicable data protection 
regulations.
Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names 
or any information that would make the participant identifiable will not be transferred.
The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
10.1.3.1
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the IRB, IEC, or similar or expert committee; affiliated institution and 
employees, only under an appropriate understanding of confidentiality with such board or 
committee, affiliated institution and employees. Data generated by this study will be 
considered confidential by the investigator, except to the extent that it is included in a 
publication as provided in the Publications section of this protocol.
10.1.3.2
Confidentiality of Participant Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/IEC, or regulatory authority representatives may consult and/or copy study documents to 
verify worksheet/CRF data. By signing the consent form, the participant agrees to this 
process. If study documents will be photocopied during the process of verifying 
worksheet/CRF information, the participant will be identified by unique code only; full 
names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules 
and regulations.
10.1.3.3
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this study. The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
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10.1.4
Committees Structure
10.1.4.1
External Data Monitoring Committee
To supplement the routine study monitoring outlined in this protocol, an external DMC will 
monitor the interim data from this study. The voting members of the committee are external 
to the Sponsor. The members of the DMC must not be involved with the study in any other 
way (eg, they cannot be study investigators) and must have no competing interests that could 
affect their roles with respect to the study.
The DMC will make recommendations to the study team regarding steps to ensure both 
participant safety and the continued ethical integrity of the study. Also, the DMC will review 
interim study results, consider the overall risk and benefit to study participants (Section 9.7) 
and recommend to the study team whether the study should continue in accordance with the 
protocol.
Specific details regarding composition, responsibilities, and governance, including the roles 
and responsibilities of the various members and the Sponsor protocol team; meeting 
facilitation; the study governance structure; and requirements for and proper documentation 
of DMC reports, minutes, and recommendations will be described in the DMC charter that is 
reviewed and approved by all the DMC members.
10.1.5
Publication Policy
The results of this study may be published or presented at scientific meetings. The Sponsor 
will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
If publication activity is not directed by the Sponsor, the investigator agrees to submit all 
manuscripts or abstracts to the Sponsor before submission. This allows the Sponsor to protect 
proprietary information and to provide comments.
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.
10.1.6
Compliance with Study Registration and Results Posting Requirements
Under the terms of the FDAAA of 2007 and the EMA clinical trial Directive 2001/20/EC, the 
Sponsor of the study is solely responsible for determining whether the study and its results 
are subject to the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu or other local registries. MSD, as Sponsor of this study, will 
review this protocol and submit the information necessary to fulfill these requirements. MSD 
entries are not limited to FDAAA or the EMA clinical trial directive mandated trials. 
Information posted will allow participants to identify potentially appropriate studies for their 
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disease conditions and pursue participation by calling a central contact number for further 
information on appropriate study locations and study site contact information.
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials directive, or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this study or its results to those 
registries.
10.1.7
Compliance with Law, Audit, and Debarment
By signing this protocol, the investigator agrees to conduct the study in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of GCP
(eg, International Council on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use GCP: Consolidated Guideline and other generally accepted 
standards of GCP); and all applicable federal, state and local laws, rules and regulations 
relating to the conduct of the clinical study.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by MSD, is provided in this appendix 
under the Code of Conduct for Clinical Trials.
The investigator agrees not to seek reimbursement from participants, their insurance 
providers, or from government programs for procedures included as part of the study 
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
The investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority inspection and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority. 
Persons debarred from conducting or working on clinical studies by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s studies. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
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10.1.8
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study site upon request for inspection, 
copying, review, and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including participants’ documented informed consent/assent, 
pertaining to the conduct of this study must be retained by the investigator for 15 years after 
study completion unless local regulations or institutional policies require a longer retention 
period. No records may be destroyed during the retention period without the written approval 
of the Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor.
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10.1.9
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. The investigator/institution should maintain adequate and 
accurate source documents and study records that include all pertinent observations on each 
of the site’s participants. Source documents and data should be attributable, legible, 
contemporaneous, original, accurate, and complete. Changes to source data should be 
traceable, should not obscure the original entry, and should be explained if necessary (eg, via 
an audit trail). Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator/institution may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available.
10.1.10
Study and Site Closure
The Sponsor or its designee may stop the study or study site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP.
In the event the Sponsor prematurely terminates a particular study site, the Sponsor or 
designee will promptly notify that study site’s IRB/IEC as specified by applicable regulatory 
requirement(s).
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10.2
Appendix 2: Clinical Laboratory Tests
•
The tests detailed in Table 7 will be performed by the local laboratory.
•
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Sections 5.1 and 5.2 of the protocol.
•
Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations.
•
Pregnancy testing:
- Pregnancy testing requirements for study inclusion are described in Section 5.1.
- Pregnancy testing (urine or serum as required by local regulations) should be 
conducted at monthly intervals during intervention.
- Pregnancy testing (urine or serum as required by local regulations) should be 
conducted at the end of relevant systemic exposure and correspond with the time 
frame for female participant contraception in Section 5.1.
- Additional serum or urine pregnancy tests may be performed, as determined 
necessary by the investigator or required by local regulation, to establish the 
absence of pregnancy at any time during the subject's participation in the study.
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Table 7
Protocol-required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count
White Blood Cell (WBC) count with Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
Red Blood Cell (RBC)
Count
Hemoglobin
Hematocrit
International 
Normalized Ratio
(INR) or prothrombin 
time (PT)a
Chemistry
Renal Function Tests
Electrolytesc
Liver Function 
Tests
Other 
Chemistries
Blood urea nitrogen 
(BUN)b
Creatinine
Potassium
Carbon dioxide (CO2) or 
bicarbonated
Sodium
Calcium
Chloride
Magnesium
Phosphorous
Aspartate 
aminotransferase 
(AST)
Alanine 
aminotransferase
(ALT)
Alkaline 
phosphatase
Total bilirubin
Direct bilirubine
Albumin
Amylase
Lipase
Glucosef
Lactate 
dehydrogenase
Total protein
Thyroid Function 
Tests
Thyroid-stimulating hormone (TSH)
Free thyroxine (T4)
Urine 
dipstick/urinalysis
testing,f, g
•
Glucose, protein, blood
•
Urinalysis for microscopyg: Microscopic examination for RBCs/high-power field.
Other Screening 
Tests
•
Serum or urine β human chorionic gonadotropin (β-hCG) pregnancy test (as needed 
for women of child-bearing potential [WOCBP]).
NOTES:
a.
INR or PT should only be performed as part of the screening assessment and as clinically indicated.
b.
Urea is acceptable if BUN is not available as per institutional standard.
c.
Electrolytes such as potassium, calcium, and magnesium should be monitored and abnormalities, when 
considered clinically significant, should be corrected in all participants before starting treatment.
d.
Perform only if considered local standard of care.
e.
Direct bilirubin should be assessed if total bilirubin is elevated.
f.
If urine protein is ≥2+, then a spot test for protein-creatinine ratio and if possible, a 24-hour urine 
collection should be done to quantify the 24-hour urine protein excretion.
g.
If urine dipstick/urinalysis testing suggests a urinary tract infection, or if clinically indicated, a urine 
microscopy, culture, and sensitivity should be performed at the institution’s laboratory.
The investigator (or medically qualified designee) must document their review of each 
laboratory safety report.
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definitions of Medication Error, Misuse, and Abuse
Medication Error
This is an unintended failure in the drug treatment process that leads to or has the potential to 
lead to harm to the patient.
Misuse
This refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the terms of the product information.
Abuse
This corresponds to the persistent or sporadic, intentional excessive use of a medicinal 
product for a perceived psychological or physiological reward or desired non-therapeutic 
effect.
10.3.2
Definition of AE
AE definition
•
An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention.
•
NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention.
•
NOTE: For purposes of AE definition, study intervention (also referred to as Sponsor’s 
product) includes any pharmaceutical product, biological product, vaccine, diagnostic 
agent, or protocol specified procedure whether investigational or marketed (including 
placebo, active comparator product, or run-in intervention), manufactured by, licensed 
by, provided by, or distributed by the Sponsor for human use in this study.
Events meeting the AE definition
•
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator.
•
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.
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•
New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.
•
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
•
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.
•
For all reports of overdose (whether accidental or intentional) with an associated AE, the 
AE term should reflect the clinical symptoms or abnormal test result. Lenvatinib 
overdose without an associated adverse event is not reportable as an AE. Refer to Section 
8.5 for the definition of overdose.
Events NOT meeting the AE definition
•
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.
•
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
•
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
•
Surgery planned prior to informed consent to treat a pre-existing condition that has not 
worsened.
•
Refer to Section 8.4.6 for protocol-specific exceptions.
10.3.3
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met.
An SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b. Is life-threatening
•
The term “life-threatening” in the definition of “serious” refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
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c.
Requires inpatient hospitalization or prolongation of existing hospitalization
•
Hospitalization is defined as an inpatient admission, regardless of length of stay, even 
if the hospitalization is a precautionary measure for continued observation. (Note: 
Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not an SAE.) A pre-existing condition is a clinical condition that is 
diagnosed prior to the use of an MSD product and is documented in the participant’s 
medical history.
d. Results in persistent or significant disability/incapacity
•
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
•
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
•
In offspring of participant taking the product regardless of time to diagnosis.
f.
Other important medical events
•
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 1 
of the other outcomes listed in the above definition. These events should usually be 
considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
10.3.4
Additional Events Reported in the Same Manner as SAE
Additional events that require reporting in the same manner as SAE
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor in the same time frame as SAEs to 
meet certain local requirements. Therefore, these events are considered serious by the 
Sponsor for collection purposes.
•
Is a new cancer (that is not a condition of the study)
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•
Is associated with an overdose
10.3.5
Recording AE and SAE
AE and SAE recording
•
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to 
the event.
•
The investigator will record all relevant AE/SAE information on the AE 
CRFs/worksheets at each examination.
•
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.
•
There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be blinded on the copies of the medical records before submission to the 
Sponsor.
•
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of intensity/toxicity
•
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe.
Assessment of causality
Follow-up of AE and SAE
•
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.
•
New or updated information will be recorded in the CRF.
•
The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
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10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool
•
The primary mechanism for reporting to the Sponsor will be the EDC tool.
-
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
-
If the electronic system is unavailable for more than 24 hours, then the site will 
use the paper AE Reporting form.
◦
Reference Section 8.4.1 for reporting time requirements.
•
The site will enter the SAE data into the electronic system as soon as it becomes 
available.
•
After the study is completed at a given site, the EDC tool will be taken off-line to prevent 
the entry of new data or changes to existing data.
•
If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the EDC tool has been taken off-line, then the site can 
report this information on a paper SAE form or by telephone (see next section).
•
Contacts for SAE reporting can be found in the Investigator Study File Binder (or 
equivalent).
SAE reporting to the Sponsor via paper CRF
•
If the EDC tool is not operational, facsimile transmission or secure e-mail of the SAE 
paper CRF is the preferred method to transmit this information to the Sponsor.
•
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.
•
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.
•
Contacts and instructions for SAE reporting and paper reporting procedures can be found 
in the Investigator Study File Binder (or equivalent).
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10.4
Appendix 4: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation
Not applicable
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10.5
Appendix 5: Contraceptive Guidance
10.5.1
Definitions
Women of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below):
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:
•
Premenarchal
•
Premenopausal female with 1 of the following:
- Documented hysterectomy
- Documented bilateral salpingectomy
- Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, Mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
•
Postmenopausal female
- A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.
◦
A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or HRT. 
However, in the absence of 12 months of amenorrhea, confirmation with two 
FSH measurements in the postmenopausal range is required.
- Females on HRT and whose menopausal status is in doubt will be required to use one 
of the nonhormonal 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.
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10.5.2
Contraception Requirements
Contraceptives allowed during the study includea:
Highly Effective Contraceptive Methods That Have Low User Dependency
Failure rate of <1% per year when used consistently and correctly.
•
Progestogen-only subdermal contraceptive implantb,c
•
IUSc
•
Non-hormonal IUD
•
Bilateral tubal occlusion
•
Azoospermic partner (vasectomized or secondary to medical cause)
This 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. A spermatogenesis cycle is approximately 90 days.
Note: Documentation of azoospermia can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
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 intervention. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual 
lifestyle of the participant.
a
Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for participants of clinical studies.
b
If locally required, in accordance with CTFG guidelines, acceptable contraceptive implants are limited to 
those which inhibit ovulation.
c
IUS is a progestin-releasing IUD.
Note: The following are not acceptable methods of contraception:
- Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus 
interruptus), spermicides only, and LAM.
- Male condom with cap, diaphragm, or sponge with spermicide.
- Male and female condom should not be used together (due to risk of failure with friction).
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10.6
Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research
Not applicable
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10.7
Appendix 7: Country-specific Requirements
10.7.1
Sweden
If serum creatinine is greater than the maximum serum creatinine for age and gender as 
shown in the table below, then creatinine clearance (or radioisotope glomerular filtration rate 
[eGFR]) must be >70 mL/min/1.73 m2. 
If applicable, the 2009 Schwartz equation must be used to estimate GFR for participants aged 
<18 years (ie, eGFR  36.5 x height [cm]/plasma creatinine [µmol/L]) [Schwartz, G. J., et al 
2009].
Age
Maximum Serum Creatinine (mg/dL)
Maximum Serum Creatinine (µmol/L)
Male
Female
Male
Female
2 to <6 years
0.8
0.8
70.72
70.72
6 to <10 years
1
1
88.4
88.4
10 to <13 years
1.2
1.2
106.08
106.08
13 to <16 years
1.5
1.4
132.6
123.76
≥16 years
1.7
1.4
150.28
123.76
10.7.2
Czech Republic
Section 5.2 Exclusion Criteria
11. Known to be HIV positive. Note: HIV testing is required at screening.
12. Has known active viral hepatitis B virus (eg, HBsAg reactive) or Hepatitis C virus (eg,
HCV RNA [qualitative] is detected) infection. Note: Testing for hepatitis B or hepatitis C is 
required at screening.
Section 8.11.1 Screening
Laboratory tests are to be performed within 7 days prior to the first dose of study 
intervention. Exceptions are hepatitis testing and HIV testing which may be performed up to 
28 days prior to the first dose of study intervention.
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10.7.3
Italy

eGFR for pediatric subjects under 18 years old should be calculated exclusively with the 
Bedside Schwartz equation for participants in Italy.

The blood volume to be taken from a pediatric participant must not exceed the allowable 
maximum outlined in “Ethical Considerations for Clinical Trials on Medicinal Products 
Conducted With Minors” (3% of the total blood volume over a 4-week period or 1% at 
any single time)[European Commission 2017]. If the blood volume is insufficient to 
conduct all planned analyses, safety laboratory tests should be prioritized for participants 
in Italy.
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10.8
Appendix 8: Response Assessment in Neuro-Oncology (RANO) Response 
Criteria
For HGG, treatment response assessment will be based on the RANO criteria [Wen PY, 
Macdonald DR, Reardon DA, Cloughesy TF, Sorensen AG, 2010], using a combination of 
clinical and imaging data. At baseline, tumor burden is documented by selection of lesions 
that will be followed quantitatively (target lesions) and qualitatively (nontarget). At each visit 
afterward, imaging assessment consists of evaluating target and nontarget lesions, searching 
for new lesions, and review of the abnormalities on Fluid Attenuated Inversion Recovery 
(T2/FLAIR) images. These assessments are combined into a radiographic response, which is 
then combined with clinical performance status and steroid dose information to determine the 
overall response for each visit. Endpoint information, such as the best overall response, is 
determined from the sequence of visit responses as described in the SAP.
Scan acquisition
Imaging will be acquired using the standardized Brain Tumor Imaging Protocol [Ellingson, 
B. M.,Bendszus, M., et al 2015]. It will include pre- and post-contrast T1-weighted MRI, as 
well as T2/FLAIR and diffusion-weighted imaging. The same technique should be used at 
baseline and all follow-up scans.
Lesion measurements
Lesions should be measured on T1 weighted post-gadolinium images, in the axial plane. The 
2 maximal perpendicular outer diameters of each enhancing lesion should be measured. In 
lesions that have cystic components, areas of necrosis, or surgical cavities, every effort 
should be made to measure only the solid portions of the lesion, excluding the non-solid 
components. In particular, if a patient has a surgical cavity surrounded by enhancement, the 
cavity should not be included in the measurement. If there is nodular enhancement associated 
with the cavity, the nodular component alone should be measured.
Baseline tumor documentation
Reviewers will document baseline tumor on post-contrast T1-weighted and T2/FLAIR 
images. They first identify all lesions, determine whether they are measurable (can be 
measured), and from these choose target lesions (will be measured throughout the trial). To 
be considered measurable, a lesion has to show enhancement, have 2 perpendicular diameters 
≥10 mm, and be suitable for reproducible repeated measurements. Enhancing non-
measurable lesions include all other enhancement that is strongly believed to represent 
tumor, but that does not meet the requirements above. Up to 5 lesions can be selected as 
target. Selected target lesions are measured, and the sum of products of diameters (SPD) 
calculated. Enhancing nontarget lesions are identified by location only. Because T2/FLAIR 
abnormalities are typically more diffuse than tumor enhancement, the T2/FLAIR images will 
be used for comparison when evaluating later visits, without identification of discrete lesions.
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Radiographic response assessment
Target lesion response is determined by the change in the sum of diameters from baseline 
and from nadir (smallest measurement seen until the visit being evaluated) (Table 8).
Table 8
Target Lesion Response
Response
Definition
Complete Response (CR)
All target lesions have completely disappeared.
Partial Response (PR)
SPD decreased by ≥50% from baseline value.
Stable Disease (SD)
SPD <50% decreased from baseline, but <25% increased from nadir.
Progressive Disease (PD)
SPD increased by ≥25% from nadir value.
Non-evaluable (NE)
The sum of diameters cannot be meaningfully evaluated (for example, because of 
technical factors such as scan quality that obscure one or more target lesions).
Nontarget lesion response is determined by visual inspection of enhancing nontarget lesions 
collectively and classification into a response category (Table 9).
Table 9
Lesion Response for Enhancing Nontarget Lesions
Response
Definition
Complete Response (CR)
All enhancing nontarget lesions have disappeared completely.
Stable Disease (SD)
Enhancing lesions present, showing no definite growth from the visit where they 
were smallest.
Progressive Disease (PD)
Unequivocal progression of enhancing lesions (see below).
Non-evaluable (NE)
The sum of diameters cannot be meaningfully evaluated (for example, because of 
technical factors such as scan quality that obscure one or more target lesions).
Note on PD: The general approach is that nontarget lesions can be the basis for a determination of PD if it is 
clear, in the context of the entire scan, that there has been a sufficient increase in the tumor burden to 
demonstrate that treatment has failed.
New lesions are assessed in a binary yes/no fashion. If any new enhancing lesions are 
present, and the reviewer is confident that these are due to the presence of new malignancy, 
the response is “Yes,” otherwise, it is “No.” New lesions do not need to meet the size criteria 
for being considered measurable at baseline, but must, in the best judgment of the reviewer, 
be true tumor lesions rather than benign or incidental findings, or caused by some 
comorbidity. If the lesion is uncertain, it should be followed. If later scans reveal it to be a 
true lesion, the record can be retrospectively updated to show the new lesion at the time it 
was first identified.
The T2/FLAIR images are reviewed to determine whether there has been an unequivocal 
increase in tumor-related T2/FLAIR abnormality. This is performed with reference to the 
scan at which the T2/FLAIR abnormality is smallest (analogous to the nadir measurement for 
target lesions), and classified as increase, decreased, or unchanged. Because of the frequently 
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diffuse nature of the T2/FLAIR abnormality, it is performed at the scan level rather than by 
evaluation of discrete T2/FLAIR lesions. The reviewer must be confident that any recorded 
increase in T2/FLAIR abnormality is due to tumor rather than some alternative etiology 
(such as infection, infarction, demyelination, or other causes). If there is question about 
whether a change seen on T2/FLAIR represents progression, the participant continues to the 
next scheduled scan. If the subsequent scan confirms progression, the date of progression can 
be assigned retrospectively to the visit where the T2/FLAIR changes were first observed.
Target, nontarget, and new lesions are combined into a radiographic response (Table 10).
Table 10
Radiographic Response
Target Lesions
Enhancing Nontarget 
Lesions
FLAIR/T2 Lesions
New Lesions
Radiographic
Response
CR
CR
No increase
No
CR
CR
SD or NE
No increase
No
PR
PR
CR, SD, or NE
No increase
No
PR
SD
CR, SD, or NE
No increase
No
SD
NE
CR, SD, or NE
No increase
No
NE
PD
Any
Any
Yes/No
PD
Any
PD
Any
Yes/No
PD
Any
Any
Any
Yes
PD
Any
Any
Increased
Yes/No
PD
NAa
CR
No increase
No
CR
NAa
SD
No increase
No
SD
NAa
NAa
No increase
No
NEDb
a NA – No lesions of this type were present at baseline.
b NED (No evidence of disease) – No enhancing lesions were present at baseline, and no new lesions have 
appeared.
Pseudoprogression associated with radiotherapy
If new or increased enhancement is seen within 12 weeks of the completion of radiation 
therapy, but the participant is clinically stable and the investigator believes that the changes 
may be due to pseudoprogression, the participant may remain on treatment. A second scan 
should be performed, at least 6 weeks after the initial scan. If the enhancement continues to 
grow on this scan, progression is considered to have been confirmed at the time of the initial 
scan that showed increased enhancement. If the enhancement has stabilized or decreased on 
this second scan, the initial scan will be considered to have been confirmed as 
pseudoprogression. For endpoint assessment purposes, the initial scan will be equivalent to 
SD. On subsequent scans, in cases of confirmed pseudoprogression, all scans prior to the 
scan at which pseudoprogression was seen will be excluded when choosing the nadir value 
against which the size of enhancing lesions is compared. 
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If the new or increased enhancement occurs in an area that is known to be outside the 
irradiated area (outside the 80% isodose line), or if the participant shows clinical 
deterioration not caused by a comorbid condition or changes in steroid dosing, 
pseudoprogression will not be considered.
Overall Response
To make a final response determination, the radiographic response (Table 10) is combined 
with assessments of clinical status and of corticosteroid dose (Table 11).
Clinical status is measured using the Karnofsky Performance Scale. A participant’s status is 
considered “stable” if there has been no definite decline in age-adjusted performance from 
their baseline state and is considered “worsening” if there has been definite decline in age-
adjusted performance that is not attributable to a non-tumor-related cause. Examples of 
definite decline include a decline from 100 or 90 to 70 or less, a decline of at least 20 points 
from 80 or less, or a decline from any baseline to 50 or less, unless attributable to comorbid 
events or changes in corticosteroid dose.
Steroid dose is defined as the average daily dose since last visit. A dose of “none” means no 
corticosteroids above physiologic replacement dose. The dose is considered “stable” if it is 
unchanged or decreased from the visit at which the scans showed the smallest tumor burden. 
The dose is considered “increased” if it has increased from the visit at which the scans 
showed the smallest tumor burden.
For any overall response except PD, all the components of the definition (radiological, 
neurological, and steroid dose) must be present. However, either radiological progression or 
clinical deterioration (not attributable to a non-tumor-related cause) qualifies a participant for 
PD. However, an increase in steroid dose alone is not sufficient for an overall visit response 
of PD in the absence of clinical or radiological evidence of progression. A participant with a 
radiological response of SD, and without neurological evidence of progression, but requiring 
an increased dose of steroids, would still be considered SD overall at that visit (because 
increase in steroids alone is not PD). However, the participant will be reassessed at the next 
visit. If either radiological or neurological progression is documented at that next visit, the 
visit at which the increased dose was first observed would be retroactively reassessed as PD 
overall.
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Table 11
Overall Response
Radiographic Response
Clinical Performance
Steroid Dose
Overall Response
CR
Stable
None
CR
CR
Stable
Stable or increased
PR
PR
Stable
Stable
PR
PR
Stable
Increased
SD
SD
Stable
Stable
SD
SD
Stable
Increased
SD or PDa
PD
Any
Any
PD
Any
Worsening
Any
PD
NE
Stable
Increased
NE or PDa
NED
Stable
Increased
NED or PDa
a PD should not be based on an increase in steroid dose alone, unless confirmed by radiographic or clinical 
deterioration. If the steroid dose is increased while the radiographic assessment and clinical performance are 
stable, the participant should be re-evaluated at the next visit. If clinical or radiographic deterioration has 
occurred, progression can be retrospectively assigned at the visit when the steroid dose was increased.
Pseudoresponse and response confirmation
Pseudoresponse is a phenomenon observed in patients treated with antiangiogenic therapy 
and manifests as a transient decrease in tumor enhancement that does not reflect a true 
reduction in tumor burden. To avoid mistaken reporting of pseudoresponse as objective 
response, a visit response of PR or CR must be confirmed with a scan performed at least 
4 weeks later that shows the same category of response or better. That is, a PR can be 
confirmed with a subsequent PR or CR, and a CR must be confirmed with a subsequent CR.
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10.9
Appendix 9: Lansky Play Score
The Lansky score should be used for children <16 years of age.
100 Fully active, normal.
90 Minor restrictions in physically strenuous activity.
80 Active, but tires more quickly.
70 Both greater restriction of and less time spent in play activity.
60 Up and around, but minimal active play; keeps busy with quieter activities.
50 Gets dressed but lies around much of the day; no active play, able to participate in all 
quiet play and activities.
40 Mostly in bed; participates in quiet activities.
30 In bed; needs assistance even for quiet play.
20 Often sleeping; play entirely limited to very passive activities.
10 No play; does not get out of bed.
0 Unresponsive.
Adapted from: [Lansky, S. B., et al 1987].
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10.10 Appendix 10: Karnofsky Performance Status Scale Definitions Rating (%) 
Criteria
Able to carry on normal activity and to work; no 
special care needed.
100 Normal no complaints; no evidence of 
disease.
90 Able to carry on normal activity; 
minor signs or symptoms of disease.
80 Normal activity with effort; some 
signs or symptoms of disease. 
Unable to work; able to live at home and care for 
most personal needs; varying amount of 
assistance needed.
70 Cares for self; unable to carry on 
normal activity or to do active work.
60
Requires occasional assistance but is 
able to care for most of his personal 
needs.
50 Requires considerable assistance and 
frequent medical care. 
Unable to care for self; requires equivalent of 
institutional or hospital care; disease may be 
progressing rapidly.
40 Disabled; requires special care and 
assistance.
30
Severely disabled; hospital admission 
is indicated although death not 
imminent.
20
Very sick; hospital admission 
necessary; active supportive treatment 
necessary.
10 Moribund; fatal processes progressing 
rapidly.
0
Dead.
Adapted from: [Crooks, V., et al 1991] [Hollen, P. J., et al 1994] [O'Toole, D. M. 1991].
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10.11 Appendix 11 Blood Pressure Levels for Boys by Age and Height Percentile
BP
Systolic BP (mm Hg)
Diastolic BP (mm Hg)
AGE
Percentile
Percentile of Height
Percentile of Height
(Year)
Ð
5th
10th
25th
50th
75th
90th
95th
5th
10th
25th
50th
75th
90th
95th
1
50th
80
81
83
85
87
88
89
34
35
36
37
38
39
39
90th
94
95
97
99
100
102
103
49
50
51
52
53
53
54
95th
98
99
101
103
104
106
106
54
54
55
56
57
58
58
99th
105
106
108
110
112
113
114
61
62
63
64
65
66
66
2
50th
84
85
87
88
90
92
92
39
40
41
42
43
44
44
90th
97
99
100
102
104
105
106
54
55
56
57
58
58
59
95th
101
102
104
106
108
109
110
59
59
60
61
62
63
63
99th
109
110
111
113
115
117
117
66
67
68
69
70
71
71
3
50th
86
87
89
91
93
94
95
44
44
45
46
47
48
48
90th
100
101
103
105
107
108
109
59
59
60
61
62
63
63
95th
104
105
107
109
110
112
113
63
63
64
65
66
67
67
99th
111
112
114
116
118
119
120
71
71
72
73
74
75
75
4
50th
88
89
91
93
95
96
97
47
48
49
50
51
51
52
90th
102
103
105
107
109
110
111
62
63
64
65
66
66
67
95th
106
107
109
111
112
114
115
66
67
68
69
70
71
71
99th
113
114
116
118
120
121
122
74
75
76
77
78
78
79
5
50th
90
91
93
95
96
98
98
50
51
52
53
54
55
55
90th
104
105
106
108
110
111
112
65
66
67
68
69
69
70
95th
108
109
110
112
114
115
116
69
70
71
72
73
74
74
99th
115
116
118
120
121
123
123
77
78
79
80
81
81
82
6
50th
91
92
94
96
98
99
100
53
53
54
55
56
57
57
90th
105
106
108
110
111
113
113
68
68
69
70
71
72
72
95th
109
110
112
114
115
117
117
72
72
73
74
75
76
76
99th
116
117
119
121
123
124
125
80
80
81
82
83
84
84
7
50th
92
94
95
97
99
100
101
55
55
56
57
58
59
59
90th
106
107
109
111
113
114
115
70
70
71
72
73
74
74
95th
110
111
113
115
117
118
119
74
74
75
76
77
78
78
99th
117
118
120
122
124
125
126
82
82
83
84
85
86
86
8
50th
94
95
97
99
100
102
102
56
57
58
59
60
60
61
90th
107
109
110
112
114
115
116
71
72
72
73
74
75
76
95th
111
112
114
116
118
119
120
75
76
77
78
79
79
80
99th
119
120
122
123
125
127
127
83
84
85
86
87
87
88
9
50th
95
96
98
100
102
103
104
57
58
59
60
61
61
62
90th
109
110
112
114
115
117
118
72
73
74
75
76
76
77
95th
113
114
116
118
119
121
121
76
77
78
79
80
81
81
99th
120
121
123
125
127
128
129
84
85
86
87
88
88
89
10
50th
97
98
100
102
103
105
106
58
59
60
61
61
62
63
90th
111
112
114
115
117
119
119
73
73
74
75
76
77
78
95th
115
116
117
119
121
122
123
77
78
79
80
81
81
82
99th
122
123
125
127
128
130
130
85
86
86
88
88
89
90
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BP
Systolic BP (mm Hg)
Diastolic BP (mm Hg)
AGE
Percentile
Percentile of Height
Percentile of Height
(Year)
Ð
5th
10th
25th
50th
75th
90th
95th
5th
10th
25th
50th
75th
90th
95th
11
50th
99
100
102
104
105
107
107
59
59
60
61
62
63
63
90th
113
114
115
117
119
120
121
74
74
75
76
77
78
78
95th
117
118
119
121
123
124
125
78
78
79
80
81
82
82
99th
124
125
127
129
130
132
132
86
86
87
88
89
90
90
12
50th
101
102
104
106
108
109
110
59
60
61
62
63
63
64
90th
115
116
118
120
121
123
123
74
75
75
76
77
78
79
95th
119
120
122
123
125
127
127
78
79
80
81
82
82
83
99th
126
127
129
131
133
134
135
86
87
88
89
90
90
91
13
50th
104
105
106
108
110
111
112
60
60
61
62
63
64
64
90th
117
118
120
122
124
125
126
75
75
76
77
78
79
79
95th
121
122
124
126
128
129
130
79
79
80
81
82
83
83
99th
128
130
131
133
135
136
137
87
87
88
89
90
91
91
14
50th
106
107
109
111
113
114
115
60
61
62
63
64
65
65
90th
120
121
123
125
126
128
128
75
76
77
78
79
79
80
95th
124
125
127
128
130
132
132
80
80
81
82
83
84
84
99th
131
132
134
136
138
139
140
87
88
89
90
91
92
92
15
50th
109
110
112
113
115
117
117
61
62
63
64
65
66
66
90th
122
124
125
127
129
130
131
76
77
78
79
80
80
81
95th
126
127
129
131
133
134
135
81
81
82
83
84
85
85
99th
134
135
136
138
140
142
142
88
89
90
91
92
93
93
16
50th
111
112
114
116
118
119
120
63
63
64
65
66
67
67
90th
125
126
128
130
131
133
134
78
78
79
80
81
82
82
95th
129
130
132
134
135
137
137
82
83
83
84
85
86
87
99th
136
137
139
141
143
144
145
90
90
91
92
93
94
94
17
50th
114
115
116
118
120
121
122
65
66
66
67
68
69
70
90th
127
128
130
132
134
135
136
80
80
81
82
83
84
84
95th
131
132
134
136
138
139
140
84
85
86
87
87
88
89
99th
139
140
141
143
145
146
147
92
93
93
94
95
96
97
Abbreviations: BP
blood pressure; SD  standard deviation.
Note: The 90th percentile is 1.28 SD, 95th percentile is 1.645 SD, and the 99th percentile is 2.326 SD over the mean.
08BFHY


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10.12 Appendix 12: Blood Pressure Levels for Girls by Age and Height Percentile
BP
Systolic BP (mm Hg)
Diastolic BP (mm Hg)
AGE
Percentile
Percentile of Height
Percentile of Height
(Year)
Ð
5th
10th
25th
50th
75th
90th
95th
5th
10th
25th
50th
75th
90th
95th
l
50th
83
84
85
86
88
89
90
38
39
39
40
41
41
42
90th
97
97
98
100
101
102
103
52
53
53
54
55
55
56
95th
100
101
102
104
105
106
107
56
57
57
58
59
59
60
99th
108
108
109
111
112
113
114
64
64
65
65
66
67
67
2
50th
85
85
87
88
89
91
91
43
44
44
45
46
46
47
90th
98
99
100
101
103
104
105
57
58
58
59
60
61
61
95th
102
103
104
105
107
108
109
61
62
62
63
64
65
65
99th
109
110
111
112
114
115
116
69
69
70
70
71
72
72
3
50th
86
87
88
89
91
92
93
47
48
48
49
50
50
51
90th
100
100
102
103
104
106
106
61
62
62
63
64
64
65
95th
104
104
105
107
108
109
110
65
66
66
67
68
68
69
99th
111
111
113
114
115
116
117
73
73
74
74
75
76
76
4
50th
88
88
90
91
92
94
94
50
50
51
52
52
53
54
90th
101
102
103
104
106
107
108
64
64
65
66
67
67
68
95th
105
106
107
108
110
111
112
68
68
69
70
71
71
72
99th
112
113
114
115
117
118
119
76
76
76
77
78
79
79
5
50th
89
90
91
93
94
95
96
52
53
53
54
55
55
56
90th
103
103
105
106
107
109
109
66
67
67
68
69
69
70
95th
107
107
108
110
111
112
113
70
71
71
72
73
73
74
99th
114
114
116
117
118
120
120
78
78
79
79
80
81
81
6
50th
91
92
93
94
96
97
98
54
54
55
56
56
57
58
90th
104
105
106
108
109
110
111
68
68
69
70
70
71
72
95th
108
109
110
111
113
114
115
72
72
73
74
74
75
76
99th
115
116
117
119
120
121
122
80
80
80
81
82
83
83
7
50th
93
93
95
96
97
99
99
55
56
56
57
58
58
59
90th
106
107
108
109
111
112
113
69
70
70
71
72
72
73
95th
110
111
112
113
115
116
116
73
74
74
75
76
76
77
99th
117
118
119
120
122
123
124
81
81
82
82
83
84
84
8
50th
95
95
96
98
99
100
101
57
57
57
58
59
60
60
90th
108
109
110
111
113
114
114
71
71
71
72
73
74
74
95th
112
112
114
115
116
118
118
75
75
75
76
77
78
78
99th
119
120
121
122
123
125
125
82
82
83
83
84
85
86
9
50th
96
97
98
100
101
102
103
58
58
58
59
60
61
61
90th
110
110
112
113
114
116
116
72
72
72
73
74
75
75
95th
114
114
115
117
118
119
120
76
76
76
77
78
79
79
99th
121
121
123
124
125
127
127
83
83
84
84
85
86
87
10
50th
98
99
100
102
103
104
105
59
59
59
60
61
62
62
90th
112
112
114
115
116
118
118
73
73
73
74
75
76
76
95th
116
116
117
119
120
121
122
77
77
77
78
79
80
80
99th
123
123
125
126
127
129
129
84
84
85
86
86
87
88
08BFHY


PRODUCT:  MK 7902  
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BP
Systolic BP (mm Hg)
Diastolic BP (mm Hg)
AGE
Percentile
Percentile of Height
Percentile of Height
(Year)
Ð
5th
10th
25th
50th
75th
90th
95th
5th
10th
25th
50th
75th
90th
95th
11
50th
100
101
102
103
105
106
107
60
60
60
61
62
63
63
90th
114
114
116
117
118
119
120
74
74
74
75
76
77
77
95th
118
118
119
121
122
123
124
78
78
78
79
80
81
81
99th
125
125
126
128
129
130
131
85
85
86
87
87
88
89
12
50th
102
103
104
105
107
108
109
61
61
61
62
63
64
64
90th
116
116
117
119
120
121
122
75
75
75
76
77
78
78
95th
119
120
121
123
124
125
126
79
79
79
80
81
82
82
99th
127
127
128
130
131
132
133
86
86
87
88
88
89
90
13
50th
104
105
106
107
109
110
110
62
62
62
63
64
65
65
90th
117
118
119
121
122
123
124
76
76
76
77
78
79
79
95th
121
122
123
124
126
127
128
80
80
80
81
82
83
83
99th
128
129
130
132
133
134
135
87
87
88
89
89
90
91
14
50th
106
106
107
109
110
111
112
63
63
63
64
65
66
66
90th
119
120
121
122
124
125
125
77
77
77
78
79
80
80
95th
123
123
125
126
127
129
129
81
81
81
82
83
84
84
99th
130
131
132
133
135
136
136
88
88
89
90
90
91
92
15
50th
107
108
109
110
111
113
113
64
64
64
65
66
67
67
90th
120
121
122
123
125
126
127
78
78
78
79
80
81
81
95th
124
125
126
127
129
130
131
82
82
82
83
84
85
85
99th
131
132
133
134
136
137
138
89
89
90
91
91
92
93
16
50th
108
108
110
111
112
114
114
64
64
65
66
66
67
68
90th
121
122
123
124
126
127
128
78
78
79
80
81
81
82
95th
125
126
127
128
130
131
132
82
82
83
84
85
85
86
99th
132
133
134
135
137
138
139
90
90
90
91
92
93
93
17
50th
108
109
110
111
113
114
115
64
65
65
66
67
67
68
90th
122
122
123
125
126
127
128
78
79
79
80
81
81
82
95th
125
126
127
129
130
131
132
82
83
83
84
85
85
86
99th
133
133
134
136
137
138
139
90
90
91
91
92
93
93
Abbreviations: BP
blood pressure; SD  standard deviation.
Note: The 90th percentile is 1.28 SD, 95th percentile is 1.645 SD, and the 99th percentile is 2.326 SD over the mean.
08BFHY


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10.13 Appendix 13: Body Mass Index-For-Age Percentiles
2 to 20 years: Girls
08BFHY


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2 to 20 years: Boys
Source: Developed by the National Center for Health Statistics in collaboration with the National Center for Chronic 
Disease Prevention and Health Promotion (2000).
http://www.cdc.gov/growthcharts
http://www.cdc.gov/healthyweight/assessing/bmi/childrens bmi/about childrens bmi.htm
08BFHY


PRODUCT:  MK 7902  
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10.14 Appendix 14: Monoclonal Antibodies Half-Lives
08BFHY


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10.15 Appendix 15: Abbreviations
Abbreviation
Expanded Term
ADL
activities of daily living
AE(s)
adverse event(s)
AFP
alpha fetoprotein
ALT
alanine aminotransferase
ANC
absolute neutrophil count
Ang
angiopoietin
AST
aspartate aminotransferase
AxMP
auxiliary medicinal product
bFGF
basic fibroblast growth factor
β-hCG
β-human chorionic gonadotropin
BMI
body mass index
BOR
best overall response
BP
blood pressure
BSA
body surface area
BUN
Blood Urea Nitrogen
CBR
clinical benefit rate
CBTRUS
The Central Brain Tumor Registry of the United States
CDC
Centers for Disease Control
CNS
central nervous system 
CONSORT
Consolidated Standards of Reporting
CR
complete response
CRF
case report form
CSR
clinical study report
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTCAE 5.0
Common Terminology Criteria for Adverse Events, Version 5.0
CTFG
Clinical Trial Facilitation Group 
C[x]D[y]
Cycle [x] Week [y]
DCR
disease control rate
DMC
Data Monitoring Committee
DNA
deoxyribonucleic acid 
DOR
duration of response
DTC
differentiated thyroid carcinoma
EAS
Evaluable Analysis Set
ECG(s)
electrocardiogram(s)
ECHO
echocardiogram
ECI
event of clinical interest
ECOG
Eastern Cooperative Oncology Group
EDC
electronic data collection 
EEA
European Economic Area
eGFR
estimated glomerular filtration rate
ELISA
enzyme-linked immunosorbent assay
EMA
European Medicines Agency
EOC
Executive Oversight Committee
EOT
end of treatment
EWS
Ewing sarcoma
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendment Acts
FGF
fibroblast growth factor 
08BFHY


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Abbreviation
Expanded Term
FGFR
fibroblast growth factor receptor
FSH
follicle-stimulating hormone 
FU
follow-up
G
gastrostomy
GCP
Good Clinical Practice
G-CSF
granulocyte colony-stimulating factor
GFR
glomerular filtration rate
GI
gastrointestinal
HBsAg
Hepatitis B surface antigen
hCG
human chorionic gonadotropin
HCV
Hepatitis C Virus
HGF
hepatocyte growth factor
HGG
high-grade glioma
HIV
human immunodeficiency virus
HR
heart rate
HRT
hormone replacement therapy
131I-MIBG
radiolabeled antibody, iodine-131 metaiodobenzylguanidine
IFN-γ
interferon gamma
IA
interim analysis
IB
Investigator’s Brochure 
ICF
informed consent form
ICH
International Council for Harmonisation of Technical Requirements for Pharmaceuticals 
for Human Use
ICMJE
International Committee of Medical Journal Editors
IEC
independent ethics committee
IHC
immunohistochemistry
IMP
investigational medicinal product
INR
International Normalized Ratio
IRB
institutional review board
IRT
interactive response technology
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
IVRS
interactive voice response system
KDR
kinase insert domain receptor
KPS
Karnofsky performance status
LAM
lactational amenorrhoea method
LVEF
left ventricular ejection fraction
MedDRA
Medical Dictionary for Regulatory Activities
MIBG
meta-iodobenzylguanidine scan
MRI
magnetic resonance imaging
mRNA
messenger ribonucleic acid
MUGA
multiple gated acquisition scan
NCT
National Clinical Trial
NG
nasogastric
NHLBI
National Heart Lung and Blood Institute
ONJ
osteonecrosis of the jaw
OR
objective response
ORR
objective response rate
OS
overall survival
P/C
protein/creatinine
PD
disease progression
PDGF(R)
platelet-derived growth factor (receptor)
08BFHY


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Abbreviation
Expanded Term
PFS
progression-free survival
PK
pharmacokinetic
PlGF
placental growth factor
po
orally
pPNET
peripheral primitive neuroectodermal tumor
PR
partial response
PRES/RPLS
Posterior Reversible Encephalopathy Syndrome/Reversible Encephalopathy Syndrome/ 
Reversible Posterior Leukoencephalopathy Syndrome
PT
prothrombin time
QD
once daily
QT
Q wave T wave
QTcF
QT interval correction by Fridericia
Q[x]W
every [x] weeks
RANO
Response Assessment in Neuro-Oncology
RBC
red blood cell
RECIST 1.1
Response Evaluation Criteria in Solid Tumors 1.1
RET/PTC
rearranged transformation/papillary thyroid carcinoma
RF
radiofrequency
RMS
rhabdomyosarcoma
RNA
ribonucleic acid
RP2D
recommended Phase 2 dose
RTK
receptor tyrosine kinase
SAE(s)
serious adverse event(s)
SAP
statistical analysis plan
SD
stable disease
SEER
Surveillance, Epidemiology, and End Results (www.seer.cancer.gov)
SIM
Site Imaging Manual
SmPC
Summary of Product Characteristics
SoA
schedule of activities
SPD
sum of product diameters
SPRT
sequential probability ratio testing
sSAP
supplemental Statistical Analysis Plan
SUSAR
suspected unexpected serious adverse reaction
T4
thyroxine
TAMs
tumor-associated macrophages
TEAE
treatment-emergent adverse event
TiTE CRM
time-to-event continual reassessment method
TKI
tyrosine-kinase inhibitor
TME
tumor microenvironment
TSH
thyroid-stimulating hormone
ULN
upper limit of normal 
US
United States
VEGF
vascular endothelial growth factor
VEGFR
vascular endothelial growth factor receptor
WBC
white blood cell
WOCBP
woman/women of childbearing potential 
XRT
radiotherapy
08BFHY


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11
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