Clinical trial NCT03245151
Conditions: Recurrent and Refractory Solid Tumors
Keywords: pediatrics central nervous system tumors lenvatinib E7080 everolimus Ewing sarcoma/peripheral primitive neuroectodermal tumor rhabdomyosarcoma high grade glioma solid tumors
Sponsor: Eisai Inc.
Start date: 2017-11-16; Completion date: 2022-09-30
Enrollment: 64 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Phase 1 of this study, utilizing a rolling 6 design, will be conducted to determine a maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D), and to describe the toxicities of lenvatinib administered in combination with everolimus once daily to pediatric participants with recurrent/refractory solid tumors. Phase 2, utilizing Simon's optimal 2-stage design, will be conducted to estimate the antitumor activity of lenvatinib in combination with everolimus in pediatric participants with selected recurrent/refractory solid tumors including Ewing sarcoma, rhabdomyosarcoma, and high grade glioma (HGG) using objective response rate (ORR) at Week 16 as the outcome measure.

Detailed description:

Arms: arm 1: During Phase 1 (Treatment Phase: 1 cycle; 28 days of treatment), utilizing a rolling 6 design, participants with recurrent or refractory solid tumors will receive escalating doses of lenvatinib in combination with everolimus for determination of the maximum tolerated dose (MTD) and the recommended Phase 2 dose (RP2D). Participants who complete 1 cycle of treatment will transition to the Extension Phase, in which they will continue to receive the same study treatment in 28-day cycles. arm 2: During Phase 2 (four 28-day cycles \[up to 16 weeks of treatment\]), utilizing Simon's optimal 2-stage design, participants with recurrent or refractory Ewing sarcoma (Cohort 1) will receive the RP2D of lenvatinib in combination with everolimus determined in Phase 1. Participants who discontinue study treatment before completing 4 cycles will transition to the Off-treatment Visit. Participants who complete 4 cycles will transition to the Extension Phase, in which they will continue to receive the same study treatment in 28-day cycles. arm 3: During Phase 2 (four 28-day cycles \[up to 16 weeks of treatment\]), utilizing Simon's optimal 2-stage design, participants with recurrent or refractory rhabdomyosarcoma (Cohort 2) will receive the RP2D of lenvatinib in combination with everolimus determined in Phase 1 (1 cycle; 4 weeks of treatment). Participants who discontinue study treatment before completing 4 cycles will transition to the Off-treatment Visit. Participants who complete 4 cycles will transition to the Extension Phase, in which they will continue to receive the same study treatment in 28-day cycles. arm 4: During Phase 2 (four 28-day cycles \[up to 16 weeks of treatment\]), utilizing Simon's optimal 2-stage design, participants with recurrent or refractory HGG (Cohort 3) will receive the RP2D of lenvatinib in combination with everolimus determined in Phase 1 (1 cycle; 4 weeks). Participants who discontinue study treatment before completing 4 cycles will transition to the Off-treatment Visit. Participants who complete 4 cycles will transition to the Extension Phase, in which they will continue to receive the same study treatment in 28-day cycles.
Interventions: intervention 1: Lenvatinib intervention 2: Everolimus
Intervention descriptions: intervention 1: oral hard capsules containing 1 mg, 4 mg, or 10 mg lenvatinib, or an extemporaneous suspension intervention 2: 2 mg, 3 mg, or 5 mg tablets for oral suspension

Protocol documents:
Prot_000.pdf: 
Clinical Study Protocol 
incorporating Amendment 03 
E7080-A001-216 
 
 
Eisai 
FINAL: 16 Aug 2021 
Confidential 
Page 1 of 151 
 
1 
TITLE PAGE 
 
Clinical Study Protocol 
Study Protocol 
Number: 
E7080-A001-216 
Study Protocol 
Title: 
A Phase 1/2 Study of Lenvatinib in Combination with Everolimus 
in Recurrent and Refractory Pediatric Solid Tumors, Including CNS 
Tumors 
Sponsor: 
Eisai Inc. 
155 Tice Boulevard 
Woodcliff Lake 
New Jersey 07677 
United States  
 
Investigational 
Product Name: 
Lenvatinib (E7080), everolimus 
 
Indication: 
Recurrent and refractory pediatric solid tumors, including central 
nervous system tumors 
Phase: 
1/2 
Approval Date(s):  
16 Mar 2017 
Original Protocol 
 
24 Sep 2018 
Amendment 01 
 
28 Apr 2020 
Amendment 02 
 
16 Aug 2021 
Amendment 03 
IND Number: 
072010 
GCP Statement: 
This study is to be performed in full compliance with International 
Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) and all applicable local 
Good Clinical Practice (GCP) and regulations.  All required study 
documentation will be archived as required by regulatory 
authorities. 
Confidentiality 
Statement: 
This document is confidential.  It contains proprietary information 
of Eisai (the Sponsor).  Any viewing or disclosure of such 
information that is not authorized in writing by the sponsor is 
strictly prohibited.  Such information may be used solely for the 
purpose of reviewing or performing this study. 


Clinical Study Protocol 
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FINAL: 16 Aug 2021 
Confidential 
Page 2 of 151 
 
REVISION HISTORY 
Amendment 03 
Date: 16 Aug 2021  
 
Change 
Rationale 
Affected Protocol Sections 
Added text:  “Subjects will meet the 
criteria for being evaluable for an 
objective response, if they have 
measurable disease present at 
baseline and at least 1 post-baseline 
efficacy assessment, unless they have 
discontinued prior to the first 
efficacy assessment due to 
progressive disease. Subjects who 
are not evaluable for objective 
response will be replaced.” 
Clarified criteria for 
subjects to be 
considered evaluable 
for objective response. 
 
Synopsis (Study Design: Cohorts 1 
– 3) 
 
Section 9.1 
Exclusion criterion 17 was added:  
Males who have not had a successful 
vasectomy (confirmed azoospermia) 
or if they and their female partners 
do not meet the criteria above (ie, 
not of childbearing potential or 
practicing highly effective 
contraception throughout the study 
period and for 7 days after 
lenvatinib discontinuation or 4 
weeks after discontinuation of 
everolimus). No sperm donation is 
allowed during the study period and 
for 7 days after lenvatinib 
discontinuation or 4 weeks after 
discontinuation of everolimus. 
Added contraception 
requirement for male 
participants. 
 
Synopsis (Study Design:  
Exclusion Criteria) 
 
Section 9.3.2 
Added the window for tumor 
assessment: performed ±1 week at the 
specified timepoints. 
Clarified tumor 
assessments window. 
 
Synopsis; Assessments 
 
Section 9.1.2 
 
Section 9.1.3 
 
Section 9.5.1.3.1 
 
Table 7 and Table 8; footnotes o 
and q 


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Added text:  Evaluable Analysis Set, 
defined as all subjects, who have 
measurable disease present at 
baseline and at least 1 post-baseline 
efficacy assessment, unless they have 
discontinued prior to the first 
efficacy assessment due to 
progressive disease.  This will be the 
analysis set for efficacy. 
Removed text:   
• “Full Analysis Set, defined as all 
subjects enrolled.” 
Clarified that the 
Evaluable Analysis Set 
is the analysis set for 
Phase 2 and for the 
efficacy analysis in 
Phase 1. 
 
Synopsis; Statistical Methods 
(Definitions of Analysis Sets / 
Statistical Analysis) 
 
Section 9.7.1 
 
Section 9.7.1.2 
Removed text:  “All subjects who have 
measurable disease present at baseline 
will be included in the denominator for 
calculating the objective response 
rate.” 
Clarified criteria for 
subjects to be 
considered evaluable 
for objective response. 
 
Synopsis; Statistical Analysis 
 
Section 9.7.1.6 
Removed “for a cohort” and added 
“evaluable”. 
Clarified that the 
Evaluable Analysis Set 
is the analysis set for 
Phase 2 and for the 
efficacy analysis in 
Phase 1. 
 
Synopsis; Efficacy Analyses, 
Interim Analysis 
 
Section 9.7.1.6 
 
Section 9.7.3 
Moved and revised the following text:  
“Lenvatinib should be discontinued in 
any subject who develops 
gastrointestinal perforation of any 
Grade or ≥Grade 4 fistula.” 
Added text:  Management of Fistula 
Formation and Gastrointestinal 
Perforation 
Lenvatinib should be discontinued in 
any subject who develops Grade 4 
fistula (gastrointestinal or non-
gastrointestinal), or gastrointestinal 
perforation of any grade. 
Added a new section 
and revised text to 
include nonGI G4 
fistula in-line with 
lenvatinib safety 
management 
guidelines. 
 
Section 9.4.1.15 


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Added text:  Management of 
Osteonecrosis of the Jaw 
Perform an oral examination prior 
to treatment with lenvatinib and 
periodically during lenvatinib 
treatment. Advise study subjects 
regarding good oral hygiene 
practices. Avoid invasive dental 
procedures, if possible, while on 
lenvatinib treatment, particularly in 
study subjects at higher risk. For 
study subjects requiring invasive 
dental procedures, discontinuation 
of bisphosphonate treatment may 
reduce the risk of osteonecrosis of 
the jaw. Withhold lenvatinib if 
osteonecrosis of the jaw develops 
and restart based on clinical 
judgement of adequate resolution 
(see Section 9.4.7). 
Added a new section 
on management of 
osteonecrosis of the 
jaw in-line with 
lenvatinib safety 
management 
guidelines and label 
update. 
 
Section 9.4.1.16 
Added text:  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. 
Added new text on 
management of QT 
prolongation in-line 
with lenvatinib safety 
management 
guidelines and label 
update. 
 
Section 9.4.1.17 
Changed “study drugs” to lenvatinib 
and added text:   
Refer to everolimus prescribing 
information for recommended 
everolimus dosing information. 
Updated to reflect US 
label wording on 
missed dose 
administration. 
 
Section 9.4.5 
Added text:  • 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. 
Added text on 
scheduled dental 
surgery or invasive 
dental procedures. 
 
Section 9.4.7 
Administrative changes 
Revised for clarity 
 
Synopsis; Primary Efficacy 
Analysis 
 
Section 9.7.1.6.1 
 
Section 9.7.1.6.2 
 


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Amendment 02 
Date: 28 Apr 2020  
 
Change 
Rationale 
Affected Protocol Sections 
Updated abbreviation for ICH as per 
current definition. 
Administrative change 
 
Title page 
 
Section 4 
 
Section 5.1 
 
Section 5.2 
 
Investigator Signature page 
The age subsets for PK data for 
subjects <12 years old were clarified 
by subset 2 to <6 years and ≥6 to <12 
years with 6 subjects in each subset 
(changes are highlighted in bold in the 
below text):  
All subjects in the Phase 1 Dose 
Escalation phase will have samples 
taken for PK analysis with the intent at 
the end of Phase 1 of having evaluable 
PK data from minimally 6 subjects 
aged 2 to <6 years old, 6 subjects ≥6 
to <12 years old, and 6 subjects ≥12 
years old.  Once the MTD or RP2D has 
been defined, 0 to 6 additional subjects 
will be enrolled to attain the goal of 
having evaluable PK data from 
minimally 6 subjects aged 2 to <6 
years old, 6 subjects aged ≥6 to 
<12 years old, and 6 subjects ≥12 years 
old. 
Clarification of the age 
subsets for PK data per 
FDA General Clinical 
Pharmacology 
Considerations for 
Pediatric Studies 
Guidance for Industry 
(2014). 
 
Synopsis; Study Design; Phase 1 
Dose Escalation and Determination 
of the MTD 
 
Section 9.1 
It was clarified that the Sponsor will 
closely monitor enrollment to ensure 
that at least 50% of subjects enrolled in 
each cohort are <18 years of age at the 
time of informed consent.   
Changes made as per 
requirement stated by 
FDA. 
 
Synopsis: Study Design 
(Cohorts 1-3) 
 
Synopsis: Number of subjects 
 
Section 9.1 
 
Section 9.3 
Inclusion criterion 15 was added:  
 
Adequate glycemic control 
defined as fasting serum glucose 
≤160 mg/dL. 
Exclusion criteria 3, 4, and 5 were 
added: 
 
Subjects having an active infection 
requiring systemic therapy 
 
Subjects with a known history of 
active hepatitis B (defined as 
hepatitis B surface antigen reactive 
or hepatitis B virus-DNA 
detected) or known active 
The selection criteria 
were updated in line 
with the Afinitor 
Product monograph, 
and as per 
recommendations from 
Health Canada. 
 
Synopsis: Inclusion criterion  
 
Section 9.3.1 
 
 
 
Synopsis: Exclusion criterion  
 
Section 9.3.2 


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hepatitis C virus (HCV, defined as 
HCV-RNA detected).  Note: No 
testing for hepatitis B and 
hepatitis C is required unless 
mandated by the local health 
authority. 
 
Known to be human 
immunodeficiency virus (HIV) 
positive. Note: HIV testing is 
required at screening only when 
mandated by the local health 
authority 
Exclusion criterion for untreated brain 
central nervous system (CNS) 
metastasis was updated to add 
exception for subjects with primary 
CNS tumors and leptomeningeal 
disease. 
Further clarification of 
the exclusion criterion. 
 
Synopsis: Exclusion criterion  
 
Section 9.3.2, Exclusion criterion  
Current guidance, that for 
asymptomatic laboratory abnormalities 
(including Grade ≥3 abnormalities) 
that are not considered clinically 
relevant by the investigator, 
continuation of treatment should be 
discussed with the sponsor, was added 
within the body text in addition to prior 
description within footnote ‘f’ of dose 
modification Table 5.  Also, clarified 
that such abnormalities should be 
managed per institutional guidance. 
Text was added for 
further clarity on 
management of 
laboratory 
abnormalities. 
 
Synopsis: Study Treatment 
 
Section 9.4.1.1 
Clarified that lenvatinib should be 
discontinued in any subject who 
develops gastrointestinal perforation of 
any Grade or ≥Grade 4 fistula. 
Updated as per 
standard guidance for 
lenvatinib. 
 
Section 9.4.1.14 
Clarified that for Phase 2 of the study, 
copies of scans for tumor assessments 
will be sent to an imaging core 
laboratory designated by the sponsor 
for quality assessment and archival and 
potential independent review.  
Also clarified that scans will not be 
sent to the imaging core lab after the 
data cutoff date. 
 
Collection and archival 
of tumor assessment 
scans by an imaging 
core laboratory will 
enable potential future 
independent review of 
tumor responses to 
corroborate 
investigator 
assessments. 
 
Synopsis: Tumor Assessments, 
Primary Efficacy Analysis 
 
Section 9.5.1.3.1 
 
Section 9.7.1.6.1 
Clarified that only subjects with BSA 
>0.68 m2 are eligible to consent 
(optional) to blood samples for plasma 
and serum studies for assessment of 
pharmacodynamic biomarkers.  
Updated in order to 
comply with standard 
guidelines for pediatric 
blood draw volumes 
and as recommended 
by Health Canada. 
 
Synopsis: Pharmacodynamic 
Assessments 
 
Section 9.5.1.4.2  
 
Section 9.5.2.1: Table 7 (footnote s) 
and Table 8 (footnote s) 


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Clarified that prior to ECG, subjects 
should be in recumbent position for 
5 minutes, if possible.  
Considering feasibility 
within pediatric age 
group, it was clarified 
that the requirement 
for subjects to remain 
in the recumbent 
position for 5 minutes 
prior to ECG is 
applicable, only if 
possible. 
 
Section 9.5.1.5.6 
 
Section 9.5.2.1: Table 7 (footnote j) 
and Table 8 (footnote j) 
Typographical error in sentence ‘For 
subjects with primary CNS tumors and 
no other known areas of disease only 
target and non-target lesions plus any 
areas of nearly newly suspected 
disease must be scanned’. 
‘nearly’ was updated to ‘newly’. 
Correction of 
typographical error in 
text. 
 
Section 9.5.2.1: Table 7 (footnote o) 
Dental examination was added at 
Baseline, every year on study, and at 
the Off-Treatment Visit. 
This was added for 
monitoring of the 
dental development. 
 
Section 9.5.2.1: Table 7 (footnote r) 
and Table 8 (footnote r) 
 
Section 9.5.1.5.7 
 
Clarified that for CTCAE, version 4.03 
will be used and not current version. 
Correction made as 
‘current version’ was 
mentioned in error. 
 
Synopsis (Safety Assessments) 
 
Section 9.7.3 
Provision of independent data 
monitoring committee (IDMC) was 
added for review of safety and efficacy 
data during the conduct of the study 
This was added to 
facilitate independent 
review of safety and 
efficacy data. 
 
Synopsis (Interim Analyses) 
 
Section 9.7.3 
Period for retention of records was 
updated as per the latest protocol 
template to 15 years following the 
completion of the study. 
Also, for sites in Canada, the retention 
period of study records was updated to 
25 years as per Health Canada 
requirement. 
To align with latest 
template requirements, 
and requirements of 
Health Canada 
 
Section 11.6 
Procedure for preparation of lenvatinib 
suspension was updated to clarify that 
the suspension should be taken 
immediately after preparation rather 
than within 24 hours.  Also added that 
for nasogastric administration, it is 
recommended where possible, that the 
syringe is held in the horizontal 
position while administering the 
suspension. 
Additional edits were made for further 
clarity of individual steps and general 
guidelines were added. 
Administrative change 
to clarify the 
preparation of 
lenvatinib suspension 
in-line with the 
lenvatinib SMPC. 
Also, the 
recommendation that 
the syringe is held in 
the horizontal position 
while administering 
the suspension was 
added to avoid the 
possibility of blocking 
 
Appendix 12 


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the nasogastric tubing 
with undissolved 
granules.  
 
Revisions per Amendment 01 
Date: 24 Sep 2018 
Change 
Rationale 
 
Affected Protocol 
Sections 
Changed “Conference” to “Council” 
Administrative change 
 
Title page 
 
Section 4, Section 5.1, 
Section 5.2 
 
Investigator Signature 
page 
Removed text: “with the exception of Dose 
Level 2B which requires a minimum BSA 
of 1.33 m2.” 
Removed text “Dose Level 2 includes 2 sub 
dose levels, 2A and 2B, depending on the 
maximum daily dose of lenvatinib allowed 
and body surface area of the subjects.  At 
Dose Level 2A, the maximum daily dose of 
lenvatinib will not exceed 18 mg daily with 
a minimum body surface area (BSA) of 0.6 
m2.  At Dose Level 2B, the maximum daily 
dose of lenvatinib allowed will not exceed 
24 mg and requires a minimum BSA of 
1.33 m2.” 
Removed text “Dose Level 2 will include 2 
sub dose levels, 2A and 2B, depending on 
the maximum daily dose of lenvatinib 
allowed.”  
Changed text “ At Dose Levels 2A -1 and 
1, maximum daily dose of lenvatinib will 
not exceed 18 mg daily.  At Dose Level 2B, 
maximum daily dose of lenvatinib allowed 
will not exceed 24 mg.  Should Dose Level 
2A and 2B be well tolerated, Dose Level 3 
may be considered to test lenvatinib at 14 
mg/m2 (capped at 24 mg) and escalate 
everolimus to 4.5 mg/m2.” 
Changed text “The actual dose to be 
administered is rounded to the nearest 
whole number.  The total lenvatinib dose is 
capped at 18 mg daily (Dose Levels -1, and 
1, and 2A), and at 24 mg daily (Dose 
Levels 2B and 3)”. 
Lenvatinib dose nomogram tables were 
updated accordingly. 
Dose levels 2 and 3 have 
been adapted to explore the 
maximum daily dose of 
lenvatinib and everolimus 
respectively.  Dose Level 2B 
was redundant and was 
therefore removed. 
 
Synopsis – Study 
Design,  Table 1, Table 
3, Table 4, Inclusion 
Criterion #15, Study 
Treatment 
 
Section 9.1, Figure 1, 
Table 1, Table 3, Table 
4,  
 
Section 9.3.1 
 
Section 9.4.1 
 


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Change 
Rationale 
 
Affected Protocol 
Sections 
Lenvatinib in “Planned Dose Escalation” 
Table 1 updated accordingly and footnotes 
corrected.  
Figure 1- Study Design updated  
Figure updated for 
clarification and consistency 
with the body of the 
protocol. 
 
Section 9.1 
Reduced maximum number of subjects in 
the dose levels -1, 1, 2 and 3 to 54 subjects 
in Phase 1 and 120 subjects in Phase 1 and 
2.  The projected maximum number of 
evaluable subjects required in Phase 1 was 
recalculated to 48 subjects.  
Sample size was reduced 
since Dose level 2B was 
redundant and was therefore 
removed.  Number of 
evaluable subjects was 
revised based on sample size 
calculations. 
 
Synopsis- Number of 
subjects, Sample Size 
Rationale 
 
Section 9.3 
 
Section 9.7.2 
Added “Subjects who on PSC review are 
not deemed evaluable for DLT assessment 
may be replaced.” 
Added for clarification 
 
Synopsis, Study Design 
 
Section 9.1 
Changed bullet 
o Grade 3 liver enzyme elevation, 
including alanine 
aminotransferase/aspartate 
aminotransferase (ALT/AST)/ 
gamma glutamyl transferase 
(GGT) /bilirubin/alkaline 
phosphatase that returns to 
Grade 1 or baseline within 7 
days 
 
The DLT criteria for Grade 3 
liver enzyme elevation has 
been updated to reflect the 
liver function tests that are 
performed in this study.  
 
Synopsis – Study 
Design,  
 
Section 9.1 
Added bullet “Grade 3 headache <3 days 
duration responsive to optimal 
management.” 
The DLT criteria for Grade 3 
non-hematological toxicities 
have been updated for 
clarification. 
 
Synopsis – Study Design  
 
Section 9.1 
Changed to “Subjects who discontinue the 
study treatment for any reason other than 
DLT (eg, early disease progression) during 
Cycle 1 (Day 1 to Day 28), and have not 
received at least 75% of the prescribed 
dose prior to discontinuation, will be 
replaced. 
Clarification text was added 
regarding replacement of 
subjects prior to 
discontinuation. 
 
Synopsis – Study Design 
 
Section 9.1 
An antihypertensive tablet or capsule that 
contains up to 2 antihypertensive ingredient 
medications will count as 1 be considered 
a single antihypertensive medication. 
Updated for clarification 
 
Synopsis – Study Design 
 
Section 9.1 
Added to inclusion criterion #1a “Subjects 
with diffuse intrinsic pontine glioma, optic 
pathway glioma, or pineal tumors with 
Update to the inclusion 
criteria to confirm that 
subjects with tumor types for 
 
Synopsis – Inclusion 
criteria 
 
Section 9.3.1 


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Change 
Rationale 
 
Affected Protocol 
Sections 
elevated tumor markers (alpha-fetoprotein 
[AFP] and beta-human chorionic 
gonadotropin [ß-hCG] [or hCG]) do not 
require histological or cytological 
confirmation of diagnosis.” 
which histological diagnosis 
is not possible due to 
inaccessibility of the tumor, 
do not require histological 
confirmation of diagnosis 
during Phase 1. 
Removed the following text from inclusion 
criterion #2a “If there is only one target 
lesion and it is a non-lymph node, it should 
have a longest diameter of ≥1.5 cm.” 
Removal of repetitive text.   
 
Synopsis – Inclusion 
criteria 
 
Section 9.3.1 
Changed inclusion criterion #5 “Male or 
female subjects must be ≥2 years and <18 
years of age for enrolment in Phase 1 or 
≥2 years and ≤21 years of age for 
enrolment in Phase 2.” 
For the purpose of dose 
determination, subjects must 
be <18 years of age in 
Phase 1. 
 
Synopsis – Inclusion 
criteria 
 
Section 9.3.1 
Changed exclusion criterion #13 “**Must 
be on a stable dose of the same oral 
hormonal contraceptive product for at least 
4 weeks before dosing with study drug, for 
the duration of the study, and for at least 8 
weeks after study drug discontinuation.” 
Contraception requirements 
have been updated to include 
the 8-week period after study 
drug discontinuation, as per 
the everolimus label and the 
study ICF. 
 
Synopsis – Exclusion 
criteria 
 
Section 9.3.2 
Added text “For subjects with primary CNS 
tumors and no other known areas of 
disease, only target and non-target lesions 
plus any areas of newly suspected disease 
must be scanned.” 
Tumor assessment 
requirements have been 
updated for subjects with 
primary CNS tumors.  
 
Synopsis – Tumor 
assessments 
 
Section 9.5.1.3.1 
 
Section 9.5.2, Table 7 
Changed text “All hematology, blood 
chemistry (including pregnancy test, as 
applicable), and urinalysis samples are to be 
obtained prior to study drug administration 
and results reviewed prior to administration 
of study drug on Cycle 1 Day 1 and within 
48 hours after prior to dispensing study 
drug for all subsequent cycles.” 
Updated text in footnote “l” of Clinical 
Chemistry and Hematology and added text 
“The results must be reviewed prior to 
administration of study drug on Cycle 1 
Day 1 and within 48 hours prior to 
dispensing study drug for all subsequent 
cycles.” to footnote “f”of Pregnancy test of 
Schedule of Assessments. 
The review of laboratory 
measurement and pregnancy 
results have been clarified to 
reflect the timing in this 
study  
 
Synopsis-Pregnancy test 
 
Section 9.5.1.5.3 
 
Section 9.5.2, Table 7 
and Table 8 
Added text “prior to Day 1 of each 
subsequent cycle” and to footnote “f” in 
Schedule of Assessments for pregnancy 
tests. 
Pregnancy test schedule has 
been updated for consistency 
with the body of the 
protocol. 
 
Synopsis – Pregnancy 
Test  
 
Section 9.5.1.6 
 
Section 9.5.2, Table 7 
and Table 8 


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Change 
Rationale 
 
Affected Protocol 
Sections 
 “X’s” added to the Schedule of 
Assessments tables to reflect pregnancy test 
prior to Day 1 of each subsequent cycle. 
Added text “In the event of nephrotic 
syndrome, lenvatinib must be 
discontinued.” 
Update to “Management of 
Proteinuria” to align with 
updates made to lenvatinib 
study protocols. 
 
Section 9.4.1.5 
Added text “If a subject experiences an 
arterial thromboembolism event of any 
grade, lenvatinib must be discontinued.” 
Update to “Management of 
Thromboembolic Events” to 
align with updates made to 
lenvatinib study protocols. 
 
Section 9.4.1.11 
Added text “Study treatment should be 
discontinued in any subject who develops 
gastrointestinal perforation or 
life-threatening fistula.” 
Update to “Management of 
Gastrointestinal Symptoms 
and Acute Abdominal Pain” 
to align with updates made to 
lenvatinib study protocols. 
 
Section 9.4.1.14 
Changed text “Palliative radiotherapy of up 
to 2 painful pre-existing, non-target bone 
metastases will be permitted without being 
considered progressive disease after 
determination of recommended dose. In the 
Phase 1 part, palliative radiotherapy will 
be allowed after the completion of 
Cycle 1.” 
Clarification text has been 
added to confirm that 
palliative radiotherapy is 
permitted in Phase 1 after the 
completion of Cycle 1. 
 
Section 9.4.7 
Expanded Footnotes in Table 7 and 8 
(Schedule of Assessments, Phase 1 and 
Phase 2) to clarify the time window for 
echocardiogram (1 week prior to the 
scheduled visit). 
Administrative change 
 
 
Section 9.5.2, Table 7 
and Table 8 
 


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2 
CLINICAL PROTOCOL SYNOPSIS 
Compound No.  E7080 
Name of Active Ingredient:  Lenvatinib and everolimus 
Study Protocol Title 
A Phase 1/2 Study of Lenvatinib in Combination With Everolimus in Recurrent and Refractory 
Pediatric Solid Tumors, Including CNS Tumors 
Investigator(s) 
Principal Investigator:  Filemon S. Dela Cruz, MD  
Sites 
Approximately 60 sites; 20 sites for the Phase 1 portion and additional 40 sites for the Phase 2 
portion. 
Study Period and Phase of Development 
Approximately 4.5 years from the first subject providing signed informed consent in Phase 1 to the 
primary endpoint completion date for Phase 2 of the study.  It is estimated that the Phase 2 portion 
will take 3 years in order to complete the final collection of data for the primary outcome analysis. 
Phase 1/2, open-label, non-randomized 
Objectives 
 Primary Objectives for Phase 1 
a. 
To determine a maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) 
of lenvatinib administered in combination with everolimus, once daily to pediatric subjects 
with recurrent/refractory solid tumors. 
b. 
To describe the toxicities of lenvatinib administered in combination with everolimus once 
daily to pediatric subjects with recurrent/refractory solid tumors. 
 Secondary Objectives for Phase 1 
a. 
To preliminarily define the antitumor activity of lenvatinib in combination with everolimus 
in pediatric subjects with recurrent/refractory solid tumors. 
b. 
To characterize the pharmacokinetics (PK) of oral lenvatinib and everolimus, when 
administered in combination to pediatric subjects with recurrent/refractory solid tumors. 
 Primary Objective for Phase 2 
a. 
To estimate the antitumor activity of lenvatinib in combination with everolimus in pediatric 
subjects with selected recurrent/refractory solid tumors including Ewing 
sarcoma/peripheral primitive neuroectodermal tumor (pPNET), rhabdomyosarcoma, and 
high-grade glioma (HGG) using objective response rate (ORR) at Week 16 as the outcome 
measure. 
 Secondary Objectives for Phase 2 
a. 
To assess other response variables including ORR at the time of data cutoff, disease control 
rate (DCR), clinical benefit rate (CBR), and duration of response (DOR). 
b. 
To evaluate the tolerability and safety profile of lenvatinib in combination with everolimus 
in pediatric subjects with recurrent/refractory Ewing sarcoma/pPNET, rhabdomyosarcoma, 
and HGG.   


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c. 
To characterize the PK of lenvatinib and everolimus, when administered in combination to 
children with recurrent/refractory Ewing sarcoma/pPNET, rhabdomyosarcoma, and HGG. 
 Exploratory Objectives for Phase 1 and Phase 2 
a. 
To evaluate blood, tumor, and safety (eg, hypertension) markers as correlative biomarkers 
of treatment effects and outcomes of lenvatinib in combination with everolimus. 
b. 
To assess candidate alterations in genes and/or proteins that may contribute to tumor 
development and serve as predictive markers of response in archival tumor tissue from 
pediatric subjects. 
c. 
To explore relationships between lenvatinib exposure and safety (eg, adverse events [AEs] 
of special interest). 
Study Design 
This is a multicenter, open-label, Phase 1/2 study of lenvatinib in combination with everolimus in 
pediatric subjects with relapsed or refractory solid tumors.   
Phase 1 Dose Escalation and Determination of the MTD 
The Phase 1 component is a dose escalation study with treatment in sequential cohorts of escalating 
doses of lenvatinib in combination with everolimus, each administered once daily in 28-day 
treatment cycles.  Pediatric subjects with a relapsed/refractory solid malignancy, including primary 
brain tumors are eligible to participate.  The initial dose level (Dose Level 1) for lenvatinib will be 
11 mg/m2, which is approximately 80% of lenvatinib single dose MTD in pediatric subjects 
determined in the ongoing Study E7080-G000-207.  The initial dose of everolimus will be 
3 mg/m2, which is 66% of the Food and Drug Administration (FDA) approved dose and a dose 
previously found to be effective in subependymal giant cell astrocytoma (SEGA).   
Dose Level 2 will escalate lenvatinib by approximately 25% to 14 mg/m2 and maintain everolimus 
at the same dose of 3 mg/m2.  At Dose Level -1 and 1, the maximum daily dose of lenvatinib will 
not exceed 18 mg daily.  At Dose Level 2, the maximum daily dose of lenvatinib allowed will not 
exceed 24 mg.  Should Dose Level 2 be well tolerated, Dose Level 3 may be considered to test 
lenvatinib at 14 mg/m2 (capped at 24 mg) and escalate everolimus to 4.5 mg/m2.  For everolimus 
dose levels of 3 mg/m2 and 4.5 mg/m2, the maximum daily dose of everolimus will not exceed 
5 mg and 7 mg, respectively.  If the MTD for combination of lenvatinib and everolimus has been 
exceeded at Dose Level 1, then the subsequent cohort of subjects will be treated at Dose Level -1 
with dose of lenvatinib 8 mg/m2 and dose of everolimus 3 mg/m2 (Table 1).  Intra-subject titration 
of everolimus will not be allowed on this study.  
At study entry, subjects must have a minimum body surface area (BSA) of 0.6 m2. 
 
Table 1 
Planned Dose-Escalation 
Dose Level 
Lenvatinib mg/m2  
(% Single-Agent MTD) 
Everolimus 
(mg/m2) 
-1 
8 (60% MTD)a 
3c 
1* 
11 (80% MTD)a 
3c 
2 
14 (100% MTD)b 
3c  
3d 
14 (100% MTD)b 
4.5e 
MTD = maximum tolerated dose 
*Starting dose level 
a:  Lenvatinib dose capped at 18 mg daily.  
b:  Lenvatinib dose capped at 24 mg daily. 
c:  Everolimus dose capped at 5 mg daily. 
d:  Dose Level 3 may be considered if Dose Level 2 is well tolerated 
e:  Everolimus dose capped at 7 mg daily. 
 


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The study will utilize a rolling 6 design (Skolnik, et al., 2008).  Two to 6 subjects can be 
concurrently enrolled into a dose level cohort.  Dose level assignment will be based on the 
following:  
1. the number of subjects currently enrolled in the dose level cohort,  
2. the number of dose-limiting toxicities (DLTs) observed, and  
3. the number of subjects at risk for developing a DLT (ie, subjects enrolled but who are not yet 
assessable for toxicity).   
For example, when 3 subjects are enrolled onto a dose cohort, if toxicity data is available for all 3 
when the fourth subject entered and there are no DLTs, the dose is escalated and the fourth subject 
is enrolled to the subsequent dose level.  If data is not yet available for one or more of the first 
3 subjects and no DLT has been observed, or if one DLT has been observed, the new subject is 
entered at the same dose level.  Lastly, if 2 or more DLTs have been observed, the dose level is 
de-escalated.  This process is repeated for Subjects 5 and 6.  In place of suspending accrual after 
every 3 subjects, accrual is only suspended when a cohort of 6 is filled (ie, subjects enrolled but are 
not yet assessable for toxicity) or when the study endpoints have been met.  When subjects are not 
evaluable for toxicity, they will be replaced with the next available subject if escalation or 
de-escalation rules have not been fulfilled at the time the next available subject is enrolled onto the 
study. 
The following table (Table 2) provides the decision rules for enrolling a subject at (i) the current 
dose level, (ii) at an escalated dose level, (iii) at a de-escalated dose level, or whether the study is 
suspended to accrual: 
Table 2 The Rolling 6 Design 
# Subjects 
Enrolled 
# Subjects 
with DLT 
# Subjects without 
DLT 
# Subjects with Data 
Pending 
Decision 
2 
0 or 1 
0, 1 or 2 
0, 1 or 2 
Same dose level 
2 
2 
0 
0 
De-escalate* 
 
 
 
 
 
3 
0 
0, 1 or 2 
1, 2 or 3 
Same dose level 
3 
1 
0, 1 or 2 
0, 1 or 2 
Same dose level 
3 
0 
3 
0 
Escalate** 
3 
≥2 
0 or 1 
0 or 1 
De-escalate* 
 
 
 
 
 
4 
0 
0, 1, 2 or 3 
1, 2, 3 or 4 
Same dose level 
4 
1 
0, 1, 2 or 3 
0, 1, 2 or 3 
Same dose level 
4 
0 
4 
0 
Escalate** 
4 
≥2 
0, 1 or 2 
0, 1 or 2 
De-escalate* 
 
 
 
 
 
5 
0 
0, 1, 2, 3 or 4 
1, 2, 3, 4 or 5 
Same dose level 
5 
1 
0, 1, 2, 3 or 4 
0, 1, 2, 3 or 4 
Same dose level 
5 
0 
5 
0 
Escalate** 
5 
≥2 
0, 1, 2 or 3 
0, 1, 2 or 3 
De-escalate* 
 
 
 
 
 
6 
0 
0, 1, 2, 3, or 4 
2, 3, 4, 5 or 6 
Suspend 
6 
1 
0, 1, 2, 3 or 4 
0, 1, 2, 3 or 4 
Suspend 
6 
0 or 1 
5 or 6 
0 or 1 
Escalate** 
6 
≥2 
0, 1, 2, 3 or 4 
0, 1, 2, 3 or 4 
De-escalate* 
DLT = dose-limiting toxicity 
*If 6 subjects already entered at next lower dose level, the maximum tolerated dose (MTD) has been defined.  
**If final dose level has been reached, the recommended dose has been reached. 
 
If 2 or more of a cohort of up to 6 subjects experience DLT at a given dose level, then the MTD has 
been exceeded and dose escalation will be stopped.  In the event that 2 DLTs observed out of 
6 evaluable subjects are of different classes of Adverse Effects (eg, hepatotoxicity and 


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myelosuppression), expansion of the cohort to 12 subjects will be considered (if one of the DLTs 
does not appear to be dose-related, the Adverse Effects are readily reversible, AND Protocol 
Steering Committee (PSC) AND sponsor all agree that expansion of the cohort is acceptable).  
Subjects who on PSC review are not deemed to be evaluable for DLT assessment may be replaced. 
All subjects in the Phase 1 Dose Escalation phase will have samples taken for PK analysis with the 
intent at the end of Phase 1 of having evaluable PK data from minimally 6 subjects aged 2 to 
<6 years old, 6 subjects ≥6 to <12 years old, and 6 subjects ≥12 years old.  Once the MTD or RP2D 
has been defined, 0 to 6 additional subjects will be enrolled to attain the goal of having evaluable 
PK data from minimally 6 subjects aged 2 to <6 years old, 6 subjects aged ≥6 to <12 years old, and 
6 subjects ≥12 years old.  
Protocol Steering Committee 
The sponsor will closely evaluate the risks and benefits of the study throughout its conduct, along 
with the PSC as needed.  The PSC may review available relevant data: DLT and safety data 
including laboratory assessments, 12-lead electrocardiograms (ECGs), dose administration, etc. 
Toxicity Monitoring 
The DLT observation period for the purposes of dose-escalation will be the first cycle of therapy.  
Routine Phase 1 monitoring for clinical and laboratory toxicities will be used.  Blood pressure (BP) 
monitoring will occur at least weekly during the first 2 cycles.   
Dose-limiting toxicity will be assessed according to Common Terminology Criteria for Adverse 
Events (CTCAE) v4.03 and is defined as any of the following events that are possibly, probably, or 
definitely attributable to lenvatinib or everolimus.  Dose-limiting hematological and 
non-hematological toxicities are defined differently. 
A. Non-hematological DLT: 
 Any Grade 3 or greater non-hematological toxicity attributable to the investigational drug 
with the specific exclusion of: 
o Grade 3 nausea and vomiting <3 days duration 
o Grade 3 diarrhea <3 days duration 
o Grade 3 weight loss 
o Grade 3 liver enzyme elevation, including alanine aminotransferase/aspartate 
aminotransferase(ALT/AST)/ gamma glutamyl transferase (GGT)/ bilirubin/alkaline 
phosphatase that returns to Grade 1 or baseline within 7 days 
o Grade 3 asymptomatic elevation in amylase or lipase that returns to Grade 1 or 
baseline within 7 days 
o Grade 3 elevation in triglycerides that returns to Grade 1 or baseline within 7 days 
o Grade 3 or 4 fever <5 days duration 
o Grade 3 infection <5 days duration 
o Grade 3 hypophosphatemia, hypokalemia, hypocalcemia or hypomagnesemia 
responsive to oral supplementation 
o Grade 3 proteinuria (urine protein:creatinine [UPC]) ratio >1.9 unless confirmed with a 
second measurement within 72 hours 
o Grade 3 headache <3 days duration responsive to optimal management 
 Any Grade 2 non-hematological toxicity that persists for ≥7 days and is considered 
sufficiently medically significant or sufficiently intolerable by subjects despite optimal 
supportive care that it requires treatment interruption. 
 Any dose interruption or reduction due to toxicity which results in administration of less 
than 75% of the planned dosage of lenvatinib and/or everolimus. 
 Note:  Allergic reactions that necessitate discontinuation of study drug will not be 
considered a DLT. 


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 Dose-limiting hypertension: 
o Any Grade 4 hypertension  
o Confirmed systolic or diastolic BP more than 25 mmHg above 95th percentile for sex, 
age, height/length, or an elevated diastolic BP (ie, >95th percentile for age) not 
controlled by a single antihypertensive medication within 14 days of use.  An 
antihypertensive tablet or capsule that contains up to 2 antihypertensive ingredient 
medications will be considered a single antihypertensive medication. 
B. Hematological DLT:    
 In subjects evaluable for hematological toxicity, DLT is defined as: 
o Grade 4 thrombocytopenia (platelet count <25,000/mm3) or Grade 4 neutropenia, not 
due to malignant infiltration. 
 Any ≥Grade 2 arterial thromboembolic events (including cerebrovascular ischemia, 
peripheral or visceral arterial ischemia). 
 Note:  Grade 3 or 4 febrile neutropenia will not be considered a DLT. 
All DLTs must be reported to the sponsor within 24 hours of their occurrence.  Determination of a 
DLT will be made by the investigator and the Eisai Medical Monitor in consultation with the PSC, 
as needed.  Subjects who discontinue the study treatment for any reason other than DLT (eg, early 
disease progression) during Cycle 1 (Day 1 to Day 28) and have not received at least 75% of the 
prescribed dose prior to discontinuation will be replaced. 
The sponsor and PSC will review all subjects’ safety and clinical data to jointly determine the 
MTD/RP2D of the combination of lenvatinib with everolimus. 
The Treatment Phase for each subject in Phase 1 ends after completing Cycle 1 of treatment unless 
subject discontinues early.  Those subjects who discontinue study treatment in Cycle 1 transition to 
the Off-treatment Visit.  Those who complete Cycle 1 will transition to the Extension Phase.  Study 
treatment and tumor assessments will continue during the Extension Phase. 
Phase 2 Cohorts 
Once the MTD/RP2D of the combination of lenvatinib and everolimus in pediatric population has 
been determined in Phase 1, the Phase 2 portion of this pediatric study will commence with 
Cohort 1 (recurrent or refractory Ewing sarcoma/pPNET), Cohort 2 (recurrent or refractory 
rhabdomyosarcoma), and Cohort 3 (recurrent or refractory HGG), opening to accrual. 
Cohorts 1 – 3  
Phase 2 Cohorts 1-3 will use a 10+10 Simon’s optimal 2-stage design for each cohort; 10 evaluable 
subjects will be enrolled to each stage.  The Sponsor will closely monitor enrollment to ensure that 
at least 50% of subjects enrolled in each cohort are <18 years of age at the time of informed 
consent.  The primary outcome measure for Ewing sarcoma/pPNET, rhabdomyosarcoma, and 
HGG will be ORR (complete or partial response) at 16 weeks.  If there are no responses among the 
10 subjects in Stage 1, then the enrollment to that disease cohort will stop and it will be concluded 
that the lenvatinib/everolimus combination therapy did not elicit a response in that disease cohort.  
If there is at least 1 response in the first stage, then the second stage will enroll 10 additional 
evaluable subjects.  If there are 2 or fewer responses among the 20 evaluable subjects, then 
lenvatinib/everolimus combination therapy will be declared a failure for that disease cohort. 
Subjects will meet the criteria for being evaluable for an objective response, if they have 
measurable disease present at baseline and at least 1 post-baseline efficacy assessment, unless they 
have discontinued prior to the first efficacy assessment due to progressive disease. Subjects who 
are not evaluable for objective response will be replaced. 


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The Treatment Phase for each subject in Phase 2 ends after completing 4 cycles of treatment unless 
the subject discontinues early.  Those who discontinue study treatment before completing 4 cycles 
transition to the Off-treatment Visit.  Those who complete 4 cycles transition to the Extension 
Phase.  Study treatment and tumor assessments will continue during the Extension Phase. 
Dosing Nomogram  
The dose nomogram in Table 3 provides dose of lenvatinib to be administered for BSA increments 
starting from 0.6 m2.  BSA must be calculated on Day 1 of each cycle based on the subject’s 
current height and body weight.  The actual dose to be administered is rounded to the nearest whole 
number. The total lenvatinib dose is capped at 18 mg daily (Dose Levels -1 and 1), and at 24 mg 
daily (Dose Levels 2 and 3).   
Table 3  Total Lenvatinib Dose (mg):  Body Surface Area (m2) * Dose Level (mg/m2) 
Lenvatinib Dose Level, 
8 mg/m2 
(Everolimus 3.0 mg/m2) 
Dose Level -1 
11 mg/m2 
(Everolimus 3.0 mg/m2) 
Dose Level 1 
14 mg/m2 
(Everolimus 3.0 mg/m2) 
Dose Level 2 
14 mg/m2 
(Everolimus 4.5 mg/m2) 
Dose Level 3 
Body 
Surface 
Area (m2) 
Dose to be 
Administered 
(mg) 
Body 
Surface 
Area (m2) 
Dose to be 
Administered 
(mg) 
Body 
Surface 
Area (m2) 
Dose to be 
Administered 
(mg) 
Body 
Surface Area 
(m2) 
Dose to be 
Administere
d (mg) 
0.60 - 0.68 
5 
0.60 - 0.68 
7 
0.60 - 0.60 
8 
0.60 - 0.60 
8 
0.69 - 0.81 
6 
0.69 - 0.77 
8 
0.61 - 0.67 
9 
0.61 - 0.67 
9 
0.82 - 0.93 
7 
0.78 - 0.86 
9 
0.68 - 0.74 
10 
0.68 - 0.74 
10 
0.94 - 1.06 
8 
0.87 - 0.95 
10 
0.75 - 0.82 
11 
0.75 - 0.82 
11 
1.07 - 1.18 
9 
0.96 - 1.04 
11 
0.83 - 0.89 
12 
0.83 - 0.89 
12 
1.19 - 1.31 
10 
1.05 - 1.13 
12 
0.90 - 0.96 
13 
0.90 - 0.96 
13 
1.32 - 1.43 
11 
1.14 - 1.22 
13 
0.97 - 1.03 
14 
0.97 - 1.03 
14 
1.44 - 1.56 
12 
1.23 - 1.31 
14 
1.04 - 1.10 
15 
1.04 - 1.10 
15 
1.57 - 1.68 
13 
1.32 - 1.40 
15 
1.11 - 1.17 
16 
1.11 - 1.17 
16 
1.69 - 1.81 
14 
1.41 - 1.49 
16 
1.18 - 1.24 
17 
1.18 - 1.24 
17 
1.82 - 1.93 
15 
1.50 - 1.59 
17 
1.25 - 1.32 
18 
1.25 - 1.32 
18 
1.94 - 2.06 
16 
≥1.60 
18 
1.33 - 1.39 
19 
1.33 - 1.39 
19 
2.07 - 2.18 
17 
 
 
1.40 - 1.46 
20 
1.40 - 1.46 
20 
≥2.19 
18 
 
 
1.47 - 1.53 
21 
1.47 - 1.53 
21 
 
 
 
 
1.54 - 1.60 
22 
1.54 - 1.60 
22 
 
 
 
 
1.61 - 1.67 
23 
1.61 - 1.67 
23 
 
 
 
 
≥1.68 
24 
≥1.68 
24 
 
 
 
 
 
 
 
 
 
The dose nomogram in Table 4 provides dose of everolimus to be administered for BSA 
increments starting from 0.6 m2.  The total everolimus dose is capped at 5 mg daily for Dose 
Levels ˗1, 1, and 2, and at 7 mg daily for Dose Level 3. 
Table 4   Total Everolimus Dose (mg):  Body Surface Area (m2) * Dose Level (mg/m2) 
Everolimus Dose Level 
3 mg/m2 
Dose Levels -1, 1, and 2 
4.5 mg/m2 
Dose Level 3 
Body Surface 
Area (m2) 
Dose to be 
Administered 
(mg) 
Body Surface 
Area (m2) 
Dose to be 
Administered 
(mg) 
0.60 – 0.83 
2 
0.60 – 0.77 
3 
0.84 – 1.16 
3 
0.78 – 0.99 
4 
1.17 – 1.49 
4 
1.00 – 1.22 
5 
≥1.50 
5 
1.23 – 1.44 
6 
 
 
≥1.45 
7 
 
Post-Treatment Follow Up:  
The post-treatment follow up begins when the subject discontinues study treatment.  All subjects 
who discontinue study treatment for reasons other than disease progression will be followed for 


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documented disease progression for 1 year or until another anticancer therapy is initiated.  Subjects 
will be followed for survival every 3 months until death or for 1 year unless the study is terminated 
or if the subject discontinues due to withdrawal of consent or is lost to follow up. 
Number of Subjects 
A maximum accrual of 120 subjects in Phase 1 and Phase 2 portions of the study is expected. 
• 
Phase 1:  4 to 48 evaluable subjects.  In the event that each of the 4 dose levels (-1, 1, 2, and 3) 
are expanded to 12 subjects and 6 additional subjects need to be enrolled in the PK Cohort, a 
maximum of 54 subjects (allowing for 20% to be non-evaluable and including the additional 
6 subjects for PK analysis) will be enrolled. 
• 
Phase 2 Cohorts 1 - 3:  10 to 20 evaluable subjects per cohort (maximum 22 subjects enrolled 
per cohort allowing for 10% to be non-evaluable).  A maximum of 66 subjects will be enrolled 
in Phase 2.  In each cohort, at least 50% of the subjects enrolled will be <18 years old at the 
time of informed consent. 
Inclusion Criteria 
1. Histologically or cytologically confirmed diagnosis of the following tumor types: 
a. Phase 1:  Recurrent or refractory solid tumors (excluding hepatoblastoma and lymphomas), 
including primary central nervous system (CNS) tumors; subjects must have either 
measurable or evaluable disease.  Subjects with diffuse intrinsic pontine glioma, optic 
pathway glioma, or pineal tumors with elevated tumor markers (alpha-fetoprotein [AFP] 
and beta-human chorionic gonadotropin [ß-hCG] [or hCG]) do not require histological or 
cytological confirmation of diagnosis. 
b. Phase 2:  Recurrent or refractory tumors; subjects must have measurable disease 
 
Cohort 1:  Ewing sarcoma/pPNET 
 
Cohort 2:  Rhabdomyosarcoma 
 
Cohort 3:  HGG (subjects with Diffuse Intrinsic Pontine Glioma are not eligible) 
2. Measurable disease that meets the following criteria (Phase 2): 
a. Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 (for all tumor types except 
HGG) 
 
At least 1 lesion of ≥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 which is serially measurable according to 
RECIST 1.1 using computed tomography /magnetic resonance imaging (CT/MRI).   
b. Response Assessment in Neuro-Oncology (RANO) for HGG (Wen, et al., 2010)  
 
At least one lesion must be measurable as defined as a bi-dimensionally 
contrast-enhancing lesion with clearly defined margins by CT or MRI scan, with a 
minimal diameter of 1 cm, and visible on 2 axial slices which are preferably at most 
5 mm apart with 0 mm skip. 
Lesions that have had external beam radiotherapy (EBRT) or locoregional therapies such as 
radiofrequency (RF) ablation must show evidence of progressive disease based on RECIST 1.1 to 
be deemed a target lesion. 
3. Karnofsky performance score 50 for subjects >16 year of age and Lansky play score 50 for 
subjects 16 years of age.  Note:  Neurologic deficits in subjects with CNS tumors must have 
been relatively stable for at least 7 days prior to study enrollment.  Subjects who are unable to 
walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for 
the purpose of assessing the performance score. 
4. Subjects must have fully recovered from the acute toxic effects of all prior anti-cancer therapy 
and must meet the following minimum duration from prior anti-cancer directed therapy prior to 


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enrollment.  If after the required timeframe, the numerical eligibility criteria are met, eg, blood 
count criteria, the subject 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. Anti-cancer 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).  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.  Subjects 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): 
 
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. 
 
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). 
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, radiolabeled antibody, iodine-131 
metaiodobenzylguanidine [131I-MIBG]):  ≥42 days after systemically administered 
radiopharmaceutical therapy. 
k. Vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR)-targeted or 
mammalian target of rapamycin (mTOR)-targeted therapies:  
 
Must not have received prior exposure to lenvatinib 
 
May have previously progressed on an mTOR inhibitor 
 
No more than 2 prior VEGF/VEGFR-targeted therapies (For Phase 2 only)  
 
Must not have received prior VEGF/VEGFR-targeted therapy in combination with an 
mTOR inhibitor (For Phase 2 only)  
5. Male or female subjects must be ≥2 years and <18 years of age for enrolment in Phase 1 or ≥2 
years and ≤21 years of age for enrolment in Phase 2. 
6. Adequate bone marrow function: 
 
For subjects with solid tumors without known bone marrow involvement: 
o Peripheral absolute neutrophil count (ANC) 1000/mm3 
o Platelet count 100,000/mm3  


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o Hemoglobin 8.0 g/dL at baseline (may receive red blood cell transfusions) 
 
For subjects with known bone marrow metastatic disease: 
o Peripheral ANC 1000/mm3 
o Platelet count 100,000/mm3 (and with no platelet transfusions for at least 7 days prior 
to enrollment) 
o May receive transfusions provided they are not known to be refractory to red cell or 
platelet transfusions.  These subjects will not be evaluable for hematologic toxicity.  At 
least 5 of every cohort of 6 subjects with a solid tumor must be evaluable for 
hematologic toxicity, for the dose-escalation part of the study.  If dose-limiting 
hematologic toxicity is observed, all subsequent subjects enrolled must be evaluable for 
hematologic toxicity. 
7. Adequate renal function:  
 
Creatinine clearance or radioisotope glomerular filtration rate (GFR) 70 mL/min/1.73 m2 
or 
 
A serum creatinine based on age/gender as follows: 
 
 
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 
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 Centers for Disease Control and Prevention 
(CDC). 
 
Urine dipstick <2+ for proteinuria.  Subjects who have ≥2+ proteinuria on dipstick 
urinalysis should undergo a spot protein-creatinine (P/C) ratio that should be Grade <2 per 
CTCAE v4.03, 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 subjects 
>12 years of age must have ≤1 g of protein/24 hours). 
8. Adequate liver function:  
 
Bilirubin (sum of conjugated + unconjugated) 1.5 × upper limit of normal (ULN) for age, 
except for unconjugated hyperbilirubinemia of Gilbert’s syndrome. 
 
ALT and AST ≤3 × ULN 
 
Serum albumin 2 g/dL 
9. Adequate cardiac function: 
 
Adequate cardiac function as evidenced by left ventricular shortening fraction of ≥27% by 
echocardiogram or left ventricular ejection fraction (LVEF) 50% at baseline as 
determined by echocardiography/multigated acquisition (MUGA) scan. 
 
QT interval corrected for heart rate using Fridericia’s formula (QTcF) ≤480 msec. 
10. Adequate neurologic function: 
 
Subjects with seizure disorder may be enrolled if on non-enzyme-inducing anticonvulsants 
and well controlled. 
 
Nervous system disorders (CTCAE v4.03) resulting from prior therapy and not 
tumor-induced must be  Grade 2. 


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11. Adequate BP control with or without antihypertensive medications, defined as: 
 
A BP < the 95th percentile for sex, age and height/length (≤150/90 mmHg for subjects 
aged 18 - 21 years) at Screening (as per National Heart Lung and Blood Institute [NHLBI] 
guidelines) and no change in antihypertensive medications within 1 week prior to Cycle 1 
Day 1. 
12. Adequate coagulation: 
 
International Normalized Ratio (INR) ≤1.5  
13. Adequate pancreatic function: 
 
Serum amylase ≤1.5 × ULN 
 
Serum lipase ≤1.5 × ULN 
14. Adequate metabolic function: 
 
Serum triglycerides ≤300 mg/dL  
15. Adequate glycemic control defined as: 
 
Fasting serum glucose ≤160 mg/dL 
16. Subjects must have a minimum BSA of 0.6 m2 at study entry.  
Exclusion Criteria 
1. Subjects who have had or are planning to have the following invasive procedures: 
 
Major surgical procedure, laparoscopic procedure, open biopsy or significant traumatic 
injury within 28 days prior to enrollment.  
 
Central line placement or subcutaneous port placement is not considered major surgery.  
External central lines must be placed at least 3 days prior to enrollment and subcutaneous 
ports must be placed at least 7 days prior to enrollment. 
 
Fine needle aspirate within 7 days prior to enrollment. 
 
Surgical or other wounds must be adequately healed prior to enrollment. 
NOTE: For purposes of this study, bone marrow aspirate and biopsy are not considered surgical 
procedures and therefore are permitted within 14 days prior to start of protocol therapy. 
2. Subjects who have non-healing wound, unhealed or incompletely healed fracture, or a 
compound (open) bone fracture at the time of enrollment 
3. Subjects having an active infection requiring systemic therapy. 
4. Subjects with a known history of active hepatitis B (defined as hepatitis B surface antigen 
reactive or hepatitis B virus-DNA detected) or known active hepatitis C virus (HCV, defined as 
HCV-RNA detected).  Note: No testing for hepatitis B and hepatitis C is required unless 
mandated by the local health authority. 
5. Known to be human immunodeficiency virus (HIV) positive. Note: HIV testing is required at 
screening only when mandated by the local health authority 
6. Clinical evidence of nephrotic syndrome prior to enrollment 
7. Gastrointestinal bleeding or active hemoptysis (bright red blood of at least half teaspoon) 
within 21 days prior to enrollment 
8. Thrombotic/ thromboembolic event requiring systemic anticoagulation within 90 days prior to 
enrollment 
9. Evidence of new intracranial hemorrhage of more than punctate size on MRI assessment 
obtained within 28 days prior to study enrollment for subjects with HGG  
10. Diagnosis of lymphoma 


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11. Radiographic evidence of major blood vessel invasion/infiltration.  
12. Evidence of untreated CNS metastases (exception: subjects with primary CNS tumors and 
leptomeningeal disease). 
13. Subjects who are currently receiving enzyme-inducing anticonvulsants 
14. Subjects chronically receiving strong cytochrome P450 3A4 (CYP3A4)/P-glycoprotein (P-gp) 
inhibitors or inducers within 7 days prior to study enrollment (See Appendix 15 for a list of 
strong inhibitors and inducers). 
15. Females who are breastfeeding or pregnant at Screening or Baseline (as documented by a 
positive ß-hCG [or hCG] test with a minimum sensitivity of 25 IU/L or equivalent units of ß-
hCG [or hCG]).  A separate baseline assessment is required if a negative screening pregnancy 
test was obtained more than 72 hours before the first dose of study drug. 
16. Females of childbearing potential* who: 
 
do not agree to use a highly effective method of contraception for the entire study period 
and for 8 weeks after study drug discontinuation, ie,: 
o total abstinence (if it is their preferred and usual lifestyle) 
o an intrauterine device (IUD) or hormone releasing system (IUS) 
o a contraceptive implant 
o an oral contraceptive** (with additional barrier method) 
OR 
 
do not have a vasectomized partner with confirmed azoospermia. 
For sites outside of the European Union (EU), it is permissible that if a highly effective method of 
contraception is not appropriate or acceptable to the subject, then the subject must agree to use a 
medically acceptable method of contraception, ie, double barrier methods of contraception such as 
condom plus diaphragm or cervical/vault cap with spermicide. 
NOTES: 
*All females will be considered to be of childbearing potential unless they are postmenopausal 
(amenorrheic for at least 12 consecutive months, in the appropriate age group, and without other 
known or suspected cause) or have been sterilized surgically (ie, bilateral tubal ligation, total 
hysterectomy, or bilateral oophorectomy, all with surgery at least 1 month before dosing), or are 
pre-menarcheal (Tanner Stage 1-3). 
**Must be on a stable dose of the same oral hormonal contraceptive product for at least 4 weeks 
before dosing with study drug, for the duration of the study, and for at least 8 weeks after study 
drug discontinuation. 
17. Males who have not had a successful vasectomy (confirmed azoospermia) or if they and their 
female partners do not meet the criteria above (ie, not of childbearing potential or practicing 
highly effective contraception throughout the study period and for 7 days after lenvatinib 
discontinuation or 4 weeks after discontinuation of everolimus). No sperm donation is allowed 
during the study period and for 7 days after lenvatinib discontinuation or 4 weeks after 
discontinuation of everolimus. 
Study Treatment 
Study drugs:  Lenvatinib will be provided as hard capsules containing 1 mg, 4 mg, or 10 mg 
lenvatinib.  An extemporaneous suspension of lenvatinib capsules should be used for children 
unable to swallow capsules. 
Everolimus will be provided as 2 mg, 3 mg, and 5 mg dispersible tablet formulations (everolimus 
tablets for oral suspension). 


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Lenvatinib and everolimus will be administered orally on a once daily schedule in continuous 
28-day cycles.  The sequence of administration is not important.  Dosing nomograms based on 
BSA and dose level will be used to prescribe lenvatinib and everolimus for subjects to minimize 
inter-subject dosing variability.  The maximum daily dose of lenvatinib administered during the 
study should not exceed 18 mg in Dose Levels -1, and 1, and 24 mg in Dose Levels 2 and 3.  The 
maximum daily dose of everolimus should not exceed 5 mg in Dose Levels -1, 1, and 2, and 7 mg 
in Dose Level 3.  Intra-subject titration of everolimus will not be allowed on this study.  Intra-
subject dose escalation will not be allowed. 
Comparator Drug (if applicable):  Not Applicable 
Study Drug Dose Interruption and Reduction Instructions: 
Dose reductions and interruptions for subjects who experience lenvatinib-everolimus combination 
therapy-related toxicity will be managed as described in Table 5.  Investigators will decide the 
probability of the event being related to protocol therapy as to whether dose modification of drug 
therapy is required. 
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. 
Doses in the Dose Adjustment column are based on a presumed starting dose of 11 mg/m2 
lenvatinib and 3 mg/m2 everolimus.  Dose reductions will occur in succession based on the 
previous dose level.  Each dose level reduction due to toxicity at a given BSA is approximately 
25% reduction from the previous dose.  Once the study drug dose has been reduced, it may not 
be increased at a later date, unless the dose was mistakenly decreased; in this situation, the 
sponsor’s approval is required to increase the dose. 
Table 5 Dose Modification Guidelines for Lenvatinib-Everolimus Combination 
Treatment-Related Toxicity 
Treatment-Related Toxicitya,b 
Management 
Dose Adjustment 
Grade 1 or Tolerable Grade 2 
 
Continue treatment 
No change 
Intolerable Grade 2c, d, e or Grade 3f 
First occurrence 
Interrupt lenvatinib and 
everolimus until resolved to 
Grade 0-1 or tolerable 
Grade 2 
Reduce lenvatinib dose to 
8 mg/m2 (or approximately 
25% reduction of the 
starting dose) orally once a 
day (one-level reduction) 
and resume everolimus at 
the same dose as prior to 
dose interruption 
Second occurrence 
(same toxicity or new toxicity) 
Interrupt lenvatinib and 
everolimus until resolved to 
Grade 0-1 or tolerable 
Grade 2 
Reduce lenvatinib dose to 
6 mg/m2 (or approximately 
25% reduction from the 
previous dose level) once a 
day (one-level reduction). 
Dose reduction of 
everolimus to 3 mg/m2 
every other day may be 
considered for Grade 3 
toxicitye 


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Third occurrence 
(same toxicity or new toxicity) 
Interrupt lenvatinib and 
everolimus until resolved to 
Grade 0-1 or tolerable 
Grade 2 
Reduce lenvatinib dose to 
4.5 mg/m2 (or 
approximately 25% 
reduction from the previous 
dose level) orally once a 
day (1-level reduction).  
Dose reduction of 
everolimus for Grade 3 
toxicity: 
i) if 3 mg/m2 daily 
everolimus at event onset, 
reduce to 3 mg/m2 every 
other day or 
ii) if 3 mg/m2 every other 
day everolimus at event 
onset, discontinue 
Fourth occurrence 
(same toxicity or new toxicity) 
Interrupt lenvatinib and 
everolimus 
Discuss with sponsor 
Grade 4g: Discontinue Study Treatment 
Note: For grading see Common Terminology Criteria for Adverse Events (CTCAE) v4.03.  Collect all CTC 
grades of adverse events, decreasing and increasing grade.  
a: An interruption of study treatment for more than 28 days will require sponsor`s approval before treatment can 
be resumed.  
b: Initiate optimal medical management for nausea, vomiting, hypothyroidism and/or diarrhea prior to any study 
treatment interruption or dose reduction.  
c: Applicable only to Grade 2 toxicities judged by the subject and/or physician to be intolerable. 
d: Obese subjects with weight loss do not need to return to the baseline weight or within10% of baseline weight 
(ie, Grade 1weight loss).  These subjects will restart the study drug(s) at a lower dose once their weight remains 
stable for at least 1 week and they reached the normal body mass index (BMI; if the weight loss occurred, but it 
is still above normal BMI, they can restart the study treatment at a lower dose once the weight has been stable 
for at least 1 week).  Normal BMI should be used as the new baseline for further dose reductions.  
e: For Grade 2 toxicity, resume everolimus at the same dose as prior to dose interruption.  For Grade 3 toxicity, 
investigator will decide the probability of the event being related to one or both drugs as to whether dose 
modification of one or both drugs is required. 
f: 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. 
g: Excluding laboratory abnormalities judged to be non-life-threatening, in which case manage as Grade 3. 
 
 
Duration of Treatment 
Study duration for each subject is estimated to be: 
 
Pretreatment Phase:  4 weeks 
 
Treatment Phase:  1 cycle (4 weeks) in Phase 1, 4 cycles (16 weeks) in Phase 2. 
 
Extension Phase: Estimated maximum time of treatment is 2 years (24 cycles)  
Subjects may remain on study treatment as long as they do not meet any of the following criteria: 
1) experience objective progression of disease (according to RECIST 1.1 or RANO criteria, as 
appropriate); 2) exhibit no clinical benefit (in the opinion of the investigator); 3) experience 
unacceptable toxicity leading to withdrawal from the study; 4) withdraw or are withdrawn from the 
study for any reason, or; 5) termination of the study program.  
As long as the subject has not experienced intolerable toxicity, he or she can continue to receive 
study treatment.  A 28-day follow-up visit from last date of receiving investigational drug will be 
performed for subjects who discontinue study treatment. 
Concomitant Drug/Therapy 


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Treatment (including blood products, blood transfusions, fluid transfusions, antibiotics, and 
antidiarrheal drugs, etc.) of complications of 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.  
An anti-diarrheal agent should be recommended to the subject at the start of study treatment and 
subjects should be instructed and educated to initiate anti-diarrheal treatment at the first onset of 
soft bowel movements.  The choice of anti-diarrheal agent should be individualized to the subject’s 
clinical circumstances and follow standard medical practice.  If signs/symptoms of diarrhea persist 
despite optimal medical management, instructions contained in the Dose Modification Guidelines 
should be followed. 
Administration of corticosteroids for progressive disease is not permitted.  Administration of 
corticosteroids will be limited to premedication or the short-term treatment of acute medical 
conditions in accordance with approved indications, institutional, or national guidelines. 
Further information on the prohibited concomitant therapies for lenvatinib and everolimus is 
included in the respective package inserts. 
Assessments 
Tumor Assessments:  
For all tumor types except HGG:  Tumor assessments will be performed using RECIST 1.1.  
Investigator-determined response assessments will be performed at each assessment time point and 
entered onto case report form.  Tumor assessments (CT chest and CT/MRI of abdomen, pelvis and 
other areas of known disease at screening plus any areas of suspected disease) should be performed 
at Screening and, for Phase 1 of the study, at Week 4 ±1 week, Week 12 ±1 week, Week 24 
±1 week and every12 weeks ±1 week thereafter, or as clinically indicated.  For subjects with 
primary CNS tumors and no other known areas of disease only CNS target and non-target lesions 
plus any areas of newly suspected disease must be scanned.  For Phase 2 of the study, tumor 
assessments should be performed at Screening, Week 8 ±1 week, Week 16 ±1 week, Week 24 ±1 
week, and then every 12 weeks ±1 week thereafter, or as clinically indicated.  All responses are to 
be confirmed at a follow-up examination after ≥28 days following the initial indication of response. 
A brain scan (CT with contrast or MRI pre-and post-contrast) will be performed at Screening, and 
during the study if clinically indicated.  
For HGG:  Tumor assessments will be performed using RANO Criteria.  A standard MRI imaging 
protocol will be performed for use in the assessments.  Investigator-determined response 
assessments at each assessment time point will be entered onto the appropriate CRFs.  Tumor 
assessments will be carried out during Screening and for Phase 1 of the study, at Week 4 ±1 week, 
Week 12 ±1 week, Week 24 ±1 week, and then every 12 weeks ±1 week thereafter, or as clinically 
indicated.  For Phase 2 of the study, tumor assessments should be performed at Screening, Week 8 
±1 week, Week 16 ±1 week, Week 24 ±1 week, and every 12 weeks ±1 week thereafter, or as 
clinically indicated.  
For Phase 2, copies of scans for tumor assessments will be sent to an imaging core laboratory 
designated by the sponsor for quality assessment and archival and potential future independent 
review. 
The imaging methodology for tumor assessments for all tumor types, including solid tumors and 
HGG, will be provided in an appendix to the study protocol. 
Pharmacokinetic Assessments:  Blood samples for plasma concentrations of lenvatinib and whole 
blood concentrations of everolimus will be collected from all subjects as described in the Schedule 
of Assessments. 
Pharmacodynamic (PD) Assessments:  Blood samples for plasma and serum studies will be 
collected from consenting subjects (optional) at Baseline and on Cycle 1 Day 15, Cycle 2 Day 1, 


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and then matched with tumor assessments and at the Off-treatment Visit, as specified in the 
Schedule of Assessments.  Only subjects with BSA >0.68 m2 are eligible to consent (optional) to 
blood samples for plasma and serum studies.  Biomarker discovery and/or validation will be 
performed to identify blood or tumor biomarkers that may be useful to predict subject response to 
study drug as well as for potential use in diagnostic development.  Blood samples may undergo 
global proteomic and/or single analyte enzyme-linked immunosorbent assays (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 subjects enrolled in this 
study.  The decision to perform exploratory biomarker analysis may be based on the clinical 
outcome of this study and/or the signals observed in other clinical studies or other information 
available at that time. 
Pharmocokinetic/Pharmacodynamic Assessments:  Relationships between lenvatinib exposure 
and safety will be explored graphically.  Pending the outcome of graphical assessments, modeling 
of potential relationships will be explored.  Details of exposure-safety analyses will be provided in 
a separate analysis plan. 
Pharmacogenomic/Pharmacogenetic Assessments:  Archived, fixed tumor tissue will be 
collected (if available) for potential assessment of mutations and other genetic alterations in genes 
and/or proteins that may be important in the development and progression of tumor biology 
relevant to the tumor types being explored, to evaluate response to study drug treatment as well as 
for potential use in diagnostic development.  Genetic alterations in target genes include lenvatinib 
targets (eg, FGF ligands and FGF receptors 1 to 4), angiogenesis-relevant targets (such as 
expression levels of VEGF, Ang 1/2, Tie-2, HGF and cMET) and markers associated with cell 
differentiation and tumorigenesis (eg, WNT/β-catenin pathway, hedgehog/PTCH pathway, and 
BMP/TGF signaling pathway).  Appropriate analytical technology/methodologies, such as next 
generation sequencing (NGS)-based whole exome sequencing (WES), whole transcriptome 
analysis or targeted re-sequencing using targeted gene panels (eg, ThermoFisher Oncomine 
Comprehensive Assay (OCA)) for gene alterations, targeted gene expression panels (eg, 
Nanostring PanCancer Pathway, PanCancer Immune) for gene expression analysis, single analyte 
or multiplex IHC, etc may be used based on the amount of tumor tissue available. 
Blood plasma samples will be collected (optional) for analysis of cell free nucleic acid (cf-nucleic 
acid).  Cell free nucleic acid isolated from plasma samples may be used to explore tumor genetic 
alterations such as mutations and other genetic alterations observed in archival tumor samples 
(using NGS-based targeted gene panels), as well as those which develop during drug treatment to 
monitor response to study drug.   
A blood sample will be collected for pharmacogenomic (PG) analysis (optional).  Variation in 
study drug exposure or the occurrence of AEs observed in the study population may be evaluated 
by correlating single–nucleotide polymorphisms with PK, safety, or PD data.  Genomic DNA 
extracted from blood samples may be used to confirm whether the DNA sequence variants 
observed in DNA extracted from tumor material are limited to the tumor. 
Data obtained will be used for research to assist in developing safer and more effective treatments 
and will not be used to change the diagnosis of the subject or alter the therapy of the subject.  The 
PD and PG samples will not be used to determine or predict risks for diseases that an individual 
subject does not currently have.  Any sample or derivatives (DNA, RNA, and protein) may be 
stored for up to 15 years after study completion to assist in research scientific questions related to 
cancer biology or for potential diagnostic development. 


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Instructions for the processing, storage, and shipping of samples will be provided in the Laboratory 
Instruction Manual. 
Safety Assessments:  Routine Phase 1 monitoring for clinical and laboratory toxicities will be 
used.  CTCAE v 4.03 will be used for grading toxicities and recording of all AEs and serious 
adverse events (SAEs).  Regular performance of physical examinations, laboratory evaluation for 
hematology, blood chemistry, and urine dipstick values, periodic measurement of vital signs, 
12-lead ECGs, echocardiography/MUGA scan, Lansky play score and Karnofsky performance 
score, baseline and periodic assessments of pancreatic enzymes, thyroid-stimulating hormone 
(TSH) levels and physeal dysplasia will be performed.  BP monitoring will occur at least weekly 
during the first 2 cycles.  BP will be assessed in terms of percentile for sex, age and height/length.  
Antihypertensive agents should be started as soon as elevated BP (systolic BP ≥95th percentile [BP 
≥140 mmHg for adult subjects] or diastolic BP ≥95th percentile [BP ≥90 mmHg for adult 
subjects]) is confirmed on 2 assessments obtained 1 hour apart.  For subjects with hypertension and 
proteinuria, treatment with an angiotensin-converting enzyme (ACE) inhibitor or angiotensin-II 
receptor antagonist is preferred.  Cardiac systolic function and corrected QT interval (QTc) will be 
assessed at screening, prior to Cycles 2 and 5, and every sixth cycle thereafter by 
echocardiography/MUGA scan and ECG.  
Other Assessments 
Pregnancy Test:  A serum β-hCG test will be performed for females of childbearing potential (see 
definition included in the Inclusion/Exclusion criteria).  A serum or urine pregnancy test will be 
performed at Screening and Baseline (or within 72 hours prior to the first dose of study 
medication), prior to Day 1 of each subsequent cycle and at the Off-treatment Visit in females of 
childbearing potential.  The results must be reviewed prior to administration of study drug on Cycle 
1 Day 1 and within 48 hours prior to dispensing study drug for all subsequent cycles. Blood and 
urine samples will be taken at designated time points as specified in the Schedule of Assessments. 
 
Bioanalytical Methods 
Lenvatinib in plasma and everolimus in whole blood will be quantified using validated liquid 
chromatography tandem mass spectrometry (LC-MS/MS) methods. 
Statistical Methods 
Study Endpoints 
Primary Endpoints for Phase 1  
 
MTD and RP2D of lenvatinib in combination with everolimus 
 
Safety and toxicity of lenvatinib in combination with everolimus 
Primary Endpoint for Phase 2  
 
ORR, defined as the proportion of subjects who have the best overall response (BOR) of 
complete response (CR) or partial response (PR) at Week 16 
Secondary Endpoints for Phase 1 and Phase 2  
 
ORR at the time of data cutoff 
 
DCR, defined as the proportion of subjects who have the BOR of CR or PR or stable disease 
(SD) (SD duration ≥7 weeks since the first dose of the study treatment) 
 
CBR, defined as the proportion of subjects who have the BOR of CR or PR or durable SD (SD 
duration ≥23 weeks since the first dose of the study treatment) 
 
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)   


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 
Plasma PK of lenvatinib and trough concentrations of everolimus when administered in 
combination 
 
Safety and toxicity of lenvatinib in combination with everolimus in Phase 2 
Exploratory Endpoints 
 
Assess candidate alterations in genes and/or proteins that may contribute to tumor development 
and predictive marker of response in archival tumor tissue 
 
Correlative blood and tumor biomarkers of treatment effects and outcomes 
Definitions of Analysis Sets 
 
Evaluable Analysis Set, defined as all subjects, who have measurable disease present at 
baseline and at least 1 post-baseline efficacy assessment, unless they have discontinued prior to 
the first efficacy assessment due to progressive disease.  This will be the analysis set for 
efficacy. 
 
Safety Analysis Set, defined as all subjects who received at least 1 dose of the study drug 
(lenvatinib or everolimus).  
 
Pharmacokinetic (PK) Analysis Set, defined as subjects in Safety Analysis Set who had at 
least 1 measurable postdose plasma concentration with an adequately documented dosing 
history. 
 
Pharmacodynamic (PD) Analysis Set, defined as all subjects in Safety Analysis Set who had 
evaluable PD data. 
Statistical Analysis 
Descriptive statistics will be used to summarize study endpoints.  Categorical variables will be 
summarized by number and percentage.  Continuous variables will be summarized using n (number 
of subjects with available data), mean, standard deviation, median, Q1, Q3, and range (minimum 
and maximum), unless otherwise specified.  
Efficacy data will be analyzed using the Evaluable Analysis Set, safety data will be analyzed using 
the Safety Analysis Set, PK data will be analyzed using the PK Analysis Set, and PD data will be 
analyzed using the PD Analysis Set.  All analyses will be performed by dose level in Phase 1 (if 
appropriate) and for each study cohort in Phase 2, unless otherwise specified.  
Efficacy Analyses 
Data cut-off for the primary study analysis in Phase 2 will occur when all subjects have completed 
at least 4 treatment cycles and, if applicable, a confirmatory scan has been performed (in case of a 
PR or CR at Week 16), or have discontinued study drug early. 
The following are evaluability criteria for objective response and non-target disease response 
analysis: 
 
Evaluable for objective response: Only those subjects who have measurable disease present 
at baseline and have their disease re-evaluated at post-baseline visits will be considered 
evaluable for objective response.  These subjects will have their response classified according 
to RECISIT 1.1 (for Ewing sarcoma/pPNET and rhabdomyosarcoma) or RANO (for HGG).   
 
Evaluable for non-target disease response:  Subjects who have lesions present at baseline 
that are evaluable but do not meet the definitions of measurable disease and have had their 
disease re-evaluated at post-baseline visits will be considered evaluable for non-target disease.  
Subjects with only non-target disease will be summarized by their best overall response.  The 
response will be classified according to RECIST 1.1 defined categories for subjects with non-
target disease only. 


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Primary Efficacy Analysis 
Phase 1: 
The study will utilize the rolling 6 design.  The primary objective of Phase 1 is to determine the 
MTD and to establish the RP2D.   
Phase 2:  
The primary efficacy endpoint in Phase 2 is ORR at 16 weeks.  Objective responses will count only 
confirmed CR and PR.  Estimated ORR and its exact 95% confidence interval (CI) using the 
method of Clopper and Pearson will be presented.   
Secondary Efficacy Analyses for Phase 1 and Phase 2 
The secondary efficacy endpoints will be ORR at the time of data cutoff, DCR, CBR and DOR.  
These endpoints in Phase 1 will be summarized if appropriate and listed by dose level, and ORR 
will be based only on subjects with measureable disease at screening/baseline.  For Phase 2, 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. 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker Analyses 
Pharmacokinetic Analysis 
Lenvatinib and everolimus concentration versus time data will be tabulated and summarized and 
graphically presented.   
Plasma concentrations of lenvatinib from the intense sampling in Phase 1 will be used to determine 
the following PK parameters: area under the plasma concentration time course profile (AUC), 
maximum observed concentration (Cmax), and time from dosing to the maximum observed 
concentration (Tmax).  Other PK parameters may be determined as data permit. 
For both lenvatinib and everolimus, data from both Phase 1 and 2 of the study will be pooled with 
available data from other studies and subjected to population PK analysis.  For each drug, the PK 
model will be parameterized in terms of clearance and volume of distribution.  Details of the 
population PK analysis will be provided in a separate analysis plan. 
Pharmacodynamic, Pharmacokinetic/Pharmacodynamic, Pharmacogenomic, and Other 
Biomarker Analyses 
Correlation between clinical response to treatment associated with a combination of lenvatinib and 
everolimus and blood or tumor biomarkers will be examined using descriptive statistics and 
graphic displays as appropriate.  Details will be provided in a separate analysis plan. 
Pharmacokinetic/PD exposure-safety relationships will be explored.  Safety endpoints will be most 
frequent AEs of special interest and dose reductions. Exploratory/graphical analyses will be 
conducted for PK/PD evaluations, and may be followed by model-based analyses.  A detailed 
analysis plan will be provided separately. 
Safety Analyses 
A descriptive summary of all toxicities will be provided. 
The following are evaluability criteria for toxicity analysis: 
 
Evaluable for toxicity:  All subjects who received at least 1 dose of study treatment are 
evaluable for toxicity.  For Phase 1, toxicities during Cycle 1 will be used for the purpose of 
dose escalations according to the rolling 6 design.  Subjects who developed a DLT or received 
at least 75% of the prescribed dose during Cycle 1 are considered fully evaluable for toxicity 
for the purpose of dose escalation. 
The incidence of treatment-emergent adverse events (TEAEs) and SAEs will be summarized by 
system organ class and preferred term.  Laboratory test data, vital signs, 12-lead ECGs, cardiac 
function by echocardiography/MUGA scan, urine dipstick, and Lansky play scores or Karnofsky 


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performance scores, and their changes or shifts from baseline will be summarized using descriptive 
statistics, as appropriate.  Summary of study drug exposure will be provided.  Prior and 
concomitant medications, medical/surgical history and subject demographics will be summarized.  
Interim Analyses 
For each disease cohort (Ewing sarcoma/pPNET, rhabdomyosarcoma, and HGG) in Phase 2, there 
will be 1 futility analysis:  this is planned for after the first 10 evaluable subjects have completed 
the Week 16 tumor assessment (or discontinued before Week 16).  At the futility analysis, if there 
are no responders (CR/PR), then the enrollment for that cohort will be discontinued for lack of 
efficacy.  If 1 or more responses are observed, the accrual will continue. 
Independent data monitoring committee (IDMC) 
Safety monitoring will be conducted by an independent data monitoring committee (IDMC). The 
frequency of safety reviews will be defined in the IDMC charter. Minutes from the open meetings 
of the IDMC will be provided if requested by regulatory agencies. The function and membership of 
the IDMC will be described in the IDMC charter. 
Sample Size Rationale 
Phase 1 – Determination of the Maximum Tolerated Dose:  The total number of subjects 
required for the Phase 1 portion of this study will depend upon the toxicities observed as the study 
progresses.  The minimum number of evaluable subjects required is 4.  The projected maximum 
number of evaluable subjects required is 48.  Once the MTD or RP2D has been defined, up to 6 
additional subjects with recurrent or refractory solid tumors may be enrolled to acquire PK data in 
a representative number of young subjects.  Therefore, a maximum of 54 subjects are expected to 
be enrolled in the 4 dose escalation levels, and PK expansion.  The Phase 1 part of the study is 
expected to be completed within 18 months.  In the event that each of Dose Levels -1, 1, 2, and 3 
are expanded to 12 subjects, an absolute maximum of 54 subjects would be required allowing for 
20% to be non-evaluable and including up to 6 additional subjects for PK analysis. 
Phase 2:  Phase 2 will require a minimum of 10 evaluable subjects per disease cohort and a 
maximum of 20 (10 evaluable subjects in each stage of Simon’s optimal 2-stage design).  
Therefore, a maximum of 22 subjects per cohort will be enrolled to allow for a 10% non-evaluable 
rate.  This design has 88% power to detect a 20% increase in the response rate at the significance 
level of one-sided alpha = 0.07 assuming a null response rate of 5% and alternative response rate 
≥25%. 


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3 
TABLE OF CONTENTS 
1 
TITLE PAGE .....................................................................................................................1 
REVISION HISTORY...............................................................................................................2 
2 
CLINICAL PROTOCOL SYNOPSIS .............................................................................12 
3 
TABLE OF CONTENTS .................................................................................................31 
4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..................................37 
5 
ETHICS............................................................................................................................39 
5.1 
Institutional Review Boards/Independent Ethics Committees ..............................39 
5.2 
Ethical Conduct of the Study .................................................................................40 
5.3 
Subject Information and Informed Consent ...........................................................40 
6 
INVESTIGATORS AND STUDY PERSONNEL ..........................................................41 
7 
INTRODUCTION ...........................................................................................................41 
7.1 
Scientific Rationale for the Combination of Lenvatinib with Everolimus ............43 
7.2 
Clinical Results Obtained with Combination Lenvatinib plus Everolimus 
Treatment ...............................................................................................................46 
7.3 
Pediatric Studies with Lenvatinib ..........................................................................47 
7.4 
Study Rationale ......................................................................................................48 
8 
STUDY OBJECTIVES ....................................................................................................48 
8.1 
Primary Objectives .................................................................................................48 
8.2 
Secondary Objectives .............................................................................................49 
8.3 
Exploratory Objectives ..........................................................................................49 
9 
INVESTIGATIONAL PLAN ..........................................................................................49 
9.1 
Overall Study Design and Plan ..............................................................................49 
9.1.1 
Pretreatment Phase .......................................................................................57 
9.1.1.1 
Screening Period ..................................................................................57 
9.1.1.2 
Baseline Period ....................................................................................58 
9.1.2 
Treatment Phase ...........................................................................................58 
9.1.3 
Extension Phase ...........................................................................................58 
9.1.4 
Treatment Discontinuation Criteria .............................................................58 
9.1.5 
Off-Treatment Visit .....................................................................................59 
9.1.6 
Post-Treatment Phase...................................................................................59 
9.1.6.1 
Follow-Up Period.................................................................................59 
9.2 
Discussion of Study Design ...................................................................................59 
9.3 
Selection of Study Population ................................................................................60 
9.3.1 
Inclusion Criteria .........................................................................................60 
9.3.2 
Exclusion Criteria ........................................................................................64 
9.3.3 
Removal of Subjects From Therapy or Assessment ....................................65 


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9.4 
Treatment ...............................................................................................................66 
9.4.1 
Treatment Administered ..............................................................................66 
9.4.1.1 
Study Treatment Dose Reduction and Interruption Instructions .........66 
9.4.1.2 
Blood Pressure .....................................................................................68 
9.4.1.3 
Management of Hypertension ..............................................................68 
9.4.1.4 
Management of Posterior Reversible Leukoencephalopathy 
Syndrome/ Reversible Posterior Leukoencephalopathy Syndrome .....71 
9.4.1.5 
Management of Proteinuria ..................................................................71 
9.4.1.6 
Management of Diarrhea .....................................................................72 
9.4.1.7 
Management of Non-Infectious Pneumonitis ......................................72 
9.4.1.8 
Management of Infections ...................................................................73 
9.4.1.9 
Management of Blood Glucose and Lipids .........................................73 
9.4.1.10 
Management of Hepatotoxicity ............................................................73 
9.4.1.11 
Management of Thromboembolic Events ............................................73 
9.4.1.12 
Management of Hypocalcemia ............................................................74 
9.4.1.13 
Management of Hemorrhage ...............................................................74 
9.4.1.14 
Management of Gastrointestinal Symptoms and Acute Abdominal 
Pain ......................................................................................................74 
9.4.1.15 
Management of Fistula Formation and Gastrointestinal Perforation ...75 
9.4.1.16 
Management of Osteonecrosis of the Jaw ...........................................75 
9.4.1.17 
Management of QT Prolongation ........................................................75 
9.4.2 
Identity of Investigational Products .............................................................75 
9.4.2.1 
Chemical Name, Structural Formula of Lenvatinib .............................76 
9.4.2.2 
Chemical Name, Structural Formula of Everolimus............................76 
9.4.2.3 
Comparator Drug .................................................................................76 
9.4.2.4 
Labeling for Study Drug ......................................................................76 
9.4.2.5 
Storage Conditions ...............................................................................76 
9.4.3 
Method of Assigning Subjects to Treatment Groups ...................................77 
9.4.4 
Selection of Doses in the Study ...................................................................77 
9.4.5 
Selection and Timing of Dose for Each Subject ..........................................77 
9.4.6 
Blinding........................................................................................................77 
9.4.7 
Prior and Concomitant Therapy ...................................................................77 
9.4.7.1 
Drug-Drug Interactions ........................................................................79 
9.4.7.2 
Prohibited Concomitant Therapies and Drugs .....................................79 
9.4.8 
Treatment Compliance .................................................................................80 
9.4.9 
Drug Supplies and Accountability ...............................................................80 
9.5 
Study Assessments .................................................................................................81 
9.5.1 
Assessments .................................................................................................81 


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9.5.1.1 
Demography .........................................................................................81 
9.5.1.2 
Baseline Assessments ..........................................................................81 
9.5.1.2.1 
Medical History and Physical Examinations .................................82 
9.5.1.3 
Efficacy Assessments ...........................................................................82 
9.5.1.3.1 
Tumor Assessments .......................................................................82 
9.5.1.4 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Assessments .............................................................83 
9.5.1.4.1 
Pharmacokinetic Assessments .......................................................83 
9.5.1.4.2 
Pharmacodynamic, Pharmacokinetic/Pharmacodynamic, 
Pharmacogenomic, and Other Biomarker, Assessments ...............84 
9.5.1.5 
Safety Assessments ..............................................................................85 
9.5.1.5.1 
Adverse Events ..............................................................................85 
9.5.1.5.2 
Serious Adverse Events and Events Associated with Special 
Situations........................................................................................87 
9.5.1.5.3 
Laboratory Measurements .............................................................88 
9.5.1.5.4 
Vital Signs and Weight Measurements ..........................................90 
9.5.1.5.5 
Physical Examinations ...................................................................90 
9.5.1.5.6 
Electrocardiograms ........................................................................90 
9.5.1.5.7 
Other Safety Assessments ..............................................................91 
9.5.1.6 
Other Assessments ...............................................................................91 
9.5.2 
Schedule of Procedures/Assessments ..........................................................91 
9.5.2.1 
Schedule of Procedures/Assessments ..................................................91 
9.5.2.2 
Description of Procedures/Assessments Schedule .............................100 
9.5.3 
Appropriateness of Measurements .............................................................100 
9.5.4 
Reporting of Serious Adverse Events, Pregnancy, and Events 
Associated with Special Situations ............................................................100 
9.5.4.1 
Reporting of Serious Adverse Events ................................................100 
9.5.4.2 
Reporting of Pregnancy and Exposure to Study Drug Through 
Breastfeeding .....................................................................................101 
9.5.4.3 
Reporting of Events Associated with Special Situations ...................101 
9.5.4.3.1 
Reporting of Adverse Events Associated With Study Drug 
Overdose, Misuse, Abuse, or Medication Error ..........................101 
9.5.4.4 
Expedited Reporting ..........................................................................102 
9.5.4.5 
Breaking the Blind .............................................................................102 
9.5.4.6 
Regulatory Reporting of Adverse Events ..........................................102 
9.5.5 
Completion/Discontinuation of Subjects ...................................................102 
9.5.6 
Abuse or Diversion of Study Drug ............................................................103 
9.5.7 
Confirmation of Medical Care by Another Physician ...............................103 
9.6 
Data Quality Assurance .......................................................................................103 


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9.6.1 
Data Collection ..........................................................................................103 
9.6.2 
Clinical Data Management ........................................................................104 
9.7 
Statistical Methods ...............................................................................................104 
9.7.1 
Statistical and Analytical Plans ..................................................................104 
9.7.1.1 
Study Endpoints .................................................................................104 
9.7.1.1.1 
Primary Endpoints .......................................................................104 
9.7.1.1.2 
Secondary Endpoints ...................................................................104 
9.7.1.1.3 
Exploratory Endpoints .................................................................105 
9.7.1.2 
Definitions of Analysis Sets...............................................................105 
9.7.1.3 
Subject Disposition ............................................................................105 
9.7.1.4 
Demographic and Other Baseline Characteristics .............................105 
9.7.1.5 
Prior and Concomitant Therapy .........................................................105 
9.7.1.6 
Efficacy Analyses ..............................................................................106 
9.7.1.6.1 
Primary Efficacy Analysis ...........................................................106 
9.7.1.6.2 
Secondary Efficacy Analyses for phase 1 and phase 2 ................106 
9.7.1.7 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Analyses .................................................................107 
9.7.1.7.1 
Pharmacokinetic Analysis ............................................................107 
9.7.1.7.2 
Pharmacodynamic, Pharmacokinetic/Pharmacodynamic, 
Pharmacogenomic,  and Other Biomarker Analyses ...................107 
9.7.1.8 
Safety Analyses ..................................................................................107 
9.7.1.8.1 
Extent of Exposure .......................................................................108 
9.7.1.8.2 
Adverse Events ............................................................................108 
9.7.1.8.3 
Laboratory Values ........................................................................109 
9.7.1.8.4 
Vital Signs ....................................................................................109 
9.7.1.8.5 
Electrocardiograms ......................................................................109 
9.7.1.8.6 
Other Safety Analyses ..................................................................109 
9.7.2 
Determination of Sample Size ...................................................................109 
9.7.3 
Interim Analysis .........................................................................................110 
9.7.4 
Other Statistical/Analytical Issues .............................................................110 
9.7.5 
Procedure for Revising the Statistical Analysis Plan .................................110 
10 REFERENCE LIST .......................................................................................................111 
11 PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE PROCEDURES) .....117 
11.1 
Changes to the Protocol .......................................................................................117 
11.2 
Adherence to the Protocol ....................................................................................117 
11.3 
Monitoring Procedures.........................................................................................117 
11.4 
Recording of Data ................................................................................................118 
11.5 
Identification of Source Data ...............................................................................118 


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11.6 
Retention of Records ............................................................................................119 
11.7 
Auditing Procedures and Inspection ....................................................................119 
11.8 
Handling of Study Drug .......................................................................................119 
11.9 
Publication of Results ..........................................................................................120 
11.10 Disclosure and Confidentiality ............................................................................120 
11.11 Discontinuation of Study .....................................................................................120 
11.12 Subject Insurance and Indemnity .........................................................................121 
12 APPENDICES ...............................................................................................................122 
 
LIST OF IN-TEXT TABLES 
Table 1 
Planned Dose-Escalation ...........................................................................51 
Table 2 
The Rolling 6 Design .................................................................................52 
Table 3 
Total Lenvatinib Dose (mg):  Body Surface Area (m2) * Dose Level 
(mg/m2) ......................................................................................................56 
Table 4 
Total Everolimus Dose (mg):  Body Surface Area (m2) * Dose Level 
(mg/m2) ......................................................................................................57 
Table 5 
Dose Modification Guidelines for Lenvatinib-Everolimus 
Combination Treatment-Related Toxicity .................................................67 
Table 6 
Clinical Laboratory Tests ...........................................................................89 
Table 7 
Schedule of Assessments – Phase 1 ...........................................................92 
Table 8 
Schedule of Assessments – Phase 2 ...........................................................96 
 
LIST OF IN-TEXT FIGURES 
Figure 1 
Study Design ..............................................................................................50 
Figure 2 
Management of Hypertension ....................................................................71 
LIST OF APPENDICES 
Appendix 1 
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 ................122 
Appendix 2 
Common Terminology Criteria for Adverse Events (v4.0) .....................123 
Appendix 3 
Monoclonal Antibodies Half-lives ...........................................................124 
Appendix 4 
Lansky Score ............................................................................................125 
Appendix 5 
Karnofsky Performance Status Scale Definitions Rating (%) Criteria ....126 
Appendix 6 
Schwartz Formula ....................................................................................127 
Appendix 7 
Blood Pressure Levels for Boys by Age and Height Percentile ..............128 
Appendix 8 
Blood Pressure Levels for Girls by Age and Height Percentile ..............130 
Appendix 9 
Body Mass Index-For-Age Percentiles ....................................................132 
Appendix 10 Body Mass Index-For-Age Percentiles ....................................................133 
Appendix 11 Pharmacodynamic, Pharmacogenomic, and Other Biomarker Research 134 
Appendix 12 Preparation of Lenvatinib suspension ......................................................137 


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Appendix 13 Imaging Scans Methodology for Tumor Assessment ..............................143 
Appendix 14 Response Assessment in Neuro-Oncology (RANO) Criteria ..................145 
Appendix 15 CYP3A4 Substrates, Inducers and Inhibitors ..........................................147 


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4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Term 
AE 
adverse event 
AFP 
alpha-fetoprotein 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
ß-hCG 
beta-human chorionic gonadotropin 
BOR 
best overall response 
BP 
blood pressure 
CBR 
clinical benefit rate 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CNS 
central nervous system 
CR 
complete response 
CRA 
clinical research associate 
CRF 
case report form 
CRO 
contract research organization 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
DCR 
disease control rate 
DLT 
dose-limiting toxicity 
IDMC 
Independent Data Monitoring Committee 
DOR 
duration of response 
ECG 
electrocardiogram 
FDA 
Food and Drug Administration 
FGF(R) 
fibroblast growth factor (receptor) 
GCP 
Good Clinical Practice 
HGG 
high grade glioma 
HR 
hazard ratio 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 


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Abbreviation 
Term 
IRB 
Institutional Review Board 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
mTOR 
mammalian target of rapamycin 
MUGA 
multigated acquisition 
ORR 
objective response rate 
PD 
pharmacodynamic(s) 
P-gp 
P-glycoprotein 
PK 
pharmacokinetic(s) 
pPNET 
peripheral primitive neuroectodermal tumor 
PR 
partial response 
PRES/RPLS 
Posterior Reversible Leukoencephalopathy Syndrome/ Reversible Posterior 
Leukoencephalopathy Syndrome  
PSC 
Protocol Steering Committee 
QTc 
corrected QT interval 
RANO 
Response Assessment in Neuro-Oncology 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D 
recommended Phase 2 dose 
RTK(I) 
receptor tyrosine kinase (inhibitor) 
SAE 
serious adverse event 
SD 
stable disease 
SmPC 
Summary of Product Characteristics 
TKI 
tyrosine kinase inhibitor 
ULN 
upper limit of normal 
VEGF 
vascular endothelial growth factor 
VEGFR 
vascular endothelial growth factor (receptor) 
XRT 
radiotherapy 


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5 
ETHICS 
5.1 
Institutional Review Boards/Independent Ethics Committees 
The protocol, informed consent form (ICF)/assent, and appropriate related documents must 
be reviewed and approved by an Institutional Review Board (IRB) or Independent Ethics 
Committee (IEC) constituted and functioning in accordance with International Council for 
Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) E6 
Good Clinical Practice (GCP), Section 3, and any local regulations (eg, Code of Federal 
Regulations, Title 21 CFR Part 56 or European Union [EU] Clinical Trials Directive 
2001/20/EC).  Any protocol amendment or revision to the ICF will be resubmitted to the 
IRB/IEC for review and approval, except for changes involving only logistical or 
administrative aspects of the study (eg, change in clinical research associate(s) [CRA(s)], 
change of telephone number[s]).  Documentation of IRB/IEC compliance with the ICH E6 
and any local regulations regarding constitution and review conduct will be provided to the 
sponsor. 
A signed letter of study approval from the IRB/IEC chairman must be sent to the principal 
investigator with a copy to the sponsor before study start and the release of any study drug to 
the site by the sponsor or its designee (ICH E6, Section 4.4).  If the IRB/IEC decides to 
suspend or terminate the study, the investigator will immediately send the notice of study 
suspension or termination by the IRB/IEC to the sponsor. 
Study progress is to be reported to IRB/IECs annually (or as required) by the investigator or 
sponsor, depending on local regulatory obligations.  If the investigator is required to report to 
the IRB/IEC, he/she will forward a copy to the sponsor at the time of each periodic report.  
The investigator(s) or the sponsor will submit, depending on local regulations, periodic 
reports and inform the IRB/IEC of any reportable adverse events (AEs) per ICH guidelines 
and local IRB/IEC standards of practice.  Upon completion of the study, the investigator will 
provide the IRB/IEC with a brief report of the outcome of the study, if required. 
At the end of the study, the sponsor should notify the IRB/IEC and Competent Authority 
within 90 days.  The definition for end of the study is the date of data cutoff for the final 
analysis or last subject/last visit including discontinuation from the study for any reason, 
whichever occurs later.  Subjects who remain on treatment at the cutoff for the final analysis 
will continue receiving the same treatment in consecutive cycles as long as they do not meet 
any of the study discontinuation criteria as detailed in the protocol. 
In the case of early termination/temporary halt of the study, the investigator should notify the 
IRB/IEC and Competent Authority within 15 calendar days, and a detailed written 
explanation of the reasons for the termination/halt should be given.   


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5.2 
Ethical Conduct of the Study 
This study will be conducted in accordance with standard operating procedures of the 
sponsor (or designee), which are designed to ensure adherence to GCP guidelines as required 
by the following: 
 
Principles of the World Medical Association Declaration of Helsinki, 2013 
 
ICH E6 Guideline for GCP (CPMP/ICH/135/95) of the European Agency for the 
Evaluation of Medicinal Products, Committee for Proprietary Medicinal Products, 
International Council for Harmonisation of of Technical Requirements for 
Pharmaceuticals for Human Use 
 
Title 21 of the United States Code of Federal Regulations (US 21 CFR) regarding clinical 
studies, including Part 50 and Part 56 concerning informed subject consent and IRB 
regulations and applicable sections of US 21 CFR Part 312 
 
European Good Clinical Practice Directive 2005/28/EC and Clinical Trial Directive 
2001/20/EC for studies conducted within any EU country.  All suspected unexpected 
serious adverse reactions (SUSARs) will be reported, as required, to the Competent 
Authorities of all involved EU member states.   
5.3 
Subject Information and Informed Consent 
As part of administering the informed consent document, the investigator must explain to 
each subject (or subject’s parent[s] or legally authorized representative) the nature of the 
study, its purpose, the procedures involved, the expected duration, the potential risks and 
benefits involved, any potential discomfort, potential alternative procedure(s) or course(s) of 
treatment available to the subject, and the extent of maintaining confidentiality of the 
subject’s records.  Each subject (or subject’s parent[s] or legally authorized representative) 
must be informed that participation in the study is voluntary, that he/she may withdraw from 
the study at any time, and that withdrawal of consent will not affect his/her subsequent 
medical treatment or relationship with the treating physician. 
This informed consent should be given by means of a standard written statement, written in 
nontechnical language.  The subject (or subject’s parent[s] or legally authorized 
representative) should understand the statement before signing and dating it and will be given 
a copy of the signed document.  If a subject is unable to read or if a subject’s parent or 
legally acceptable representative is unable to read, an impartial witness should be present 
during the entire informed consent discussion.  After the written informed consent/assent 
form and any other written information to be provided to subjects is read and explained to the 
subject, the subject’s parent(s) or legally acceptable representative, and after the subject or 
the subject’s legally acceptable representative has orally consented to the subject’s 
participation in the study and, if capable of doing so, has signed and personally dated the 
ICF, the witness should sign and personally date the consent form.   


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The subject and/or the subject’s parent(s) or legally authorized representative(s) will be asked 
to sign an informed consent/assent form at the Screening Visit before any study-specific 
procedures are performed.  No subject can enter the study before his/her informed consent 
has been obtained.  Informed consent from the parents or subject’s legally acceptable 
representative and informed consent (or assent) from the subject must be obtained prior to 
any study specific procedures are performed. 
An unsigned copy of an IRB/IEC-and sponsor approved written ICF/assent must be prepared 
in accordance with ICH E6, Section 4, and all applicable local regulations (eg, Title 21 CFR 
Part 50 or EU Clinical Trials Directive 2001/20/EC) and provided to the sponsor.  Each 
subject and the subject’s parent(s) or legally acceptable representative must sign an approved 
informed consent/assent form before study participation.  The form must be signed and dated 
by the appropriate parties.  The original, signed and dated informed consent/assent form for 
each subject will be verified by the sponsor and kept in the investigator site file and a copy 
must be given to the subject   
The subject or the subject’s parent(s) or legally authorized representative should be informed 
in a timely manner if new information becomes available that may be relevant to the 
subject’s willingness to continue participation in the study.  The communication of this 
information should be documented. 
When the subject reaches the age of 18 years while on study, and becomes competent to give 
informed consent, his/her consent will be obtained using separate ICFs to continue on the 
study. 
With regard to the pharmacogenomic assessments described in Section 9.5.1.4.2, an informed 
consent for collection of samples during the study for gene analysis will be prepared 
separately.  Subjects may still be eligible to enroll in the study if they do not give informed 
consent for gene analysis. 
6 
INVESTIGATORS AND STUDY PERSONNEL 
This study will be conducted by qualified investigators under the sponsorship of Eisai (the 
sponsor) at approximately 60 sites: 20 sites for the Phase 1 portion and an additional 40 sites 
for the Phase 2 portion. 
The name and telephone and fax numbers of the medical monitor and other contact personnel 
at the sponsor and of the contract research organizations (CROs) are listed in Investigator 
Study File provided to each site. 
7 
INTRODUCTION 
Solid tumors make up about 30% of all cancers in children.  Current strategies for treatment 
of solid tumors in children have greatly improved in the last few decades.  The success of 
curing nearly 80% of children diagnosed with cancer is tempered by the inability to cure the 
remaining 20% with conventional approaches.  There remains a significant unmet medical 


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need for more effective treatment options with a manageable safety profile and for 
identifying biomarkers to more accurately diagnose these tumors and determine the level of 
risk in pediatric patients with solid tumors. 
Some of the most common types of solid tumors found in children are brain tumors, 
rhabdomyosarcoma, and Ewing sarcoma/peripheral primitive neuroectodermal tumor 
(pPNET).  
High grade gliomas (HGGs) represent approximately 8–12% of all pediatric central nervous 
system (CNS) tumors.  The overall total incidence of HGG (including anaplastic 
astrocytoma, anaplastic oligodendrioglioma, glioblastoma, mixed glioma, and malignant 
glioma) among children 0-19 years old is approximately 0.85 per 100,000 (CBTRUS 2012).  
The distribution of HGGs between males and females is relatively equal (Finlay, et al., 
2005).  Pediatric HGGs are very aggressive and malignant lesions.  Initial treatment 
strategies typically consist of a gross total resection when feasible followed by focal 
radiotherapy combined with chemotherapy.  Despite improvements in neurosurgery, 
radiotherapy, and chemotherapy, the outcome for children with HGG remains poor.  No 
effective chemotherapy regimens have been identified for any pediatric HGG 
(MacDonald, et al., 2011).  Two-year survival rates range from 10% to 30%.  
Rhabdomyosarcoma is the most common soft tissue sarcoma in children, with approximately 
350 new cases diagnosed each year in the US among the population age group between 0 and 
19 years (Linet, et al., 1999).  There is slight male predominance, and approximately 
two-thirds of the cases are diagnosed in children younger than 6 years of age 
(Dasgupta, et al., 2012).  Rhabdomyosarcoma usually manifests as an expanding mass in 
different body locations.  The most common primary tumor sites include the head and neck 
region (35%), followed by the genitourinary and extremity primaries (Pappo, et al., 1995).  In 
patients with localized disease, overall 5-year survival rates are over 80% with the combined 
use of surgery, radiation therapy, and 3-drug chemotherapy of vincristine, actinomycin D, 
and cyclophosphamide (VAC).  However, in patients with metastatic disease, little progress 
has been made in survival rates, with a 5-year, failure-free survival rate of less than 30% 
(Egas-Bejar, et al., 2014). 
Ewing’s sarcoma/pPNET also called Ewing’s sarcoma family of tumors (ESFT) constitutes 
5% to 10% of primary bone tumors (Gurney, et al., 1999).  It occurs predominantly in 
children and young adults and shows a slight predominance for males.  Ewing’s 
sarcoma/pPNET is very rare with an incidence of just less than 3 per 1 million people under 
20 years of age (Esiashvili, et al., 2008).  It occurs most frequently in the pelvis, long bones 
of the legs or arms, chest wall, spine and the skull.  The first line treatment consists of 
neoadjuvant chemotherapy followed by local control surgery (which frequently involves 
limb-sparing surgery with prosthetic reconstruction) with or without radiation, followed by 
adjuvant chemotherapy.  Chemotherapy involves a 5-drug regimen of vincristine, 
doxorubicin, cyclophosphamide alternating with ifosfamide and etoposide in 2-3 weeks 
intervals (VDC-IE).  Presence of metastases is the most prominent adverse prognostic factor 
in Ewing’s sarcoma/pPNET.  Metastases at diagnosis are detected in 15% to 33% of patients, 


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with survival rates from 9% to 41%, as compared with the survival expectancy of patients 
with localized disease of approximately 70% (Ladenstein, et al., 2010). 
7.1 
Scientific Rationale for the Combination of Lenvatinib with 
Everolimus 
Angiogenesis is vital for the growth and metastatic behavior of malignant solid tumors.  
Vascular endothelial growth factor (VEGF) is critical to both physiologic and pathologic 
angiogenesis, and ligand-binding to VEGF receptor (VEGFR1-3) has been shown to drive 
tumor growth and facilitate metastasis (Ferrara, et al., 2002).  VEGFR-predominating 
receptor tyrosine kinase inhibitors (RTKIs) have emerged as successful anticancer agents, 
with numerous Food and Drug Administration (FDA) approved drugs in class, and several 
indications for renal and hepatic carcinomas, thyroid cancer and soft tissue sarcoma (Brose, 
et al., 2014; van der Graaf, et al., 2012; Llovet, et al., 2008; Escudier, et al, 2007; Motzer, et 
al., 2007).  RTKIs have consistently demonstrated anti-tumor activity in preclinical models 
of pediatric solid tumors, notably rhabdomyosarcoma, Ewing sarcoma, and neuroblastoma 
models (Maris, (a) et al., 2008; Maris, (b) et al., 2008).  Factors limiting the clinical efficacy 
of RTKIs in pediatric tumors to date may include the early acquisition of drug resistance, 
tumor heterogeneity, and utilization of alternative survival pathways in tumors.  Classic 
resistance to RTKIs include secondary mutations that disrupt target binding, increased RTK 
expression, increased ligand expression, increased drug efflux, and altered drug metabolism 
pathways (Engelman, et al., 2008), and altered energy (glucose) metabolism (Hudson, et al., 
2014).   
Lenvatinib is a potent multiple RTKI that selectively inhibits VEGFRs (VEGFR1 [FLT1], 
VEGFR2 [KDR], VEGFR3 [FLT4]) in addition to other pro-angiogenic and oncogenic 
pathway-related RTKs, including fibroblast growth factor (FGF) receptors FGFR1-4, 
platelet-derived growth factor (PDGF) receptor α, KIT, and RET.  Lenvatinib has potent 
anti-angiogenic properties not only towards VEGF-driven angiogenesis and 
lymphangiogenesis but also towards FGF-driven angiogenesis.  Through established VEGF- 
and FGF-dependent angiogenesis mouse models, lenvatinib significantly inhibited both 
VEGF- and FGF-induced in vivo angiogenesis in a dorsal air sac assay at doses of 10 and 
30 mg/kg (Ichikawa, et al., 2015; Yamamoto, et al., 2014).  A subset of glioblastomas harbor 
oncogenic chromosomal translocations involving the in-frame fusion of the tyrosine kinase 
domains of FGFR1 or FGFR3 with TACC genes which result in constitutive kinase activity 
(Parker, et al., 2013; Singh, et al., 2012).  Treatment of in vivo models harboring the 
FGFR-TACC fusions with an FGFR inhibitor prolongs survival suggesting a role for 
FGFR-targeted therapies in high grade CNS tumors.  The studies also demonstrated 
activating recurrent hotspot mutations and intragenic duplications of the tyrosine kinase 
domain of FGFR1 in pediatric pilocytic astrocytomas and diffuse pediatric gliomas 
respectively providing further rationale for exploring agents targeting FGFR (Zhang, 
et al., 2013; Jones, et al., 2013).  
In addition to the anti-proliferative activity of lenvatinib, target engagement of the FGFR 
signaling pathway has been evaluated in both in vitro and in vivo models (Tohyama, 
et al., 2014).  Lenvatinib treatment at doses as low as 3 mg/kg and 10 mg/kg demonstrated a 


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decrease in phosphorylation of FRS2 levels in the RO82-W-1 xenograft model 
(Tohyama, et al., 2014).  These results demonstrate that lenvatinib effectively engages and 
inhibits the FGFR signaling pathway in vitro and in vivo which contributes to the observed 
anti-tumor activity of lenvatinib.  Further in vitro and in vivo studies confirm the inhibition 
of FGFR1 and downstream targets including MEK and Erk (Nakazawa, et al., 2015). 
FGF ligand levels, such as FGF23, may be useful biomarkers for FGFR inhibition by 
lenvatinib (Ichikawa, et al., 2015).  FGF23, a protein hormone regulating mineral 
metabolism, is a potential pharmacodynamics (PD) marker for FGFR inhibition in vivo, since 
plasma levels are elevated as a compensatory response to FGFR inhibition 
(Wohrle, et al., 2011; Kim, et al., 2011).  Plasma FGF23, was significantly increased 
(2.6-fold, compared to vehicle control) in mice 24 hours after a single oral administration of 
lenvatinib mesylate (10 mg/kg) (Ichikawa, et al., 2015).  Inhibition of multiple receptors is 
also postulated as a mechanism to decrease the rate of drug resistance to anti-angiogenic 
therapy (Sonpavde, et al., 2012).  
Lenvatinib showed a favorable profile for combination in preclinical studies on 5 human 
osteosarcoma tumor xenograft models demonstrating that lenvatinib enhances the anti-tumor 
activity of conventional cytotoxic chemotherapy with ifosfamide and etoposide (IE) 
(Matsuki, et al., 2016).  Lenvatinib also appears to be effective in sensitizing chemo-resistant 
osteosarcoma models.  Gene expression profiling studies (RNAseq analysis) conducted on 
5 human pediatric osteosarcoma xenograft models identified genes and signaling pathways 
associated with tumor response to the combination treatment (Lenvatinib + Ifosfamide + 
Etoposide) (Dezso, et al., 2016).  Genes included in these pathways were related to cell 
differentiation, RTKs, and angiogenic and pro-oncogenic pathways.  These genes and 
signaling pathways may be relevant targets of lenvatinib and everolimus, and have all been 
demonstrated to play key roles in the pathogenesis of pediatric sarcomas and HGGs (Pressey, 
et al., 2011; Oue, et al., 2010; Matushansky, et al., 2008).  For example, activation of Wnt/β-
catenin, SHH/PTCH/GLI1, BMP/TGF, and the HGF/MET axes have all been implicated in 
the development and progression of several soft tissue sarcomas and gliomas (Lin and Chen, 
2014; Graveel, et al., 2013; Yoshikawa, et al., 2004;).  The hyperactivation and 
overexpression of these pathways may also play critical roles in the development of 
chemoresistance (WNT5A) and can serve as prognostic biomarkers (FGF23, BMP2/4) 
(Hung, et al., 2014; Yoshikawa, et al., 2004;).   
An alternative angiogenic pathway is mediated by mammalian target of rapamycin (mTOR).  
mTOR is a serine/threonine kinase involved in integrating growth factor-activated and 
nutrient-sensing signals which regulate diverse cellular processes including growth, survival, 
differentiation, autophagy and metabolism (Shimobayashi, et al., 2014).  Deregulation of 
mTOR signaling has been described for numerous cancer types and familial cancer 
syndromes.  mTOR activation can result from the overexpression or presence of activating 
mutations in RTKs such as insulin like growth factor 1 receptor (IGF-1R), FGFR, or 
epidermal growth factor receptor (EGFR) and has been described in different solid tumors 
including various sarcoma subtypes and gliomas (Wan, et al., 2005).  Similarly, downstream 
mutations or overexpression of PI3K and Akt, or loss of tumor suppressor protein function, 


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have been associated with various tumors and cancer predisposition syndromes due to the 
aberrant activation of the TSC-Rheb-mTOR axis (Engelman, et al., 2006).  
Everolimus is an oral rapamycin analogue that forms a complex with FK506 Binding 
Protein-12 (FKBP12) and acts as a highly selective allosteric inhibitor of the mTOR 
complex 1 (mTORC1) causing the dissociation of regulatory-associated protein of mTOR 
(Raptor) and loss of mTORC1 substrate interactions (Chiarini, et al., 2015).  Everolimus has 
been FDA-approved for the treatment of various cancers including advanced renal 
carcinoma, unresectable neuroendocrine pancreatic adenocarcinoma, and advanced estrogen 
receptor-positive/HER2- breast carcinoma.  Most notably, everolimus has a pediatric specific 
approval for the treatment of subependymal giant cell astrocytoma (SEGA) associated with 
tuberous sclerosis (Franz, et al., 2012; Krueger, et al., 2010;).  The anti-tumor effects of 
everolimus have also been demonstrated in a number of in vitro and in vivo models of 
sarcomas including synovial sarcoma, osteosarcoma, chondrosarcoma, and leiomyosarcoma 
(Yasui, et al., 2014; Pignochino, et al., 2013; Perez, et al., 2012; Hernando, et al., 2007).  
These results provide a strong biologic rationale for further evaluating the role of everolimus 
in pediatric solid tumors. 
Proangiogenic signaling pathways (VEGF, FGF) cooperate with mTOR-mediated regulation 
of cell growth and maintenance to drive the development of pediatric solid tumors.  The 
agents that target both the proangiogenic pathways and mTOR signaling are attractive 
candidate agents for study.  Combinations of molecularly targeted agents guided by the 
genetics and biology of sarcoma may aid in overcoming the resistance that is inevitable with 
single-agent therapy by blocking several pathways critical to cancer progression.  This can be 
achieved by simultaneous inhibition of several mediators (eg, simultaneous inhibition of 
VEGF, FGF, platelet derived growth factor) or targeted inhibition at several levels within the 
same pathway (eg, inhibition of VEGF/mTOR/HIF).  Thus, a multi-target therapeutic 
approach may help overcome drug resistance leading to enhanced and prolonged efficacy.  
Indeed, combined VEGF and mTOR pathway inhibition has shown promise in preclinical 
solid tumor models (Molhoek, et al., 2008; Ikezoe, et al., 2006). 
Combination of the multi-RTKI sorafenib and the mTOR inhibitor, everolimus, has shown 
enhancement of the anti-angiogenic, anti-proliferative, and pro-apoptotic effects of RTK 
inhibition in various in vitro and in vivo solid tumor models including pancreatic cancer, 
hepatocellular carcinoma, mesothelioma, and osteosarcoma (Pignochino, et al., 2015; 
Pignochino, et al., 2013; Pawaskar, et al., 2013; Piguet, et al., 2011;).  
The combination of lenvatinib with everolimus has also been shown to exert a significantly 
higher anti-tumor effect compared to either agent alone in mouse models of renal cell 
carcinoma (Adachi, et al., 2016).  In xenograft models of Ewing sarcoma and osteosarcoma, 
the lenvatinib-everolimus combination was more potent in abrogating tumor growth than 
either agent alone (Eisai Co. Ltd. Data on File). 
Overcoming RTKI-induced resistance has been shown to be effectively accomplished by 
inhibiting alternative survival pathways.  In preclinical studies, sensitivity of 
lenvatinib-resistant tumor xenograft models was restored after sequential treatment with the 


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dual-RTKI, golvatinib which targets not only VEGFR, but also c-MET (Nakagawa, et al., 
2014).  mTOR inhibition is anticipated to abrogate several alternative survival pathways 
providing biologic rationale for combined treatment with lenvatinib and everolimus 
(Yasui, et al., 2014; Etnyre, et al., 2014; Imura, et al., 2014). 
A preclinical study of lenvatinib plus everolimus demonstrates enhanced inhibition of VEGF 
and FGF-induced angiogenesis than for either agent alone in human endothelial cell models 
(Mitsuhashi, et al., 2016).  The combination also showed synergistic enhancement against 
bFGF-driven angiogenesis, distinguishing this from other VEGFR2 tyrosine kinase inhibitors 
(TKIs).  Effects of lenvatinib, everolimus, and its combination on VEGF or bFGF activated 
intracellular signaling were analyzed in human umbilical vein endothelial cells (HUVEC) by 
western blotting.  Lenvatinib inhibited the VEGF or bFGF-driven phosphorylation of Erk1/2 
(Thr202/Tyr204), S6K (Thr389), and S6K (Thr421/Ser424), and S6 (Ser235/Ser236), 
indicating the inhibition of both the MAPK pathway and the mTOR-S6K-S6 pathway.  
Everolimus inhibited the phosphorylation of S6K (Thr389), S6K (Thr421/Ser424), and S6 
(Ser235/Ser236), but not Erk1/2.  The combination showed greater inhibition for the 
phosphorylation of S6K (Thr421/Ser424) and S6 (Ser235/Ser236) than each single agent.  
Combination effects of lenvatinib and everolimus on VEGF and bFGF-induced proliferation 
or tube formation of human umbilical vein endothelial cells (HUVEC) were examined using 
combination indexes.  Inhibitory activity of the combination at several molar ratios was 
mostly additive for VEGF-driven proliferation (combination index: 0.799-1.167) and mostly 
synergistic for bFGF-driven tube formation (combination index: 0.469-0.741).  Antitumor 
activities were tested in the KP-1/VEGF or KP-1/FGF models, where VEGF or FGF-induced 
tumor angiogenesis and tumor growth were enhanced in nude mice due to overexpressed 
VEGF or FGF in human pancreatic cancer KP-1cells (Mitsuhashi, et al., 2016).  In the KP-
1/VEGF or KP-1/FGF xenograft models, lenvatinib, everolimus, and the combination (orally, 
once daily x 14) significantly inhibited tumor growth compared to vehicle.  In addition the 
combination of lenvatinib (7.5 mg/kg) and everolimus (15 mg/kg) showed significantly 
greater antitumor activity than higher dose of either lenvatinib (10 mg/kg) or everolimus 
(30 mg/kg) monotherapy.  The vertical inhibition of angiogenic signaling pathways with 
lenvatinib (RTK) and everolimus (mTOR) may contribute to enhanced antiangiogenic 
activity by dual targeting of the mTOR-S6K-S6 pathway. 
In addition to the results obtained in the extensive in vitro and in vivo pre-clinical studies, the 
strong rationale for pediatric evaluation of the combination of lenvatinib and everolimus is 
the positive randomized trial in renal cell carcinoma resulting in FDA approval of lenvatinib 
combination with everolimus for patients with advanced renal cell carcinoma following 
1 prior antiangiogenic therapy.   
7.2 
Clinical Results Obtained with Combination Lenvatinib plus 
Everolimus Treatment  
The safety and efficacy of lenvatinib and everolimus combination treatment was investigated 
in the randomized, multi-center, open-label trial E7080-G000-205 (Study 205) in subjects 
with unresectable, advanced or metastatic RCC.  In the Phase 1b portion the recommended 


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Phase 2 dose (RP2D) for the lenvatinib/everolimus combination was determined as 
lenvatinib 18 mg plus everolimus 5 mg administered daily.  
The Phase 2 portion enrolled subjects with advanced or metastatic, clear-cell, renal cell 
carcinoma who had a history of receiving one prior VEGF agent.  A total of 153 subjects 
were randomized in a 1:1:1 ratio to receive treatment with lenvatinib (18 mg) plus 
everolimus (5 mg), lenvatinib (24 mg), or everolimus (10 mg) administered once daily. 
The primary analysis demonstrated median PFS for lenvatinib of 7.4 months (5.6-10.2, 95% 
confidence interval [CI]) vs everolimus 5.5 months (3.5-7.1) vs combination 14.6 months 
(5.9-20.1) with a hazard ratio (HR) of combination vs everolimus of 0.40 (0.24-0.68; 
p = 0.0005) and HR of lenvatinib vs everolimus of 0.61 (0.38-0.98; p = 0.0479).  The 
objective response rate (ORR) for lenvatinib was 27% (16-41), everolimus 6% (1-17%), and 
combination 43% (29-58%) with a median duration of objective response of lenvatinib 
7.5 months (3.8-not estimable), everolimus 8.5 months (7.5-9.4), and combination 
13.1 months (3.8-not estimable).  The ORR ratio between combination vs everolimus was 7.2 
(2.3-22.5; p <0.0001) and lenvatinib vs everolimus was 4.5 (1.4-14.7; p = 0.0067).  Updated 
overall survival analysis suggests a survival benefit for the combination over everolimus with 
an overall survival for lenvatinib of 19.1 months (13.6-26.2), everolimus 15.4 months 
(11.8-19.6), and the combination of 25.5 months (16.4-not estimable).  The HR for 
combination vs everolimus is 0.51 (0.30-0.88; p = 0.024) and 0.68 for lenvatinib vs 
everolimus (0.41-1.14; p = 0.118) in support of a potential survival benefit with combination 
therapy (Motzer, et al., 2015). 
The average duration of therapy for lenvatinib was 7.4 months (range 0.1-23.0), everolimus 
4.1 months (0.3-20.1), and combination 7.6 months (0.7-22.6).  The reported Grade 3/4 AEs 
included diarrhea, fatigue/asthenia, vomiting, nausea, hypertension, decreased weight and 
dyspnea.  Discontinuations due to AEs were as follows: lenvatinib 25%, everolimus 12%, 
and combination 24%.  The rates of AEs were generally higher for the combination arm, but 
they were predictable and generally managed with concomitant medication and dose 
modifications.  
7.3 
Pediatric Studies with Lenvatinib 
The safety, tolerability, and activity of lenvatinib in pediatric population is being evaluated in 
an ongoing Phase 1/2 study E7080-G000-207 (Study 207) of lenvatinib in children and 
adolescents with refractory or relapsed solid malignancies.  During Phase 1 portion of the 
study, the maximum tolerated dose (MTD) and a recommended dose of lenvatinib as a single 
agent in this subject population was identified.  The Time-to-Event Continuous Reassessment 
Method (TiTE-CRM) was used to identify the recommended dose of lenvatinib 
(Cheung, et al., 2000).  Twenty three subjects were enrolled across 3 dose groups.  Three of 
those subjects were treated at 11 mg/m2, 9 subjects were treated at 14 mg/m2, and 11 subjects 
were treated at 17 mg/m2.  Twenty of 23 enrolled subjects were evaluable for dose-limiting 
toxicity (DLT) assessment.  Three DLTs were reported at dose level 14 mg/m2, including 
alanine aminotransferase (ALT) increase (Grade 3), hypertension (Grade 3), and 
hypertension (Grade 4).  The Protocol Steering Committee (PSC) confirmed that the 14 


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mg/m2 was the recommended dose for single agent lenvatinib in children and adolescents 
with refractory or relapsed solid tumors (Eisai Co Ltd Data on File).  Phase 2 portion of 
Study 207 evaluating lenvatinib as a single agent or lenvatinib in combination with 
ifosfamide and etoposide in children and adolescents with osteosarcoma and 131I-refractory 
differentiated thyroid cancer is ongoing. 
7.4 
Study Rationale 
There remains a significant unmet medical need for more effective treatment options for 
pediatric subjects with solid tumors.  Overall solid tumors make up to 30% of all cancers in 
children.  Approximately 80% of these tumors are cured with conventional approaches.  This 
study will be performed on pediatric subjects with solid tumors, which were resistant to 
conventional therapy, and for whom there are no alternative therapies that might lead to cure. 
The proposed multicenter, Phase 1/2 study (E7080-G000-216) will determine (in Phase 1 
portion) a MTD and RP2D of lenvatinib administered in combination with everolimus.  
Phase 2 portion will estimate the antitumor activity, safety and tolerability of the lenvatinib 
and everolimus combination in pediatric subjects with recurrent/refractory solid tumors 
including HGG, rhabdomyosarcoma, and Ewing’s sarcoma/pPNET. 
The initial dose level (Dose Level 1) for lenvatinib will be 11 mg/m2, which is approximately 
80% of lenvatinib single dose MTD in pediatric subjects determined in the ongoing 
Study 207.  The initial dose of everolimus will be 3 mg/m2, which is 66% of the FDA 
approved dose and a dose previously found to be effective in subependymal giant cell 
astrocytoma (SEGA), as per everolimus package insert (Afinitor package insert). 
Due to a lower starting dose determined for adult subjects with hepatocellular cancer (HCC): 
12 mg (baseline body weight [BW] ≥60 kg) or 8 mg (baseline BW <60 kg) given once daily 
for the Phase 3 study in subjects with HCC, as opposed to the approved dose of lenvatinib 
monotherapy in adult subjects with differentiated thyroid cancer, which is 24 mg once daily, 
subjects with hepatoblastoma will be excluded from participation in this study.  
8 
STUDY OBJECTIVES 
8.1 
Primary Objectives 
 
Primary Objectives for Phase 1 
a. 
To determine maximum tolerated dose (MTD) and recommended Phase 2 dose 
(RP2D) of lenvatinib administered in combination with everolimus, once daily to 
pediatric subjects with recurrent/refractory solid tumors. 
b. 
To describe the toxicities of lenvatinib administered in combination with everolimus 
once daily to pediatric subjects with recurrent/refractory solid tumors. 
 
Primary Objective for Phase 2 
a. 
To estimate the antitumor activity of lenvatinib in combination with everolimus in 
pediatric subjects with selected recurrent/refractory solid tumors including Ewing 


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sarcoma/pPNET, rhabdomyosarcoma, and HGG using objective response rate (ORR) 
at Week 16 as the outcome measure. 
8.2 
Secondary Objectives 
 
Secondary Objectives for Phase 1 
a. 
To preliminarily define the antitumor activity of lenvatinib in combination with 
everolimus in pediatric subjects with recurrent/refractory solid tumors. 
b. 
To characterize the pharmacokinetics (PK) of oral lenvatinib and everolimus, when 
administered in combination to pediatric subjects with recurrent/refractory solid 
tumors. 
 
Secondary Objectives for Phase 2 
a. 
To assess other response variables including ORR at the time of data cutoff, disease 
control rate (DCR), clinical benefit rate (CBR), and duration of response (DOR). 
b. 
To evaluate the tolerability and safety profile of lenvatinib in combination with 
everolimus in pediatric subjects with recurrent/refractory Ewing sarcoma/pPNET, 
rhabdomyosarcoma, and HGG.   
c. 
To characterize the PK of lenvatinib and everolimus, when administered in 
combination to children with recurrent/refractory Ewing sarcoma/pPNET, 
rhabdomyosarcoma, and HGG. 
8.3 
Exploratory Objectives 
 
Exploratory Objectives for Phase 1 and Phase 2 
a. To evaluate blood, tumor, and safety (eg, hypertension) markers as correlative 
biomarkers of treatment effects and outcomes of lenvatinib in combination with 
everolimus. 
b. To assess candidate alterations in genes and/or proteins that may contribute to tumor 
development and serve as predictive markers of response in archival tumor tissue 
from pediatric subjects. 
c. To explore relationships between lenvatinib exposure and safety (eg, AEs of special 
interest). 
9 
INVESTIGATIONAL PLAN 
9.1 
Overall Study Design and Plan 
This is a multicenter, open-label, Phase 1/2 study of lenvatinib in combination with 
everolimus in pediatric subjects with relapsed or refractory solid tumors.  The overall study 
design is depicted in Figure 1. 


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Figure 1 
Study Design 
EVE = everolimus, LEN = lenvatinib, MTD = maximum tolerated dose, ORR = objective response rate, 
PK = pharmacokinetic, pPNET = peripheral primitive neuroectodermal tumor, RP2D = recommended Phase 2 dose. 
Phase 1 Dose Escalation and Determination of the MTD 
The Phase 1 component is a dose escalation study with treatment in sequential cohorts of 
escalating doses of lenvatinib in combination with everolimus, each administered once daily 
in 28-day treatment cycles.  Pediatric subjects with a relapsed/refractory solid malignancy, 
including primary brain tumors are eligible to enroll.  The initial dose level (Dose Level 1) 
for lenvatinib will be 11 mg/m2.  The initial dose of everolimus will be 3 mg/m2.  Dose 
Level 2 will escalate lenvatinib by approximately 25% to 14 mg/m2 and maintain everolimus 
at the same dose of 3 mg/m2.  At Dose Levels -1 and 1, maximum daily dose of lenvatinib 
will not exceed 18 mg daily.  At Dose Level 2, maximum daily dose of lenvatinib allowed 
will not exceed 24 mg.  Should Dose Level 2 be well tolerated, Dose Level 3 may be 
considered to test lenvatinib at 14 mg/m2 (capped at 24 mg) and escalate everolimus to 
4.5 mg/m2.  For everolimus dose levels of 3 mg/m2 and 4.5 mg/m2, the maximum daily dose 
of everolimus will not exceed 5 mg and 7 mg, respectively.  If the MTD for combination of 
lenvatinib and everolimus has been exceeded at Dose Level 1, then the subsequent cohort of 
subjects will be treated at Dose Level ˗1 with dose of lenvatinib 8 mg/m2 and dose of 
everolimus 3 mg/m2 (Table 1).  Intra-subject titration of everolimus will not be allowed on 
this study. 
At study entry, subjects must have a minimum BSA of 0.6 m2.   


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Table 1 
Planned Dose-Escalation 
Dose Level 
Lenvatinib mg/m2 
(% Single-Agent MTD) 
Everolimus 
(mg/m2) 
-1 
8 (60% MTD)a 
3c 
1* 
11 (80% MTD)a 
3c 
2 
14 (100% MTD)b 
3c 
3d 
14 (100% MTD)b 
4.5e 
MTD = maximum tolerated dose  
*Starting dose level 
a:  Lenvatinib dose capped at 18 mg daily. 
b:  Lenvatinib dose capped at 24 mg daily. 
c:  Everolimus dose capped at 5 mg daily. 
d:  Dose Level 3 may be considered if Dose Level 2 is well tolerated. 
e:  Everolimus dose capped at 7 mg daily. 
 
The Phase 1 portion of the study will utilize a rolling 6 design (Skolnik, et al., 2008).  Two to 
6 subjects can be concurrently enrolled into a dose level cohort.   
Dose level assignment will be based on:  
1. the number of subjects currently enrolled in the dose level cohort,  
2. the number of DLTs observed, and  
3. the number of subjects at risk for developing a DLT (ie, subjects enrolled but who are not 
yet assessable for toxicity).   
For example, when 3 subjects are enrolled onto a dose cohort, if toxicity data is available for 
all 3 when the fourth subject entered and there are no DLTs, the dose will be escalated and 
the fourth subject will be treated at the subsequent dose level.  If data is not yet available for 
1 or more of the first 3 subjects and no DLT has been observed, or if one DLT has been 
observed, the new subject will be treated at the same dose level.  Lastly, if 2 or more DLTs 
have been observed, the dose level will be de-escalated.  This process will be repeated for 
Subjects 5 and 6.  In place of suspending accrual after every 3 subjects, accrual will be 
suspended when a cohort of 6 potentially evaluable subjects has enrolled (ie, subjects 
enrolled but are not yet assessable for toxicity) or when the study endpoints have been met.  
When subjects are not evaluable for toxicity, they will be replaced with the next available 
subject if escalation or de-escalation rules have not been fulfilled at the time the next 
available subject is enrolled in the study. 
The following table (Table 2) provides the decision rules for enrolling a subject at (i) the 
current dose level (ii) at an escalated dose level, (iii) at a de-escalated dose level, or whether 
the study is suspended to accrual: 


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Table 2 
The Rolling 6 Design 
# Subjects 
Enrolled 
# Subjects with 
DLT 
# Subjects 
without DLT 
# Subjects with 
Data Pending 
Decision 
2 
0 or 1 
0, 1 or 2 
0, 1 or 2 
Same dose level 
2 
2 
0 
0 
De-escalate* 
 
 
 
 
 
3 
0 
0, 1 or 2 
1, 2 or 3 
Same dose level 
3 
1 
0, 1 or 2 
0, 1 or 2 
Same dose level 
3 
0 
3 
0 
Escalate** 
3 
≥2 
0 or 1 
0 or 1 
De-escalate* 
 
 
 
 
 
4 
0 
0, 1, 2 or 3 
1, 2, 3 or 4 
Same dose level 
4 
1 
0, 1, 2 or 3 
0, 1, 2 or 3 
Same dose level 
4 
0 
4 
0 
Escalate** 
4 
≥2 
0, 1 or 2 
0, 1 or 2 
De-escalate* 
 
 
 
 
 
5 
0 
0, 1, 2, 3 or 4 
1, 2, 3, 4 or 5 
Same dose level 
5 
1 
0, 1, 2, 3 or 4 
0, 1, 2, 3 or 4 
Same dose level 
5 
0 
5 
0 
Escalate** 
5 
≥2 
0, 1, 2 or 3 
0, 1, 2 or 3 
De-escalate* 
 
 
 
 
 
6 
0 
0, 1, 2, 3, or 4 
2, 3, 4, 5 or 6 
Suspend 
6 
1 
0, 1, 2, 3 or 4 
0, 1, 2, 3 or 4 
Suspend 
6 
0 or 1 
5 or 6 
0 or 1 
Escalate** 
6 
≥2 
0, 1, 2, 3 or 4 
0, 1, 2, 3 or 4 
De-escalate* 
DLT = dose-limiting toxicity 
*If 6 subjects already entered at next lower dose level, the maximum tolerated dose (MTD) has been defined.  
**If final dose level has been reached, the recommended dose has been reached. 
 
If 2 or more of a cohort of up to 6 subjects experience DLT at a given dose level, then the 
MTD has been exceeded and dose escalation will be stopped.  In the event that 2 DLTs 
observed out of 6 evaluable subjects are of different classes of Adverse Effects (eg, 
hepatotoxicity and myelosuppression), expansion of the cohort to 12 subjects will be 
considered (if one of the DLTs does not appear to be dose-related, the Adverse Effects are 
readily reversible, AND Protocol Steering Committee (PSC) AND sponsor all agree that 
expansion of the cohort is acceptable). Subjects who on PSC review are not deemed to be 
evaluable for DLT assessment may be replaced. 


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All subjects in the Phase 1 Dose Escalation phase will have samples taken for PK analysis 
with the intent at the end of Phase 1 of having evaluable PK data from minimally 6 subjects 
aged 2 to <6 years old, 6 subjects ≥6 to <12 years old, and 6 subjects ≥12 years old.  Once 
the MTD or RP2D has been defined, 0 to 6 additional subjects will be enrolled to attain the 
goal of having evaluable PK data from minimally 6 subjects aged 2 to <6 years old, 
6 subjects ≥6 to <12 years old, and 6 subjects ≥12 years old.  
Protocol Steering Committee 
The sponsor will closely evaluate the risks and benefits of the study throughout its conduct, 
along with the PSC as needed.  The PSC may review available relevant data:  DLT and safety 
data including laboratory assessments, 12-lead electrocardiograms (ECGs), dose 
administration, etc. 
Toxicity Monitoring 
The DLT observation period for the purposes of dose-escalation will be the first cycle of 
therapy.  Routine Phase 1 monitoring for clinical and laboratory toxicities will be used.  
Blood pressure (BP) monitoring will occur at least weekly during the first 2 cycles.   
Dose-Limiting Toxicity 
Dose-limiting toxicity will be assessed according to Common Terminology Criteria for 
Adverse Events (CTCAE) v4.03 and is defined as any of the following events that are 
possibly, probably, or definitely attributable to lenvatinib or everolimus.  Dose-limiting 
hematological and non-hematological toxicities are defined differently. 
A. Non-hematological DLT: 
 Any Grade 3 or greater non-hematological toxicity attributable to the investigational 
drug with the specific exclusion of: 
o Grade 3 nausea and vomiting <3 days duration 
o Grade 3 diarrhea <3 days duration 
o Grade 3 weight loss 
o Grade 3 liver enzyme elevation, including ALT/aspartate aminotransferase (AST)/ 
gamma glutamyl transferase (GGT)/ bilirubin/alkaline phosphatase that returns to 
Grade 1 or baseline within 7 days 
o Grade 3 asymptomatic elevation in amylase or lipase that returns to Grade 1 or 
baseline within 7 days 
o Grade 3 elevation in triglycerides that returns to Grade 1 or baseline within 7 days 
o Grade 3 or 4 fever <5 days duration 
o Grade 3 infection <5 days duration 
o Grade 3 hypophosphatemia, hypokalemia, hypocalcemia or hypomagnesemia 
responsive to oral supplementation 
o Grade 3 proteinuria (UPC) ratio >1.9 unless confirmed with a second measurement 
within 72 hours 
o Grade 3 headache <3 days duration responsive to optimal management. 


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 Any Grade 2 non-hematological toxicity that persists for ≥7 days and is considered 
sufficiently medically significant or sufficiently intolerable by subjects despite 
optimal supportive care that it requires treatment interruption. 
 Any dose interruption or reduction due to toxicity which results in administration of 
less than 75% of the planned dosage of lenvatinib and/or everolimus. 
 Note:  Allergic reactions that necessitate discontinuation of study drug will not be 
considered a DLT. 
 Dose-limiting hypertension: 
o Any Grade 4 hypertension  
Confirmed systolic or diastolic BP more than 25 mmHg above 95th percentile for sex, age, 
height/length, or an elevated diastolic BP (ie, >95th percentile for age) not controlled by a 
single antihypertensive medication within 14 days of use.  An antihypertensive tablet or 
capsule that contains up to 2 antihypertensive ingredient medications will be considered a 
single antihypertensive medication. 
B. Hematological DLT:    
 In subjects evaluable for hematological toxicity, DLT is defined as: 
o Grade 4 thrombocytopenia (platelet count <25,000/mm3) or Grade 4 neutropenia, 
not due to malignant infiltration. 
 Any ≥Grade 2 arterial thromboembolic events (including cerebrovascular ischemia, 
peripheral or visceral arterial ischemia). 
 Note:  Grade 3 or 4 febrile neutropenia will not be considered a DLT. 
All DLTs must be reported to the sponsor within 24 hours of their occurrence.  
Determination of a DLT will be made by the investigator and the Eisai Medical Monitor in 
consultation with the PSC, as needed.  Subjects who discontinue the study treatment for any 
reason other than DLT (eg, early disease progression) during Cycle 1 (Day 1 to Day 28), and 
have not received at least 75% of the prescribed dose prior to discontinuation, will be 
replaced. 
The sponsor and PSC will review all subjects’ safety and clinical data to jointly determine 
the MTD/RP2D of the combination of lenvatinib with everolimus.  The Treatment Phase for 
each subject in Phase 1 ends after completing Cycle 1 of treatment unless subject 
discontinues early.  Those subjects who discontinue study treatment in Cycle 1 transition to 
the Off-treatment Visit.  Those who complete Cycle 1 will transition to the Extension Phase.  
Study treatment and tumor assessments will continue during the Extension Phase. 
Phase 2 Cohorts 
Once the MTD/RP2D of the combination of lenvatinib and everolimus in pediatric 
population has been determined in Phase 1, the Phase 2 portion of this pediatric study will 
commence with Cohort 1 (recurrent or refractory Ewing sarcoma/pPNET), Cohort 2 
(recurrent or refractory rhabdomyosarcoma), and Cohort 3 (recurrent or refractory HGG), 
opening to accrual. 


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Cohorts 1 – 3  
Phase 2 Cohorts 1 to 3 will use a 10+10 Simon’s optimal 2-stage design for each cohort; 
10 evaluable subjects will be enrolled to each stage.  The Sponsor will closely monitor 
enrollment to ensure that at least 50% of subjects enrolled in each cohort are <18 years of age 
at the time of informed consent.  The primary outcome measure for Ewing sarcoma/pPNET, 
rhabdomyosarcoma, and HGG will be ORR (complete or partial response) at 16 weeks.  If 
there are no responses among the 10 subjects in Stage 1, then the enrollment to that disease 
cohort will stop and conclude that the lenvatinib/everolimus combination therapy does not 
elicit a response in that disease cohort.  If there is at least 1 response in the first stage, then 
the second stage will enroll 10 additional evaluable subjects.  If there are 2 or fewer 
responses among the 20 evaluable subjects, then lenvatinib/everolimus combination therapy 
will be declared a failure for that disease cohort. Subjects will meet the criteria for being 
evaluable for an objective response if they have measurable disease present at baseline and at 
least 1 post-baseline efficacy assessment, unless they have discontinued prior to the first 
efficacy assessment due to progressive disease. Subjects who are not evaluable for objective 
response will be replaced. 
The Treatment Phase for each subject in Phase 2 ends after completing 4 cycles of treatment 
unless subject discontinues early.  Those subjects who discontinue study treatment before 
completing 4 cycles transition to the Off-treatment Visit.  Those who complete 4 cycles will 
transition to the Extension Phase.  Study treatment and tumor assessments will continue 
during the Extension Phase. 
Dosing Nomogram  
The dose nomogram in Table 3 provides the dose of lenvatinib to be administered for BSA 
increments starting from 0.6 m2.  BSA must be calculated on Day 1 of each cycle based on 
the subject’s current height and body weight.  The actual dose to be administered is rounded 
to the nearest whole number.  The total lenvatinib dose is capped at 18 mg daily (Dose 
Levels -1 and 1), and at 24 mg (Dose Levels 2 and 3).  
 


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Table 3 
Total Lenvatinib Dose (mg):  Body Surface Area (m2) * Dose 
Level (mg/m2) 
Lenvatinib Dose Levels 
8 mg/m2 
Everolimus 3.0 mg/m2) 
Dose Level -1 
11 mg/m2 
Everolimus 3.0 mg/m2) 
Dose Level 1 
14 mg/m2 
(Everolimus 3.0 mg/m2) 
Dose Level 2 
14 mg/m2 
(Everolimus 4.5 mg/m2) 
Dose Level 3 
Body 
Surface 
Area (m2) 
Dose to be 
Administered 
(mg) 
Body 
Surface 
Area (m2) 
Dose to be 
Administered 
(mg) 
Body 
Surface 
Area (m2) 
Dose to be 
Administered 
(mg) 
Body 
Surface 
Area (m2) 
Dose to be 
Administered 
(mg) 
0.60 – 0.68 
5 
0.60 – 0.68 
7 
0.60 – 0.60 
8 
0.60 – 0.60 
8 
0.69 – 0.81 
6 
0.69 – 0.77 
8 
0.61 – 0.67 
9 
0.61 – 0.67 
9 
0.82 – 0.93 
7 
0.78 – 0.86 
9 
0.68 – 0.74 
10 
0.68 – 0.74 
10 
0.94 – 1.06 
8 
0.87 – 0.95 
10 
0.75 – 0.82 
11 
0.75 – 0.82 
11 
1.07 – 1.18 
9 
0.96 – 1.04 
11 
0.83 – 0.89 
12 
0.83 – 0.89 
12 
1.19 – 1.31 
10 
1.05 – 1.13 
12 
0.90 – 0.96 
13 
0.90 – 0.96 
13 
1.32 – 1.43 
11 
1.14 – 1.22 
13 
0.97 – 1.03 
14 
0.97 – 1.03 
14 
1.44 – 1.56 
12 
1.23 – 1.31 
14 
1.04 – 1.10 
15 
1.04 – 1.10 
15 
1.57 – 1.68 
13 
1.32 – 1.40 
15 
1.11 – 1.17 
16 
1.11 – 1.17 
16 
1.69 – 1.81 
14 
1.41 – 1.49 
16 
1.18 – 1.24 
17 
1.18 – 1.24 
17 
1.82 – 1.93 
15 
1.50 – 1.59 
17 
1.25 – 1.32 
18 
1.25 – 1.32 
18 
1.94 – 2.06 
16 
≥1.60 
18 
1.33 – 1.39 
19 
1.33 – 1.39 
19 
2.07 – 2.18 
17 
 
 
1.40 – 1.46 
20 
1.40 – 1.46 
20 
≥2.19 
18 
 
 
1.47 – 1.53 
21 
1.47 – 1.53 
21 
 
 
 
 
1.54 – 1.60 
22 
1.54 – 1.60 
22 
 
 
 
 
1.61 – 1.67 
23 
1.61 – 1.67 
23 
 
 
 
 
≥1.68 
24 
≥1.68 
24 
 
The dose nomogram in Table 4 provides the dose of everolimus to be administered for BSA 
increments starting from 0.6 m2.  The total everolimus dose is capped at 5 mg daily for Dose 
Levels -1, 1, and 2, and at 7 mg daily for Dose Level 3. 


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Table 4 
Total Everolimus Dose (mg):  Body Surface Area (m2) * 
Dose Level (mg/m2) 
Everolimus Dose Level 
3 mg/m2 
Dose Levels -1, 1, and 2 
4.5 mg/m2 
Dose Level 3 
Body Surface Area 
(m2) 
Dose to be Administered 
(mg) 
Body Surface Area 
(m2) 
Dose to be Administered 
(mg) 
0.60 – 0.83 
2 
0.60 – 0.77 
3 
0.84 – 1.16 
3 
0.78 – 0.99 
4 
1.17 – 1.49 
4 
1.00 – 1.22 
5 
≥1.50 
5 
1.23 – 1.44 
6 
 
 
≥1.45 
7 
 
Study Duration 
Approximately a total of 4.5 years from the first subject providing signed informed consent 
in Phase 1 to the primary endpoint completion date for Phase 2 of the study.  It is estimated 
that the Phase 2 portion will take 3 years in order to complete the final collection of data for 
the primary outcome analysis. 
Study duration for each subject is estimated to be: 
 
Pretreatment Phase:  4 weeks 
 
Treatment Phase:  1 cycle (4 weeks) in Phase 1; 4 cycles (16 weeks) in Phase 2. 
 
Extension Phase:  Estimated maximum time of treatment is 2 years (24 cycles).  
Subjects may remain on study treatment as long as they do not meet any of the following 
criteria:  1) experience objective progression of disease (according to RECIST 1.1 or 
RANO, as appropriate), 2) exhibit no clinical benefit (in the opinion of the investigator), 
3) experience unacceptable toxicity leading to withdrawal from the study, 4) withdraw or 
are withdrawn from the study for any reason, or, 5) termination of the study program.  As 
long as the subject has not experienced intolerable toxicity, he or she can continue to 
receive study treatment.  A 28-day follow up visit from last date of receiving 
investigational drug will be performed for subjects who discontinue study treatment. 
9.1.1 
Pretreatment Phase 
The Pretreatment Phase will last up to 28 days and will include a Screening Period and a 
Baseline Period. 
9.1.1.1 
Screening Period 
Screening will occur between Day –28 and Day –2.  The purpose of the Screening Period is 
to obtain informed consent and to establish protocol eligibility.  Informed consent will be 
obtained after the study has been fully explained to each subject and before the conduct of 


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any screening procedures or assessments.  Procedures to be followed when obtaining 
informed consent are detailed in Section 5.3. 
The Screening Disposition case report form (CRF) must be completed to indicate whether the 
subject is eligible to enroll in the study and to provide reasons for screen failure, if 
applicable. 
The results of all screening assessments and evaluations must be completed and reviewed by 
the investigator prior to the Baseline Visit.  
9.1.1.2 
Baseline Period 
The purpose of the Baseline Period is to confirm protocol eligibility as specified in the 
inclusion/exclusion criteria (as detailed in Section 9.3.1 and Section 9.3.2).  Results of 
baseline assessments must be obtained prior to the first dose of study treatment (Cycle 1 
Day 1).  Baseline assessments can be performed on Day –1 or on Cycle 1 Day 1 prior to start 
of study treatment.   
Subjects who complete the baseline assessments and continue to meet the criteria for 
inclusion/exclusion (Sections 9.3.1 and 9.3.2) will begin the Treatment Phase. 
9.1.2 
Treatment Phase 
The Treatment Phase will begin with the first dose of study drug administration in Cycle 1.  
The duration of the Treatment Phase is 1 cycle (4 weeks of treatment) in Phase 1 of the 
study, and 4 cycles (16 weeks of treatment) in Phase 2 of the study.  Subjects will receive 
study treatment in 28-day cycles.  Tumor assessments will be performed during the 
Treatment Phase at Week 4 ±1 week (Phase 1) and at Week 8 ±1 week and Week 16 ±1 week 
(Phase 2). 
Subjects who discontinue study treatment during Cycle 1 (Phase 1), or before completing 
4 cycles of treatment (Phase 2), will transition to the Off-treatment Visit.  
9.1.3 
Extension Phase 
All subjects who are still on study treatment following completion of Cycle 1 in Phase 1, or 
after completing 4 cycles in Phase 2 of the study, will transition to the Extension Phase.  
During the Extension Phase, subjects will continue to receive the same study treatment in 
28-day cycles.  Tumor assessments will be performed during the Extension Phase at Week 12 
±1 week and Week 24 ±1 week, and every 12 weeks ±1 week thereafter (Phase 1) and at 
Week 24 ±1 week, and every 12 weeks ±1 week thereafter (Phase 2). 
9.1.4 
Treatment Discontinuation Criteria  
Subjects may remain on study treatment as long as they do not meet any of the following 
criteria:  1) experience objective progression of disease (according to Response Evaluation 
Criteria in Solid Tumors [RECIST] 1.1 or Response Assessment in Neuro-Oncology 


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[RANO] criteria, as appropriate), 2) exhibit no clinical benefit (in the opinion of the 
investigator), 3) experience unacceptable toxicity leading to withdrawal from the study, 
4) withdraw or are withdrawn from the study for any reason, or, 5) termination of the study 
program.  
As long as the subject has not experienced intolerable toxicity, he or she can continue to 
receive study treatment.   
9.1.5 
Off-Treatment Visit 
After subject discontinues treatment, an Off-Treatment Visit and the procedures noted in the 
Schedule of Assessments (Table 7 and Table 8) should be completed within 28 days after the 
last dose of study treatment.   
9.1.6 
Post-Treatment Phase 
9.1.6.1 
Follow-Up Period 
The post-treatment follow up will begin when the subject discontinues study treatment and 
all off-treatment assessments have been completed.  Subjects who discontinue study 
treatment for reasons other than disease progression will be followed for documented disease 
progression for 1 year or until another anticancer therapy is initiated whichever occurs first.  
Subjects will be followed for survival every 3 months until death or for 1 year, whichever 
occurs first, unless the study is terminated or if the subject discontinues due to withdrawal of 
consent or is lost to follow up. 
After data cutoff, tumor assessments may be performed as clinically indicated using the 
institutional guidelines, following the prevailing local standard of care. 
As required by some regulatory agencies, the following estimates are provided:  
 
The study is planned to begin in April 2017 and to end in March 2022.   
 
The maximum estimated period for each subject on study is anticipated to be 
approximately 2 years (24 treatment cycles).  However, subjects will continue to receive 
study treatment as long as they demonstrate clinical benefit. 
9.2 
Discussion of Study Design 
This multicenter, open-label, Phase 1/2 study will investigate safety, tolerability and 
antitumor activity of lenvatinib in combination with everolimus in pediatric subjects with 
relapsed or refractory solid tumors.   
The Phase 1 portion of the study utilizes dose-finding rolling 6 design (Skolnik, et al., 2008), 
which allows enrollment of more than 3 subjects at the particular dose level, unlike the 
traditional 3+3 Phase 1 study design.  If there is no DLTs in the first 3 subjects enrolled 
under rolling 6 design, then the fourth subject can be allocated to the next higher dose level.  
If toxicity data are not available on the first 3 subjects, or if one DLT is observed, in which 


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case the new subject will be kept at the same dose level.  The main advantage of the rolling 6 
design is the reduction of the overall study duration as it aims to decrease the number of 
times the study is suspended to accrual.  
The Simon-optimal 2-stage design utilized for Phase 2 portion of the study allows for interim 
evaluation for futility.  The traditional single-stage study designs evaluate drug response rate 
on the predetermined number of subjects, possibly unnecessarily exposing children to the 
risk of ineffective new agents.  For ethical reasons, Simon’s 2-stage design utilizes a small 
number of subjects to determine drug activity and allows early termination of the study if 
activity criteria are not met.  This prevents exposure of too many pediatric subjects to an 
inactive study drug. 
Toxicity will be assessed according to National Cancer Institute’s CTCAE v4.03.  In this 
study, the subjects will remain on treatment as long as they do not experience progression of 
disease or unacceptable toxicity.  This will allow evaluation of short-term toxicity, as well as, 
side effects after prolonged use of combination of lenvatinib and everolimus, which is 
particularly important for pediatric population where physical growth and tissue maturation 
continues. 
9.3 
Selection of Study Population 
A maximum accrual of 120 subjects in Phase 1 and Phase 2 portions of the study is expected 
at approximately 60 sites (20 sites for the Phase 1 portion and an additional 40 sites for the 
Phase 2 portion).   
Phase 1:  4 to 48 evaluable subjects.  In the event that each of the Dose Levels -1, 1, 2 , and 
3 is expanded to 12 subjects, a maximum of 54 subjects (allowing for 20% to be 
non-evaluable and including the additional 6 subjects for PK analysis) will be enrolled. 
Phase 2 Cohorts 1 to 3:  10 to 20 evaluable subjects per cohort (maximum 22 subjects per 
cohort allowing for 10% to be non-evaluable).  A maximum of 66 subjects will be enrolled in 
Phase 2.  In each cohort, at least 50% of the subjects enrolled will be <18 years old at the 
time of informed consent. 
Subjects who do not meet all of the inclusion criteria or who meet any of the exclusion 
criteria will not be eligible to receive study treatment. 
9.3.1 
Inclusion Criteria 
Subjects must meet all of the following criteria to be included in this study: 
1. Histologically or cytologically confirmed diagnosis of the following tumor types: 
a. Phase 1: Recurrent or refractory solid tumors (excluding hepatoblastoma and 
lymphomas), including primary CNS tumors; subjects must have either measurable or 
evaluable disease.  Subjects with diffuse intrinsic pontine glioma, optic pathway 
glioma, or pineal tumors with elevated tumor markers (alpha-fetoprotein [AFP] and 


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beta-human chorionic gonadotropin [ß-hCG] [or hCG]) do not require histological or 
cytological confirmation of diagnosis. 
b. Phase 2 : Recurrent or refractory tumors; subjects must have measurable disease 
 Cohort 1:  Ewing sarcoma/pPNET 
 Cohort 2:  Rhabdomyosarcoma 
 Cohort 3:  HGG (subjects with Diffuse Intrinsic Pontine Glioma are not eligible) 
2. Measurable disease that meets the following criteria (Phase 2): 
a. RECIST 1.1 (for all tumor types except HGG) 
 At least 1 lesion of ≥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 which is serially measurable 
according to RECIST 1.1 using computed tomography /magnetic resonance 
imaging (CT/MRI).   
b. Response Assessment in Neuro-Oncology (RANO) for high grade glioma (HGG) 
(Wen, et al., 2010) 
 At least one lesion must be measurable as defined as a bi-dimensionally 
contrast-enhancing lesion with clearly defined margins by CT or MRI scan, with a 
minimal diameter of 1 cm, and visible on 2 axial slices which are preferably at 
most 5 mm apart with 0 mm skip. 
Lesions that have had external beam radiotherapy (EBRT) or locoregional therapies such as 
radiofrequency (RF) ablation must show evidence of progressive disease based on 
RECIST 1.1 to be deemed a target lesion. 
3. Karnofsky performance score 50 for subjects >16 year of age and Lansky play score 
50 for subjects 16 years of age.  Note:  Neurologic deficits in subjects with CNS 
tumors must have been relatively stable for at least 7 days prior to study enrollment.  
Subjects who are unable to walk because of paralysis, but who are up in a wheelchair, 
will be considered ambulatory for the purpose of assessing the performance score. 
4. Subjects must have fully recovered from the acute toxic effects of all prior anti-cancer 
therapy and must meet the following minimum duration from prior anti-cancer directed 
therapy prior to enrollment.  If after the required timeframe, the numerical eligibility 
criteria are met, eg, blood count criteria, the subject 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. Anti-cancer 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 
immune checkpoint inhibitors).  (Appendix 3).  Toxicity related to prior antibody 
therapy must be recovered to Grade ≤1. 
d. Corticosteroids:  If used to modify immune adverse events (AEs) related to prior 
therapy, ≥14 days must have elapsed since last dose of corticosteroid.  Subjects 


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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 [TBI]): 
 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 (GVHD). 
 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). 
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, radiolabeled antibody, iodine-131 
metaiodobenzylguanidine [131I-MIBG]):  ≥42 days after systemically administered 
radiopharmaceutical therapy. 
k. VEGF/VEGFR-targeted or mTOR-targeted therapies:  
 Must not have received prior exposure to lenvatinib 
 May have previously progressed on an mTOR inhibitor 
 No more than 2 prior VEGF/VEGFR-targeted therapies (For Phase 2 only)  
 Must not have received prior VEGF/VEGFR-targeted therapy in combination 
with an mTOR inhibitor (For Phase 2 only)  
5. Male or female subjects must be ≥2 years and <18 years of age for enrolment in Phase 1 
or ≥2 years and ≤21 years of age for enrolment in Phase 2. 
6. Adequate bone marrow function: 
 
For subjects with solid tumors without known bone marrow involvement: 
o Peripheral absolute neutrophil count (ANC) 1000/mm3 
o Platelet count 100,000/mm3  
o Hemoglobin 8.0 g/dL at baseline (may receive red blood cell transfusions) 
 
For subjects with known bone marrow metastatic disease: 
o Peripheral ANC 1000/mm3 
o Platelet count 100,000/mm3 ( and with no platelet transfusions for at least 7 days 
prior to enrollment) 
o May receive transfusions provided they are not known to be refractory to red cell 
or platelet transfusions.  These subjects will not be evaluable for hematologic 


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toxicity.  At least 5 of every cohort of 6 subjects with a solid tumor must be 
evaluable for hematologic toxicity, for the dose-escalation part of the study.  If 
dose-limiting hematologic toxicity is observed, all subsequent subjects enrolled 
must be evaluable for hematologic toxicity. 
7. Adequate renal function:  
 
Creatinine clearance or radioisotope glomerular filtration rate (GFR) 
70 mL/min/1.73 m2 or 
 
A serum creatinine based on age/gender as follows: 
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 
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 Centers for 
Disease Control and Prevention (CDC). 
 
Urine dipstick <2+ for proteinuria.  Subjects who have ≥2+ proteinuria on dipstick 
urinalysis should undergo a spot protein-creatinine (P/C) ratio that should be 
Grade <2 per CTCAE v4.03, 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 subjects >12 years of age must have ≤1 g of protein/24 hours). 
8. Adequate liver function:  
 
Bilirubin (sum of conjugated + unconjugated) 1.5 × upper limit of normal (ULN) for 
age, except for unconjugated hyperbilirubinemia of Gilbert’s syndrome. 
 
ALT and AST ≤3 × ULN  
 
Serum albumin 2 g/dL 
9. Adequate cardiac function: 
 
Adequate cardiac function as evidenced by left ventricular shortening fraction of 
≥27% by echocardiogram or left ventricular ejection fraction (LVEF) 50% at 
baseline, as determined by echocardiography/multigated acquisition (MUGA) scan. 
 
QT interval corrected for heart rate using Fridericia’s formula (QTcF) ≤480 msec. 
10. Adequate neurologic function: 
 
Subjects with seizure disorder may be enrolled if on non-enzyme-inducing 
anticonvulsants and well controlled. 
 
Nervous system disorders (CTCAE v4.03) resulting from prior therapy and not 
tumor-induced must be Grade 2. 
11. Adequate BP control with or without antihypertensive medications, defined as:  A BP  
< the 95th percentile for sex, age and height/length (≤150/90 mmHg for subjects aged 
18 - 21 years) at Screening (as per National Heart Lung and Blood Institute [NHLBI] 
guidelines; Appendix 7 and Appendix 8) and no change in antihypertensive medications 
within 1 week prior to Cycle 1 Day 1. 


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12. Adequate coagulation: 
 
International Normalized Ratio (INR) ≤1.5  
13. Adequate pancreatic function: 
 
Serum amylase ≤1.5 × ULN 
 
Serum lipase ≤1.5 × ULN 
14. Adequate metabolic function: 
 
Serum triglycerides ≤300 mg/dL 
15. Adequate glycemic control defined as: 
 
Fasting serum glucose ≤160 mg/dL 
16. Subjects must have a minimum BSA of 0.6 m2 at study entry. 
9.3.2 
Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from this study: 
1. Subjects who have had or are planning to have the following invasive procedures: 
 
Major surgical procedure, laparoscopic procedure, open biopsy or significant 
traumatic injury within 28 days prior to enrollment.  
 
Central line placement or subcutaneous port placement is not considered major 
surgery.  External central lines must be placed at least 3 days prior to enrollment and 
subcutaneous ports must be placed at least 7 days prior to enrollment. 
 
Fine needle aspirate within 7 days prior to enrollment. 
 
Surgical or other wounds must be adequately healed prior to enrollment. 
NOTE: For purposes of this study, bone marrow aspirate and biopsy are not considered 
surgical procedures and therefore are permitted within 14 days prior to start of protocol 
therapy. 
2. Subjects who have non-healing wound, unhealed or incompletely healed fracture, or a 
compound (open) bone fracture at the time of enrollment 
3. Subjects having an active infection requiring systemic therapy 
4. Subjects with a known history of active hepatitis B (defined as hepatitis B surface antigen 
reactive or hepatitis B virus-DNA detected) or known active hepatitis C virus (HCV, 
defined as HCV-RNA detected).  Note: No testing for hepatitis B and hepatitis C is 
required unless mandated by the local health authority. 
5. Known to be human immunodeficiency virus (HIV) positive. Note: HIV testing is 
required at screening only when mandated by the local health authority 
6. Clinical evidence of nephrotic syndrome prior to enrollment 
7. Gastrointestinal bleeding or active hemoptysis (bright red blood of at least half teaspoon) 
within 21 days prior to enrollment 
8. Thrombotic/ thromboembolic event requiring systemic anticoagulation within 90 days 
prior to enrollment 
9. Evidence of new intracranial hemorrhage of more than punctate size on MRI assessment 
obtained within 28 days prior to study enrollment for subjects with high-grade glioma  
10. Diagnosis of lymphoma 
11. Radiographic evidence of major blood vessel invasion/infiltration. 


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12. Evidence of untreated CNS metastases (exception: subjects with primary CNS tumors 
and leptomeningeal disease).  
13. Subjects who are currently receiving enzyme-inducing anticonvulsants 
14. Subjects chronically receiving strong cytochrome P450 3A4 (CYP3A4)/ P-glycoprotein 
(P-gp) inhibitors or inducers within 7 days prior to study enrollment (See Appendix 15 
for a list of strong inhibitors and inducers). 
15. Females who are breastfeeding or pregnant at Screening or Baseline (as documented by a 
positive ß-hCG [or hCG] test with a minimum sensitivity of 25 IU/L or equivalent units 
of ß-hCG [or hCG]).  A separate baseline assessment is required if a negative screening 
pregnancy test was obtained more than 72 hours before the first dose of study drug. 
16. Females of childbearing potential* who: 
 
do not agree to use a highly effective method of contraception for the entire study 
period and for 8 weeks after study drug discontinuation, ie,: 
o total abstinence (if it is their preferred and usual lifestyle) 
o an intrauterine device (IUD) or hormone releasing system (IUS) 
o a contraceptive implant 
o an oral contraceptive** (with additional barrier method) 
OR 
 
do not have a vasectomized partner with confirmed azoospermia. 
For sites outside of the EU, it is permissible that if a highly effective method of contraception 
is not appropriate or acceptable to the subject, then the subject must agree to use a medically 
acceptable method of contraception, ie, double barrier methods of contraception such as 
condom plus diaphragm or cervical/vault cap with spermicide. 
NOTES: 
*All females will be considered to be of childbearing potential unless they are 
postmenopausal (amenorrheic for at least 12 consecutive months, in the appropriate age 
group, and without other known or suspected cause) or have been sterilized surgically 
(ie, bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, all with surgery at 
least 1 month before dosing), or are pre-menarcheal (Tanner Stage 1-3). 
**Must be on a stable dose of the same oral hormonal contraceptive product for at least 
4 weeks before dosing with study drug, for the duration of the study, and for at least 8 weeks 
after study drug discontinuation. 
17. Males who have not had a successful vasectomy (confirmed azoospermia) or if they and 
their female partners do not meet the criteria above (ie, not of childbearing potential or 
practicing highly effective contraception throughout the study period and for 7 days after 
lenvatinib discontinuation or 4 weeks after discontinuation of everolimus). No sperm 
donation is allowed during the study period and for 7 days after lenvatinib 
discontinuation or 4 weeks after discontinuation of everolimus. 
9.3.3 
Removal of Subjects From Therapy or Assessment 
The investigator may discontinue treating a subject with study treatment or withdraw the 
subject from the study at any time for safety or administrative reasons.  The subject may 
decide to discontinue study treatment or withdraw from the study at any time for any reason.  


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The reason for discontinuation will be documented.  If a subject discontinues study 
treatment, the subject will enter the Follow-Up Period and complete survival follow-up 
unless the subject withdraws consent.  The investigator should confirm whether a subject will 
withdraw from study treatment but agree to continue protocol-specified, off-treatment study 
visits, procedures, and survival follow-up, or whether the subject will withdraw consent.  If a 
subject withdraws consent, the date will be documented in the source documents.  The 
Subject Disposition CRF will be completed indicating the primary reason for discontinuation 
and all other reason(s) contributing to the subject’s discontinuation from treatment.  In 
addition, the date of last dose of study drug(s) will be recorded on the Study Medication 
CRF. 
9.4 
Treatment 
9.4.1 
Treatment Administered 
Lenvatinib will be provided as hard capsules containing 1 mg, 4 mg, or 10 mg lenvatinib.  An 
extemporaneous suspension of lenvatinib capsules should be used for children unable to 
swallow capsules (Appendix 12). 
Everolimus will be provided as 2 mg, 3 mg, and 5 mg dispersible tablet formulations 
(everolimus tablets for oral suspension).   
Lenvatinib and everolimus will be administered orally on a once daily schedule in continuous 
28-day cycles.  The sequence of administration is not important.  Dosing nomograms based 
on BSA and dose level will be used to prescribe lenvatinib and everolimus for subjects to 
minimize inter-subject dosing variability.  The maximum daily dose of lenvatinib 
administered during the study should not exceed 18 mg in Dose Levels -1, and 1, and 24 mg 
in Dose Levels 2 and 3.  The maximum daily dose of everolimus should not exceed 5 mg in 
Dose Levels -1, 1, and 2, and 7 mg in Dose Level 3.  Intra-subject titration of everolimus will 
not be allowed on this study.  Intra-subject dose escalation of both lenvatinib and everolimus 
will not be allowed. 
Subjects benefiting from study treatment in the opinion of the investigator will continue 
treatment until disease progression, development of unacceptable toxicity, withdrawal of 
consent or are withdrawn from the study for any reason, or termination of the study by the 
sponsor. 
9.4.1.1 
Study Treatment Dose Reduction and Interruption Instructions 
Dose reduction and interruptions for subjects who experience lenvatinib-everolimus 
combination therapy-related toxicity will be managed as described in Table 5.  Investigators 
will decide the probability of the event being related to protocol therapy as to whether dose 
modification of drug therapy is required. 
Doses in the Dose Adjustment column are based on a presumed starting dose of 11 mg/m2 
lenvatinib and 3 mg/m2 everolimus.  Dose reductions will occur in succession based on the 
previous dose level.  Each dose level reduction due to toxicity at a given BSA is 


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approximately 25% reduction from the previous dose.  Once the study drug dose has been 
reduced, it may not be increased at a later date, unless the dose was mistakenly decreased; in 
this situation, the sponsor’s approval is required to increase the dose. 
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. 
 
Table 5 
Dose Modification Guidelines for Lenvatinib-Everolimus 
Combination Treatment-Related Toxicity 
Treatment-Related Toxicitya,b 
Management 
Dose Adjustment 
Grade 1 or Tolerable Grade 2 
 
Continue treatment 
No change 
Intolerable Grade 2c, d, e or Grade 3f 
First occurrence 
Interrupt lenvatinib and 
everolimus until resolved to 
Grade 0-1 or tolerable 
Grade 2 
Reduce lenvatinib dose to 
8 mg/m2 (or approximately 
25% reduction of the 
starting dose) orally once a 
day (one-level reduction) 
and resume everolimus at 
the same dose as prior to 
dose interruption 
Second occurrence 
(same toxicity or new toxicity) 
Interrupt lenvatinib and 
everolimus until resolved to 
Grade 0-1 or tolerable 
Grade 2 
Reduce lenvatinib dose to 
6 mg/m2 (or approximately 
25% reduction from the 
previous dose level) once a 
day (one-level reduction).  
Dose reduction of 
everolimus to 3 mg/m2 
every other day may be 
considered for Grade 3 
toxicitye 
Third occurrence 
(same toxicity or new toxicity) 
Interrupt lenvatinib and 
everolimus until resolved to 
Grade 0-1 or tolerable 
Grade 2 
Reduce lenvatinib dose to 
4.5 mg/m2 (or 
approximately 
25% reduction from the 
previous dose level) orally 
once a day (1-level 
reduction).  Dose reduction 
of everolimus for Grade 3 
toxicity: 
i) if 3 mg/m2 daily 
everolimus at event onset, 
reduce to 3 mg/m2 every 
other day or 


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ii) if 3 mg/m2 every other 
day everolimus at event 
onset, discontinue 
Fourth occurrence 
(same toxicity or new toxicity) 
Interrupt lenvatinib and 
everolimus 
Discuss with sponsor 
Grade 4g: Discontinue Study Treatment 
Note: For grading see Common Terminology Criteria for Adverse Events (CTCAE) v4.03.  Collect all CTC grades 
of adverse events, decreasing and increasing grade.  
a: An interruption of study treatment for more than 28 days will require sponsor`s approval before treatment can 
be resumed.  
b: Initiate optimal medical management for nausea, vomiting, hypothyroidism and/or diarrhea prior to any study 
treatment interruption or dose reduction.  
c: Applicable only to Grade 2 toxicities judged by the subject and/or physician to be intolerable. 
d: Obese subjects with weight loss do not need to return to the baseline weight or 10% of baseline weight (ie, 
Grade 1weight loss).  These subjects will restart the study drug(s) at a lower dose once their weight remains 
stable for at least 1 week and they reached the normal body mass index (BMI; if the weight loss occurred but it 
is still above normal BMI, they can restart the study treatment at a lower dose once the weight has been stable 
for at least 1 week).  Normal BMI should be used as the new baseline for further dose reductions.  See BMI 
charts for boys (Appendix 9) and girls (Appendix 10). 
e: For Grade 2 toxicity, resume everolimus at the same dose as prior to dose interruption.  For Grade 3 toxicity, 
investigator will decide the probability of the event being related to one or both drugs as to whether dose 
modification of one or both drugs is required. 
f: 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. 
g: Excluding laboratory abnormalities judged to be non-life-threatening, in which case manage as Grade 3. 
 
9.4.1.2 
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-specific percentiles of BP are provided in Appendix 7 and  
Appendix 8.  BP that is consistently above the 95th percentile [for subjects age 18-21 years 
BP ≥140/90 mmHg] for age and height/length requires further evaluation.  A referral to a 
cardiologist is recommended for subjects 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 mmHg 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 subject with 
hypertension.  BP values for management of hypertension for subjects 18 to 21 years of 
age are included in parenthesis. 
9.4.1.3 
Management of Hypertension 
Hypertension is a recognized side-effect of treatment with drugs inhibiting VEGF signaling.  
Investigators should therefore ensure that subjects enrolled to receive treatment with 
lenvatinib have BP <95th percentile [BP ≤150/90 mmHg] 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 


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effective management of hypertension are important to minimize the need for dose 
interruptions and reductions.  Antihypertensive agents should be started as soon as elevated 
BP (systolic BP ≥95th percentile [BP ≥140 mmHg] or diastolic BP ≥95th percentile [BP 
≥90 mmHg]) is confirmed on 2 assessments obtained 1 hour apart.  One BP assessment is 
defined as the mean value of 3 measurements obtained at least 5 minutes apart.  The choice 
of antihypertensive treatment should be individualized to the subject’s clinical circumstances 
and follow standard medical practice.  For previously normotensive subjects, monotherapy 
with one of the classes of antihypertensives should be started when systolic BP 
≥95th percentile [BP ≥140 mmHg] or diastolic BP ≥95th percentile [BP ≥90 mmHg] is first 
observed on 2 assessments obtained 1 hour apart.  For those subjects 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.  For subjects 
with hypertension and proteinuria, treatment with an angiotensin-converting enzyme (ACE) 
inhibitor or angiotensin-II receptor antagonist is preferred.  
Study treatment should be withheld in any instances where a subject is at imminent risk to 
develop a hypertensive crisis or has significant risk factors for severe complications of 
uncontrolled hypertension (eg, BP ≥99th percentile [BP ≥160/100 mmHg], significant risk 
factors for cardiac disease, intracerebral hemorrhage, or other significant comorbidities).  
Once the subject has been on the same antihypertensive medications for at least 48 hours and 
the BP is controlled, study treatment should be resumed as described below.  
During the Treatment Period, subjects with systolic BP ≥99th percentile [BP ≥160 mmHg] or 
diastolic BP ≥99th percentile [BP ≥100 mmHg] must have their BP monitored every 2 weeks 
(on Day 15 or more frequently as clinically indicated) until systolic BP has been 
<95th percentile [≤150 mmHg] and diastolic BP has been <95th percentile [≤95 mmHg] for 
3 consecutive months.  If a new event of systolic BP ≥99th percentile [BP ≥160 mmHg] or 
diastolic BP ≥99th percentile [BP ≥100 mmHg] occurs, the subject must resume the Day 15 
evaluation until systolic BP has been <95th percentile [≤150 mmHg] and diastolic BP has 
been <95th percentile [≤95 mmHg] for 3 consecutive months.  
The following guidelines should be followed for the management of systolic BP ≥99th 
percentile [BP ≥160 mmHg] or diastolic BP ≥99th percentile [BP ≥100 mmHg] confirmed on 
repeat measurements after an hour:  
 
Continue study treatment and institute antihypertensive therapy for subjects not 
already receiving antihypertensive medication.  
 
For those subjects 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 mmHg) or diastolic BP ≥99th percentile 
(BP ≥100 mmHg) persists despite maximal antihypertensive therapy, then study 
treatment administration should be interrupted and restarted at a lower dose once 
daily (one dose level reduction as specified in Table 5) only when systolic BP 
<95th percentile (BP ≤150 mmHg) and diastolic BP <95th percentile (BP 


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≤95 mmHg) and the subject has been on a stable dose of antihypertensive medication 
for at least 48 hours.  
o If systolic BP ≥99th percentile (BP ≥160 mmHg) or diastolic BP 
≥99th percentile (BP ≥100 mmHg) recurs despite optimal management of 
hypertension with antihypertensive medications (either by dose increase or the 
addition of a different class of antihypertensive), then study treatment 
administration should be interrupted and restarted at a lower dose once daily 
(one dose level reduction as specified in the Table 5) only when systolic 
BP <95th percentile (BP ≤150 mmHg) and diastolic BP <95th percentile ([BP 
≤95 mmHg] and the subject has been on a stable dose of antihypertensive 
medication for at least 48 hours.  
o If systolic BP ≥99th percentile ([BP ≥160 mmHg) or diastolic BP 
≥99th percentile ([BP ≥100 mmHg] recurs despite optimal management of 
hypertension with antihypertensive medications (either by dose increase or the 
addition of a different class of antihypertensive), then study treatment 
administration should be interrupted and a restart of treatment 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 study treatment 
Figure 2 shows the procedures associated with the management of hypertension. 


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Figure 2 
Management of Hypertension 
BP = blood pressure, HTN = hypertension, Tx = treatment. 
9.4.1.4 
Management of Posterior Reversible Leukoencephalopathy Syndrome/ 
Reversible Posterior Leukoencephalopathy Syndrome  
Posterior Reversible Leukoencephalopathy Syndrome/ Reversible Posterior 
Leukoencephalopathy Syndrome (PRES/RPLS) is a neurological disorder that can present 
with headache, seizure, lethargy, confusion, altered mental function, blindness, and other 
visual or neurological disturbances.  Mild to severe hypertension may be present.  MRI is 
necessary to confirm the diagnosis of PRES/RPLS.  Appropriate measures should be taken to 
control BP.  In subjects with signs or symptoms of PRES/RPLS, the Dose Modification 
Guidelines (Table 5) should be followed.  
9.4.1.5 
Management of Proteinuria 
Regular assessment for proteinuria should be conducted as detailed in the Schedule of 
Assessments (Table 7 and Table 8).  Guidelines for assessment and management of 
proteinuria are summarized as follows:  
1. Grading according to CTCAE v4.03 will be based on the protein-creatinine ratio, and 
whenever possible, also on the 24-hour urinary protein result per investigator’s 


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discretion.  Management of study treatment administration will be based on the grade of 
proteinuria according to the Dose Modification Guidelines. 
2. A spot protein-creatinine ratio test, and if possible a 24-hour urinary protein test as per 
investigator’s discretion, to verify the grade of proteinuria is required in the following 
situations: 
 The first (initial) occurrence of ≥2+ proteinuria on urine dipstick while on study 
treatment 
 A subsequent increase in severity of urine dipstick proteinuria occurring on the same 
lenvatinib/everolimus dose level 
 When there has been a lenvatinib/everolimus dose reduction and at the new dose level 
the urine protein dipstick result is 2+, 3+, or 4+ 
3. Urine dipstick testing for subjects with proteinuria ≥2+ should be performed every 
2 weeks (or on Day 1 and Day 15 or more frequently as clinically indicated) until the 
results have been 1+ or negative for 3 consecutive months.   
4. In the event of nephrotic syndrome, lenvatinib must be discontinued. 
9.4.1.6 
Management of Diarrhea 
An anti-diarrheal agent should be recommended to the subject at the start of study treatment 
and subjects should be instructed and educated to initiate anti-diarrheal treatment at the first 
onset of soft bowel movements.  The choice of anti-diarrheal agent should be individualized 
to the subject’s clinical circumstances and follow standard medical practice.  If 
signs/symptoms of diarrhea persist despite optimal medical management, instructions 
contained in the Dose Modification Guidelines should be followed. 
9.4.1.7 
Management of Non-Infectious Pneumonitis 
Non-infectious pneumonitis is a recognized class effect of rapamycin derivatives, including 
everolimus.  Non-infectious pneumonitis was described in 19% of subjects taking everolimus 
(Afinitor package insert).  Some cases were severe and on rare occasions, a fatal outcome 
was observed.  Investigators should therefore consider a diagnosis of non-infectious 
pneumonitis in subjects presenting with non-specific respiratory signs and symptoms and in 
whom infectious, neoplastic and other non-medicinal causes have been excluded by means of 
appropriate investigations. 
Subjects who develop radiological changes suggestive of non-infectious pneumonitis and 
have few or no symptoms (Common Terminology Criteria for Adverse Events [CTCAE] 
Grade 1) may continue study dosing without dose adjustments. 
1. If symptoms are moderate (CTCAE Grade 2): 
 Study treatment (lenvatinib-everolimus combination) should be interrupted and the 
use of corticosteroids may be indicated until symptoms abate (resolved to CTCAE 
Grade 0-1) and may then be restarted at the same doses prior to study treatment 
interruption.  


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 If Grade 2 non-infectious pneumonitis recurs despite optimal management, then study 
treatment administration should be interrupted and the use of corticosteroids may be 
indicated until symptoms abate (resolved to CTCAE Grade 0-1).   
2. If symptoms are severe (CTCAE Grade 3): 
 Study treatment should be interrupted and the use of corticosteroids may be indicated 
until clinical symptoms resolve (to CTCAE Grade 0-1).   
3. If symptoms are life-threatening (CTCAE Grade 4): 
 Study medications should be discontinued. 
9.4.1.8 
Management of Infections 
Everolimus has immunosuppressive properties and may predispose subjects to infections.  It 
is important therefore to monitor for signs and symptoms of infection, and treat promptly.  
Dose alterations of everolimus may be required in accordance with everolimus prescribing 
information, ie, Afinitor Disperz package insert or Votubia Summary of Product 
Characteristics (SmPC). 
9.4.1.9 
Management of Blood Glucose and Lipids 
Hyperglycemia, hyperlipidemia and hypertriglyceridemia are recognized class effects of 
rapamycin derivatives, including everolimus.  Glycemic and lipid control should be 
optimized before starting a subject on this study.  Blood glucose will be monitored as 
specified in the Schedule of Procedures/Assessments.  For subjects with blood glucose 
>ULN, a fasting (>6 hour, water only) blood glucose sample will be obtained.  Grading will 
be based on the fasting blood glucose result.  The choice of hypoglycemic agent should be 
individualized to the subject’s clinical circumstances and follow standard medical practice.  
Dose alterations of everolimus may be required in accordance with everolimus prescribing 
information, ie, Afinitor Disperz package insert or Votubia SmPC. 
9.4.1.10 
Management of Hepatotoxicity 
Regular monitoring of liver function tests (ALT, AST, bilirubin levels) should be conducted 
as detailed in the Schedule of Assessments (Table 7 and Table 8) and as clinically indicated.  
If signs/symptoms indicating liver injury occur, instructions contained in the table for dose 
reduction and interruptions of the protocol should be followed (see Table 5), for Study 
Treatment Dose Reduction and Interruption Instructions).  Appropriate supportive care 
should be provided together with close monitoring.  If hepatic failure occurs the study 
treatment must be discontinued. 
9.4.1.11 
Management of Thromboembolic Events 
Subjects 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, subjects should be instructed to report such symptoms promptly to the 


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treating physician.  If a thromboembolic event is confirmed, instructions contained in the 
table for dose reduction and interruptions of the protocol should be followed, (see Table 5), 
for Study Treatment Dose Reduction and Interruption Instructions).  Appropriate supportive 
care should be provided together with close monitoring.  If a subject experiences 
life-threatening (Grade 4) thromboembolic reactions, including pulmonary embolism, the 
study treatment must be discontinued.  If a subject experiences an arterial thromboembolism 
event of any grade, lenvatinib must be discontinued. 
9.4.1.12 
Management of Hypocalcemia 
Serum calcium should be monitored per the Schedule of Assessments.  Corrected serum 
calcium should be used to assess the grade of hypocalcemia per CTCAE v 4.03, using the 
following formula:  
Corrected calcium = ([4 – serum albumin in g/dL] x 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. 
9.4.1.13 
Management of Hemorrhage 
For subjects with hemorrhage, either resume at a reduced dose or discontinue study treatment 
depending on the severity and persistence of hemorrhage. 
9.4.1.14 
Management of Gastrointestinal Symptoms and Acute Abdominal Pain 
Initial management of acute abdominal pain in these study subjects should be focused on 
treating the underlying cause where possible, ensuring appropriate hydration/rehydration, and 
symptomatic pain improvement consistent with subject’s age and in accordance to 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, instructions contained in 
Table 5 regarding study treatment dose reduction and interruption instructions.  For Grade 4 
AEs that result in abdominal pain, study treatment must be discontinued. 
Gastrointestinal symptoms including diarrhea should be managed by providing symptomatic 
treatment.  If the symptoms persist (eg, diarrhea for more than 10 days), Study Treatment 
Interruption and Reduction guideline should be followed.  Gastrointestinal 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.  It is recommended 
that all gastrointestinal symptoms should be recorded in the diary provided. 


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9.4.1.15 
Management of Fistula Formation and Gastrointestinal Perforation 
Lenvatinib should be discontinued in any subject who develops Grade 4 fistula 
(gastrointestinal or non-gastrointestinal), or gastrointestinal perforation of any grade. 
9.4.1.16 
Management of Osteonecrosis of the Jaw 
Perform an oral examination prior to treatment with lenvatinib and periodically during 
lenvatinib treatment. Advise study subjects regarding good oral hygiene practices. Avoid 
invasive dental procedures, if possible, while on lenvatinib treatment, particularly in study 
subjects at higher risk. For study subjects requiring invasive dental procedures, 
discontinuation of bisphosphonate treatment may reduce the risk of osteonecrosis of the jaw. 
Withhold lenvatinib if osteonecrosis of the jaw develops and restart based on clinical 
judgement of adequate resolution (see Section 9.4.7). 
9.4.1.17 
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. 
9.4.2 
Identity of Investigational Products 
The study drugs under evaluation in this study are lenvatinib in combination with everolimus.  
The sponsor will provide the study drugs packaged as open-label supplies. 
Lenvatinib 
Lenvatinib will be supplied by the sponsor in labeled containers.  The sponsor will package 
lenvatinib as open-label supplies.  Lenvatinib will be provided to the sites as #4 size 
hydroxypropyl methylcellulose (HPMC) capsules in 3 strengths differentiated by color (iron 
oxide red and iron oxide yellow); 1-mg capsule (yellowish red cap and white body, 
containing 1 mg E7080 anhydrous-free base), 4 mg capsule (yellowish-red cap and body, 
containing 4 mg E7080 anhydrous-free base); and 10 mg capsule (yellowish-red cap with 
yellow body, containing 10 mg E7080 anhydrous-free base).  Excipients of the E7080 
formulation will be calcium carbonate, mannitol, microcrystalline cellulose, 
hydroxypropylcellulose, low-substituted hydroxypropylcellulose, talc, hypromellose, 
titanium dioxide, iron oxide yellow, and iron oxide red.  Lenvatinib capsules may be 
suspended in water or apple juice for children unable to swallow capsules.  Appendix 12 
provides instructions for the preparation of the lenvatinib suspension. 
Everolimus 
Everolimus dispersible tablets for oral suspension will be provided as commercial drug 
product such as ‘Afinitor Disperz’ or ‘Votubia dispersible tablets’ in strengths of 2 mg, 3 mg, 
and 5 mg.  Note that everolimus tablets contain lactose.  


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9.4.2.1 
Chemical Name, Structural Formula of Lenvatinib 
 
Study drug code:  E7080 
 
Generic name:  lenvatinib 
 
Chemical name:  4-[3-Chloro-4-(N’-cyclopropylureido)phenoxy]-7-methoxyquinoline-6-
carboxamide methanesulfonate 
 
Molecular formula:  C21H19CLN4O4•CH4O3S 
 
Molecular weight:  522.96 
 
Structural formula:   
 
 
9.4.2.2 
Chemical Name, Structural Formula of Everolimus 
 
Generic name:  everolimus 
 
Chemical name:  -O-(2-hydroxyethyl)-rapamycin 
 
Molecular formula: C53H83NO14 
Refer to the latest everolimus prescribing information, ie, Afinitor Disperz package insert or 
Votubia SmPC. 
9.4.2.3 
Comparator Drug 
Not applicable 
9.4.2.4 
Labeling for Study Drug 
Lenvatinib and everolimus will be labeled in accordance with text that is in full regulatory 
compliance with each participating country and is translated into the required language(s) for 
each of those countries. 
9.4.2.5 
Storage Conditions 
Study drug will be stored in accordance with the labeled storage conditions.  Temperature 
monitoring is required at the storage location to ensure that the study drug is maintained 
within an established temperature range.  The investigator or designee is responsible for 
ensuring that the temperature is monitored throughout the total duration of the study and that 
records are maintained; the temperature should be monitored continuously by using either an 


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in-house validated data acquisition system, a mechanical recording device, such as a 
calibrated chart recorder, or by manual means, such that minimum and maximum 
thermometric values over a specific time period can be recorded and retrieved as required. 
9.4.3 
Method of Assigning Subjects to Treatment Groups 
This is an open-label, single-arm study.  All subjects who provide signed informed consent to 
participate in this study and satisfy all eligibility requirements (see Section 9.3) will be 
assigned to receive lenvatinib in combination with everolimus in 28-day treatment cycles.  
There is no randomization in this study. 
9.4.4 
Selection of Doses in the Study 
The purpose of the Phase 1 portion of the study is to determine the MTD and the RP2D of 
lenvatinib administered in combination with everolimus in this pediatric population.  The 
dose levels of lenvatinib and everolimus to be evaluated in the study are pre-specified.  The 
starting dose level of lenvatinib is 11 mg/m2, which is approximately 80% of lenvatinib 
single dose MTD in pediatric subjects determined in the ongoing Study E7080-G000-207.  
The initial dose of everolimus is 3 mg/m2, which is 66% of the FDA approved dose and dose 
previously found effective in subependymal giant cell astrocytoma. 
9.4.5 
Selection and Timing of Dose for Each Subject 
Lenvatinib and everolimus are to be administered orally once a day at approximately the 
same time without regard to food intake for 28 days from Cycle 1 onward.  If a subject 
misses a dose of lenvatinib, it may be taken within the 12 hours following 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 subject vomits after 
study drug administration, the subject should not take another dose until the next scheduled 
dose.   
Refer to everolimus prescribing information for recommended everolimus dosing 
information. 
Study drugs should be administered at the clinic on PK sampling days.  All scheduled visits 
must be conducted as per protocol, irrespective of treatment interruption.  If holidays or 
personal schedules make administration impossible on the scheduled days, then 
administration should be resumed as soon as possible. 
9.4.6 
Blinding 
The study will not be blinded. 
9.4.7 
Prior and Concomitant Therapy 
All prior medications (including over-the-counter medications) administered 28 days before 
the first dose of study drug and any concomitant therapy administered to the subject during 


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the course of the study (starting at the date of informed consent) until 28 days after the final 
dose of study drug will be recorded.  Additionally, all diagnostic, therapeutic, or surgical 
procedures relating to malignancy should be recorded.  Any medication that is considered 
necessary for the subject’s health and that is not expected to interfere with the evaluation of 
or interact with the study medication may be continued during the study. 
Aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), and low-molecular-weight heparin 
(LMWH) are permissible but should be used with caution.  Erythropoietic stimulating agents 
(ESAs) may be used according to the American Society of Clinical Oncology (ASCO), 
institutional, or national guidelines and according to the SmPC or local labeling instructions, 
but the subject should be carefully monitored for increases in red blood cell counts.   
Treatment (including blood products, blood transfusions, fluid transfusions, antibiotics, and 
antidiarrheal drugs, etc) of complications of 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.  
An anti-diarrheal agent should be recommended to the subject at the start of study treatment 
and subjects should be instructed and educated to initiate anti-diarrheal treatment at the first 
onset of soft bowel movements.  The choice of anti-diarrheal agent should be individualized 
to the subject’s clinical circumstances and follow standard medical practice.  If 
signs/symptoms of diarrhea persist despite optimal medical management, instructions 
contained in the Dose Modification Guidelines should be followed. 
Administration of corticosteroids for progressive disease is not permitted.  Administration of 
corticosteroids will be limited to premedication or the short-term treatment of acute medical 
conditions in accordance with approved indications, institutional, or national guidelines. 
Palliative radiotherapy of up to 2 painful pre-existing, non-target bone metastases will be 
permitted without being considered progressive disease.  In the Phase 1 part, palliative 
radiotherapy will be allowed after the completion of Cycle 1. 
If a subject receiving treatment with lenvatinib 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 1 week 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. 
If concomitant medication/therapy is administered for an AE, investigators will record that 
AE on the Adverse Events CRF. 


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9.4.7.1 
Drug-Drug Interactions 
Lenvatinib’s weak in vitro inhibitory and induction potential on CYP enzymes 
(Study No. XT063020) suggests a low risk of lenvatinib interference with the PK of other 
drugs metabolized by CYP enzymes which are co-administered in usual clinical practice.  
Nonclinical studies identify CYP3A4 as the important CYP isozyme responsible for human 
hepatic metabolism of lenvatinib.  However, clinical studies conducted showed that 
coadministration of lenvatinib with CYP3A4/P-gp inhibitors or inducers is not of clinical 
concern.  The main metabolic pathways for lenvatinib in humans were identified as 
enzymatic (CYP3A and aldehyde oxidase) and non-enzymatic processes (Lenvima® package 
insert).   
For subjects receiving everolimus, drugs or substances (including herbal supplements or 
grapefruit juice) known to be potent inhibitors of CYP3A4/P-gp should not be used.  Potent 
inducers of CYP3A4/P-gp should not be used unless there is no alternative treatment 
available.  Dose increase of everolimus may be considered when co-administering strong 
CYP3A4 or P-gp inducers.  Moderate/ weak inhibitors or inducers or substrates of CYP3A4 
and/or P-gp should be used with caution.  Dose reduction of everolimus may be considered 
when co-administering moderate CYP3A4 or P-gp inhibitors.  For further information, please 
refer to everolimus prescribing information. 
9.4.7.2 
Prohibited Concomitant Therapies and Drugs 
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase of this study: 
 
Concurrent anticancer therapies such as chemotherapy, TKIs, radiotherapy (with the 
exception of palliative radiotherapy as specified in Section 9.4.7), antitumor interventions 
(surgical resection, surgical debulking of tumor, etc), or cancer immunotherapy 
 
Concurrent other investigational drugs 
 
Live vaccines are prohibited while participating in the study.  Examples of live vaccines 
include, but are not limited to, the following: measles, mumps, rubella, chicken pox, 
yellow fever, rabies, BCG, and typhoid (oral) vaccine.  Seasonal influenza vaccines for 
injection are generally killed virus vaccines and are allowed.  However intranasal 
influenza vaccines (eg, Flu-Mist®) are live attenuated vaccines, and are not allowed. 
For subjects 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 subjects receive additional anticancer therapies, this will be judged to represent evidence of 
disease progression, and study medication will be discontinued.  These subjects should 
complete all off-treatment assessments and continue to be followed for survival in the 
Follow-Up Period. 


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Further information on the prohibited concomitant therapies for lenvatinib and everolimus is 
included in the respective prescribing information. 
9.4.8 
Treatment Compliance 
Records of treatment compliance for each subject will be kept during the study.  CRAs will 
review treatment compliance during site visits and at the completion of the study. 
9.4.9 
Drug Supplies and Accountability 
In compliance with local regulatory requirements, drug supplies will not be sent to the 
investigator (or if regionally required, the head of the medical institution or the designated 
pharmacist) until the following documentation has been received by the sponsor: 
 
A signed and dated confidentiality agreement 
 
A copy of the final protocol signature page, signed and dated by both the sponsor and 
investigator 
 
Written proof of approval of the protocol, the ICFs, and any other information provided 
to the subjects by the IRB/IEC for the institution where the study is to be conducted 
 
A copy of the IRB/IEC-approved ICF and any other documentation provided to the 
subjects to be used in this study 
 
The IRB/IEC membership list and statutes or Health and Human Services Assurance 
number 
 
A copy of the certification and a table of the normal laboratory ranges for the reference 
laboratory conducting the clinical laboratory tests required by this protocol 
 
An investigator-signed and dated FDA Form FDA 1572, where applicable 
 
Financial Disclosure form(s) for the principal investigator (PI) and all subinvestigators 
listed on Form FDA 1572, where applicable 
 
A signed and dated curriculum vitae (CV) of the PI including a copy of the PI’s current 
medical license or medical registration number on the CV 
 
A signed and dated clinical studies agreement 
 
A copy of the regulatory authority approval for the country in which the study is being 
conducted (if required), and the Import License (if required) 
The investigator and the study staff (or if regionally required, the head of the medical 
institution or the designated pharmacist) will be responsible for the accountability of all study 
drugs (dispensing, inventory, and record keeping) following the sponsor’s instructions and 
adherence to GCP guidelines as well as local or regional requirements. 
Under no circumstances will the investigator allow the study drugs to be used other than as 
directed by this protocol.  Study drugs will not be dispensed to any individual who is not 
enrolled in the study other than the parent, guardian, or authorized legal representative of a 
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The site must maintain an accurate and timely record of the following:  receipt of all study 
drugs, dispensing of study drugs to the subject, collection and reconciliation of unused study 
drugs that are either returned by the subjects or shipped to site but not dispensed to subjects, 
and return of reconciled study drugs to the sponsor or (where applicable) destruction of 
reconciled study drugs at the site.  This includes, but may not be limited to:  (a) 
documentation of receipt of study drugs, (b) study drugs dispensing/return reconciliation log, 
(c) study drugs accountability log, (d) all shipping service receipts, (e) documentation of 
returns to the sponsor, and (f) certificates of destruction for any destruction of study 
drugs/study supplies that occurs at the site.  All forms will be provided by the sponsor.  Any 
comparable forms that the site wishes to use must be approved by the sponsor. 
The study drugs and inventory records must be made available, upon request, for inspection 
by a designated representative of the sponsor or a representative of a health authority (eg, 
FDA, MHRA).  As applicable, all unused study drugs and empty and partially empty 
containers from used study drugs are to be returned to the investigator (or if regionally 
required, the head of the medical institution or the designated pharmacist) by the subject and, 
together with unused study drugs that were shipped to the site but not dispensed to subjects, 
are to be returned to the sponsor’s designated central or local depot(s) during the study or at 
the conclusion of the study, unless provision is made by the sponsor for destruction of study 
drugs and containers at the site.  Destruction at the site will only occur under circumstances 
where regulation or supply type prohibits the return of study drugs to the central or local 
depot(s).  Approval for destruction to occur at the site must be provided by the sponsor in 
advance.  Upon completion of drug accountability and reconciliation procedures by the site’s 
personnel and documentation procedures by the sponsor’s personnel, study drugs that are to 
be returned to the sponsor’s designated central or local depot(s) must be boxed, sealed, and 
shipped back to the central or local depot(s) following all local regulatory requirements.  In 
some regions, study drugs may be removed from the site and hand delivered to the central or 
local depot by sponsor representatives.  Where study drugs are approved for destruction at 
the site, destruction will occur following the site’s standard procedures and certificates of 
destruction will be provided to the sponsor. 
Drug accountability will be reviewed during site visits and at the completion of the study. 
9.5 
Study Assessments 
9.5.1 
Assessments 
9.5.1.1 
Demography 
Subject demography information will be collected at the Screening Visit.  Demography 
information includes date of birth (or age), sex, and race/ethnicity.  
9.5.1.2 
Baseline Assessments 
Baseline assessments will be performed at Day -1 or at Cycle 1 Day 1 prior to treatment.  
The screening assessment can serve as the baseline assessment, if performed within 72 hours 
of the first dose of study treatment.  Assessments will include confirmation of subject 


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eligibility with the inclusion and exclusion criteria, medical and surgical history, prior 
medications and procedures, pregnancy test (serum or urine) within 72 hours prior to the first 
dose of study treatment, Lansky play score (see Appendix 4) or Karnofsky performance 
status score (see Appendix 5), tumor staging (as appropriate) at the time of initial diagnosis, 
vital signs, clinical chemistry and hematology, urine dipstick testing, 
echocardiogram/MUGA scan, proximal tibial growth plates x-ray, PD biomarkers and 
optional biomarkers, and blood sample collection for pharmacogenomics analysis. 
9.5.1.2.1 MEDICAL HISTORY AND PHYSICAL EXAMINATIONS 
Medical and surgical history and current medical conditions will be recorded at the Screening 
and Baseline Visits.  All medical and surgical history must be noted in the Medical History 
and Current Medical Conditions CRF. 
Physical examinations (comprehensive or symptom directed) will be performed as designated 
in the Schedule of Assessments (Table 7 and Table 8).  A comprehensive physical 
examination will include evaluations of the head, eyes, ears, nose, throat, neck, chest 
(including heart and lungs), abdomen, limbs, skin, and a complete neurological examination.  
Documentation of the physical examination will be included in the source documentation at 
the site.  Significant findings at the Screening Visit will be recorded on the Medical History 
and Current Medical Conditions CRF.  Changes from screening physical examination 
findings that meet the definition of an AE will be recorded on the Adverse Events CRF. 
9.5.1.3 
Efficacy Assessments 
9.5.1.3.1 TUMOR ASSESSMENTS 
For all tumor types except HGG:  Tumor assessments will be performed using RECIST 1.1 
(Appendix 1).  Investigator-determined response assessments will be performed at each 
assessment time point and entered onto the CRF.  Tumor assessments (CT chest and CT/MRI 
of abdomen, pelvis and other areas of known disease at screening plus any areas of suspected 
disease) should be performed at Screening and, for Phase 1 of the study, at Week 4 ±1 week, 
Week 12 ±1 week, Week 24 ±1 week, and every 12 weeks ±1 week thereafter, or as 
clinically indicated.  For subjects with primary CNS tumors and no other known areas of 
disease only target and non-target lesions plus any areas of newly suspected disease must be 
scanned.  For Phase 2 of the study, tumor assessments should be performed at Screening, 
Week 8 ±1 week, Week 16 ±1 week, Week 24 ±1 week, and then every 12 weeks ±1 week 
thereafter, or as clinically indicated.  All responses are to be confirmed at a follow-up 
examination after ≥28 days following the initial indication of response.  Historical scans 
(within 28 days prior) that do not follow the guidelines completely may be used.  
A brain scan (CT with contrast or MRI pre- and post-contrast) will be performed at 
Screening and during the study if clinically indicated. 
For Phase 1 of the study, subsequent tumor assessments will occur at Week 4 ±1 week, 
Week 12 ±1 week, Week 24 ±1 week and every 12 weeks ±1 week thereafter, or as clinically 
indicated.  For Phase 2 of the study, tumor assessments should be performed at Week 8 ±1 


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week, Week 16 ±1 week, Week 24 ±1 week, and then every 12 weeks ±1 week thereafter, or 
as clinically indicated.  Tumor assessments will be performed based on RECIST 1.1 
beginning from the date of first dose, continuing during treatment cycles until documentation 
of disease progression.  This schedule for tumor assessments will be maintained irrespective 
of treatment delays.  All responses are to be confirmed at a follow-up examination after ≥28 
days following the initial indication of response.  The same methodology (CT or MRI) and 
scan acquisition techniques (including use or nonuse of intravenous contrast) as was used for 
the Screening assessments should be utilized across all time points to allow consistent 
comparison of lesions.  After treatment discontinuation for a reason other than disease 
progression, tumor assessments should continue to be performed every 12 weeks until 
documentation of progression or start of a new anticancer agent.  Please see Appendix 13 for 
imaging methodology for tumor assessment. 
If protocol eligible brain metastases are present at Screening, a CT/MRI of the brain must be 
performed at all tumor assessment time points.  
For HGG:  Tumor assessments will be performed using RANO Criteria (Appendix 14).  A 
standard MRI-imaging protocol will be performed for use in the assessments.  
Investigator-determined response assessments at each assessment time point will be entered 
onto the appropriate CRFs.  Tumor assessments will be carried out during Screening and for 
Phase 1 of the study, at Week 4 ±1 week, Week 12 ±1 week, Week 24 ±1 week, and then 
every 12 weeks ±1 week thereafter, or as clinically indicated.  For Phase 2 of the study, 
tumor assessments should be performed at Screening, Week 8 ±1 week, Week 16 ±1 week, 
Week 24 ±1 week, and every 12 weeks ±1 week thereafter, or as clinically indicated. 
For Phase 2, copies of scans for tumor assessments will be sent to an imaging core laboratory 
designated by the sponsor for quality assessment and archival and potential future 
independent review.  
After data cutoff, tumor assessments may be performed as clinically indicated as per the 
institutional guidelines, following the prevailing local standard of care and scans will not be 
sent to the imaging core laboratory. 
The imaging methodology for tumor assessments for all tumor types, including solid tumors 
and HGG, is provided in Appendix 13. 
9.5.1.4 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Assessments 
9.5.1.4.1 PHARMACOKINETIC ASSESSMENTS 
Blood samples (2 mL each) for plasma concentrations of lenvatinib and whole blood 
concentrations of everolimus will be collected from all subjects as described in the Schedule 
of Assessments (Table 7 and Table 8).  Instructions for the collection, handling, and shipping 
procedures of the plasma and blood PK samples will be provided in a separate laboratory 
manual.   


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If dose interruption is necessary at the PK time points, the sponsor should be consulted. 
Lenvatinib in plasma and everolimus in whole blood will be quantified using validated liquid 
chromatography tandem mass spectrometry (LC-MS/MS) methods. 
9.5.1.4.2 PHARMACODYNAMIC, PHARMACOKINETIC/PHARMACODYNAMIC, PHARMACOGENOMIC, 
AND OTHER BIOMARKER, ASSESSMENTS 
Pharmacodynamic Assessments:  Blood samples for plasma and serum studies will be 
collected from consenting subjects (optional) at Baseline and on Cycle 1 Day 15, Cycle 2 
Day 1, and then matched with tumor assessments and at the Off-treatment Visit, as specified 
in the Schedule of Assessments (Table 7 and Table 8).  Only subjects with BSA >0.68 m2 are 
eligible to consent (optional) to blood samples for plasma and serum studies.  Biomarker 
discovery and/or validation will be performed to identify blood or tumor biomarkers that may 
be useful to predict subject response to study drug as well as for potential use in diagnostic 
development (see Appendix 11).  Blood samples may undergo global proteomic and/or single 
analyte enzyme-linked immunosorbent assays (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 subjects enrolled in this 
study.  The decision to perform exploratory biomarker analysis may be based on the clinical 
outcome of this study and/or the signals observed in other clinical studies or other 
information available at that time. 
Pharmocokinetic/Pharmacodynamic Assessments: Relationships between lenvatinib 
exposure and safety will be explored graphically.  Pending the outcome of graphical 
assessments, modeling of potential relationships will be explored.  Details of exposure-safety 
analyses will be provided in a separate analysis plan. 
Pharmacogenomic/Pharmacogenetic Assessments:  Archived, fixed tumor tissue will be 
collected (if available), as specified in the Schedule of Assessments (Table 7 and Table 8), 
for potential assessment of mutations and other genetic alterations in genes and/or proteins 
that may be important in the development and progression of tumor biology relevant to the 
tumor types being explored, to evaluate response to study drug treatment, as well as for 
potential use in diagnostic development.  Genetic alterations in target genes include 
lenvatinib targets (eg, FGF ligands and FGF receptors 1-4), angiogenesis-relevant targets 
(such as expression levels of VEGF, Ang 1/2, Tie-2, HGF and cMET) and markers 
associated with cell differentiation and tumorigenesis (eg, WNT/β-catenin pathway, 
hedgehog/PTCH pathway, and BMP/TGF signaling pathway).  Appropriate analytical 
technology/methodologies, such as next generation sequencing (NGS)-based whole exome 
sequencing (WES), whole transcriptome analysis or targeted re-sequencing using targeted 
gene panels (eg, ThermoFisher Oncomine Comprehensive Assay (OCA)) for gene 
alterations, targeted gene expression panels (eg, Nanostring PanCancer Pathway, PanCancer 
Immune) for gene expression analysis, single analyte or multiplex IHC, etc may be used 
based on the amount of tumor tissue available. 


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Blood plasma samples will be collected (optional) for analysis of cell-free nucleic acid 
(cf-nucleic acid).  Cell-free nucleic acid isolated from plasma samples may be used to 
explore tumor genetic alterations such as mutations and other genetic alterations observed in 
archival tumor samples (using NGS-based targeted gene panels), as well as those which 
develop during drug treatment to monitor response to study drug.   
A blood sample will be collected for PG analysis (optional).  Variation in study drug 
exposure or the occurrence of AEs observed in the study population may be evaluated by 
correlating single–nucleotide polymorphisms with PK, safety, or PD data.  Genomic DNA 
extracted from blood samples may be used to confirm whether the DNA sequence variants 
observed in DNA extracted from tumor material are limited to the tumor. 
Data obtained will be used for research to assist in developing safer and more effective 
treatments and will not be used to change the diagnosis of the subject or alter the therapy of 
the subject.  The PD and PG samples will not be used to determine or predict risks for 
diseases that an individual subject does not currently have.  Any sample or derivatives (DNA, 
RNA, and protein) may be stored for up to 15 years after study completion to assist in 
research scientific questions related to cancer biology or for potential diagnostic 
development. 
Instructions for the processing, storage, and shipping of samples will be provided in the 
Laboratory Instruction Manual. 
9.5.1.5 
Safety Assessments 
Safety assessments will consist of monitoring and recording all AEs and serious adverse 
events (SAEs) using CTCAE v4.03; regular laboratory evaluation for hematology, blood 
chemistry, and urine dipstick values; regular performance of physical examinations; periodic 
measurement of vital signs, 12-lead ECGs, echocardiography/MUGA scan, Lansky play 
score and Karnofsky performance score as detailed in the Schedule of Assessments (Table 7 
and Table 8).   
BP monitoring will occur at least weekly during the first 2 cycles.  BP will be assessed in 
terms of percentile for sex, age and height/length.  Antihypertensive agents should be started 
as soon as elevated BP (systolic BP ≥95th percentile [BP ≥140 mmHg for adult subjects] or 
diastolic BP ≥95th percentile [BP ≥90 mmHg for adult subjects]) is confirmed on 
2 assessments obtained 1 hour apart.  For subjects with hypertension and proteinuria, 
treatment with an angiotensin-converting enzyme (ACE) inhibitor or angiotensin-II receptor 
antagonist is preferred.  Cardiac systolic function and QTc will be assessed at screening, 
prior to Cycles 2 and 5, and every sixth cycle thereafter by echocardiography/MUGA scan 
and electrocardiogram.  
9.5.1.5.1 ADVERSE EVENTS  
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered an investigational product.  An AE does not necessarily have a causal 


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relationship with the medicinal product.  For this study, the study drugs are lenvatinib and 
everolimus.  
The criteria for identifying AEs in this study are: 
 
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of an investigational product, 
whether or not considered related to the investigational product (Note:  Every sign or 
symptom should not be listed as a separate AE if the applicable disease [diagnosis] is 
being reported as an AE) 
 
Any new disease or exacerbation of an existing disease.  However, worsening of the 
primary disease should be captured under efficacy assessments as disease progression 
rather than as an AE. 
 
Any deterioration in nonprotocol-required measurements of a laboratory value or other 
clinical test (eg, ECG or x-ray) that results in symptoms, a change in treatment, or 
discontinuation of study drug 
 
Recurrence of an intermittent medical condition (eg, headache) not present pretreatment 
(Baseline) 
 
An abnormal laboratory test result should be considered an AE if the identified laboratory 
abnormality leads to any type of intervention, withdrawal of study drug, or withholding 
of study drug, whether prescribed in the protocol or not. 
All AEs observed during the study will be reported on the CRF.  All AEs, regardless of 
relationship to study drug or procedure, should be collected beginning from the time the 
subject signs the study ICF through the last visit and for 28 days after the last dose of study 
treatment.  Serious AEs (SAEs) will be collected for 28 days after the last dose of study 
treatment. 
Abnormal laboratory values should not be listed as separate AEs if they are considered to be 
part of the clinical syndrome that is being reported as an AE.  It is the responsibility of the 
investigator to review all laboratory findings in all subjects and determine if they constitute 
an AE.  Medical and scientific judgment should be exercised in deciding whether an isolated 
laboratory abnormality should be classified as an AE.  Any laboratory abnormality 
considered to constitute an AE should be reported on the Adverse Event CRF.  
Abnormal ECG (corrected QT interval [QTc]) results, if not otherwise considered part of a 
clinical symptom that is being reported as an AE, should be considered an AE if the QTc 
interval is more than 450 msec and there is an increase of more than 60 msec from baseline.  
Any ECG abnormality that the investigator considers as an AE should be reported as such. 
All AEs must be followed for 28 days after the subject’s last dose, or until resolution, 
whichever comes first.  All SAEs must be followed to resolution or, if resolution is unlikely, 
to stabilization.   
Every effort must be made by the investigator to categorize each AE according to its 
severity and its relationship to the study treatment. 


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Assessing Severity of Adverse Events 
The criteria for assessing severity are different than those used for seriousness (see 
Section 9.5.1.5.2 for the definition of an SAE). 
Adverse events will be graded on a 5-point scale according to CTCAE v4.03 (Appendix 2).  
Investigators will report CTCAE grades for all AEs.  
Assessing Relationship to Study Treatment 
Items to be considered when assessing the relationship of an AE to the study treatment are: 
 
Temporal relationship of the onset of the event to the initiation of the study treatment 
 
The course of the event, especially the effect of discontinuation of study treatment or 
reintroduction of study treatment, as applicable 
 
Whether the event is known to be associated with the study treatment or with other 
similar treatments 
 
The presence of risk factors in the study subject known to increase the occurrence of the 
event 
 
The presence of nonstudy, treatment-related factors that are known to be associated with 
the occurrence of the event 
Classification of Causality 
The relationship of each AE to the study drug will be recorded on the CRF in response to the 
following question: 
Is there a reasonable possibility that the study drug caused the AE? 
Yes (related) 
A causal relationship between the study drug and the AE is a reasonable 
possibility. 
No (not related) A causal relationship between the study drug and the AE is not a 
reasonable possibility. 
9.5.1.5.2 SERIOUS ADVERSE EVENTS AND EVENTS ASSOCIATED WITH SPECIAL SITUATIONS 
SAE is any untoward medical occurrence that at any dose: 
 
Results in death 
 
Is life-threatening (ie, the subject was at immediate risk of death from the AE as it 
occurred; this does not include an event that, had it occurred in a more severe form or 
was allowed to continue, might have caused death) 
 
Requires inpatient hospitalization or prolongation of existing hospitalization 
 
Results in persistent or significant disability/incapacity 
 
Is a congenital anomaly/birth defect (in the child of a subject who was exposed to the 
study drug) 


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Other important medical events that may not be immediately life-threatening or result in 
death or hospitalization but, when based on appropriate medical judgment, may jeopardize 
the subject or may require intervention to prevent one of the outcomes in the definition of 
SAE listed above should also be considered SAEs.  Medical and scientific judgment should 
be exercised in deciding whether expedited reporting is appropriate in such situations.  In 
addition to the above, events associated with special situations include pregnancy or 
exposure to study drug through breastfeeding, AEs associated with study drug overdose, 
misuse, abuse, or medication error.  These events associated with special situations are to be 
captured using the SAE procedures but are to be considered as SAEs only if they meet one of 
the above criteria.  All AEs associated with special situations are to be reported on the CRF 
whether or not they meet the criteria for SAEs.   
All SAEs must be followed to resolution or, if resolution is unlikely, to stabilization. 
The following hospitalizations are not considered to be SAEs because there is no “adverse 
event” (ie, there is no untoward medical occurrence) associated with the hospitalization: 
 
Hospitalizations for respite care  
 
Planned hospitalizations required by the protocol 
 
Hospitalization planned before informed consent (where the condition requiring the 
hospitalization has not changed after study drug administration) 
 
Hospitalization for administration of study drug or insertion of access for administration 
of study drug 
 
Hospitalization for routine maintenance of a device (eg, battery replacement) that was in 
place before study entry 
9.5.1.5.3 LABORATORY MEASUREMENTS 
Clinical laboratory tests to be performed, including hematology, chemistry, and urinalysis, 
are summarized in Table 6.  Subjects should be in a seated or supine position during blood 
collection.  The Schedule of Assessments (Table 7 and Table 8) shows the visits and time 
points at which blood for clinical laboratory tests and urine for urinalysis will be collected in 
the study. 


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Table 6 
Clinical Laboratory Tests 
Category 
Parameters 
Hematology 
Hematocrit, hemoglobin, platelets, red blood cell count, and white 
blood cell count with differential (bands, basophils, eosinophils, 
lymphocytes, monocytes, neutrophils) 
International Normalized Ratioa 
Chemistry 
 
 Electrolytes 
Bicarbonate, calcium, chloride, potassium, sodium, magnesium, 
phosphorus 
 Liver function tests 
Alanine aminotransferase, alkaline phosphatase, aspartate 
aminotransferase, direct bilirubinb, total bilirubin 
 Renal function tests 
Blood urea/blood urea nitrogen, creatinine 
 Thyroid function testsc 
Thyroid stimulating hormone, free thyroxine (T4) level  
 Other chemistries 
Albumin, amylase, calcium, glucosed, lactate dehydrogenase, 
lipase, total protein, triglycerides, cholesterol 
Urinalysis for microscopye 
RBCs/high-power-field (HPF) 
Urine dipstick testinge 
Blood, protein, glucose 
Other 
Pregnancy test (serum or urine beta-human chorionic gonadotropin) 
a:  INR should only be performed as part of the screening assessment and when clinically indicated. 
b:  Direct bilirubin should be assessed if total bilirubin is elevated. 
c:  Thyroid function will be assessed every cycle  
d:  For subjects with blood glucose>ULN, a fasting (>6h, water only) blood glucose sample will be obtained. 
e:  If urine dipstick testing suggests a urinary tract infection, or if clinically indicated, a urine microscopy, culture, and 
sensitivity should be performed at the institution’s laboratory.  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.  
 
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 prior to study drug administration and results reviewed prior to 
administration of study drug on Cycle 1 Day 1 and within 48 hours prior to dispensing study 
drug 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 5 for the management of clinically significant laboratory abnormalities. 
A laboratory abnormality may meet the criteria to qualify as an AE as described in this 
protocol (see Section 9.5.1.5.1 and the CRF Completion Guidelines).  In these instances, the 
AE corresponding to the laboratory abnormality will be recorded on the Adverse Event CRF. 


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For laboratory abnormalities meeting the criteria of SAEs (Section 9.5.1.5.2), the site must 
send the SAE report including the laboratory report (as regionally required) to the SAE fax 
number or email provided in the Investigator File. 
9.5.1.5.4 VITAL SIGNS AND WEIGHT MEASUREMENTS 
Vital sign measurements (ie, systolic and diastolic BP [mmHg], pulse rate [beats per minute], 
respiratory rate [per minute], body temperature [in centigrade]), and weight (kg) and height 
(cm) will be obtained at the visits designated in the Schedule of Assessments (Table 7 and 
Table 8) by a validated method.  BP and pulse rate will be measured after the subject has 
been resting for 5 minutes.  All BP measurements should be performed on the same arm, 
preferably by the same person.  For subjects with an elevated BP (≥95th percentile for sex, 
age, and height/length) it should be confirmed by 2 assessments obtained 1 hour apart.  One 
BP assessment is defined as the mean value of 3 measurements obtained at least 5 minutes 
apart.  Subjects with elevated BP (≥99th percentile for sex, age and height/length) must have 
their BP monitored every 2 weeks (on Day 15 or more frequently as clinically indicated) 
until BP has been <95th percentile for 3 consecutive months.  If a new event of elevated BP 
occurs, the subject must resume the Day 15 evaluation until BP has been <95th percentile for 
3 consecutive months.  BP that is consistently above the 95th percentile for sex, age, and 
height/length requires further evaluation. 
9.5.1.5.5 PHYSICAL EXAMINATIONS 
Physical examinations will be performed as designated in the Schedule of Assessments 
(Table 7 and Table 8).  Documentation of the physical examination will be included in the 
source documentation at the site.  Only changes from screening physical examination 
findings that meet the definition of an AE will be recorded on the Adverse Events CRF. 
9.5.1.5.6 ELECTROCARDIOGRAMS 
Electrocardiograms will be obtained as designated in the Schedule of Assessments (Table 7 
and Table 8).  Complete, standardized, single 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.  If possible, subjects 
should be in the recumbent position for a period of 5 minutes prior to the ECG. 
An ECG abnormality may meet the criteria of an AE as described in this protocol (see 
Section 9.5.1.5.1) and the CRF Completion Guidelines.  In these instances, the AE 
corresponding to the ECG abnormality will be recorded on the Adverse Events CRF. 
Cardiac systolic function and QTc will be assessed using echocardiography and ECG.  See 
Table 7 and Table 8 for test schedules. 


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9.5.1.5.7 OTHER SAFETY ASSESSMENTS 
A Lansky play score or Karnofsky performance status score will be obtained at the 
Screening, Baseline, and Cycle 2 Day 1 visits, and every subsequent cycle visit thereafter and 
at the Off-treatment Visit. 
Proximal tibial growth plates x-rays will be taken at baseline and at the Off-treatment Visit 
(for subjects with open plates at the Baseline Visit). 
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 subjects for potential anomalies in tooth formation and eruption 
schedule. 
A dental examination by a qualified healthcare professional should be conducted per local 
institutional guidelines at baseline (C1D1±4 weeks), and thereafter per local standard of care 
(but no less than annually), and as part of the Off-treatment assessment.  If the most recent 
dental exam is within 6 months prior to the Off-treatment Visit, the dental examination is not 
required.  Postbaseline dental examinations are not required for subjects for whom permanent 
teeth (excluding third molars) are evaluated to be fully erupted at Baseline. 
An echocardiogram to assess left ventricular shortening fraction or echocardiogram/MUGA 
scan to assess left ventricular ejection fraction (LVEF) will be performed during screening, 
Cycle 2 Day 1 (predose), Cycle 5 Day 1 (predose) and every 6th Cycle thereafter (Cycle 11 
Day 1, Cycle 17 Day 1, etc predose each) and at the Off-treatment Visit or sooner if 
clinically indicated. 
9.5.1.6 
Other Assessments 
Pregnancy Test 
A serum β-hCG test will be performed for females of childbearing potential (see definition 
included in the Inclusion/Exclusion criteria).  A serum or urine pregnancy test will be 
performed at Screening and Baseline (or within 72 hours prior to the first dose of study 
treatment), prior to Day 1 of each subsequent cycle and at the Off-treatment Visit in females 
of childbearing potential.  The results must be reviewed prior to administration of study drug 
on Cycle 1 Day 1 and within 48 hours prior to dispensing study drug for all subsequent 
cycles.  Blood and urine samples will be taken at designated time points as specified in the 
Schedule of Assessments (Table 7 and Table 8). 
9.5.2 
Schedule of Procedures/Assessments 
9.5.2.1 
Schedule of Procedures/Assessments 
Table 7 and Table 8 present the Schedule of Procedures/Assessments for the study. 


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Table 7 
Schedule of Assessments – Phase 1  
Phase 
Pretreatment 
Treatmenta (All cycles are 28 days in duration) 
Post-
Treatment 
Period 
Screening
b 
Baselinec 
Treatment Phased 
Extension Phased 
Off-Treatment 
Visit 
Follow-upe 
Visit  
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
99x 
 
Cycle 
 
 
Cycle 1 
Cycle 2 - Last 
 
 
Day 
-28 to -2 
-1 
1 
2 
8 
15 
22 
1 
8 
15 
22 
 
 
Procedures/Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/surgical history 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Prior anticancer medication/ procedures 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy testf 
X 
X 
 
 
 
 
 
X 
 
 
 
X 
 
Lansky play score/ Karnofsky  PSg 
X 
X 
 
 
 
 
 
X 
 
 
 
X 
 
Physical examinationh 
X 
X 
 
 
 
X 
 
X 
 
 
 
X 
 
Vital signsi 
X 
X 
X 
 
X 
X 
X 
X 
Xi 
X 
Xi 
X 
 
12-lead ECGj 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
Echocardiogram/MUGA scank  
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
Clinical chemistry and hematologyl 
X 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
INR 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Urine dipstick testingm 
X 
 
X 
 
X 
X 
X 
X 
Xm 
X 
Xm 
X 
 
PK blood samplesn 
 
 
X 
X 
 
X 
X 
Xn 
 
 
 
 
 
Study treatment  
 
 
Combination of lenvatinib (QD) and everolimus (QD) based on BSA calculations at 
Day 1 of each cycle 
 
 
Tumor assessments: RECIST 1.1o 
X 
 
Scans will be performed at  
Week 4 ±1 week 
Scans will be performed at Week 12 ±1 week, 
Week 24 ±1 week, and then every 12 weeks 
±1 week thereafter, or as clinically indicated 
 
 
Brain CT/MRI (RECIST l.1)p 
X 
 
Brain scans will be performed at screening, and if clinically indicated.   
 
 
Brain MRI (RANO)q  
X 
 
Scans will be performed at  
Week 4 ±1 week 
Scans will be performed at Week 12 ±1 week, 
Week 24 ±1 week, and then every 12 weeks 
±1 week thereafter, or as clinically indicated 
 
 


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Table 7 
Schedule of Assessments – Phase 1  
Phase 
Pretreatment 
Treatmenta (All cycles are 28 days in duration) 
Post-
Treatment 
Period 
Screening
b 
Baselinec 
Treatment Phased 
Extension Phased 
Off-Treatment 
Visit 
Follow-upe 
Visit  
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
99x 
 
Cycle 
 
 
Cycle 1 
Cycle 2 - Last 
 
 
Day 
-28 to -2 
-1 
1 
2 
8 
15 
22 
1 
8 
15 
22 
 
 
Procedures/Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
Proximal tibial growth plates x-rayr 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
Dental examinationr 
X 
 
 
 
 
 
 
X 
X 
 
Pharmacodynamic biomarkerss 
 
X 
 
 
 
X 
 
X 
 
 
 
X 
 
Blood sample for cf-nucleic acids 
 
X 
 
 
 
X 
 
X 
 
 
 
X 
 
Archival tumor block or slidest 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Blood genomic DNA u 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medicationsv 
Throughout 
 
AEs/SAEsw 
Throughout 
 
AE = adverse event, BP = blood pressure, C1D1 = Cycle 1/Day 1, C1D2 = Cycle 1/Day 2, C1D8 = Cycle 1/Day 8, C1D15 = Cycle 1/Day 15, CR = complete response, CT = computerized 
tomography, ECG = electrocardiogram, h = hour, HR = heart rate, MRI = magnetic resonance imaging, MUGA = multigated acquisition, PK = pharmacokinetics, PR = partial 
response, PS = performance score, RECIST 1.1 = Response Evaluation Criteria in Solid Tumors, version 1.1, RANO =  Response Assessment in Neuro-Oncology, RR = respiratory 
rate, SAE = serious adverse event, TNM = tumor-node-metastasis, Tx = treatment. 
a. Efforts should be made to conduct study visits on the day scheduled (1 day). 
b. The results of all screening assessments and evaluations must be completed and reviewed by the investigator prior to the Baseline Visit.  Informed consent may be obtained up 
to 4 weeks prior to C1D1. 
c. Baseline assessments can be performed on Day -1 or on C1D1 prior to treatment. 
d. Duration of Treatment Phase: 1 Cycle (Visit 3-7); Duration of Extension Phase Cycle 2 – Last (Visit 8 – Last).  Subjects benefiting from study treatment in the opinion of the 
investigator will continue treatment until disease progression, development of unacceptable toxicity, or protocol off study criteria are met, whichever occurs first.   
e. Subjects will be followed every 3 months for 1 year or until death whichever occurs first, as per the protocol. 
f. A serum or urine pregnancy test will be performed at the Screening and Baseline Visits (or within 72 hours prior to the first dose of study medication), prior to Day 1 of each 
subsequent cycle and at the off-treatment visit in females of childbearing potential.  The results must be reviewed prior to administration of study drug on Cycle 1 Day 1 and 
within 48 hours prior to dispensing study drug for all subsequent cycles. 
g. A Lansky play score or Karnofsky performance status score will be obtained at the Screening, Baseline, and Cycle 2 Day 1 visits, and every subsequent cycle visit thereafter 
and at the Off-treatment Visit.  
h. A comprehensive physical examination (including a neurological examination) will be performed at the Screening and Baseline Visits (only if screening physical examination 
was performed >7 days prior to C1D1), C1D15, Day 1 visit of each subsequent cycle, and at the Off-treatment Visit.  A symptom-directed physical examination will be 
performed on C1D1 and at any time during the study, as clinically indicated. 


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i. Assessments will include vital signs (resting BP, HR, RR, and body temperature, and weight.  Height measurement will be obtained at Baseline Visit, at C4D1 and thereafter at 
D1 of every third cycle.  Blood pressure that is consistently above the 95th percentile for sex, age, and height/length requires further evaluation.  For blood pressure 
management, please refer to in the protocol.  Blood pressure (BP) monitoring will occur at least weekly during the first 2 cycles.  
j. Single 12-lead ECG.  If possible, the subject should be in the recumbent position for a period of 5 minutes prior to the ECG.  It should be performed at screening, Cycle 2 Day 
1 (predose), Cycle 5 Day 1 (predose) and every 6th Cycle thereafter (C11D1, C17D1, etc. predose each) and at the off-treatment visit.  
k. An echocardiogram/MUGA scan will be performed during screening, Cycle 2 Day 1 (predose), Cycle 5 Day 1 (predose) and every 6th Cycle thereafter (C11D1, C17D1, etc 
predose each) and at the Off-treatment Visit or sooner if clinically indicated.  The assessments may be performed within 1 week prior to Day 1 of each scheduled cycle. 
l. Clinical chemistry and hematology results must be reviewed prior to administration of study drug on C1D1 and within 48 hours prior to dispensing study drug for all 
subsequent cycles.  Scheduled assessments may be performed within 72 hours prior to the visit.  If ≥Grade 3 hematologic or clinical chemistry toxicity, repeat laboratory test 
and AEs assessment at least every 3 days (until improvement to <Grade 3).   
m. Urine dipstick testing should be performed at screening and on Day 1, 8, 15 and 22 for Cycle 1 (Treatment Phase) and on Day 1, 8, 15 and 22 for Cycle 2 (Extension Phase), 
bi-weekly thereafter in the Extension Phase or more frequently as clinically indicated and at the Off-treatment Visit.  For subjects with history of proteinuria ≥2+, and 
management of proteinuria please refer to the protocol.  Subjects who have ≥2+ 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.  
n. PK blood samples (2 mL per time point) will be drawn for lenvatinib  during the Treatment Phase on Cycle 1 Day 1 and Cycle 1 Day 15 at predose and at 30 min, 1h, 2h, 3h, 
4h and 8 h postdose, and predose on Cycle 1 Day 2 and Cycle 1 Day 22, and during the Extension Phase on Cycle 2 Day 1 and Cycle 3 Day 1 samples will be collected at 
predose and at 2-8 hours postdose from Phase 1 subjects remaining on study.  PK blood samples (2 mL per time point) will be drawn for everolimus during the Treatment 
Phase on Cycle 1 Day 1 at predose and 1h postdose, Cycle 1 Day 2 at predose, Cycle 1 Day 15 at predose and at 1 hour postdose, and on Cycle 1 Day 22 at predose and at 
1 hour postdose.  With the exception of the predose samples on Cycle 1 Day 1, all other predose samples are to be drawn at 24 hour post dose administered on the previous 
day.  If dose interruption is necessary at these time points, please contact the sponsor. 
o. For all tumor types except HGG, Screening:  Tumor assessments using CT chest and CT/MRI of the abdomen, pelvis, and other areas of known disease or newly suspected 
disease should be performed within 28 days prior to C1D1.  Scans of the abdomen, pelvis, and other areas of the body may be done with MRI instead of CT, but evaluation of 
the chest should be done with CT.  During the Treatment Phase tumor assessments using CT chest and CT/MRI of the abdomen, pelvis, and other areas of known disease or 
newly suspected disease should be performed at Week 4 ±1 week, and in the Extension Phase at Week 12 ±1 week, Week 24 ±1 week and every 12 weeks ±1 week thereafter 
or as clinically indicated.  For subjects with primary CNS tumors and no other known areas of disease only target and non-target lesions plus any areas of newly suspected 
disease must be scanned.  All responses are to be confirmed at a follow-up examination after ≥28 days following the initial indication of response.  Scans should be performed 
using the same methodology (CT or MRI) and scan acquisition techniques (including use or nonuse of IV contrast) as was used for the screening assessments.  Tumor response 
will be assessed according to RECIST 1.1.  All responses should be confirmed at a follow-up examination after ≥28 days. 
p. Brain CT with contrast or MRI pre- and post- gadolinium contrast will be performed at Screening, and if clinically indicated. 
q. For HGG, RANO criteria will be followed, Screening:  Tumor assessments using MRI of the brain that will be followed as target lesions and non-target lesions should be 
performed within 28 days prior to the C1D1.  During the Treatment Phase tumor assessments of the same brain lesions as at Screening, should be performed at Week 4 
±1 week, and in the Extension Phase at Week 12 ±1 week, Week 24 ±1 week and every 12 weeks ±1 week thereafter, or as clinically indicated.  All responses should be 
confirmed at a follow-up examination after ≥28 days following the initial indication of response.  The same methodology (MRI) and scan acquisition techniques (including use 
or nonuse of IV contrast) should be used as was used for the screening assessments. 
r. Proximal tibial growth plates x-rays should be conducted at Baseline and at the Off-treatment visit (for subjects with open plates at the baseline visit).  A dental examination 
by a qualified healthcare professional should be conducted per local institutional guidelines at baseline (C1D1±4 weeks), and thereafter per local standard of care (but no less 
than annually) and as part of the Off-treatment assessment.  If the most recent dental examination is within 6 months prior to the Off-treatment Visit, the dental exam is not 
required. Post-baseline dental exams are not required for subjects for whom permanent teeth (excluding third molars) are evaluated to be fully erupted at baseline. 
s. Blood samples will be collected from consenting subjects (optional) for plasma and serum at Baseline, and predose on Cycle 1 Day15, Cycle 2 Day 1, and then matched with 
tumor assessments, and at the Off-treatment Visit.  Only subjects with BSA >0.68 m2 are eligible to consent (optional) to blood samples for plasma and serum studies.  Serum 
sample will be used for evaluating biomarkers of response and plasma sample for cf-nucleic acid to explore proteins and genetic alterations in genes implicated in angiogenesis.  


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t. An archival tumor sample from the most recent surgery or biopsy for identification of predictive biomarkers will be collected (if available) from all enrolled subjects at any 
time during the study. 
u. Collection of whole blood to obtain genomic DNA will be performed at the Baseline Visit.  If sampling is not performed predose, sampling may occur at any subsequent visit 
in which other blood sampling is scheduled to occur.  Pharmacogenomic markers of drug metabolism and drug transport may be assessed. 
v. Concomitant medications will be recorded throughout the study and for 28 days after last dose.  All anticancer therapy will be recorded until time of death or termination of 
survival follow-up. 
w. AEs will be recorded from the date of signed informed consent, throughout the study, and for 28 days after last dose.  SAEs irrespective of relationship to study treatment must 
be reported as soon as possible but not later than 24 hours. 
x. The off-treatment assessments should occur within 28 days of the final dose of study treatment.  
 
 


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Table 8 
Schedule of Assessments – Phase 2 
Phase 
Pretreatment 
Treatmenta 
(All cycles are 28 days in duration) 
Post-
Treatme
nt 
Period 
Screeningb Baselinec 
Treatment Phased 
Extension Phase 
Off-
Treatment 
Visit 
Follow-
upe 
Visit  
1 
2 
3 4 5 6 7 
8 
9 10 11 12 13 14 15 
16 
17 
99x 
 
Cycle 
 
 
Cycle 1 
Cycle 2 
Cycle 3 Cycle 4 
Cycle 5 - Last 
 
 
Day 
-28 to -2 
-1 
1 2 8 15 22 1 
8 15 22 1 
15 
1 
15 
1 
15 
 
 
Procedures/Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/surgical history 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior anticancer medication/ 
procedures 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy testf 
X 
X 
 
 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
Lansky play score/ Karnofsky  PSg 
X 
X 
 
 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
Physical examinationh 
X 
X 
 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
Vital signsi 
X 
X 
X 
 
X X X X 
Xi X Xi X 
 
X 
 
X 
X 
X 
 
12-lead ECGj 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
X 
 
Echocardiogram/MUGA scank  
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
X 
 
Clinical chemistry and hematologyl 
X 
X 
 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
INR 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine dipstick testingm 
X 
 
X 
 
X X X X Xm X Xm X 
X 
X 
X 
X 
X 
X 
 
PK blood samplesn 
 
 
X 
 
 
X 
 
Xn 
 
 
 
Xn 
 
 
 
 
 
 
 
Study treatment  
 
 
Combination of lenvatinib (QD) and everolimus (QD) based on BSA calculations at Day 1 
of each cycle 
 
 


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Table 8 
Schedule of Assessments – Phase 2 
Phase 
Pretreatment 
Treatmenta 
(All cycles are 28 days in duration) 
Post-
Treatme
nt 
Period 
Screeningb Baselinec 
Treatment Phased 
Extension Phase 
Off-
Treatment 
Visit 
Follow-
upe 
Visit  
1 
2 
3 4 5 6 7 
8 
9 10 11 12 13 14 15 
16 
17 
99x 
 
Cycle 
 
 
Cycle 1 
Cycle 2 
Cycle 3 Cycle 4 
Cycle 5 - Last 
 
 
Day 
-28 to -2 
-1 
1 2 8 15 22 1 
8 15 22 1 
15 
1 
15 
1 
15 
 
 
Procedures/Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor assessments: RECIST 1.1o 
X 
 
Scans will be performed at Week 8 ±1 week and 
Week 16 ±1 week 
Scans will be performed at Week 24 
±1 week and every 12 weeks 
±1 week thereafter, or as clinically 
indicated 
 
 
Brain CT/MRI (RECIST l.1)p 
X 
 
Brain scans will be performed at screening, and if clinically indicated.   
 
 
Brain MRI (RANO)q 
X 
 
Scans will be performed at Week 8 ±1 week and 
Week 16 ±1 week 
Scans will be performed at Week 24 
±1 week and every 12 weeks 
±1 week thereafter, or as clinically 
indicated 
 
 
Proximal tibial growth plates x-rayr 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Dental examinationr 
X 
 
X 
X 
 
Pharmacodynamic biomarkerss 
 
X 
 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
Blood sample for cf-nucleic acids 
 
X 
 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
Archival tumor block or slidest 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood genomic DNA u 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medicationsv 
Throughout 
 
AEs/SAEsw 
Throughout 
 
AE = adverse event, BP = blood pressure, C1D1 = Cycle 1/Day 1, C1D2 = Cycle 1/Day 2, C1D8 = Cycle 1/Day 8, C1D15 = Cycle 1/Day 15, CR = complete response, 
CT = computerized tomography, ECG = electrocardiogram, h = hour, HR = heart rate, MRI = magnetic resonance imaging, MUGA = multigated acquisition, PK = 
pharmacokinetics, PR = partial response, PS = performance score, RECIST 1.1 = Response Evaluation Criteria in Solid Tumors, version 1.1, RR = respiratory rate, RANO = 
Response Assessment in Neuro-Oncology, SAE = serious adverse event, TNM = tumor-node-metastasis, Tx = treatment. 
a. Efforts should be made to conduct study visits on the day scheduled (1 day). 
b. The results of all screening assessments and evaluations must be completed and reviewed by the investigator prior to the Baseline Visit.  Informed consent may be obtained up 


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to 4 weeks prior to C1D1. 
c. Baseline assessments can be performed on Day -1 or on C1D1 prior to treatment. 
d. Duration of Treatment Phase: 4 Cycles (Visit 3-15); Duration of Extension Phase Cycle 5 – Last (Visit 16 – Last).  Subjects benefiting from study treatment in the opinion of 
the investigator will continue treatment until disease progression, development of unacceptable toxicity, or protocol off study criteria are met, whichever occurs first.   
e. Subjects will be followed every 3 months for 1 year or until death whichever occurs first, as per the protocol. 
f. A serum or urine pregnancy test will be performed at the Screening and Baseline Visits (or within 72 hours prior to the first dose of study medication), prior to Day 1 of each 
subsequent cycle and at the off-treatment visit in females of childbearing potential. The results must be reviewed prior to administration of study drug on Cycle 1 Day 1 and 
within 48 hours prior to dispensing study drug for all subsequent cycles. 
g. A Lansky play score or Karnofsky performance status score will be obtained at the Screening, Baseline, and Cycle 2 Day 1 visits, and every subsequent cycle visit in the 
Treatment Phase and Extension Phase thereafter and at the Off-treatment Visit. 
h. A comprehensive physical examination (including a neurological examination) will be performed at the Screening and Baseline Visits (only if screening physical examination 
was performed >7 days prior to C1D1), C1D15, Day 1 visit of each subsequent cycle in the Treatment Phase and Extension Phase, and at the Off-treatment Visit.  A 
symptom-directed physical examination will be performed on C1D1 and at any time during the study, as clinically indicated. 
i. Assessments will include vital signs (resting BP, HR, RR, and body temperature, and weight).  Height measurement will be obtained at Baseline Visit, at C4D1 and thereafter at 
D1 of every third cycle.  Blood pressure that is consistently above the 95th percentile for sex, age, and height/length requires further evaluation.  For blood pressure 
management, please refer to in the protocol.  Blood pressure (BP) monitoring will occur at least weekly during the first 2 cycles. 
j. Single 12-lead ECG.  If possible, the subject should be in the recumbent position for a period of 5 minutes prior to the ECG.  It should be performed at screening, Cycle 2 Day 
1 (predose) in the Treatment Phase, and at Cycle 5 Day 1 (predose) and every 6th Cycle thereafter (C11D1, C17D1, etc predose each) in the Extension Phase, and at the Off-
treatment visit.  
k. An echocardiogram/MUGA scan will be performed during screening, Cycle 2 Day 1 (predose) in the Treatment Phase, and at Cycle 5 Day 1 (predose) and every 6th Cycle 
thereafter (C11D1, C17D1, etc predose each) in the Extension Phase, and at the Off-treatment Visit or sooner if clinically indicated.  The assessments may be performed within 
1 week prior to Day 1 of each scheduled cycle. 
l. Clinical chemistry and hematology results must be reviewed prior to administration of study drug on C1D1 and within 48 hours prior to dispensing study drug for all 
subsequent cycles in the Treatment Phase and Extension Phase.  Scheduled assessments may be performed within 72 hours prior to the visit.  If ≥Grade 3 hematologic or 
clinical chemistry toxicity, repeat laboratory test and AEs assessment at least every 3 days (until improvement to <Grade 3).   
m. Urine dipstick testing should be performed at screening and on Day 1, 8, 15 and 22 for Cycles 1-2 in the Treatment Phase, bi-weekly thereafter or more frequently in the 
Treatment Phase and Extension Phase as clinically indicated and at the Off-treatment Visit.  For subjects with history of proteinuria ≥2+, and management of proteinuria please 
refer to the protocol.  Subjects who have ≥2+ 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.  
n. Sparse sampling (two 2 mL samples [total 4 mL blood] per time point) for PK analysis of lenvatinib and everolimus will be performed in the Treatment Phase during Cycle 1 
Day 1 at 0.5-4 hours and 6-10 hours postdose and on Cycle 1 Day15 at predose and 0.5-4 hours and 6-10 hours postdose and on Cycles 2 and 3 predose.  With the exception of 
the predose samples on Cycle 1 Day 1, all other predose samples are to be drawn at 24 hour post dose administered on the previous day.  If dose interruption is necessary at 
these time points, please contact the sponsor. 
o. For all tumor types except HGG, Screening:  Tumor assessments using CT chest and CT/MRI of the abdomen, pelvis, and other areas of known disease or newly suspected 
disease should be performed within 28 days prior to C1D1.  Scans of the abdomen, pelvis, and other areas of the body may be done with MRI instead of CT, but evaluation of 
the chest should be done with CT.  In the Treatment Phase tumor assessments using CT chest and CT/MRI of the abdomen, pelvis, and other areas of known disease or newly 
suspected disease should be performed at Week 8 ±1 week and Week 16 ±1 week, and in the Extension Phase at Week 24 ±1 week, and then every 12 weeks ± 1 week 
thereafter or as clinically indicated.  All responses are to be confirmed at a follow-up examination after ≥28 days following the initial indication of response.  Scans should be 
performed using the same methodology (CT or MRI) and scan acquisition techniques (including use or nonuse of IV contrast) as was used for the screening assessments.  
Tumor response will be assessed according to RECIST 1.1.  All responses should be confirmed at a follow-up examination after ≥28 days. 
p. Brain CT with contrast or MRI pre- and post-gadolinium contrast will be performed at Screening, and if clinically indicated. 


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q. For HGG, RANO criteria will be followed, Screening: Tumor assessments using MRI of the brain that will be followed as target lesions and non-target lesions should be 
performed within 28 days prior to the C1D1.  In the Treatment Phase tumor assessments of the same brain lesions as at Screening, should be performed at Week 8 ±1 week 
and Week 16 ±1 week, and in the Extension Phase at Week 24 ±1 week and every 12 weeks ±1 week thereafter, or as clinically indicated.  All responses should be confirmed 
at a follow-up examination after ≥28 days following the initial indication of response.  The same methodology (MRI) and scan acquisition techniques (including use or nonuse 
of IV contrast) should be used as was used for the screening assessments. 
r. Proximal tibial growth plates x-rays should be conducted at Baseline and at the Off-treatment visit (for subjects with open plates at the Baseline Visit).  A dental examination 
by a qualified healthcare professional should be conducted per local institutional guidelines at baseline (C1D1±4 weeks), and thereafter per local standard of care (but no less 
than annually), and as part of the Off-treatment assessment.  If the most recent dental examination is within 6 months prior to the Off-treatment Visit, the dental exam is not 
required. Post-baseline dental exams are not required for subjects for whom permanent teeth (excluding third molars) are evaluated to be fully erupted at baseline.  
s. Blood samples will be collected from consenting subjects (optional) for plasma and serum at Baseline, and predose on Cycle 1 Day15, Cycle 2 Day 1, and then matched with 
tumor assessments, and at the Off-treatment Visit.  Only subjects with BSA >0.68 m2 are eligible to consent (optional) to blood samples for plasma and serum studies.  Serum 
sample will be used for evaluating biomarkers of response and plasma sample for cf-nucleic acid to explore proteins and genetic alterations in genes implicated in angiogenesis.  
t. An archival tumor sample from the most recent surgery or biopsy for identification of predictive biomarkers will be collected (if available) from all enrolled subjects at any 
time during the study. 
u. Collection of whole blood to obtain genomic DNA will be performed at the Baseline Visit.  If sampling is not performed predose, sampling may occur at any subsequent visit 
in which other blood sampling is scheduled to occur.  Pharmacogenomic markers of drug metabolism and drug transport may be assessed. 
v. Concomitant medications will be recorded throughout the study and for 28 days after last dose.  All anticancer therapy will be recorded until time of death or termination of 
survival follow-up. 
w. AEs will be recorded from the date of signed informed consent, throughout the study, and for 28 days after last dose.  SAEs irrespective of relationship to study treatment must 
be reported as soon as possible but not later than 24 hours. 
x. The off-treatment assessments should occur within 28 days of the final dose of study treatment. 
 


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9.5.2.2 
Description of Procedures/Assessments Schedule 
Please refer to the Schedule of Procedures/Assessments (Table 7 and Table 8). 
9.5.3 
Appropriateness of Measurements 
All clinical assessments are standard measurements commonly used in studies of solid 
tumors. 
The safety assessments to be performed in this study, including hematology analyses, blood 
chemistry tests, urinalysis, ECGs/echocardiograms, and assessment of AEs, are standard 
evaluations to ensure subject safety.  The use of RECIST 1.1 for tumor assessments of solid 
tumors is widely accepted (see Appendix 1) (Eisenhauer, et al., 2009). 
9.5.4 
Reporting of Serious Adverse Events, Pregnancy, and Events Associated 
with Special Situations 
9.5.4.1 
Reporting of Serious Adverse Events 
All SERIOUS ADVERSE EVENTS, regardless of their relationship to study treatment, 
must be reported on a completed SAE form by email or fax as soon as possible but no 
later than 1 business day (or 24 hours for EU sites) from the date the investigator 
becomes aware of the event. 
Serious adverse events, regardless of causality assessment, must be collected through the last 
visit.  All SAEs must be followed to resolution or, if resolution is unlikely, to stabilization.  
Any SAE judged by the investigator to be related to the study treatment or any 
protocol-required procedure should be reported to the sponsor regardless of the length of 
time that has passed since study completion. 
The detailed contact information for reporting of SAEs is provided in the Investigator 
Study File. 
For urgent safety issues, please ensure all appropriate medical care is administered to the 
subject and contact the appropriate study team member listed in the Investigator Study 
File. 
It is very important that the SAE report form be filled out as completely as possible at the 
time of the initial report.  This includes the investigator’s assessment of causality. 
Any follow-up information received on SAEs should be forwarded within 1 business day of 
its receipt.  If the follow-up information changes the investigator’s assessment of causality, 
this should also be noted on the follow-up SAE form. 
Preliminary SAE reports should be followed as soon as possible by detailed descriptions 
including copies of hospital case reports, autopsy reports, and other documents requested by 
the sponsor. 


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The investigator must notify his/her IRB/IEC of the occurrence of the SAE in writing, if 
required by their institution.  A copy of this communication must be forwarded to the sponsor 
to be filed in the sponsor’s Trial Master File. 
9.5.4.2 
Reporting of Pregnancy and Exposure to Study Drug Through Breastfeeding 
Any pregnancy in which the estimated date of conception is either before the last visit or 
within 28 days of last study treatment, or any exposure to study drug through breastfeeding 
during study treatment or within 28 days of last study treatment, must be reported.  
If an adverse outcome of a pregnancy is suspected to be related to study drug exposure, this 
should be reported regardless of the length of time that has passed since the exposure to study 
treatment. 
A congenital anomaly, death during perinatal period, an induced abortion, or a spontaneous 
abortion are considered to be an SAE and should be reported in the same time frame and in 
the same format as all other SAEs (see Reporting of Serious Adverse Events 
[Section 9.5.4.1]). 
Pregnancies or exposure to study drug through breastfeeding must be reported by fax or 
email as soon as possible but no later than 1 business day from the date the investigator 
becomes aware of the pregnancy.  The contact information for the reporting of pregnancies 
and exposure to study drug through breastfeeding is provided in the Investigator Study File.  
The Pregnancy Report Form must be used for reporting.  All pregnancies must be followed to 
outcome.  The outcome of the pregnancy must be reported as soon as possible but no later 
than 1 business day from the date the investigator becomes aware of the outcome. 
A subject who becomes pregnant must be withdrawn from the study.  
9.5.4.3 
Reporting of Events Associated with Special Situations 
9.5.4.3.1 REPORTING OF ADVERSE EVENTS ASSOCIATED WITH STUDY DRUG OVERDOSE, 
MISUSE, ABUSE, OR MEDICATION ERROR 
Adverse events associated with study drug overdose, misuse, abuse, and medication error 
refer to AEs associated with uses of the study drug outside of that specified by the protocol.  
Overdose, misuse, abuse, and medication error are defined as follows:  
Overdose 
Accidental or intentional use of the study drug in an amount higher 
than the protocol-defined dose  
Misuse 
Intentional and inappropriate use of study drug not in accordance with 
the protocol  
Abuse 
Sporadic or persistent intentional excessive use of study drug 
accompanied by harmful physical or psychological effects 


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Medication error 
Any unintentional event that causes or leads to inappropriate study 
drug use or subject harm while the study drug is in the control of site 
personnel or the subject.   
All AEs associated with overdose, misuse, abuse, or medication error should be captured on 
the Adverse Event CRF and also reported using the procedures detailed in Reporting of 
Serious Adverse Events (Section 9.5.4.1) even if the AEs do not meet serious criteria.  Abuse 
is always to be captured as an AE.  If the AE associated with an overdose, misuse, abuse, or 
medication error does not meet serious criteria, it must still be reported using the SAE form 
and in an expedited manner but should be noted as nonserious on the SAE form and the 
Adverse Event CRF.  
9.5.4.4 
Expedited Reporting 
The sponsor must inform investigators and regulatory authorities of reportable events, in 
compliance with applicable regulatory requirements, on an expedited basis (ie, within 
specific time frames).  For this reason, it is imperative that sites provide complete SAE 
information in the manner described above. 
9.5.4.5 
Breaking the Blind 
Not applicable 
9.5.4.6 
Regulatory Reporting of Adverse Events 
Adverse events will be reported by the sponsor or a third party acting on behalf of the 
sponsor to regulatory authorities in compliance with local and regional law and established 
guidance.  The format of these reports will be dictated by the local and regional 
requirements. 
All studies that are conducted within any European country will comply with European Good 
Clinical Practice Directive 2005/28/EC and Clinical Trial Directive 2001/20/EC.  All 
suspected unexpected serious adverse reactions (SUSARs) will be reported, as required, to 
the competent authorities of all involved European member states. 
9.5.5 
Completion/Discontinuation of Subjects 
A subject (or subject’s parent or guardian) may elect to discontinue the study at any time for 
any reason.  All subjects who discontinue the study are to complete the study’s early 
discontinuation procedures indicated in the Schedule of Procedures/Assessments (Table 7 
and Table 8). 
The investigator will promptly explain to the subject involved that the study will be 
discontinued for that subject and provide appropriate medical treatment and other necessary 
measures for the subject.  A subject who has ceased to return for visits will be followed up by 
mail, phone, or other means to gather information such as the reason for failure to return, the 


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status of treatment compliance, the presence or absence of AEs, and clinical courses of signs 
and symptoms.   
Subjects who discontinue early from the study will be discontinued for 1 of these primary 
reasons: AE(s), lost to follow-up, subject choice, progression of disease, withdrawal of 
consent, pregnancy, study terminated by sponsor, or other.   
9.5.6 
Abuse or Diversion of Study Drug 
Not applicable 
9.5.7 
Confirmation of Medical Care by Another Physician 
The investigator will instruct subjects (or guardian/legally authorized representative) to 
inform site personnel when they are planning to receive medical care by another physician.  
At each visit, the investigator will ask the subject (or guardian/legally authorized 
representative) whether the subject has received medical care by another physician since the 
last visit or is planning to do so in the future.  When the subject is going to receive medical 
care by another physician, the investigator, with the consent of the subject (or 
guardian/legally authorized representative), will inform the other physician that the subject is 
participating in the clinical study. 
9.6 
Data Quality Assurance 
This study will be organized, performed, and reported in compliance with the protocol, 
SOPs, working practice documents, and applicable regulations and guidelines.  Site audits 
will be made periodically by the sponsor’s or the CRO’s qualified compliance auditing team, 
which is an independent function from the study team responsible for conduct of the study.   
9.6.1 
Data Collection 
Data required by the protocol will be collected on the CRFs and entered into a validated data 
management system that is compliant with all regulatory requirements.  As defined by ICH 
guidelines, the CRF is a printed, optical, or electronic document designed to record all of the 
protocol-required information to be reported to the sponsor on each study subject. 
Data collection on the CRF must follow the instructions described in the CRF Completion 
Guidelines.  The investigator has ultimate responsibility for the collection and reporting of all 
clinical data entered on the CRF.  The investigator or designee as identified on Form 
FDA 1572 must sign the completed CRF to attest to its accuracy, authenticity, and 
completeness. 
Completed, original CRFs are the sole property of Eisai and should not be made available in 
any form to third parties without written permission from Eisai, except for authorized 
representatives of Eisai or appropriate regulatory authorities. 


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9.6.2 
Clinical Data Management 
All software applications used in the collection of data will be properly validated following 
standard computer system validation that is compliant with all regulatory requirements.  All 
data, both CRF and external data (eg, laboratory data), will be entered into a clinical system. 
9.7 
Statistical Methods 
All statistical analyses will be performed by the sponsor or designee after the study is 
completed and the database is locked and released.  Statistical analyses will be performed 
using SAS software or other validated statistical software as required.  Details of the 
statistical analyses will be included in a separate statistical analysis plan (SAP). 
9.7.1 
Statistical and Analytical Plans 
Descriptive statistics will be used to summarize study endpoints.  Categorical variables will 
be summarized by number and percentage.  Continuous variables will be summarized using n 
(number of subjects with available data), mean, standard deviation, median, Q1, Q3, and 
range (minimum and maximum), unless otherwise specified.  
Efficacy data will be analyzed using the Evaluable Analysis Set, safety data will be analyzed 
using the Safety Analysis Set, PK data will be analyzed using the PK Analysis Set, and PD 
data will be analyzed using the PD Analysis Set.  All analyses will be performed by dose 
level in Phase 1 (if appropriate) and for each study cohort in Phase 2, unless otherwise 
specified. 
9.7.1.1 
Study Endpoints 
9.7.1.1.1 PRIMARY ENDPOINTS 
Primary Endpoints for Phase 1  
 
MTD and RP2D of lenvatinib in combination with everolimus 
 
Safety and toxicity of lenvatinib in combination with everolimus 
Primary Endpoint for Phase 2  
 
ORR, defined as the proportion of subjects who have the best overall response (BOR) of 
complete response (CR) or partial response (PR), at Week 16 
9.7.1.1.2 
SECONDARY ENDPOINTS 
Secondary Endpoints for Phase 1 and Phase 2  
 
ORR at the time of data cutoff  
 
DCR, defined as the proportion of subjects who have the BOR of CR or PR or stable 
disease (SD) (SD duration ≥7 weeks since the first dose of the study treatment) 
 
CBR, defined as the proportion of subjects who have the BOR of CR or PR or durable 
SD (SD duration ≥23 weeks since the first dose of the study treatment) 
 
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) 


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 
Plasma PK of lenvatinib and trough concentrations of everolimus when administered in 
combination 
 
Safety and toxicity of lenvatinib in combination with everolimus in Phase 2 
9.7.1.1.3 
EXPLORATORY ENDPOINTS 
 
Assess candidate alterations in genes and/or proteins that may contribute to tumor 
development and predictive marker of response in archival tumor tissue 
 
Correlative blood and tumor biomarkers of treatment effects and outcomes 
9.7.1.2 
Definitions of Analysis Sets 
 
Evaluable Analysis Set, defined as all subjects, who have measurable disease present at 
baseline and at least 1 post-baseline efficacy assessment, unless they have discontinued 
prior to the first efficacy assessment due to progressive disease. This will be the analysis 
set for efficacy. 
 
Safety Analysis Set, defined as all subjects who received at least 1 dose of study drug 
(lenvatinib or everolimus).  
 
Pharmacokinetic (PK) Analysis Set, defined as subjects in Safety Analysis Set who had 
at least 1 measurable postdose plasma concentration with an adequately documented 
dosing history. 
 
Pharmacodynamic (PD) Analysis Set, defined as all subjects in Safety Analysis Set 
who had evaluable PD data. 
9.7.1.3 
Subject Disposition 
The number (percentage) of subjects who completed the study treatment/study and 
discontinued from the study treatment/study and reasons for discontinuation will be provided.   
9.7.1.4 
Demographic and Other Baseline Characteristics 
Demographic and other baseline characteristics will be summarized for each cohort in Phase 
2 as well as by dose level in Phase 1 if appropriate.  Demographic and baseline variables 
include, but are not limited to age, sex, race, Lansky score, and Karnofsky score.   
9.7.1.5 
Prior and Concomitant Therapy 
All investigator terms for medications recorded in the CRF will be coded to an 11-digit code 
using the World Health Organization Drug Dictionary (WHO DD).  The number 
(percentage) of subjects who took prior and concomitant medications will be summarized, 
using Anatomical Therapeutic Chemical (ATC) class and WHO DD preferred term.  Prior 
medications will be defined as medications that started before the first dose of study drug.  
Concomitant medications will be defined as medications that (1) started before the first dose 
of study drug and were continuing at the time of the first dose of study drug, or (2) started on 
or after the date of the first dose of study drug or started up to 28 days after the subject’s last 
dose.  All medications will be presented in subject data listings. 


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9.7.1.6 
Efficacy Analyses 
Data cutoff for the primary study analysis in Phase 2 will occur when all evaluable subjects 
have completed at least 4 treatment cycles and, if applicable, a confirmatory scan has been 
performed (in case of a PR or CR at Week 16), or have discontinued study treatment early. 
The following are evaluability criteria for objective response and non-target disease response 
analysis: 
 
Evaluable for objective response:  Only those subjects who have measurable disease 
present at baseline and have their disease re-evaluated at post-baseline visits will be 
considered evaluable for objective response.  These subjects will have their response 
classified according to RECIST 1.1 (for Ewing sarcoma/pPNET and rhabdomyosarcoma) 
or RANO (for HGG). 
 
Evaluable for non-target disease response:  Subjects who have lesions present at 
baseline that are evaluable but do not meet the definitions of measurable disease and have 
had their disease re-evaluated at post-baseline visits will be considered evaluable for non-
target disease.  Subjects with only non-target disease will be summarized by their best 
overall response.  The response will be classified according to RECIST 1.1 defined 
categories for subjects with non-target disease only. 
9.7.1.6.1 PRIMARY EFFICACY ANALYSIS 
Phase 1 
The study will utilize the rolling 6 design.  The primary objective of Phase 1 is to determine 
the MTD and to establish the RP2D.   
Phase 2 
The primary efficacy endpoint in Phase 2 is ORR at 16 weeks.  Objective responses will 
count only confirmed CR and PR.  Estimated ORR and its exact 95% CI using the 
Clopper-Pearson method will be presented. 
9.7.1.6.2 SECONDARY EFFICACY ANALYSES FOR PHASE 1 AND PHASE 2 
The secondary efficacy endpoints will be ORR at the time of data cutoff, DCR, CBR and 
DOR.  These endpoints in Phase 1 will be summarized if appropriate and listed by dose level, 
and ORR will be based on only subjects with measureable disease at screening/baseline.  For 
Phase 2, the ORR, DCR and CBR will be provided with exact 95% CIs using the 
Clopper-Pearson method.  The DOR will be analyzed using Kaplan-Meier approach among 
the responders (CR or PR).  If a subject had no record of disease progression or did not die 
before the data cutoff date, or before early discontinuation (including discontinuations due to 
toxicity, undocumented clinical progression, change of cancer treatment, or decreasing 
performance status), then the subject will be censored at the last available tumor assessment. 


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9.7.1.7 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Analyses 
9.7.1.7.1 PHARMACOKINETIC ANALYSIS 
Lenvatinib and everolimus concentration versus time data will be tabulated and summarized 
and graphically presented.   
Plasma concentrations of lenvatinib from the intense sampling in Phase 1 will be used to 
determine the following PK parameters: area under the plasma concentration time course 
profile (AUC), maximum observed concentration (Cmax), and time from dosing to the 
maximum observed concentration (Tmax).  Other PK parameters may be determined as data 
permit. 
For both lenvatinib and everolimus, data from Phase 1 and 2 of the study will be pooled with 
available data from other studies and subjected to population PK analysis.  For each drug, the 
PK model will be parameterized in terms of clearance and volume of distribution. 
Details of the population PK analysis will be provided in a separate analysis plan. 
9.7.1.7.2 PHARMACODYNAMIC, PHARMACOKINETIC/PHARMACODYNAMIC, PHARMACOGENOMIC, 
 
AND OTHER BIOMARKER ANALYSES 
Correlation between clinical response to treatment associated with a combination of 
lenvatinib and everolimus and blood or tumor biomarkers will be examined using descriptive 
statistics and graphic displays as appropriate.  Details will be provided in a separate analysis 
plan. 
Pharmacokinetic/PD exposure-safety relationships will be explored.  Safety endpoints will be 
most frequent AEs of special interest and dose reductions.  Exploratory/graphical analyses 
will be conducted for PK/PD evaluations, and may be followed by model-based analyses.  A 
detailed analysis plan will be provided separately. 
9.7.1.8 
Safety Analyses 
Safety variables include study drug exposure, treatment-emergent adverse events (TEAEs), 
laboratory tests, vital signs, 12-lead ECGs, cardiac function by echocardiography/MUGA 
scan, urine dipstick, and Lansky play scores or Karnofsky performance scores.  
All toxicities will be summarized.  The following are evaluability criteria for toxicity 
analysis: 
 
Evaluable for toxicity:  All subjects who received at least one dose of study treatment 
are evaluable for toxicity.  For Phase 1, toxicities during Cycle 1 will be used for the 
purpose of dose escalations according to the rolling 6 design.  Subjects who developed a 
DLT or received at least 75% of the prescribed dose during cycle 1 are considered fully 
evaluable for toxicity for the purpose of dose escalation. 


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The incidence of treatment-emergent adverse events (TEAEs) and SAEs will be summarized 
by system organ class and preferred term.  Laboratory test data, vital signs, 12-lead ECGs, 
cardiac function by echocardiography/MUGA scan, urine dipstick, Lansky play scores or 
Karnofsky performance scores, and their changes or shifts from baseline will be summarized 
using descriptive statistics, as appropriate.  Summary of study drug exposure will be 
provided.  Prior and concomitant medications, medical/surgical history and subject 
demographics will be summarized. 
9.7.1.8.1 EXTENT OF EXPOSURE 
The number of cycles/days on treatment, quantity of study drug administered, and the 
number of subjects requiring dose reductions, treatment interruption, and treatment 
discontinuation due to AEs will be summarized. 
9.7.1.8.2 ADVERSE EVENTS 
The AE verbatim descriptions (investigator terms from the CRF) will be classified into 
standardized medical terminology using the Medical Dictionary for Regulatory Activities 
(MedDRA).  Adverse events will be coded to the MedDRA lower level term (LLT) closest to 
the verbatim term.  The linked MedDRA preferred term (PT) and primary system organ class 
(SOC) are also captured in the database. 
A TEAE is defined as an AE that emerges during treatment, having been absent at 
pretreatment (baseline) or  
 
Reemerges during treatment, having been present at pretreatment (baseline) but stopped 
before treatment, or  
 
Worsens in severity during treatment relative to the pretreatment state, when the AE is 
continuous. 
Only those AEs that are treatment emergent will be included in summary tables.  All AEs, 
treatment emergent or otherwise, will be presented in subject data listings. 
The incidence of TEAEs will be reported as the number (percentage) of subjects with TEAEs 
by SOC and PT.  A subject will be counted only once within an SOC and PT, even if the 
subject experienced more than 1 TEAE within a specific SOC and PT.  The number 
(percentage) of subjects with TEAEs will also be summarized by CTCAE grade if 
appropriate. 
The number (percentage) of subjects with treatment-related TEAEs will be summarized by 
SOC and PT.  Treatment-related TEAEs include those events considered by the investigator 
to be related to study treatment.   
The number (percentage) of subjects with treatment-emergent SAEs will be summarized by 
MedDRA SOC and PT.  A subject data listing of all SAEs will be provided. 
The number (percentage) of subjects with TEAEs leading to discontinuation from study drug 
or leading to study drug dose changes will be summarized by MedDRA SOC and PT.  A 


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subject data listing of all AEs leading to discontinuation from study drug or leading to study 
drug dose changes will be provided. 
9.7.1.8.3 LABORATORY VALUES 
Laboratory results will be summarized using Système International (SI) units, as appropriate.  
For all quantitative parameters listed in Section 9.5.1.5.3, the actual value and the change 
from baseline to each post-baseline visit will be summarized by visit using descriptive 
statistics.  Qualitative parameters listed in Section 9.5.1.5.3 will be summarized using 
frequencies (number and percentage of subjects), and shifts from baseline to worst 
postbaseline will be reported using shift tables.  Percentages will be based on the number of 
subjects with both nonmissing baseline and at least 1 post-baseline results. 
Laboratory parameters will be categorized according to CTCAE grades, and shift tables from 
baseline CTCAE grades to the worst post-baseline grades will be provided.   
9.7.1.8.4 VITAL SIGNS 
Descriptive statistics for vital signs parameters (ie, systolic and diastolic BP, pulse, 
respiratory rate, temperature, weight) and changes from baseline will be presented by visit.  
A shift table of hypertension from baseline to worst post-baseline grades will be provided.  
9.7.1.8.5 ELECTROCARDIOGRAMS 
Descriptive statistics for ECG parameters and changes from baseline will be presented by 
visit.  Shift tables will present shifts from baseline in ECG interpretation (categorized as 
normal, abnormal, not clinically significant, and abnormal clinically significant) to the worst 
post-baseline assessment. 
9.7.1.8.6 OTHER SAFETY ANALYSES 
Shift tables of Lansky play scores and Karnofsky performance scores from baseline will be 
provided.  
Descriptive statistics and changes from baseline for left ventricular shortening fraction 
assessed on echocardiogram and LVEF assessed on echocardiogram or MUGA scans will be 
presented.  Percent reduction from baseline will also be summarized. 
9.7.2 
Determination of Sample Size 
Phase 1 – Determination of the Maximum Tolerated Dose:  The total number of subjects 
required for the Phase 1 portion of this study will depend upon the toxicities observed as the 
study progresses.  The minimum number of evaluable subjects required for this study is 4.  
The projected maximum number of evaluable subjects required is 48.  Once the MTD or 
RP2D has been defined, up to 6 additional subjects with recurrent or refractory solid tumors 
may be enrolled to acquire PK data in a representative number of young subjects.  Therefore, 
a maximum of 54 subjects are expected to be enrolled in the 4 dose escalation levels, and PK 
expansion.  The Phase 1 part of the study is expected to be completed within 18 months.  In 


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the event that each of Dose Levels -1, 1, 2, and 3 are expanded to 12 subjects, an absolute 
maximum of 54 subjects would be required allowing for 20% to be non-evaluable and 
including up to 6 additional subjects for PK analysis. 
Phase 2:  Phase 2 will require a minimum of 10 evaluable subjects per disease cohort and a 
maximum of 20 (10 evaluable subjects in each stage of Simon’s optimal 2-stage design).  
Therefore, a maximum of 22 subjects per cohort will be enrolled to allow for a 10% 
non-evaluable rate.  This design has 88% power to detect a 20% increase in the response rate 
at the significance level of one-sided alpha = 0.07 assuming a null response rate of 5% and 
alternative response rate ≥25%.  
9.7.3 
Interim Analysis 
For each disease cohort (Ewing sarcoma/pPNET, rhabdomyosarcoma and HGG) in Phase 2, 
there will be 1 futility analysis: this is planned for after the first 10 evaluable subjects have 
completed at least 4 treatment cycles and, if applicable, a confirmatory scan has been 
performed (in case of a PR or CR at week 16), or have discontinued study drug early (before 
Week 16).  At the futility analysis, if there are no responders (CR/PR), then the enrollment 
for that cohort will be discontinued for lack of efficacy.  If 1 or more responses are observed, 
the accrual will continue. 
Independent data monitoring committee (IDMC) 
Safety monitoring will be conducted by an independent data monitoring committee (IDMC).  
The frequency of safety reviews will be defined in the IDMC charter.  Minutes from the open 
meetings of the IDMC will be provided if requested by regulatory agencies.  The function 
and membership of the IDMC will be described in the IDMC charter. 
9.7.4 
Other Statistical/Analytical Issues 
Not applicable. 
9.7.5 
Procedure for Revising the Statistical Analysis Plan 
If the SAP needs to be revised after the study starts, the sponsor will determine how the 
revision impacts the study and how the revision should be implemented.  The details of the 
revision will be documented and described in the clinical study report. 


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Yasui H, Naka N, Imura Y, Outani H, Kaneko K, Hamada K, et al. Tailored therapeutic 
strategies for synovial sarcoma: receptor tyrosine kinase pathway analyses predict sensitivity 
to the mTOR inhibitor RAD001. Cancer Lett. 2014;347:114-22. 
Yoshikawa H, Nakase T, Myoui A, Ueda T. Bone morphogenetic proteins in bone tumors. J 
Orthop Sci. 2004;9:334-40. 
Zhang J, Wu G, Miller CP, Tatevossian RG, Dalton JD, Tang B, et al. Whole-genome 
sequencing identifies genetic alterations in pediatric low-grade gliomas. Nat Genet. 
2013;45:602-12.  


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11 PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE 
PROCEDURES) 
11.1 Changes to the Protocol 
Any change to the protocol requires a written protocol amendment or administrative change 
that must be approved by the sponsor before implementation.  Amendments specifically 
affecting the safety of subjects, the scope of the investigation, or the scientific quality of the 
study require submission to health or regulatory authorities as well as additional approval by 
the applicable IRBs/IECs.  These requirements should in no way prevent any immediate 
action from being taken by the investigator, or by the sponsor, in the interest of preserving 
the safety of all subjects included in the study.  If the investigator determines that an 
immediate change to or deviation from the protocol is necessary for safety reasons to 
eliminate an immediate hazard to the subjects, the sponsor’s medical monitor (or appropriate 
study team member) and the IRB/IEC for the site must be notified immediately.  The sponsor 
must notify the health or regulatory authority as required per local regulations. 
Protocol amendments that affect only administrative aspects of the study may not require 
submission to health or regulatory authority or the IRB/IEC, but the health or regulatory 
authority and IRB/IEC (or if regionally required, the head of the medical institution) should 
be kept informed of such changes as required by local regulations.  In these cases, the 
sponsor may be required to send a letter to the IRB/IEC and the Competent Authorities (or, if 
regionally required, the head of the medical institution) detailing such changes. 
11.2 Adherence to the Protocol 
The investigator will conduct the study in strict accordance with the protocol (refer to 
ICH E6, Section 4.5). 
11.3 Monitoring Procedures 
The sponsor’s/CRO’s CRA will maintain contact with the investigator and designated staff 
by telephone, letter, or email between study visits.  Monitoring visits to each site will be 
conducted by the assigned CRA as described in the monitoring plan.  The investigator (or if 
regionally required, the head of the medical institution) will allow the CRA to inspect the 
clinical, laboratory, and pharmacy facilities to assure compliance with GCP and local 
regulatory requirements.  The CRFs and subject’s corresponding original medical records 
(source documents) are to be fully available for review by the sponsor’s representatives at 
regular intervals.  These reviews verify adherence to study protocol and data accuracy in 
accordance with local regulations.  All records at the site are subject to inspection by the 
local auditing agency and to IRB/IEC review. 
In accordance with ICH E6, Section 1.52, source documents include, but are not limited to, 
the following: 
 
Clinic, office, or hospital charts 


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 
Copies or transcribed health care provider notes that have been certified for accuracy 
after production 
 
Recorded data from automated instruments such as IxRS, x-rays, and other imaging 
reports (eg, sonograms, CT scans, magnetic resonance images, radioactive images, ECGs, 
rhythm strips, electroencephalograms, polysomnographs, pulmonary function tests) 
regardless of how these images are stored, including microfiche and photographic 
negatives 
 
Pain, quality of life, or medical history questionnaires completed by subjects 
 
Records of telephone contacts 
 
Diaries or evaluation checklists 
 
Drug distribution and accountability logs maintained in pharmacies or by research 
personnel 
 
Laboratory results and other laboratory test outputs (eg, urine pregnancy test result 
documentation and urine dip-sticks) 
 
Correspondence regarding a study subject’s treatment between physicians or memoranda 
sent to the IRBs/IECs 
 
CRF components (eg, questionnaires) that are completed directly by subjects and serve as 
their own source 
11.4 Recording of Data 
A CRF is required and must be completed for each subject by qualified and authorized 
personnel.  All data on the CRF must reflect the corresponding source document, except 
when a section of the CRF itself is used as the source document.  Any correction to entries 
made on the CRF must be documented in a valid audit trail where the correction is dated, the 
individual making the correct is identified, the reason for the change is stated, and the 
original data are not obscured.  Only data required by the protocol for the purposes of the 
study should be collected. 
The investigator must sign each CRF.  The investigator will report the CRFs to the sponsor 
and retain a copy of the CRFs. 
11.5 Identification of Source Data 
All data to be recorded on the CRF must reflect the corresponding source documents.  For 
the following items, the data recorded directly on the CRF are to be considered source data: 
 
Study drug compliance (eg, the reason for any change of dosage) 
 
Indication for prior/concomitant medication (drug/therapy) 
 
Discontinuation information (eg, in the case of lost to follow-up due to the subject 
choice) 
 
Sampling date and time for the drug concentration 
 
Sampling date for the clinical laboratory tests 


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 
Comments and other information on AEs (eg, severity, relationship to study drug, 
outcome) 
11.6 Retention of Records 
The circumstances of completion or termination of the study notwithstanding, the 
investigator (or if regionally required, the head of the medical institution or the designated 
representative) is responsible for retaining all study documents, including but not limited to 
the protocol, copies of CRFs, the Investigator's Brochure, and regulatory agency registration 
documents (eg, Form FDA 1572, ICFs, and IRB/IEC correspondence).  The site should plan 
to retain study documents, as directed by the sponsor, for at least 15 years following the 
completion of the study. 
For sites in Canada, the Sponsor should retain all study documents to maintain complete and 
accurate records, including those specified above, for a period of 25 years. 
It is requested that at the completion of the required retention period, or should the 
investigator retire or relocate, the investigator contact the sponsor, allowing the sponsor the 
option of permanently retaining the study records. 
11.7 Auditing Procedures and Inspection 
In addition to routine monitoring procedures, the sponsor’s Clinical Quality Assurance 
department conducts audits of clinical research activities in accordance with the sponsor’s 
SOPs to evaluate compliance with the principles of ICH GCP and all applicable local 
regulations.  If a government regulatory authority requests an inspection during the study or 
after its completion, the investigator must inform the sponsor immediately. 
11.8 Handling of Study Drug 
All study drug will be supplied to the principal investigator (or a designated pharmacist) by 
the sponsor.  Drug supplies must be kept in an appropriate secure area (eg, locked cabinet) 
and stored according to the conditions specified on the drug labels.  The investigator (or a 
designated pharmacist) must maintain an accurate record of the shipment and dispensing of 
the study drug in a drug accountability ledger, a copy of which must be given to the sponsor 
at the end of the study.  An accurate record of the date and amount of study drug dispensed to 
each subject must be available for inspection at any time.  The CRA will visit the site and 
review these documents along with all other study conduct documents at appropriate 
intervals once study drug has been received by the site. 
All drug supplies are to be used only for this study and not for any other purpose.  The 
investigator (or site personnel) must not destroy any drug labels or any partly used or unused 
drug supply before approval to do so by the sponsor.  At the conclusion of the study and as 
appropriate during the study, the investigator (or a designated pharmacist) will return all used 
and unused drug containers, drug labels, and a copy of the completed drug disposition form 
to the sponsor’s CRA (or designated contractor) or, when approval is given by the sponsor, 
will destroy supplies and containers at the site. 


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11.9 Publication of Results 
All manuscripts, abstracts, or other modes of presentation arising from the results of the 
study must be reviewed and approved in writing by the sponsor in advance of submission 
pursuant to the terms and conditions set forth in the executed Clinical Trial Agreement 
between the sponsor/CRO and the institution/investigator.  The review is aimed at protecting 
the sponsor's proprietary information existing either at the date of the commencement of the 
study or generated during the study. 
The detailed obligations regarding the publication of any data, material results, or other 
information generated or created in relation to the study shall be set out in the agreement 
between each investigator and the sponsor or CRO, as appropriate. 
11.10 Disclosure and Confidentiality 
The contents of this protocol and any amendments and results obtained during the study 
should be kept confidential by the investigator, the investigator’s staff, and the IRB/IEC and 
will not be disclosed in whole or in part to others, or used for any purpose other than 
reviewing or performing the study, without the written consent of the sponsor.  No data 
collected as part of this study will be used in any written work, including publications, 
without the written consent of the sponsor.  These obligations of confidentiality and non-use 
shall in no way diminish such obligations as set forth in either the Confidentiality Agreement 
or Clinical Trial Agreement executed between the sponsor/CRO and the 
institution/investigator. 
All persons assisting in the performance of this study must be bound by the obligations of 
confidentiality and non-use set forth in either the Confidentiality Agreement or Clinical Trial 
Agreement executed between the institution/investigator and the sponsor/CRO. 
11.11 Discontinuation of Study 
The sponsor reserves the right to discontinue the study for medical reasons or any other 
reason at any time.  If a study is prematurely terminated or suspended, the sponsor will 
promptly inform the investigators/institutions and regulatory authorities of the termination or 
suspension and the reason(s) for the termination or suspension.  The IRB/IEC will also be 
informed promptly and provided the reason(s) for the termination or suspension by the 
sponsor or by the investigator/institution, as specified by the applicable regulatory 
requirement(s). 
The investigator reserves the right to discontinue the study should his/her judgment so 
dictate.  If the investigator terminates or suspends a study without prior agreement of the 
sponsor, the investigator should inform the institution where applicable, and the 
investigator/institution should promptly inform the sponsor and the IRB/IEC and provide the 
sponsor and the IRB/IEC with a detailed written explanation of the termination or 
suspension.  Study records must be retained as noted above. 


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11.12 Subject Insurance and Indemnity 
The sponsor will provide insurance for any subjects participating in the study in accordance 
with all applicable laws and regulations. 


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12 APPENDICES 
Appendix 1 
Response Evaluation Criteria in Solid Tumors 
(RECIST) 1.1 
Tumor response assessments in this clinical trial will use Response Evaluation Criteria in 
Solid Tumors (RECIST 1.1) based on the 2009 article by Eisenhauer et al entitled New 
response evaluation criteria in solid tumors: revised RECIST guideline (version 1.1) 
(Eisenhauer, et al., 2009). 
The sole modification to RECIST 1.1 to be implemented in this trial is that chest x-rays may 
not be used to follow disease; only CT scans may be used to follow chest disease.  As 
required by RECIST 1.1, the protocol states that the minimum duration of stable disease is 
7 weeks following the date of first dose of study drug. 
The Eisenhauer article published in the European Journal of Cancer, is available online at: 
http://linkinghub.elsevier.com/retrieve/pii/S0959804908008733. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix 2 
Common Terminology Criteria for Adverse Events 
(v4.0) 
The National Cancer Institute’s Common Terminology Criteria for Adverse Events provides 
descriptive terminology to be used for adverse event reporting in clinical trials.  An updated 
version (4.03) is now in use as of 14 Jun 2010.  Version 4.03 includes clarifications for a 
select few grading scales and adverse event term definitions.  A brief definition is provided to 
clarify the meaning of each AE term.  To increase the accuracy of AE reporting, all adverse 
event terms in CTCAE version 4.03 have been correlated with single-concept, Medical 
Dictionary for Regulatory Activities (MedDRA®) terms. 
CTCAE v4.03 grading refers to the severity of the AE.  CTCAE grades 1 through 5, with 
unique clinical descriptions of severity for each AE, are based on this general guideline: 
Grade 
CTCAE Status 
1 
Mild: asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
2 
Moderate: minimal, local, or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living (ADL).a 
3 
Severe or medically significant but not immediately life-threatening: 
hospitalization or prolongation of hospitalization indicated; disabling, limiting 
self-care ADL.b 
4 
Life-threatening consequences: urgent intervention indicated. 
5 
Death related to adverse event. 
CTCAE = Common Terminology Criteria for Adverse Events. 
a:  Instrumental ADL refers to preparing meals, shopping for groceries or clothes, using the telephone, managing money, 
etc. 
b:  Self-care ADL refers to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not 
bedridden. 
Adapted from the Cancer Therapy Evaluation Program, NCI.  CTCAE v4.03.  Available from: 
https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf] 
 
 
 


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Appendix 3 
Monoclonal Antibodies Half-lives  
 
 


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Appendix 4 
Lansky 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 SB, List MA, Lansky LL, Ritter-Sterr C, Miller DR. The measurement of performance 
in childhood cancer patients. Cancer. 1987 Oct 1;60(7):1651-6. 


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Appendix 5 
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 
 
Crooks V, Waller S, Smith T, Hahn TJ. The use of the Karnofsky Performance Scale in determining outcomes and risk in 
geriatric outpatients. J Gerontol. 1991;46(4):M139-44. 
Hollen PJ, Gralla RJ, Kris MG, Cox C, Belani CP, Grunberg SM, et al. Measurement of quality of life in patients with lung 
cancer in multicenter trials of new therapies: Psychometric assessment of the Lung Cancer Symptom Scale. Cancer. 
1994;73(8):2087-98. 
O'Toole DM, Golden AM. Evaluating cancer patients for rehabilitation potential. West J Med. 1991;155:384-7. 
 
 
 


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Appendix 6 
Schwartz Formula 
The pediatric Schwartz equation is as follows: 
 
GFR (mL/min/1.73 m2) = (0.41 x Height) / Scr were Scr is serum/plasma creatinine in mg/dL 
Related References 
Francis GL, Waguespack SG, Bauer AJ, Angelos P, Benvenga S, Cerutti JM, et al for The 
American Thyroid Association Guidelines Task. Management Guidelines for Children with 
Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid. 2015;25(7):716-59. 
Kumagai A, Reiners C, Drozd V, Yamashita S. Childhood thyroid cancers and radioactive iodine 
therapy: necessity of precautious radiation health risk management. Endocr J. 2007;54(6):839-47. 
Schwartz GJ, Muñoz A, Schneider MF, Mak RH, Kaskel F, Warady BA, et al. New equations to 
estimate GFR in children with CKD. J Am Soc Nephrol. 2009a;20:629-37. 
Schwartz GJ, Work DF. Measurement and estimation of GFR in children and adolescents. Clin J 
Am Soc Nephrol. 2009b;4(11):1832-43. 
Selistre L, De Souza V, Cochat P et al. GFR estimation in adolescents and young adults. J Am 
Soc Nephrol. 2012;23:989-96. 
UPMC Transplant Services. About Glomerular Filtration Rate (GFR). Accessed 01 May 2020: 
https://www.upmc.com/services/transplant/kidney-pancreas/glomerular-filtration-rate-
calculator?&utm_kxconfid=sws256pg0&utm_source=GOOGLE&utm_medium=cpc&utm_camp
aign=71700000037477855&utm_adgroup=58700004162372724&utm_term=gfr&utm_advertiser
id=700000001755088&gclid=EAIaIQobChMIkZ69w6eT6QIVGa_ICh3JhwrqEAAYASAAEgLu
JfD_BwE  


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Appendix 7 
Blood Pressure Levels for Boys by Age and Height 
Percentile 
 
 
 
BP 
Systolic BP (mmHg) 
Diastolic BP (mmHg) 
AGE 
Percentile 
Percentile of Height 
Percentile of Height 
(Year) 
↓ 
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 


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BP 
Systolic BP (mmHg) 
Diastolic BP (mmHg) 
AGE 
Percentile 
Percentile of Height 
Percentile of Height 
(Year) 
↓ 
5th 
10th 
25th 
50th 
75th 
90th 
95th 
5th 
10th 
25th 
50th 
75th 
90th 
95th 
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 
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 
BP = blood pressure 
The 90th percentile is 1.28 SD, 95th percentile is 1.645 SD, and the 99th percentile is 2.326 SD over the mean. 
Guidelines to sex, age, and height-specific percentiles of blood pressure can be accessed at 
http://www.nhlbi.nih.gov/ 
 
 
 
 


Clinical Study Protocol 
incorporating Amendment 03 
E7080-A001-216 
 
 
Eisai 
FINAL: 16 Aug 2021 
Confidential 
Page 130 of 151 
 
 
Appendix 8 
Blood Pressure Levels for Girls by Age and Height Percentile 
 
 
BP 
Systolic BP (mmHg) 
Diastolic BP (mmHg) 
AGE 
Percentile 
Percentile of Height 
Percentile of Height 
(Year) 
↓ 
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 


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Confidential 
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BP 
Systolic BP (mmHg) 
Diastolic BP (mmHg) 
AGE 
Percentile 
Percentile of Height 
Percentile of Height 
(Year) 
↓ 
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 
BP = blood pressure 
The 90th percentile is 1.28 SD, 95th percentile is 1.645 SD, and the 99th percentile is 2.326 SD over the mean. 
Guidelines to sex, age, and height-specific percentiles of blood pressure can be accessed at 
http://www.nhlbi.nih.gov/ 
 
 
 


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E7080-A001-216 
 
Eisai 
FINAL: 16 Aug 2021 
Confidential 
Page 132 of 151 
 
 
Appendix 9 
Body Mass Index-For-Age Percentiles 
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 
Link for the charts is provided below 
http://www.cdc.gov/healthyweight/assessing/bmi/childrens_bmi/about_childrens_bmi.html 
 


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Appendix 10 
Body Mass Index-For-Age Percentiles 
2 to 20 years: Girls 
 
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 
Link for the charts is provided below 
http://www.cdc.gov/healthyweight/assessing/bmi/childrens_bmi/about_childrens_bmi.html


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Confidential 
Page 134 of 151 
 
Appendix 11 
Pharmacodynamic, Pharmacogenomic, and Other 
Biomarker Research 
Subjects enrolled in this clinical study will have biologic samples collected for 
pharmacodynamic (PD), pharmacogenomic (PG), and other biomarker analysis.  These 
samples may be used for discovery or validation to identify biomarkers that may be used for 
exploratory evaluation of response and/or safety-related outcomes as well as for use in 
diagnostic development. 
The PG samples may be used to identify genetic factors that may influence a subject’s 
exposure to the study drug, as well as genetic factors that may have an effect on clinical 
response or potential adverse events related to study treatment, and to explore the role of 
genetic variability in response.  Samples may be analyzed to determine a subject’s genotypes 
or sequence for a number of genes or non-coding regulatory regions.  The research may 
include the investigation of polymorphisms in genes that are likely to influence the study 
drug pharmacokinetics or therapeutic response. 
Collection of the PD, PG, and other biomarker samples (optional) will be bound by the 
sample principles and processes outlined in the main/separate study protocol.   
Sample Collection and Handling 
The samples will be collected according to the study flow chart.  If, for operational or 
medical reasons, the genomic DNA blood sample cannot be obtained at the prespecified visit, 
the sample can be taken at any study center visit at the discretion of the investigator and site 
staff. 
Security of the Samples, Use of the Samples, Retention of the Samples 
Sample processing, for example DNA and/or RNA extraction, genotyping, sequencing, or 
other analysis will be performed by a laboratory under the direction of the sponsor.  
Processing, analysis, and storage will be performed at a secure laboratory facility to protect 
the validity of the data and maintain subject privacy. 
Samples will only be used for the purposes described in this protocol.  Laboratories 
contracted to perform the analysis on behalf of the sponsor will not retain rights to the 
samples beyond those necessary to perform the specified analysis and will not transfer or sell 
those samples.  The sponsor will not sell the samples to a third party. 
Samples will be stored for up to 15 years after the completion of the study (defined as 
submission of the clinical study report to the appropriate regulatory agencies).  At the end of 
the storage period, samples will be destroyed.  Samples may be stored longer if a health 
authority (or medicinal product approval agency) has active questions about the study.  In 
this special circumstance, the samples will be stored until the questions have been adequately 
addressed. 


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It is possible that future research and technological advances may identify genomic variants 
of interest, or allow alternative types of genomic analysis not foreseen at this time.  Because 
it is not possible to prospectively define every avenue of future testing, all samples collected 
will be single or double coded (according to the ICH E15 guidelines) in order to maintain 
subject privacy.  
Right to Withdraw 
If, during the time the samples are stored, a participant would like to withdraw his/her 
consent for participation in this research, Eisai will destroy the samples.  Information from 
any assays that have already been completed at the time of withdrawal of consent will 
continue to be used as necessary to protect the integrity of the research project. 
Subject Privacy and Return of Data 
No subject-identifying information (eg, initials, date of birth, government identifying 
number) will be associated with the sample.  All PD and other biomarker samples will be 
single coded.  Genomic DNA samples used to explore the effects on PK, treatment response, 
and safety will be single coded.  Genomic DNA samples that will be stored for long-term use 
(defined as 15 years after the completion of the study) will be double coded.  Double coding 
involves removing the initial code (subject ID) and replacing with another code such that the 
subject can be re-identified by use of 2 code keys.  The code keys are usually held by 
different parties.  The key linking the sample ID to the subject number will be maintained 
separately from the sample.  At this point, the samples will be double-coded, the first code 
being the subject number.  Laboratory personnel performing genetic analysis will not have 
access to the “key.”  Clinical data collected as part of the clinical trial will be cleaned of 
subject identifying information and linked by use of the sample ID “key.” 
The sponsor will take steps to ensure that data are protected accordingly and confidentiality 
is maintained as far as possible.  Data from subjects enrolled in this study may be analyzed 
worldwide, regardless of location of collection. 
The sponsor and its representatives and agents may share coded data with persons and 
organizations involved in the conduct or oversight of this research.  These include: 
 
Clinical research organizations retained by the sponsor  
 
Independent ethics committees or institutional review boards that have responsibility for 
this research study  
 
National regulatory authorities or equivalent government agencies 
At the end of the analysis, results may be presented in a final report which can include part or 
all of the coded data, in listing or summary format.  Other publication (eg, in peer-reviewed 
scientific journals) or public presentation of the study results will only include summaries of 
the population in the study, and no identified individual results will be disclosed. 


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Given the research nature of the PD, PG, and other biomarker analysis, it will not be possible 
to return individual data to subjects.  The results that may be generated are not currently 
anticipated to have clinical relevance to the patients or their family members.  Therefore, 
these results will not be disclosed to the patients or their physicians. 
If at any time, PD, PG, and/or other biomarker results are obtained that may have clinical 
relevance, IRB review and approval will be sought to determine the most appropriate manner 
of disclosure and to determine whether or not validation in a Clinical Laboratory 
Improvement Amendments (CLIA)-certified setting will be required.  Sharing of research 
data with individual patients should only occur when data have been validated by multiple 
studies and testing has been done in CLIA-approved laboratories. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix 12 
Preparation of Lenvatinib suspension 
Wash hands thoroughly with soap and water before putting on and after removing gloves.  
Double gloves should be worn at all times during preparation and administration of 
lenvatinib. 
Young and other children in the home should not be near the area where lenvatinib 
suspension is being prepared or administered. 
Ensure proper disposal of all the materials for administration by disposing directly into the 
designated waste container to protect children or anyone who may handle the trash. 
Caregivers should not open the capsule in order to avoid repeated exposure to the 
contents of the capsule. 
If a dose is missed and cannot be taken within 12 hours, skip that dose and take the next dose 
at the usual time of administration. 
All unused products and packaging from used products should be returned to the site by the 
patient or caregiver at the next visit.  Do not throw away any medicines via wastewater or 
household waste. 
Preparation of suspension: Prepare the suspension as illustrated below by either the oral 
method (a) or by a nasogastric tube (b).  Prepare the suspension with water or apple juice.  
The suspension should be directly administered into the mouth of the subject and washed 
down with additional fluid added to the syringe after the medication is administered; likewise 
for nasogastric administration.  The suspension should be administered immediately after 
preparation. 
 
a. 
Procedure for suspension administration by syringe orally: 
A: Water or apple juice 
B: Cap 
C: Syringe (20 mL, Baxa preferred) 
D: Syringe for rinse (20 mL, Baxa preferred) 
 
 
 
 
 


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Place 1 capsule* into a syringe.  Close the tip port of the syringe 
with a cap. 
* One to 5 capsules are allowed to be placed into a 20 mL syringe. 
 
 
 
 
 
 
 
Add 3 mL of water or apple juice into the syringe using another 
(new) 20 mL syringe. 
 
 
 
 
 
 
 
Insert the plunger into the syringe (cylinder) about 2 cm from the 
end.  Leave the syringe upright in a flask for not less than 10 
minutes. 
 
 
 
 
 
After 10 minutes, shake the syringe for not less than 3 minutes to 
dissolve the capsule shell completely to make a suspension of the 
granules (The capsule shell needs to be dissolved and the  granules 
well suspended). 
 
 
 
 
 
Remove the cap from the syringe.  Slide the plunger toward the 
solution to remove air from the syringe, and then administer the 
3 mL of suspension into the mouth of the subject. 
 
 
 
 
 


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Rinse step 
After the administration of the 3 mL suspension from the syringe, 
recap the syringe for reuse. 
 
 
 
 
 
 
 
Draw up 2 mL of water or apple juice into a new syringe.  
 
 
 
 
 
 
 
 
 
 
Insert the 2 mL of water or apple juice into the first syringe 
(which was used for the 3 mL suspension). 
 
 
 
 
 
 
 
 
Shake the syringe 10 times to dissolve the remaining granules. 
 
 
 
 
 
 
 
 
 


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Remove the cap from the syringe and push the air out of the syringe 
with the plunger, and then insert the syringe into the mouth and 
administer the 2 mL of rinse liquid.  
 
 
 
 
 
 
 
 
Total volume of suspension to be administrated is 5 mL (3mL for suspension + 2 mL of water of apple 
juice for rinse) for 1 to 5 capsules. 
 
b. Procedure of suspension administering by syringe with nasogastric tube: 
 
A: Water or apple juice 
B: NG tube (Vygon, 6FR) 
C: Cap 
D: Syringe (20 mL, Baxa, preferred) 
E: Syringe for rinse (20 mL, Baxa preferred) 
 
 
Place 1 capsule* into a syringe with the tip of the port of the 
syringe closed with a cap and place into a flask.  
* One to 5 capsules are allowed to be placed in a 20 mL 
syringe. 
 
 
 
 
Use a new 20 mL syringe and draw up 3 mL of water or apple 
juice and insert it into the medication syringe. 
 
 
 
 
 


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Insert the plunger into the syringe about 2 cm from the end.  
Leave the syringe upright in the flask for not less than 10 
minutes. 
 
 
 
 
 
After 10 minutes, shake the syringe for not less than 3 minutes 
to dissolve the capsule shell completely and to suspend the 
granules (the capsule shell needs to be dissolved and the 
granules well suspended). 
 
 
 
 
 
Remove the cap from the syringe and slide the plunger to 
remove the air from the syringe.  
 
 
 
 
 
 
Connect the syringe to an NG tube and administer the 3 mL of 
suspension through the NG tube.  It is recommended where 
possible, that the syringe is held in the horizontal position 
while administering the suspension to avoid the possibility of 
blocking the nasogastric tubing with undissolved granules. 
 
 
 
 
 
 
 


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Rinse step 
After inserting the suspension, disconnect the NG tube  from 
the syringe. 
 
 
 
 
 
 
Reconnect the cap (reuse) of the syringe. 
 
 
 
 
 
Draw up 2 mL of water or apple juice a in a new 20 mL 
syringe and insert the liquid into the medication syringe. 
 
 
 
 
 
Reinsert the plunger to about 2 cm from the end and shake the 
syringe for 10 times 
 
 
 
 
 
Remove the cap and slide the plunger to about 2 mL from the 
end to remove the air from the syringe.  
 
Reconnect the NG tube to the syringe and insert the 2 mL of 
rinse liquid through the NG tube. 
 
 
 
Total volume of suspension to be administered is 5 ml (3 mL 
for suspension + 2 mL of water of apple juice for rinse) for 1 to 5 capsules. 
 
 


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Appendix 13 
Imaging Scans Methodology for Tumor Assessment 
For All Tumor Types Except High Grade Glioma (HGG) 
Screening computed tomography (CT) scans should be performed with oral and iodinated 
intravenous contrast and magnetic resonance imaging (MRI) scans should be performed with 
IV gadolinium chelate.  Post-screening scans may be performed without contrast if a medical 
contraindication develops while on study treatment.  If iodinated IV contrast is 
contraindicated, chest CT should be done without IV contrast.  MRI should be performed for 
all other body regions (with gadolinium unless contraindicated (eg, severe renal dysfunction). 
CT scans should be of diagnostic quality spiral/multidetector CT with oral and iodinated IV 
contrast, and the MRI scans should be performed with IV gadolinium chelate.  Scans of the 
abdomen, pelvis, and other areas of the body may be done with MRI instead of CT, but 
evaluation of the chest should be done with CT.  Spiral/multidetector CT should be 
performed with a t-mm contiguous slice reconstruction algorithm.  If body MRI scans are 
performed, contiguous slices of 5 mm should also be performed.  If a subject develops a 
contraindication to CT contrast during the study, the chest evaluation should be done with 
non-contrast CT, and the other body scans should be done with MRI with gadolinium chelate 
IV. 
The same imaging modality and image-acquisition protocol (including use or non-use of 
contrast) should be used consistently across all time points to allow consistent comparison of 
lesions.  Low-dose non-contrast CT transmission scans from a positron emission 
tomography-CT (PET-CT) combination scanner are not acceptable.  Ultrasound should not 
be used for radiographic tumor assessment.  A chest x-ray or skeletal x-ray which clearly 
demonstrates a new metastatic lesion may be used to document progression in lieu of the 
CT/MRI scans. 
If subcutaneous masses or nodes are palpable (eg, bulky) and are assess by both clinical and 
radiographic techniques, the radiographic (CT/MRI) technique should be used for the 
assessment of target and non-target lesions. 
18-Fluoro-2-deoxyglucose whole-body positron emission tomography (18FDG-PET) scans 
may be used to assess new lesions if used according to RECIST 1.1 (a new FDG-avid lesion 
if there is a negative 18FDG-PET scan at baseline; if there was no baseline 18FDG-PET scan, 
a potential new lesion must be demonstrated with CT or MRI). 
For HGG 
A standard MRI imaging protocol will be performed for use in the assessment.  The brain 
MRI sequences will include axial T1-weighted spin-echo imaging obtained using a TR of 
400 – 600 ms, a TE of 15 ms or less, a field of view of 22 – 24 cm, a matrix of 256 x 256, a 
slice thickness of 5 mm and intraslice gaps of 1.5 mm or less; axial T2-weighted fast spin 
echo images using a TR of 2500 – 4500 ms, TE of 100 – 130 ms, echo train length (ETL) of 
13 – 25, FOV or 22 – 24 cm, a matrix of 256 x 256, a slice thickness of 5 mm and intraslice 
gaps of 1.5 mm or less; axial FLAIR images using a TR of 6000 – 9000 ms, TE of 100 – 130 


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ms, TI of 2000 – 2500 ms,  ETL of 13 – 25, a matrix of 256 x 192-256, a slice thickness of 5 
mm and intraslice gaps of 1.5 mm or less.  After the intravenous injection of 0.1 mmol/kg of 
gadolinium containing contrast agent, a T1-weighted axial acquisition will be performed 
using the same parameter ranges as above, followed by a whole brain sagittal or coronal 3D 
volumetric T1-weighted spoiled gradient echo or fast low angle shot sequence using TR less 
than 10 ms, TE less than 5 ms, FOV of 25.6 cm or less, and a matrix size appropriate for 
obtained voxels that are 1.3 mm or less in any direction.


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Appendix 14 
Response Assessment in Neuro-Oncology (RANO) 
Criteria 
The RANO guidelines are as follows: 
Specific lesions are to be evaluated serially with comparative analysis of changes in the area 
of contrast enhancement, as well as the non-enhancing component will be performed.  The 
product of the maximal cross sectional enhancing diameters will be used to determine the 
size of the contrast-enhancing lesions as follows: 
 
Measurable disease is defined as bidimensionally contrast-enhancing lesions with 
clearly defined margins by CT or MRI scan, with a minimal diameter of 1 cm, and visible 
on 2 axial slices which are preferably at most 5 mm apart with 0 mm skip.  
 
Non-measurable disease is defined as either unidimensionally measurable lesions, 
masses with margins not clearly defined, or lesions with maximal perpendicular 
diameters <1cm. If there are multiple contrast-enhancing lesions, a maximum of 5 of the 
largest lesions may be measured and the sum of the products of the perpendicular 
diameters of these lesions determined. 
 
For subjects with recurrent disease who have multiple lesions of which only 1 or 2 are 
increasing in size, the enlarging lesions should be considered the target lesions for 
evaluation of response. 
 
Given the difficulty of differentiating “pseudoprogression” from true progression in the 
first 3 months after irradiation, subjects in this window should only be classified as 
progressive disease if the progression is outside the radiation field (beyond the high dose 
region or 80% isodose line) or if there is pathologic confirmation of disease progression. 
 
Radiographic response should be determined in comparison to the tumor measurement 
obtained at pretreatment baseline for determination of response, and the smaller of 
baseline or the smallest tumor measurement following initiation of therapy (nadir) for 
determination of progression: 
- 
Complete Response (CR):  Complete disappearance of all enhancing measurable and 
non-measurable disease sustained for at least 4 weeks.  In the absence of a confirming 
scan at least 4 weeks later, this scan will be considered only stable disease.  No new 
lesions.  Stable or improved non-enhancing (T2/FLAIR) lesions.  Subjects must be on 
no corticosteroids and stable or improved clinically. 
- 
Partial Response (PR):  Greater than or equal to 50% decrease, compared to baseline, 
in the sum of products of perpendicular diameters of all measurable enhancing lesions 
sustained for at least 4 weeks.  In the absence of a confirming scan 4 weeks later, this 
scan will be considered only stable disease.  No progression of non-measurable 
disease.  No new lesions.  Stable or improved nonenhancing (T2/FLAIR) lesions on 
same or lower dose of corticosteroids compared to baseline scan.  Subjects should be 
on a corticosteroid dose that should not be greater than the dose at time of baseline 
scan, and should be stable or improved clinically. 
- 
Stable Disease (SD):  This occurs if the subjects did not qualify for CR, PR, or 
progressive disease (PD) (see below).  There should be stable or improved 


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nonenhancing (T2/FLAIR) lesions on same or lower dose of corticosteroids compared 
to baseline scan.  In the event that the corticosteroid dose has been increased, the last 
scan considered to show stable disease will be the scan obtained when the 
corticosteroid dose was equivalent to the baseline dose.  The subject should be stable 
or improved clinically. 
- 
Progressive Disease (PD):  Progression is defined as >25% increase in sum of the 
products of perpendicular diameters of enhancing lesions (over baseline if no 
decrease) on stable or increasing doses of corticosteroids and/or a significant increase 
in T2/FLAIR non-enhancing lesion on stable or increasing doses of corticosteroids 
compared to baseline scan or best response following initiation of therapy, not due to 
co-morbid events.  Any new lesion.  Clear clinical deterioration not attributable to 
other causes apart from the tumor.  Failure to return for evaluation due to death or 
deteriorating condition is considered progressive disease as well. 
 
Reference: 
Wen P, Macdonald DR, Reardon DA, Cloughesy TF, Sorenson AG, Galanis E, et al. for the 
Response Assessment in Neuro-Oncology Working Group. Updated Response Assessment 
Criteria for High-Grade Gliomas. J Clin Oncol. 2010;28:1963-72. 
 


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Appendix 15 
CYP3A4 Substrates, Inducers and Inhibitors 
This is not an inclusive list.  Because the lists of these agents are constantly changing, it is important 
to regularly consult frequently updated medical references. 
CYP3A4 Substrates 
Strong Inhibitors1 
Moderate 
Inhibitors 
Weak 
Inhibitors 
Inducers 
alfentanil4,5 
amiodarone4 
aprepitant5 
atorvastatin5 
benzodiazepines 
bortezomib 
brentuximab 
budesonide5 
buspirone5 
calcium channel blockers 
cisapride 
citalopram/escitalopram 
conivaptan5 
glucocorticoids2 
crizotinib 
cyclosporine4 
cyclophosphamide 
dapsone 
darifenacin5 
darunavir5 
dasatinib5 
dihydroergotamine 
docetaxel 
doxorubicin 
dronedarone5 
eletriptan5 
ergotamine4 
eplerenone5 
erlotinib 
esomeprazole 
estrogens 
etoposide 
everolimus5 
felodipine5 
fentanyl4 
fosaprepitant5 
gefitinib 
atazanavir 
boceprevir 
clarithromycin 
cobicistat 
darunavir 
delavirdine 
grapefruit3 
grapefruit juice3 
indinavir 
itraconazole 
ketoconazole 
lopinavir/ritonavir 
nefazodone 
nelfinavir 
posaconazole 
ritonavir 
saquinavir 
telaprevir 
telithromycin 
voriconazole 
aprepitant 
conivaptan 
crizotinib 
diltiazem 
dronedarone 
erythromycin 
fluconazole 
fosamprenavir 
grapefruit3 
grapefruit juice3 
imatinib 
mifepristone 
nilotinib 
verapamil 
alprazolam 
amiodarone 
amlodipine 
atorvastatin 
bicalutamide 
cilostazol 
cimetidine 
ciprofloxacin 
cyclosporine 
fluvoxamine 
fosaprepitant 
isoniazid 
nicardipine 
propofol 
quinidine 
ranolazine 
 
 
 
armodafinil 
barbiturates 
bosentan 
carbamazepine 
deferasirox 
echinacea 
efavirenz 
etravirine 
fosphenytoin 
glucocorticoids2 
modafinil 
nafcillin 
nevirapine 
oxcarbazepine 
phenobarbital 
phenytoin 
pioglitazone 
primidone 
rifabutin 
rifampin 
rifapentin 
ritonavir 
St. John’s wort 
topiramate 
 


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CYP3A4 Substrates 
Strong Inhibitors1 
Moderate 
Inhibitors 
Weak 
Inhibitors 
Inducers 
haloperidol 
HIV antiretrovirals 
HMG Co-A inhibitors5 
ifosfamide 
imatinib 
indinavir5 
irinotecan 
itraconazole 
ketoconazole 
lansoprazole 
lapatinib 
losartan 
lovastatin5 
lurasidone5 
macrolide antibiotics 
maraviroc5 
medroxyprogesterone 
methadone 
midazolam5 
modafinil 
montelukast 
nefazodone 
nilotinib 
nisoldipine5 
omeprazole 
ondansetron 
paclitaxel 
pazopanib 
quetiapine5 
quinidine4 
saquinavir5 
sildenafil5 
simvastatin5 
sirolimus4,5 
sunitinib 
tacrolimus4,5 
telaprevir 
tamoxifen 
temsirolimus 
teniposide 
tetracycline 
tipranavir5 


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CYP3A4 Substrates 
Strong Inhibitors1 
Moderate 
Inhibitors 
Weak 
Inhibitors 
Inducers 
tolvaptan5 
triazolam5 
trimethoprim 
vardenafil5 
vinca alkaloids 
zolpidem 
1Certain fruits, fruit juices and herbal supplements (star fruit, Seville oranges, pomegranate, gingko, goldenseal) may inhibit 
CYP3A4 isozyme; however, the degree of that inhibition is unknown.  
2Dexamethasone is considered a weak CYP3A4 inducer. 
3The effect of grapefruit juice (strong vs moderate CYP3A4 inhibition) varies widely among brands and is concentration-, 
dose-, and preparation-dependent. 
4Narrow therapeutic range substrates. 
5Sensitive substrates. 
 


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PROTOCOL SIGNATURE PAGE 
Study Protocol Number: E7080-A001-216 
Study Protocol Title: 
A Phase 1/2 Study of Lenvatinib in Combination With 
Everolimus in Recurrent and Refractory Pediatric Solid Tumors, 
Including CNS Tumors 
Investigational Product 
Name: 
Lenvatinib (E7080), everolimus 
 
IND Number: 
072010 
 
SIGNATURES 
 
 
Authors: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Oncology Business Group, Eisai Ltd. 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
Oncology Business Group, Eisai Ltd. 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
Oncology Business Group, Eisai Inc. 
 
 
Date 
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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INVESTIGATOR SIGNATURE PAGE 
Study Protocol Number: 
E7080-A001-216 
Study Protocol Title: 
A Phase 1/2 Study of Lenvatinib in Combination With 
Everolimus in Recurrent and Refractory Pediatric Solid 
Tumors, Including CNS Tumors 
Investigational Product 
Name: 
Lenvatinib (E7080), everolimus 
IND Number: 
072010 
 
I have read this protocol and agree to conduct this study in accordance with all stipulations of 
the protocol and in accordance with International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use (ICH) and all applicable local Good 
Clinical Practice (GCP) guidelines, including the Declaration of Helsinki. 
 
 
<Name of institution> 
Medical Institution 
 
<Name, degree> 
  
  
Investigator 
 Signature 
 Date 
 
 

SAP_001.pdf: 
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STATISTICAL ANALYSIS PLAN 
Study Protocol 
Number: 
E7080-A001-216 
Study Protocol 
Title: 
A Phase 1/2 Study of Lenvatinib in Combination With Everolimus in 
Recurrent and Refractory Pediatric Solid Tumors, Including CNS 
Tumors 
Date: 
22 Sep 2022 
Version: 
Final Version 2.0 
 
 


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DATE 
Highlights of Major Changes 
Sections/Changes 
22 Sep 2022 
Version 2.0: 
 
Section 3.2 
 
Added definition of being evaluable for an objective response. 
Added definition of evaluable participants. 
 
Section 3.2.2 and 3.2.3 
 
Added ±1 week window for tumor assessment timepoints.  
 
Section 5.2.1 
Added Evaluable Analysis Set for efficacy analysis of Phase 2 and 
updated Safety Analysis Set will be used for disposition, 
demographic and baseline characteristics, previous anticancer 
medications, prior and concomitant medications, procedures and 
radiotherapy, medical history, efficacy analysis of Phase 1 as well as 
all safety evaluations. 
 
Section 5.2.4 
Updated to TNM will be listed only. Tumor-node-metastasis (TNM) 
staging, stage group of Ewing sarcoma/PNET and 
Rhabdomyosarcoma at diagnosis and WHO Grading of Glioma for 
subjects evaluated by RANO will be provided in listing only. 
 
Section 5.2.5 
Prior medications definition updated to medications that started 
prior to the first dose of study drug and discontinued before the first 
dose of study drug. 
 
Section 5.4.1.2 
 
Remove “As an example, if a subject had an SD at the timepoint 1, a 
PR at the timepoint 2, a CR at the timepoint 3, and another CR at 
the timepoint 4, then the BOR for this subject is CR, which was 
confirmed at timepoint 4” for conciseness. 
 


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Section 5.4.2 
 
Added DOR to the secondary endpoints in Phase 2. 
Updated the definition of more than 1 missed visit/adequate tumor 
assessment in Table 3 DOR and Censoring Rules.  
 
Section 5.4.3 
 
Removed spider plot. 
 
Section 5.6.2 
 
Combined the following tables into one table. 
Treatment-related TEAEs by decreasing frequency of PT 
Treatment-related TEAEs by decreasing frequency of PT with 
&7&$(*UDGHV 
Added bone and teeth abnormalities, removed impaired wound 
healing and weight loss in CSAE for Lenvatinib. 
Replaced CSAE with AEOSI, removed Edema, Rash and added 
Angioedema in AEOSI for Everolimus. 
 
Section 5.6.3.1 
Shift table will include all chemistry parameters and hematology 
parameters.  
Shifts from Baseline to worst postbaseline CTCAE grade for all 
clinical chemistry parameters and hematology parameters. 
 
Section 5.6.3.4 
Added height to the list of vital sign parameters that will be 
summarized.  
Added analysis for height percentiles. 
Updated the percentile categories for analysis of change in BP 
percentile categories for Shift in BP Percentile from Baseline to 
Worst Postbaseline Measurement (Subjects <18 Years Old). 
 
Section 5.6.4 
Added descriptive statistics and changes from baseline for left 
ventricular shortening fraction assessed on echocardiogram and 
LVEF assessed on echocardiogram or MUGA scans will be 


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presented.  Percent reduction from baseline will also be 
summarized. 
In addition, Radiographic findings of proximal tibial growth plates 
and dental examination will also be summarized. 
 
Section 8.2.1.6 
 
Added partial dates imputation rule for previous radiotherapy. 
 
Section 8.1 
 
Updated visit window added efforts should be made to 1 week. Visit 
windows will be defined to be upper and lower bounds of 1 week of 
conduct tumor assessments on the day scheduled visit. (±7 day). 
 
Appendix 
Updated Summary of Efficacy Analyses of Phase 1 and Phase 2. 


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1 
TABLE OF CONTENTS 
1 
TABLE OF CONTENTS ...................................................................................................5 
2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ....................................8 
3 
INTRODUCTION ...........................................................................................................10 
3.1 
Study Objectives ....................................................................................................10 
3.1.1 
Primary Objectives.......................................................................................10 
3.1.1.1 
Phase 1 ...............................................................................................10 
3.1.1.2 
Phase 2 ...............................................................................................10 
3.1.2 
Secondary Objectives...................................................................................10 
3.1.2.1 
Phase 1 ...............................................................................................10 
3.1.2.2 
Phase 2 ...............................................................................................10 
3.1.3 
Exploratory Objectives for Phase 1 and Phase 2 .........................................11 
3.2 
Overall Study Design and Plan ..............................................................................11 
3.2.1 
Pretreatment Phase .......................................................................................16 
3.2.1.1 
Screening Period ................................................................................16 
3.2.1.2 
Baseline Period ..................................................................................17 
3.2.2 
Treatment Phase ...........................................................................................17 
3.2.3 
Extension Phase ...........................................................................................17 
3.2.4 
Treatment Discontinuation Criteria .............................................................17 
3.2.5 
Off-Treatment Visit .....................................................................................18 
3.2.6 
Posttreatment Phase .....................................................................................18 
3.2.6.1 
Follow-Up Period...............................................................................18 
4 
DETERMINATION OF SAMPLE SIZE ........................................................................18 
5 
STATISTICAL METHODS ............................................................................................19 
5.1 
Study Endpoints .....................................................................................................19 
5.1.1 
Primary Endpoints .......................................................................................19 
5.1.1.1 
Primary Endpoints for Phase 1 ..........................................................19 
5.1.1.2 
Primary Endpoint for Phase 2 ............................................................19 
5.1.2 
Secondary Endpoints ...................................................................................20 
5.1.3 
Exploratory Endpoints .................................................................................20 
5.2 
Study Subjects ........................................................................................................20 
5.2.1 
Definitions of Analysis Sets.........................................................................20 
5.2.2 
Subject Disposition ......................................................................................21 
5.2.3 
Protocol Deviations ......................................................................................21 
5.2.4 
Demographic and Other Baseline Characteristics .......................................21 
5.2.5 
Prior and Concomitant Therapy ...................................................................23 
5.2.6 
Treatment Compliance .................................................................................24 
5.3 
Data Analysis General Considerations ..................................................................24 
5.3.1 
Pooling of Centers........................................................................................24 


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5.3.2 
Adjustments for Covariates..........................................................................24 
5.3.3 
Multiple Comparisons/Multiplicity .............................................................24 
5.3.4 
Examination of Subgroups ...........................................................................24 
5.3.5 
Handling of Missing Data, Dropouts, and Outliers .....................................24 
5.3.5.1 
 Adverse Events .................................................................................24 
5.3.5.2 
 Concomitant Medications .................................................................24 
5.3.6 
Other Considerations ...................................................................................25 
5.3.6.1  
BSA Dose Adjustment and Dose Capping ........................................25 
5.3.6.2  
Summarization of Safety Data ...........................................................25 
5.4 
Primary, Secondary and Exploratory Analyses .....................................................25 
5.4.1 
Primary Analyses .........................................................................................25 
5.4.1.1 
Dose-Finding Analysis in Phase 1 .....................................................25 
5.4.1.2 
Primary Efficacy Analysis for Phase 2 ..............................................25 
5.4.2 
Secondary Efficacy Analyses ......................................................................26 
5.4.2.1 
Phase 1 ...............................................................................................26 
5.4.2.2 
Phase 2 ...............................................................................................27 
5.4.3 
Exploratory Efficacy Analyses ....................................................................30 
5.4.3.1 
Biomarkers, Archival Tumor Tissue, Lenvatinib Exposure and 
AEs of Special Interest.......................................................................30 
5.4.3.2 
Other Exploratory Efficacy Analyses ................................................30 
5.5 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other 
Biomarker Analyses ...............................................................................................30 
5.5.1 
Pharmacokinetic Analysis ............................................................................30 
5.5.1.1 
Pharmacodynamic, Pharmacokinetic, Pharmacogenomic, and 
Other Biomarker Analyses .................................................................31 
5.6 
Safety Analyses ......................................................................................................31 
5.6.1 
Extent of Exposure .......................................................................................31 
5.6.1.1 
Extent of Exposure of Study Drug .....................................................31 
5.6.1.2 
Study Drug Administration ................................................................32 
5.6.1.3 
Study Drug Dose Modifications ........................................................32 
5.6.1.4 
Dose Limiting Toxicity ......................................................................33 
5.6.2 
Adverse Events ............................................................................................33 
5.6.3 
Laboratory Values ........................................................................................36 
5.6.3.1 
Hematology and Clinical Chemistry ..................................................36 
5.6.3.2 
Thyroid-Stimulating Hormone...........................................................37 
5.6.3.3 
Urinalysis ...........................................................................................37 
5.6.3.4 
Vital Signs ..........................................................................................37 
5.6.3.5 
Electrocardiograms ............................................................................37 
5.6.4 
Other Safety Analyses..................................................................................38 
5.7 
Other Analyses .......................................................................................................38 
5.8 
Exploratory Analyses .............................................................................................38 
6 
INTERIM ANALYSES ...................................................................................................38 


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7 
CHANGES IN THE PLANNED ANALYSES ...............................................................38 
8 
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING...............................39 
8.1 
Visit Windows .......................................................................................................39 
8.2 
Safety and Efficacy Data Handling ........................................................................39 
8.2.1 
Partial dates ..................................................................................................39 
8.2.1.1 
Diagnosis date ....................................................................................39 
8.2.1.2 
Date of Death .....................................................................................39 
8.2.1.3 
Date of Progression ............................................................................40 
8.2.1.4 
Date of Last Tumor Assessment ........................................................40 
8.2.1.5 
Date of Start of Subsequent Anticancer Therapy ..............................40 
8.2.1.6 
Date of Previous Radiotherapy ..........................................................40 
8.3 
Definitions, Derived Variables, and Data Sets ......................................................41 
8.3.1 
Baseline ........................................................................................................41 
8.3.2 
Date/Time Definitions .................................................................................41 
8.3.3 
Creatinine Clearance ....................................................................................41 
8.3.4 
Last Known Alive Date ...............................................................................42 
8.4 
Pharmacokinetics/Pharmacodynamics Data Handling ..........................................42 
8.4.1 
Lower Limit of Quantification of Lenvatinib Plasma Concentration ..........42 
8.4.2 
BLQ Handling for Developing Concentration-Time Profiles .....................42 
9 
PROGRAMMING SPECIFICATIONS ..........................................................................42 
10 STATISTICAL SOFTWARE ..........................................................................................42 
11 MOCK TABLES, LISTINGS, AND GRAPHS ..............................................................42 
12 REFERENCES ................................................................................................................42 
13 APPENDICES .................................................................................................................44 
13.1 
Summary of Efficacy Analyses of Phase 1 ............................................................44 
13.2 
Summary of Efficacy Analyses of Phase 2 ............................................................45 
 


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2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Term 
AE 
adverse event 
ATC 
anatomical therapeutic class 
AUC 
area under curve 
BLQ 
below limit of quantification 
BMI 
body mass index 
BSA 
body surface area  
BOR 
best overall response 
C#/D# 
Cycle#/Day# 
CBR 
clinical benefit rate 
CI 
confidence interval 
Cmax 
concentration maximum 
CNS 
central nervous system 
CR 
complete response 
CRF 
case report form 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
coefficient of variation 
DBP 
diastolic blood pressure 
DCR 
disease control rate 
DLT 
dose limiting toxicity 
DOR 
duration of response 
ECG 
electrocardiogram 
HGG 
high grade glioma 
IDMC 
independent data monitoring committee  
KM 
Kaplan-Meier 
KPS 
Karnofsky performance status  
LVEF 
left ventricular ejection fraction 
MedDRA 
Medical Dictionary for Regulatory Activities 
MTD 
maximum tolerated dose 
MUGA 
multiple gated acquisition 


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Abbreviation 
Term 
NA 
not applicable 
NE 
not evaluable 
ORR 
objective response rate 
PD 
progressive disease 
PK 
pharmacokinetic 
pPNET 
peripheral primitive neuroectodermal tumor 
PR 
partial response 
PSC 
Protocol Steering Committee 
PT 
preferred term 
QT 
time from the beginning of the QRS complex to the end of the 
T wave 
RANO 
Response Assessment in Neuro-Oncology 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D 
recommended Phase 2 dose 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SBP 
systolic blood pressure 
SD 
stable disease  
SOC 
System organ class 
TEAE 
treatment-emergent adverse event 
TLG 
tables, listings, and graphs 
TNM 
tumor-node-metastasis staging system 
WHO 
World Health Organization 
 


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3 
INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to describe the procedures and the 
statistical methods that will be used to analyze, and report results for the Phase 1/2 Study 
E7080-A001-216.  This SAP is based on the Protocol Amendment 03 (16 Aug 2021) and 
final electronic Case Report Form (eCRF) (23 May 2022). 
3.1 
Study Objectives 
3.1.1 
Primary Objectives 
3.1.1.1 
Phase 1 
a. 
To determine maximum tolerated dose (MTD) and recommended Phase 2 dose 
(RP2D) of lenvatinib administered in combination with everolimus, once daily to 
pediatric subjects with recurrent/refractory solid tumors. 
b. 
To describe the toxicities of lenvatinib administered in combination with everolimus 
once daily to pediatric subjects with recurrent/refractory solid tumors. 
 
3.1.1.2 
Phase 2 
a. To estimate the antitumor activity of lenvatinib in combination with everolimus in 
pediatric subjects with selected recurrent/refractory solid tumors including Ewing 
sarcoma/peripheral primitive neuroectodermal tumor (pPNET), rhabdomyosarcoma, 
and high grade glioma (HGG) using objective response rate (ORR) at Week 16 as the 
outcome measure. 
 
3.1.2 
Secondary Objectives 
3.1.2.1 
Phase 1 
a. To preliminarily define the antitumor activity of lenvatinib in combination with 
everolimus in pediatric subjects with recurrent/refractory solid tumors. 
b. To characterize the pharmacokinetics (PK) of oral lenvatinib and everolimus, when 
administered in combination to pediatric subjects with recurrent/refractory solid 
tumors. 
 
3.1.2.2 
Phase 2 
a. To assess other response variables including ORR at the time of data cutoff, disease 
control rate (DCR), clinical benefit rate (CBR), and duration of response (DOR). 
b. To evaluate the tolerability and safety profile of lenvatinib in combination with 
everolimus in pediatric subjects with recurrent/refractory Ewing sarcoma/pPNET, 
rhabdomyosarcoma, and HGG. 


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c.
To characterize the PK of lenvatinib and everolimus, when administered in 
combination to children with recurrent/refractory Ewing sarcoma/pPNET, 
rhabdomyosarcoma, and HGG.
3.1.3
Exploratory Objectives for Phase 1 and Phase 2
a.
To evaluate blood, tumor, and safety (eg, hypertension) markers as correlative 
biomarkers of treatment effects and outcomes of lenvatinib in combination with 
everolimus.
b.
To assess candidate alterations in genes and/or proteins that may contribute to tumor 
development and serve as predictive markers of response in archival tumor tissue from 
pediatric subjects
c.
To explore relationships between lenvatinib exposure and safety (eg, adverse events 
[AEs] of special interest).
3.2
Overall Study Design and Plan
This is a multicenter, open-label, Phase 1/2 study of lenvatinib in combination with 
everolimus in pediatric subjects with relapsed or refractory solid tumors.  The overall study 
design is depicted in Figure 1.
Figure 1
Study Design
EVE = everolimus, LEN = lenvatinib, MTD = maximum tolerated dose, ORR = objective response rate, 
PK = pharmacokinetic, pPNET = peripheral primitive neuroectodermal tumor, RP2D = recommended Phase 2 dose.
Phase 1 Dose Escalation and Determination of the MTD
The Phase 1 component is a dose escalation study with treatment in sequential cohorts of 
escalating doses of lenvatinib in combination with everolimus, each administered once daily 


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in 28-day treatment cycles.  Pediatric subjects with a relapsed/refractory solid malignancy, 
including primary brain tumors are eligible to enroll.  The initial dose level (Dose Level 1) 
for lenvatinib will be 11 mg/m2.  The initial dose of everolimus will be 3 mg/m2.  Dose 
Level 2 will escalate lenvatinib by approximately 25% to 14 mg/m2 and maintain everolimus 
at the same dose of 3 mg/m2.  At Dose Levels -1 and 1, maximum daily dose of lenvatinib 
will not exceed 18 mg daily.  At Dose Level 2, maximum daily dose of lenvatinib will not 
exceed 24 mg.  Should Dose Level 2 be well tolerated, Dose Level 3 may be considered to 
test lenvatinib at 14 mg/m2 (capped at 24 mg) and escalate everolimus to 4.5 mg/m2.  For 
everolimus dose levels of 3 mg/m2 and 4.5 mg/m2, the maximum daily dose of everolimus 
will not exceed 5 mg and 7 mg, respectively.  If the MTD for combination of lenvatinib and 
everolimus has been exceeded at Dose Level 1, then the subsequent cohort of subjects will be 
treated at Dose Level ޤZLWKGRVHRIOHQYDWLQLE mg/m2 and dose of everolimus 3 mg/m2 
(Table 1).  Intra-subject titration of everolimus is not allowed on this study. 
At study entry, subjects must have a minimum body surface area (BSA) of 0.6 m2.   
Table 1 
Planned Dose-Escalation 
Dose Level 
Lenvatinib mg/m2 
(% Single-Agent MTD) 
Everolimus 
(mg/m2) 
-1 
8 (60% MTD)a 
3c 
1* 
11 (80% MTD)a 
3c 
2 
14 (100% MTD)b 
3c 
3d 
14 (100% MTD)b 
4.5e 
MTD = maximum tolerated dose  
*Starting dose level 
a:  Lenvatinib dose capped at 18 mg daily. 
b:  Lenvatinib dose capped at 24 mg daily. 
c:  Everolimus dose capped at 5 mg daily. 
d:  Dose Level 3 may be considered if Dose Level 2 is well tolerated. 
e:  Everolimus dose capped at 7 mg daily. 
The Phase 1 portion of the study will utilize a rolling 6 design [Skolnik, et al., 2008].  Two to 
6 subjects can be concurrently enrolled into a dose level cohort.   
Dose level assignment will be based on:  
1. the number of subjects currently enrolled in the dose level cohort,  
2. the number of DLTs observed, and  
3. the number of subjects at risk for developing a DLT (ie, subjects enrolled but who are not 
yet assessable for toxicity).   
For example, when 3 subjects are enrolled onto a dose cohort, if toxicity data is available for 
all 3 when the fourth subject entered and there are no DLTs, the dose will be escalated and 
the fourth subject will be treated at the subsequent dose level.  If data is not yet available for 
1 or more of the first 3 subjects and no DLT has been observed, or if one DLT has been 
observed, the new subject will be treated at the same dose level.  Lastly, if 2 or more DLTs 
have been observed, the dose level will be de-escalated.  This process will be repeated for 
Subjects 5 and 6.  In place of suspending accrual after every 3 subjects, accrual will be 


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suspended when a cohort of 6 potentially evaluable subjects has enrolled (ie, subjects 
enrolled but are not yet assessable for toxicity) or when the study endpoints have been met.  
When subjects are not evaluable for toxicity, they will be replaced with the next available 
subject if escalation or de-escalation rules have not been fulfilled at the time the next 
available subject is enrolled in the study. 
The following table (Table 2) provides the decision rules for enrolling a subject at (i) the 
current dose level (ii) at an escalated dose level, (iii) at a de-escalated dose level, or whether 
the study is suspended to accrual: 
Table 2 
The Rolling 6 Design 
# Subjects 
Enrolled 
# Subjects with 
DLT 
# Subjects 
without DLT 
# Subjects with 
Data Pending 
Decision 
2 
0 or 1 
0, 1 or 2 
0, 1 or 2 
Same dose level 
2 
2 
0 
0 
De-escalate* 
 
 
 
 
 
3 
0 
0, 1 or 2 
1, 2 or 3 
Same dose level 
3 
1 
0, 1 or 2 
0, 1 or 2 
Same dose level 
3 
0 
3 
0 
Escalate** 
3 
 
0 or 1 
0 or 1 
De-escalate* 
 
 
 
 
 
4 
0 
0, 1, 2 or 3 
1, 2, 3 or 4 
Same dose level 
4 
1 
0, 1, 2 or 3 
0, 1, 2 or 3 
Same dose level 
4 
0 
4 
0 
Escalate** 
4 
 
0, 1 or 2 
0, 1 or 2 
De-escalate* 
 
 
 
 
 
5 
0 
0, 1, 2, 3 or 4 
1, 2, 3, 4 or 5 
Same dose level 
5 
1 
0, 1, 2, 3 or 4 
0, 1, 2, 3 or 4 
Same dose level 
5 
0 
5 
0 
Escalate** 
5 
 
0, 1, 2 or 3 
0, 1, 2 or 3 
De-escalate* 
 
 
 
 
 
6 
0 
0, 1, 2, 3, or 4 
2, 3, 4, 5 or 6 
Suspend 
6 
1 
0, 1, 2, 3 or 4 
0, 1, 2, 3 or 4 
Suspend 
6 
0 or 1 
5 or 6 
0 or 1 
Escalate** 
6 
 
0, 1, 2, 3 or 4 
0, 1, 2, 3 or 4 
De-escalate* 
DLT = dose-limiting toxicity 
*If 6 subjects already entered at next lower dose level, the maximum tolerated dose (MTD) has been defined.  
**If final dose level has been reached, the recommended dose has been reached. 
 


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If 2 or more of a cohort up to 6 subjects experience DLT at a given dose level, then the MTD 
has been exceeded and dose escalation will be stopped.  In the event that 2 DLTs observed 
out of 6 evaluable subjects are of different classes of Adverse Effects (eg, hepatotoxicity and 
myelosuppression), expansion of the cohort to 12 subjects will be considered (if one of the 
DLTs does not appear to be dose-related, the Adverse Effects are readily reversible, AND 
Protocol Steering Committee (PSC) AND sponsor all agree that expansion of the cohort is 
acceptable).  Subjects after PSC review are not deemed to be evaluable for DLT assessment 
may be replaced. 
All subjects in the Phase 1 Dose Escalation phase will have samples taken for PK analysis 
with the intent of having evaluable PK at the end of Phase I data from minimally 6 subjects 
DJHGWR\HDUVROGVXEMHFWVWR<12 years old,  DQGVXEMHFWV12 years old. Once 
the MTD or RP2D has been defined, up to 6 additional subjects will be enrolled to attain the 
goal of having evaluable PK data from minimally 6 subjects aged 2 to < 6 years old, 6 
VXEMHFWVWR <12 years old, and 6 VXEMHFWV years old).  Additional subjects enrolled for 
PK once the MTD or RP2D has been defined will not be included the DLT Rolling 6 
analysis. 
 
 Protocol Steering Committee 
The sponsor will closely evaluate the risks and benefits of the study throughout its conduct, 
along with the PSC as needed.  The PSC may review available relevant data:  DLT and safety 
data including laboratory assessments, 12-lead electrocardiograms (ECGs), dose 
administration, etc. 
Independent Data Monitoring Committee  
In addition to Protocol Steering Committee, the safety monitoring will be conducted by the 
Independent Data Monitoring Committee (IDMC). The frequency of safety reviews will be 
defined in the IDMC charter. Minutes from the open meetings of the IDMC will be provided 
if requested by regulatory agencies. The function and membership of the IDMC will be 
described in the IDMC charter.  
Toxicity Monitoring 
The DLT observation period for the purposes of dose-escalation will be the first cycle of 
therapy.  Routine Phase 1 monitoring for clinical and laboratory toxicities will be used.  
Blood pressure monitoring will occur at least weekly during the first 2 cycles.   
Dose-Limiting Toxicity 
Dose-limiting toxicity (DLT) will be assessed according to Common Terminology Criteria 
for Adverse Events (CTCAE) v4.03 and is defined as any of the following events that are 
possibly, probably, or definitely attributable to lenvatinib or everolimus.  Dose-limiting 
hematological and nonhematological toxicities are defined differently (see Protocol Section 
9.1 for definitions of nonhematological and hematological DLTs). 


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All DLTs must be reported to the sponsor within 24 hours of their occurrence.  
Determination of a DLT will be made by the investigator and the Eisai Medical Monitor in 
consultation with the PSC, as needed.  Subjects who discontinue the study treatment for any 
reason other than DLT (eg, early disease progression) during Cycle 1 (Day 1 to Day 28), and 
have not received at least 75% of the prescribed dose prior to discontinuation, will be 
replaced. 
The sponsor and PSC will review all subjects’ safety and clinical data to jointly determine 
the MTD/RP2D of the combination of lenvatinib with everolimus.  The Treatment Phase for 
each subject in Phase 1 ends after completing Cycle 1 of treatment unless subject 
discontinues early.  Those subjects who discontinue study treatment in Cycle 1 transition to 
the Off-treatment Visit.  Those who complete Cycle 1 will transition to the Extension Phase.  
Study treatment and tumor assessments will continue during the Extension Phase. 
Phase 2 Cohorts 
Once the MTD/RP2D of the combination of lenvatinib and everolimus in pediatric 
population has been determined in Phase 1, the Phase 2 portion of this study will commence 
with Cohort 1 (recurrent or refractory Ewing sarcoma/pPNET), Cohort 2 (recurrent or 
refractory rhabdomyosarcoma), and Cohort 3 (recurrent or refractory HGG), opening to 
accrual. 
Cohorts 1 – 3  
Phase 2 Cohorts 1 to 3 will use a 10+10 Simon’s optimal 2-stage design [Simon, 1989] for 
each cohort; 10 evaluable subjects will be enrolled in Stage 1 for each cohort. The primary 
outcome measure for Ewing sarcoma/pPNET, rhabdomyosarcoma, and HGG will be ORR 
(complete or partial response) at 16 weeks. If there are no responses among the 10 subjects in 
Stage 1, then the enrollment to that disease cohort will stop for futility. If there is at least 
1 response in the first stage, then the second stage will enroll 10 additional evaluable 
subjects. If there are 2 or fewer responses among the 20 evaluable subjects, then 
lenvatinib/everolimus combination therapy will be declared a failure for that disease cohort. 
Subjects 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. 
The Treatment Phase for each subject in Phase 2 ends after completing 4 cycles of treatment 
unless subject discontinues early. Those subjects who discontinue study treatment before 
completing 4 cycles transition to the Off-treatment Visit. Those who complete 4 cycles will 
transition to the Extension Phase. Study treatment and tumor assessments will continue 
during the Extension Phase. 
Dosing Nomogram  
The dose nomogram (see Protocol Section 9.1 Table 3) provides the dose of lenvatinib to be 
administered for BSA increments starting from 0.6 m2.  BSA must be calculated on Day 1 of 
each cycle based on the subject’s current height and body weight.  The actual dose to be 


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administered is rounded to the nearest whole number. The total lenvatinib dose is capped at 
18 mg daily (Dose Levels -1 and 1), and at 24 mg (Dose Levels 2 and 3).  
The dose nomogram (see Protocol Section 9.1 Table 4) provides the dose of everolimus to be 
administered for BSA increments starting from 0.6 m2. The total everolimus dose is capped 
DWPJGDLO\IRU'RVH/HYHOVޤDQG and at 7 mg daily for Dose Level 3. 
Study Duration 
It is estimated that it will take approximately 4.5 years from the first subject providing signed 
informed consent in Phase 1 to the primary endpoint completion date for Phase 2 of the 
study.  It is estimated that the Phase 2 portion will take 3 years in order to complete the final 
collection of data for the primary outcome analysis. 
Study duration for each subject is estimated to be: 
• Pretreatment Phase:  4 weeks 
• Treatment Phase:  1 cycle (4 weeks) in Phase 1; 4 cycles (16 weeks) in Phase 2. 
• Extension Phase:  Estimated maximum time of treatment is 2 years (24 cycles).  
Subjects may remain on study treatment as long as they do not meet any of the following 
criteria:  1) experience objective progression of disease (according to Response 
Evaluation Criteria in Solid Tumors [RECIST 1.1] or Response Assessment in Neuro-
Oncology [RANO], as appropriate), 2) exhibit no clinical benefit (in the opinion of the 
investigator), 3) experience unacceptable toxicity leading to withdrawal from the study, 
4) withdraw or are withdrawn from the study for any reason, or, 5) termination of the 
study program.  As long as the subject has not experienced intolerable toxicity, he or she 
can continue to receive study treatment.  A 28-day follow up visit from last date of 
receiving investigational drug will be performed for subjects who discontinue study 
treatment. 
3.2.1 
Pretreatment Phase 
The Pretreatment Phase will last up to 28 days and will include a Screening Period and a 
Baseline Period. 
3.2.1.1 
Screening Period 
Screening will occur between Day –28 and Day –2.  The purpose of the Screening Period is 
to obtain informed consent and to establish protocol eligibility.  Informed consent will be 
obtained after the study has been fully explained to each subject and before the conduct of 
any screening procedures or assessments.  Procedures to be followed when obtaining 
informed consent are detailed in Protocol Section 5.3. 
The Screening Disposition case report form (CRF) must be completed to indicate whether the 
subject is eligible to enroll in the study and to provide reasons for screen failure, if 
applicable. 
The results of all screening assessments and evaluations must be completed and reviewed by 
the investigator prior to the Baseline Visit.  


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3.2.1.2 
Baseline Period 
The purpose of the Baseline Period is to confirm protocol eligibility as specified in the 
inclusion/exclusion criteria (as detailed in Protocol Section 9.3.1 and Section 9.3.2).  Results 
of baseline assessments must be obtained prior to the first dose of study treatment (Cycle 1 
Day 1).  Baseline assessments can be performed on Day –1 or on Cycle 1 Day 1 prior to start 
of study treatment.   
Subjects who complete the baseline assessments and continue to meet the criteria for 
inclusion/exclusion (see Protocol Section 9.3.1 and Section 9.3.2) will begin the Treatment 
Phase. 
3.2.2 
 Treatment Phase 
The Treatment Phase will begin with the first dose of study drug administration in Cycle 1.  
The duration of the Treatment Phase is 1 cycle (4 weeks of treatment) in Phase 1 of the 
study, and 4 cycles (16 weeks of treatment) in Phase 2 of the study.  Subjects will receive 
study treatment in 28-day cycles.  Tumor assessments will be performed during the 
Treatment Phase at Week 4 ±1 week (Phase 1) and at Week 8 ±1 week and Week 16 ±1 week 
(Phase 2). 
Subjects who discontinue study treatment during Cycle 1 (Phase 1), or before completing 
4 cycles of treatment (Phase 2), will transition to the Off-treatment Visit.  
3.2.3 
 Extension Phase 
All subjects who are still on study treatment following completion of Cycle 1 in Phase 1, or 
after completing 4 cycles in Phase 2 of the study, will transition to the Extension Phase.  
During the Extension Phase, subjects will continue to receive the same study treatment in 
28-day cycles.  Tumor assessments will be performed during the Extension Phase at Week 12 
±1 week and Week 24 ±1 week, and every 12 weeks ±1 week thereafter (Phase 1) and at 
Week 24 ±1 week, and every 12 weeks ±1 week thereafter (Phase 2).  
3.2.4 
 Treatment Discontinuation Criteria  
Subjects may remain on study treatment as long as they do not meet any of the following 
criteria:  1) experience objective progression of disease (according to Response Evaluation 
Criteria in Solid Tumors [RECIST] 1.1 or Response Assessment in Neuro-Oncology 
[RANO] criteria, as appropriate), 2) exhibit no clinical benefit (in the opinion of the 
investigator), 3) experience unacceptable toxicity leading to withdrawal from the study, 
4) withdraw or are withdrawn from the study for any reason, or, 5) termination of the study 
program.  
As long as the subject has not experienced intolerable toxicity, he or she can continue to 
receive study treatment.   


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3.2.5 
 Off-Treatment Visit 
After subject discontinues treatment, an Off-Treatment Visit and the procedures noted in the 
Schedule of Assessments (See Protocol Section 9.5.2.1, Tables 7 and 8) should be completed 
within 28 days after the last dose of study treatment.   
3.2.6 
 Posttreatment Phase 
3.2.6.1 
Follow-Up Period 
The posttreatment follow up will begin when the subject discontinues study treatment and all 
off-treatment assessments have been completed. Subjects who discontinue study treatment 
for reasons other than disease progression will be followed for documented disease 
progression for 1 year or until another anticancer therapy is initiated whichever occurs first.  
Subjects will be followed for survival every 3 months until death or for 1 year, whichever 
occurs first, unless the study is terminated or if the subject discontinues due to withdrawal of 
consent or is lost to follow up. 
After data cutoff, tumor assessments may be performed as clinically indicated using the 
institutional guidelines, following the prevailing local standard of care. 
As required by some regulatory agencies, the following estimates are provided:  
• The study is planned to begin in April 2017 and to end in March 2022.   
• The maximum estimated period for each subject on study is anticipated to be 
approximately 2 years (24 treatment cycles).  However, subjects will continue to receive 
study treatment as long as they demonstrate clinical benefit. 
4 
DETERMINATION OF SAMPLE SIZE 
Phase 1 – Determination of the Maximum Tolerated Dose:  The total number of subjects 
required for the Phase 1 portion of this study will depend upon the toxicities observed as the 
study progresses.  The minimum number of evaluable subjects required for this study is 4.  
The projected maximum number of evaluable subjects required is 48.  Once the MTD or 
RP2D has been defined, up to 6 additional subjects with recurrent or refractory solid tumors 
may be enrolled at the RP2D to acquire PK data in a representative number of young 
subjects.  Therefore, a maximum of 54 subjects are expected to be enrolled in the 4 dose 
escalation levels, and PK expansion.  The Phase 1 part of the study is expected to be 
completed within 18 months.  In the event that each of Dose Levels -1, 1, 2, and 3 are 
expanded to 12 subjects, an absolute maximum of 54 subjects would be required allowing for 
20% to be nonevaluable and including up to 6 additional subjects for PK analysis. 
Phase 2:  Phase 2 will require a minimum of 10 evaluable subjects per disease cohort and a 
maximum of 20 (10 evaluable subjects in each stage of Simon’s optimal 2-stage design).  
Therefore, a maximum of 22 subjects per cohort will be enrolled to allow for a 10% 
nonevaluable rate. This design has 88% power to detect a 20% increase in the response rate 


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at the significance level of one-sided alpha = 0.07 assuming a null response rate of 5% and 
DOWHUQDWLYHUHVSRQVHUDWH 
5 
STATISTICAL METHODS 
All descriptive statistics for continuous variables will be reported using n, mean, SD, median, 
25th percentile (Q1), 75th percentile (Q3), minimum and maximum.  Categorical variables 
will be summarized as number (percentage) of subjects.  The statistical analyses of the study 
data as described in this section will be performed as further outlined in this SAP, which will 
be finalized before database lock and included in the CSR. 
For Phase 1, data cutoff will occur when the MTD/RP2D for the lenvatinib/everolimus 
combination is determined, or if the PK expansion is needed, will occur when the last subject 
in the PK expansion completes 1 cycle of treatment or discontinues before the end of Cycle 
1, whichever occurs first.  Additional subjects enrolled for PK once the MTD or RP2D has 
been defined will not be included in the DLT analysis. 
 
For each cohort in Phase 2, there will be 1 futility analysis: this is planned after the first 10 
subjects have completed at least 4 treatment cycles and, if applicable, a confirmatory scan 
has been performed (in case of a PR or CR at week 16), or have discontinued study drug 
early (i.e. before Week 16).  At the futility analysis, if there are no responders (CR/PR), then 
enrollment for that cohort will be discontinued for lack of efficacy.  If 1 or more responses 
are observed, accrual will continue up to a total of 20 subjects.  Data cut-off for the primary 
study analysis for each cohort in Phase 2 will occur when all subjects in Stage 1 and/or Stage 
2, as applicable, have completed at least 4 treatment cycles and, if applicable, a confirmatory 
scan has been performed (in case of a PR or CR at Week 16), or have discontinued study 
drug early. 
5.1 
Study Endpoints 
5.1.1 
Primary Endpoints 
5.1.1.1 
Primary Endpoints for Phase 1  
• MTD and RP2D of lenvatinib in combination with everolimus 
• Safety and toxicity of lenvatinib in combination with everolimus 
 
5.1.1.2 
Primary Endpoint for Phase 2  
• ORR, defined as the proportion of subjects who have the best overall response (BOR) 
of complete response (CR) or partial response (PR), at Week 16. 
 


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5.1.2 
Secondary Endpoints 
Secondary endpoints for Phase 1 and Phase 2 are listed below. 
• ORR at the time of data cutoff  
• DCR, defined as the proportion of subjects who have the BOR of CR or PR or stable 
GLVHDVH6'6'GXUDWLRQZHHNVVLQFHWKHILUVWGRVHRIWKHVWXG\WUHDWPHQW 
• CBR, defined as the proportion of subjects who have the BOR of CR or PR or durable 
6'6'GXUDWLRQZHHNVVLQFHWKHILUVWGRVHRIWKHVWXG\WUHDWPHQW 
• 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)  
• Plasma PK of lenvatinib and trough concentrations of everolimus when administered 
in combination 
• Safety and toxicity of lenvatinib in combination with everolimus in Phase 2. 
 
5.1.3 
Exploratory Endpoints  
• Assess candidate alterations in genes and/or proteins that may contribute to tumor 
development and predictive marker of response in archival tumor tissue 
• Correlative blood and tumor biomarkers of treatment effects and outcomes 
 
5.2 
Study Subjects 
5.2.1 
Definitions of Analysis Sets 
The following analysis sets will be defined: 
• Evaluable Analysis Set, defined as all evaluable subjects, 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. 
Efficacy analyses in Phase 2 will primarily be based on the Evaluable Analysis Set. 
• Safety Analysis Set, defined as all subjects who received at least 1 dose of study drug 
(lenvatinib or everolimus).  This will be the analysis set for disposition, demographic 
and baseline characteristics, previous anticancer medications, prior and concomitant 
medications, procedures and radiotherapy, medical history, efficacy analysis in Phase 
1 as well as all safety evaluations.  
x Pharmacokinetic (PK) Analysis Set, defined as subjects in the Safety Analysis Set 
who had at least 1 measurable postdose plasma concentration with an adequately 
documented drug administration history.  
x Pharmacodynamic Analysis Set, defined as all subjects in Safety Analysis Set who 
had evaluable pharmacodynamic data. 
 


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All analyses will be presented by planned dose level group in Phase 1 and separately for each 
study cohort in Phase 2, unless otherwise specified.  A summary table and listing will also be 
provided to identify subjects in each analysis set.  
5.2.2 
Subject Disposition 
Subject disposition will be summarized using the Safety Analysis Set. 
The number of subjects who were screened, and the number and percentage of subjects who 
enrolled, treated, and discontinued study treatment at the time of data cutoff will be 
summarized. The subjects who discontinued study treatment will be tabulated according to the 
primary reason for discontinuation by dose level group and overall in Phase 1, and separately 
for each study cohort in Phase 2. The reasons for prematurely discontinuing either lenvatinib 
or everolimus will be provided in a listing. 
The end of study status (e.g., alive, death, withdrew consent, or lost to follow-up) at the data 
cutoff will also be summarized using the data from the survival follow-up eCRF by dose level 
group and overall in Phase 1, and separately for each study cohort in Phase 2.  
Additionally, all subjects who failed screening will be listed with the primary reason for failure.  
Subject listings with relevant disposition information will be provided. 
 
5.2.3 
Protocol Deviations 
All important protocol deviations will be determined and agreed upon after review of 
individual subject data prior to database lock.  This review will be undertaken by the Study 
Director, Study Statistician, Study Data Manager and Study Clinical Operations Manager, in 
collaboration. 
Important protocol deviations will be summarized and listed by dose level group in Phase 1 
and separately for each cohort in Phase 2. 
5.2.4 
Demographic and Other Baseline Characteristics 
Demographic and baseline characteristics for the Safety Analysis Set will be summarized by 
dose level group and overall in Phase 1, and separately for each study cohort in Phase 2.  
The following demographic and baseline characteristics will be summarized as appropriate: 
• Age (years) 
• Age group (2 to <6 years, 6 to <12 years, 12 to <16 years, 16 to <18 years, 18 to 21 
years, if applicable) 
• Gender 
• Race  


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• Ethnicity   
• Baseline Karnofsky/Lanksy performance status score  
• Height (cm) 
• Height Percentile 
• Baseline weight (kg)  
• Baseline body mass index (BMI) (kg/m2) 
• Body Surface Area 
Previous anticancer medication will be summarized by dose level group and overall in Phase 
1, and separately for each study cohort in Phase 2 as follows: 
• Number of previous therapy regimens 
• Duration of most recent previous anticancer therapy (months) 
• Best response for most recent previous anticancer therapy (CR, PR, SD, progressive 
disease (PD), not evaluable, not applicable, unknown) 
• Time from end of most recent previous anticancer therapy to first dose of study drug 
(months) 
• Previous anticancer therapy (administered as adjuvant, neoadjuvant, metastatic, 
locally advanced, maintenance and unknown) 
x Previous anticancer therapy preferred term  
Previous anthracycline therapy will be summarized by dose level in Phase 1 and by each 
cohort in Phase 2 as follows: 
• Number of subjects with any previous anthracycline therapy 
• Duration of most recent previous anthracycline therapy (months) 
• Time from end of most recent previous anthracycline therapy to first dose of study 
drug 
• Previous anthracycline therapy preferred term  
 
Previous radiotherapy will be summarized by dose level in Phase 1 and by cohort in Phase 2 
as follows: 
x Subjects with any previous radiotherapy 
x Radiotherapy site (lymph node [neck/thoracic/abdominal and pelvic/other], bone 
[skull/spine/thorax/pelvis/extremities], brain, visceral [colorectal mass, lung mass, 
liver mass, chest, abdomen/pelvis], skin [trunk, extremity, head and neck], 
musculoskeletal [soft tissue-trunk, extremity, head and neck], miscellaneous) 
x Tumor lesion at the site progressed since most recent previous radiotherapy (yes, no, 
not evaluated) 
x Time from most recent previous radiotherapy to the first dose. 


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x Duration of most recent previous radiotherapy 
Disease history and characteristics at study entry will be summarized by dose level in Phase 
1 and by cohort in Phase 2 as follows:  
• Solid tumor diagnosis classification 
• Time since first diagnosis of solid tumor to date of first dose (months) 
• Time since metastatic diagnosis to date of the first dose (months) 
• Age at diagnosis (in years) 
• Target lesions [yes/no] and nontarget lesions [yes/no] based on the measurable 
disease criteria at study entry using RECIST 1.1. or RANO as appropriate. 
Tumor-node-metastasis (TNM) staging, stage group of Ewing sarcoma/PNET and 
Rhabdomyosarcoma at diagnosis and WHO Grading of Glioma for subjects evaluated by 
RANO will be provided in listing only. 
Previous anticancer therapies, anthracycline therapy, previous radiotherapies, and disease 
history and characteristics at study entry will also be listed for each subject. 
A subject data listing of medical history will be provided, including system organ class; 
current medical condition; date of diagnosis, surgical procedure, or onset of symptoms; and 
end date/ongoing. Coding will be done using the Medical Dictionary for Regulatory 
Activities (MedDRA) version 21.1 or higher. 
5.2.5 
Prior and Concomitant Therapy 
All investigator terms for medications recorded in the CRF will be coded using the WHO 
Drug Dictionary (using the 2018 B2 version or later). The number (percentage) of subjects 
who have taken prior and concomitant antihypertensive, antidiarrheal and anthracycline 
medications will be summarized on the Safety Analysis Set, by the Anatomical Therapeutic 
Chemical (ATC) Classification, WHO drug dictionary preferred term, and by dose level in 
Phase 1 and by cohort in Phase 2. Other prior and concomitant medications, excluding 
antihypertensive, antidiarrheal and anthracycline will be summarized similarly. If a subject 
has taken prior and concomitant medications more than once within the same preferred term, 
the subject will be counted only once for the respective preferred term. Prior medications will 
be defined as medications that stopped prior to the first dose of study drug. Concomitant 
medications will be defined as medications that (i) have started before the first dose of study 
drug and are continuing at the time of the first dose of study drug, or (ii) have started on or 
after the date of the first dose of study drug up to 28 days following the last dose. 
Medications that cannot be determined to be prior/concomitant due to missing or incomplete 
dates will be regarded as concomitant (see Section 5.3.5.2). 
Data listings will be provided for all prior and concomitant medications. 
All other concomitant therapies or diagnostic, therapeutic, or anticancer procedures relating 
to malignancy, and palliative radiotherapy will also be summarized and/or listed as 
applicable. 


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5.2.6 
Treatment Compliance 
Not collected on CRF. 
5.3 
Data Analysis General Considerations 
For incomplete dates involving efficacy and other safety data, a conservative imputation will 
be used for calculation. See Section 8.2.1 for the outline of imputation rules, which will be 
specified in the study analysis dataset specifications with more details. 
5.3.1 
Pooling of Centers  
Subject data from all centers will be pooled for all analyses. Center will not be considered as 
a factor in the analyses. 
5.3.2 
Adjustments for Covariates 
No adjustment for covariates will be made for this study. 
5.3.3 
Multiple Comparisons/Multiplicity 
No multiplicity adjustment will be made for this study. 
5.3.4 
Examination of Subgroups 
Subgroup analyses may be conducted if appropriate. 
5.3.5 
Handling of Missing Data, Dropouts, and Outliers 
5.3.5.1  
Adverse Events 
Adverse events with incomplete start dates will be considered as treatment emergent if: 
• Day and month are missing, and the year is equal to or after the year of the first study 
drug dose date 
• Day is missing, and the year is after the year of the first study drug dose 
• Day is missing and the year is equal to the year of the first study drug dose date and 
the month is equal to or after the month of the first dose date 
• Year is missing; or complete date is missing 
5.3.5.2  
Concomitant Medications 
Medications will be considered concomitant if: 
• Day and month are missing, and the year is equal to or after the year of the first study 
drug dose date 
• Day is missing, and the year is after the year of the first study drug dose 


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• Day is missing and the year is equal to the year of the first dose date and the month is 
equal to or after the month of the first study drug dose date 
• Year is missing; or complete date is missing 
5.3.6 
Other Considerations 
5.3.6.1  
BSA Dose Adjustment and Dose Capping 
Subjects in Phase 1 will receive study drug as described in Protocol Section 9.1, Tables 3 
(lenvatinib) and 4 (everolimus). 
The actual dose level of lenvatinib and everolimus could be different from the planned dose 
level due to the adjustment of BSA and dose capping.  The actual dose level of lenvatinib and 
everolimus will be calculated from actual daily dose and BSA.  The subject with dose 
capping will be listed. For Phase 1 and Phase 2 the planned dose level will be used for 
column grouping across all analyses. 
5.3.6.2  
Summarization of Safety Data 
Regarding summarization of mean and mean change from Baseline for laboratory, vital sign, 
and ECG data, if 2 or fewer subjects in each of the treatment groups have data for a given 
cycle, the applicable cycle(s) will not be summarized, and the table will be curtailed. For 
example, if at Cycle 10 the 3 treatment groups have 4, 3 and 1 subjects, respectively, then 
Cycle 10 will be summarized for all treatment groups. If at Cycle 11, the 3 treatment groups 
have 2, 2 and 1 subject, respectively, and at subsequent cycles no treatment has 3 or more 
subjects, then the table will not be produced for Cycle 11 and all subsequent cycles. 
However, for shift tables and other analyses of worst postbaseline values, all data will be 
included. 
5.4 
Primary, Secondary and Exploratory Analyses 
5.4.1 
Primary Analyses 
5.4.1.1 
Dose-Finding Analysis in Phase 1 
The primary objective of Phase 1 is to determine the MTD and to establish RP2D of 
lenvatinib administered in combination with everolimus. The study will utilize the rolling 6 
design detailed in SAP Section 3.2. 
5.4.1.2 
Primary Efficacy Analysis for Phase 2 
Efficacy analyses for Phase 2 will be performed separately for each study cohort. 
The primary objective of Phase 2 is to estimate the antitumor activity of lenvatinib in 
combination with everolimus in pediatric subjects with Ewing sarcoma/peripheral primitive 
neuroectodermal tumor (pPNET), rhabdomyosarcoma, and HGG using the ORR at 16 weeks. 
The ORR at Week 16 is defined as the proportion of subjects who have the BOR of CR or 
PR at Week 16.  


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Subjects must have measurable disease present at baseline for Phase 2.  Those who have their 
disease re-evaluated at postbaseline visits will be considered evaluable for objective 
response.  Estimated ORR and its exact 95% CI using the Clopper-Pearson [Clopper and 
Pearson, 1934] method will be presented. 
The data cutoff for the primary study analysis in Phase 2 will occur when all evaluable 
subjects have completed at least 4 treatment cycles and, if applicable, a confirmatory scan 
has been performed (in case of a PR or CR at Week 16), or have discontinued study 
treatment early. 
Tumor response data utilized in the primary analysis of ORR will be obtained from 
investigator’s assessment of the imaging scans.  No independent tumor assessments will be 
performed as part of this study.  Tumor response will be assessed by RECIST 1.1 criteria 
[Eisenhauer, et al., 2009] in pediatric subjects with Ewing sarcoma/peripheral primitive 
neuroectodermal tumor (pPNET) and rhabdomyosarcoma, and RANO criteria will be used 
for subjects with HGG [Wen, et al., 2010].  Efficacy analyses in Phase 2 will primarily be 
based on the Evaluable Analysis Set .  
The BOR is determined once all data for a subject is known. For this study, a confirmation of 
CR or PR is required for both RECIST 1.1 and RANO.  The confirmation assessments 
VKRXOGEHPDGHZHHNVafter the initial response assessment.  The BOR is determined by 
sequentially checking two adjacent assessmHQWVZHHNVDSDUW  
5.4.2 
Secondary Efficacy Analyses 
5.4.2.1 
Phase 1 
The secondary efficacy analyses in Phase 1 subjects will be summarized by planned dose 
level and overall if appropriate and listed by dose level group and based on the Safety 
Analysis Set.  Subjects with measurable disease (target lesions at baseline with or without 
nontarget lesions at baseline) and evaluable disease (only nontarget disease at baseline) will 
be summarized separately for their best overall response.  The response will be classified 
according to RECIST 1.1 and RANO defined categories for subjects. 
• BOR will be analyzed separately for subjects with measurable disease and for 
subjects with only evaluable disease. 
o To be assigned a best overall response of SD (measurable disease), Non-CR/Non-
PD or IR/SD (evaluable disease), the time from the first administration of study 
drug until the date of documented SD, Non-CR/Non-PD, or IR/SD VKRXOGEH
weeks.  IR/SD is Incomplete Response/Stable Disease from RANO. 
• ORR at the time of cut off:  defined as the proportion of subjects with measurable 
disease at screening/baseline achieving a best overall response of confirmed PR or 
CR at the time of data cutoff.  ORR will be estimated by dose level, and by exact 
Clopper-Pearson 95% CI if appropriate.  


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• DCR: For subjects with measurable disease, defined as the proportion of subjects who 
achieved a best overall response of CR, PR, RU6'PLQLPXPGXUDWLRQRI6'
weeks).  For subjects with evaluable disease, defined as the proportion of subjects:  
o those assessed by RECIST 1.1 who have a BOR of CR, or Non-CR/Non-PD 
weeks 
o those assessed by RANO who have a BOR of CR, or IR/SD ZHeks.   
The count and percentage will be summarized by dose level, and by exact Clopper-
Pearson 95% CI if appropriate. 
• Clinical Benefit Rate (CBR):  For subjects with measurable disease, defined as the 
proportion of subjects with measurable disease who have a BOR of CR or PR, or 
durable SD lasting 23 weeks.  For subjects with evaluable disease, defined as the 
proportion of subjects: 
o those assessed by RECIST 1.1 who have a BOR of CR, or Non-CR/Non-PD lasting 
23 weeks, 
o those assessed by RANO who have a BOR of CR, or IR/SD lasting 23 weeks. 
The count and percentage will be summarized by dose level, and by exact Clopper-
Pearson 95% CI if appropriate. 
• DOR:  defined as the time from the date of first documented confirmed CR or PR to 
disease progression objectively documented or death (whichever comes first).  The 
DOR will be analyzed using the Kaplan-Meier (KM) (Kaplan and Meier, 1958) 
method among the responders (CR or PR).  The DOR will be analyzed using the KM 
approach among the responders (CR or PR) according to the rules in Table 3.  
5.4.2.2 
Phase 2 
Subjects must have measurable disease at baseline for enrollment in Phase 2.  The secondary 
efficacy endpoints ORR at the time of data cutoff, DCR, CBR and DOR will be performed 
for subjects in the Evaluable Analysis Set. 
• ORR at the time of data cutoff:  defined as the proportion of subjects achieving a best 
overall response of confirmed PR or CR at the time of data cutoff. ORR and 
corresponding exact 95% CI using the Clopper-Pearson method will estimated for all 
Phase 2 treatment disease cohorts. 
• DCR:  defined as the proportion of subjects who have a BOR of CR or PR or stable 
disease (SD).  To be assigned a best overall response of SD, the time from the first 
dose of study treatment XQWLOWKHGDWHRIGRFXPHQWHG6'VKRXOGEHZHHNV.  The 
count and percentage with exact Clopper-Pearson 95% CI for the DCR will be 
summarized for all Phase 2 treatment disease cohorts. 
• CBR:  defined as the proportion of subjects with who have a BOR of CR or PR or 
durable SD lasting 23 weeks.  The count and percentage with exact Clopper–
Pearson 95% CI for the CBR will be summarized for each Phase 2 treatment disease 
cohort. 


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• DOR:  defined as the time from the date of first documented confirmed CR or PR to 
disease progression objectively documented or death (whichever comes first).  The 
DOR will be analyzed using the Kaplan-Meier (KM) (Kaplan and Meier, 1958) 
method among the responders (CR or PR) according to the rules in Table 3.  
 
 
 


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x Table 3 DOR and Censoring Rules 
No. 
Situation 
Date of Progression or Censoring 
Outcome 
1 
Progression documented 
between scheduled visits, on or 
prior to new anticancer therapy 
Date of first radiologic PD assessment  
PFS Event  
2 
No progression at the time of 
data cutoff  
Date of last adequate radiologic 
assessment on or prior to data cutoff  
Censored  
3 
New anticancer therapy started 
before the first PD or death 
Date of last adequate radiologic 
assessment on or prior to the start of 
new anticancer therapy  
Censored  
4 
Death before first PD 
assessment, on or prior to start 
of new anticancer therapy  
Date of death  
PFS Event  
5 
Death between adequate 
assessment*  
Date of death  
PFS Event  
6 
Death or progression after 
more than one missed 
visit/tumor assessment**  
Date of last adequate radiologic 
assessment before missed tumor 
assessments  
Censored 
Note:  
* Adequate tumor assessment is radiologic assessment at regular interval as defined in the protocol.  
** More than 1 missed visit/adequate tumor assessment of subjects is defined as having the duration between 
the last adequate tumor assessment and PD or death being longer than 125 days in Treatment Phase of Phase 
2  and longer than 181 days in Extension Phase for both Phase I and II. 
If a subject had PFS event (#1, #4 or #5), the earliest event date will be used.  
The priority of the censoring rules is described as follows: 
• If a subject missed two or more tumor assessments before PD or death (#6), the 
subject will be censored at the date of the last adequate tumor assessment before the 
missed tumor assessments.   
Note that if a subject is censored by both this criterion and start of new anticancer 
therapy criterion, the earliest censoring date will be used. 
 
• If a subject did not have PD or death, the censoring date will be the earliest censoring 
date if the subject met multiple censoring criteria (#2, #3, #6). 
 
 


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5.4.3 
Exploratory Efficacy Analyses 
5.4.3.1 
Biomarkers, Archival Tumor Tissue, Lenvatinib Exposure and AEs of Special 
Interest 
• To evaluate blood, tumor, and safety (eg, hypertension) markers as correlative 
biomarkers of treatment effects and outcomes of lenvatinib in combination with 
everolimus. 
• To assess candidate alterations in genes and/or proteins that may contribute to tumor 
development and serve as predictive markers of response in archival tumor tissue 
from pediatric subjects. 
• To explore relationships between lenvatinib exposure and safety (eg, adverse events 
[AEs] of special interest). 
 
A separate analysis plan will be developed for these analyses. 
5.4.3.2 
Other Exploratory Efficacy Analyses 
• Graphical displays will be prepared for the maximum tumor shrinkage in target 
lesions, defined as the maximum percentage change from Baseline in the sum of the 
diameters of the target lesions at data cutoff.  
 
5.5 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other 
Biomarker Analyses 
5.5.1 
Pharmacokinetic Analysis 
Lenvatinib and everolimus concentration versus time data will be tabulated and summarized 
and graphically presented (Box and Whisker plots). 
 
Plasma concentrations of lenvatinib from the intense sampling in Phase 1 will be used to 
determine the following PK parameters for Cycle 1, Day 1 and Cycle 1, Day 15: area under 
the plasma concentration time course profile (AUC0-t), maximum observed concentration 
(Cmax), time from drug administration to the maximum observed concentration (Tmax).  Other 
PK parameters (AUC0-inf, half-life [t1/2], clearance [CL/F], and volume of distribution [VZ/F]) 
may be determined as data permit.  The following graphical displays will be prepared: 
• Trellis plots of plasma concentrations at Cycle 1, Day 1 and Cycle 1, Day 15 
• Mean and SD of lenvatinib plasma concentration by planned dose level group over 
time 
(Cycle 1, Day 1 and Cycle 1, Day 15) 
• Box and Whisker plots of PK parameters by planned dose level group at Cycle 1, Day 
1 and Cycle 1, Day 15 
 


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For both lenvatinib and everolimus, data from Phase 1 and 2 of the study will be pooled with 
available data from other studies and subjected to population PK analysis. For each drug, the 
PK model will be parameterized in terms of clearance and volume of distribution.  Details of 
the population PK analysis will not be included in the study SAP and will be provided in a 
separate analysis plan. 
 
5.5.1.1 
Pharmacodynamic, Pharmacokinetic, Pharmacogenomic, and Other Biomarker 
Analyses 
Correlation between clinical response to treatment associated with a combination of 
lenvatinib and everolimus and blood or tumor biomarkers will be examined using descriptive 
statistics and graphic displays as appropriate. Details will be provided in a separate analysis 
plan. 
 
Pharmacokinetic/pharmacodynamic exposure-safety relationships will be explored. Safety 
endpoints will be most frequent AEs of special interest and dose reductions. 
Exploratory/graphical analyses will be conducted for Pharmacokinetic/pharmacodynamic 
evaluations and may be followed by model-based analyses. A detailed analysis plan will be 
provided separately. 
 
5.6 
Safety Analyses 
All safety analyses will be performed on the Safety Analysis Set. Safety data will be 
presented by planned dose level in Phase 1 and study cohort in Phase 2 and summarized on 
an “as treated” basis using descriptive statistics (e.g., n, mean, SD, median, Q1, Q3, 
minimum, and maximum values for continuous variables; n (%) for categorical variables). 
Safety variables include study drug exposure, treatment-emergent adverse events (TEAEs), 
laboratory tests, vital signs, 12-lead ECGs, cardiac function by echocardiography/MUGA 
scan, urine dipstick, and Lansky play scores or Karnofsky performance scores. Study Day 1 
for all safety analyses is defined as the date of the first dose of study drug. 
 
5.6.1 
Extent of Exposure 
5.6.1.1 
Extent of Exposure of Study Drug  
Parameters that represent the extent of exposure will be presented per dose level in Phase 1 
and per study cohort in Phase 2, summarized separately for lenvatinib and everolimus.  These 
include: 
• No. of Cycles Received 
• Cumulative No. of Cycles Received 
• Duration of Treatment 
• No. of Subject Weeks 
 


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Number of cycles received will be summarized by descriptive statistics and by categories. 
Duration of treatment (presented separately as days, weeks, and months) for oral drug 
Lenvatinib and everolimus will be summarized by descriptive statistics. Overall Duration of 
Treatment and No. of Subject Weeks will also be tabulated by dose level in Phase 1 and 
study cohort in Phase 2. 
 
5.6.1.2 
Study Drug Administration 
Total cumulative dose per subject (mg) will be summarized separately for lenvatinib and 
everolimus by descriptive statistics. It is calculated as the sum of daily doses. 
 
Dose intensity (mg/m2/day) will be summarized separately for lenvatinib and everolimus by 
descriptive statistics. It is calculated as: Total cumulative dose per subject (mg) /BSA (m2)/ 
Duration of treatment (day). 
 
The percentage of received dose relative to planned dose will be summarized separately for 
lenvatinib and everolimus by descriptive statistics. It is calculated as: dose intensity / planned 
dose level × 100. Interpretation: 100 means received dose was the same as the planned, 90 
means that the actual dose was 90% of the planned. 
 
5.6.1.3 
Study Drug Dose Modifications 
Study drug dose modifications will be summarized separately for lenvatinib and everolimus, 
respectively. 
 
Number of subjects with dose reductions or interruptions will be summarized by counts and 
percentage according to drug administration data, respectively. Cycle of first dose 
interruption/reduction will be summarized by descriptive statistics, respectively. Frequency 
of dose interruptions and dose reductions will also be summarized by appropriate categories 
HJ4).  
 
The first dose reduction is defined as the first time the subject’s daily dose level was reduced 
to a nonzero value from its maximum designated prescribed BSA-adjusted dose level and did 
not go back to the maximum designated BSA-adjusted dose level due to a reason other than 
BSA adjustment or drug administration error. For example, lenvatinib 11 mg/m2 followed by 
0 mg/m2 followed by 8 mg/m2. If there is only dose interruption with no reduction in dose, 
such an event will not be considered as a dose reduction. The second and subsequent dose 
reductions will be defined accordingly. In addition, time to first dose reduction among 
subjects with dose reduction will also be summarized. 
 
Dose interruptions defined as below: 
1. Only includes the scenario that before and after dose 0 mg/m2 (interruption period), the 


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dose levels are the same. For example: 11 mg/m2 followed by 0 mg/m2 and followed by 11 
mg/m2; 8 mg/m2 followed by 0 mg/m2 followed by 8 mg/m2. 
2. If dose level reduces from previous dose level after dose interruption period (dose 0 
mg/m2), it should count as dose reduction and not dose interruption. For example: 11 mg/m2 
followed by 0 mg/m2 followed by 8 mg/m2, the period with 0 mg/m2 should not count as dose 
interruption instead it should count as dose reduction. 
3. If after dose level 0 mg/m2, the subject discontinued from treatment permanently, it should 
count as treatment discontinuation instead of dose interruption. 
 
Subject data listings will be provided for all dose administration records and for the variables 
calculated as above. 
 
5.6.1.4 
Dose Limiting Toxicity 
DLTs will be recorded during Cycle 1 (Day 1 to Day 28) for subjects in Phase 1. The BSA, 
DLT (Yes/No/Not Evaluable) and reason(s) for each subject will be listed, as well as the 
date, and dosage of drug when the DLT occurred. 
 
5.6.2 
Adverse Events 
The adverse event (AE) verbatim descriptions (investigator terms from the eCRF) will be 
classified into standardized medical terminology using MedDRA version 21.1 or higher. 
Adverse events will be coded to the MedDRA lower level term (LLT) closet to the verbatim 
term. The linked MedDRA preferred term (PT) and primary system organ class (SOC) are 
also captured in the database. 
 
A treatment-emergent adverse event (TEAE) is defined as an AE that had an onset date on or 
after the first dose of study drug up to 28 days following the last dose of study drug, or a 
worsening in severity from Baseline (pretreatment). In addition, if an AE reemerges during 
treatment, having been present at pretreatment (Baseline) but stopped before treatment, it is 
also counted as TEAE. The Common Terminology Criteria for Adverse Events (CTCAE) 
version 4.03 will be used to assess the severity of AEs. 
 
Only those AEs that are treatment emergent will be included in summary tables. All AEs, 
treatment emergent or otherwise, will be presented in subject data listings. TEAEs will be 
summarized by dose level in Phase 1 and by cohort in Phase 2. 
 
The incidence of TEAEs will be reported as the number (percentage) of subjects with TEAEs 
by SOC and PT. A Subject will be counted only once within an SOC and PT, even if the 
subject experiences more than 1 TEAE within a specific SOC and PT. The number 
(percentage) of subjects with TEAEs will also be summarized by highest CTCAE grade. The 
number (percentage) of subjects with treatment-related TEAEs will also be summarized by 
SOC and PT. Treatment-related TEAEs include those events considered by the investigator 


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to be related to study treatment or missing causality. 
 
In summary, the following TEAE tables will be provided if appropriate: 
x Overview of TEAEs 
x TEAEs by SOC and PT 
x TEAEs in decreasing frequency of PT 
x TEAEs by SOC, PT, and CTCAE grade 
x 7($(VZLWK&7&$(*UDGHVE\GHFUHDVLQJIUHTXHQF\RI37  
x Overview of treatment-related TEAEs 
x Treatment-related TEAEs by SOC and PT 
x Treatment-related TEAEs by SOC, PT, and Worst CTCAE grade 
x Treatment-UHODWHG7($(VE\GHFUHDVLQJIUHTXHQF\RI37ZLWK&7&$(*UDGHV 
The number (percentage) of subjects with Grade 5 (fatal) TEAEs will be summarized by 
MedDRA SOC and PT and a subject data listing of all deaths (whether or not treatment 
emergent) will be provided. All deaths reported will also be summarized in a table. 
 
The number (percentage) of subjects with treatment-emergent SAEs will be summarized by 
MedDRA SOC and PT. A subject data listing of all SAEs will be provided. The number 
(percentage) of subjects with TEAEs leading to discontinuation, dose reduction, or dose 
interruption of study drug will also be summarized by MedDRA SOC and PT.A subject data 
listing of all AEs leading to discontinuation, dose modification (reduction or interruption) of 
study drug will be provided.  
 
In summary, the following tables will be provided if appropriate: 
x All deaths in the safety analysis set 
x Grade 5 (fatal) TEAEs by decreasing frequency of PT 
x Grade 5 (fatal) TEAEs by SOC and PT 
x Treatment-emergent SAEs by SOC and PT  
x Treatment-emergent SAEs by SOC, PT and Worst CTCAE Grade 
x Treatment-related treatment-emergent SAEs by SOC and PT 
x Treatment-related treatment-emergent SAEs by SOC, PT and Worst CTCAE Grade 
x Treatment-emergent SAEs by decreasing frequency of PT 
x Nonfatal treatment-emergent SAEs by SOC and PT 
x TEAEs leading to study drug discontinuation by SOC and PT 
x TEAEs leading to study drug dose reduction and/or dose interruption by SOC and PT 


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x TEAEs leading to study drug dose reduction by SOC and PT 
 
Clinically significant treatment-emergent AEs (CSAEs) for lenvatinib include: arterial TE 
(thromboembolic) events, bone and teeth abnormalities, cardiac dysfunction, 
hypothyroidism, GI (gastrointestinal) perforation, fistula formation, hemorrhage, 
hypertension, hypocalcemia, hepatotoxicity, palmar plantar erythrodysesthesia syndrome 
(PPE), proteinuria, QT prolongation, renal events, posterior reversible encephalopathy 
syndrome (PRES), and pneumothorax.  
Adverse events of special interest (AEOSI) for everolimus include: Angioedema , 
Dyslipidemia, Pneumonitis, and Stomatitis. 
The number and percentage of each category of treatment-emergent CSAEs for lenvatinib 
and AEOSI for everolimus will be summarized by overall, CTCAE grade and by dose level 
for Phase 1 and by cohort for Phase 2. Time to first onset of CSAEs for lenvatinib and 
AEOSI for everolimus will also be summarized. 
 
The following tables will be provided only for CSAEs for lenvatinib and AEOSI for 
everolimus . 
x Summary of CSAEs for lenvatinib and AEOSI for everolimus by category and PT 
x Summary of serious CSAEs for lenvatinib and AEOSI for everolimus by category 
and PT 
x Overview of CSAEs for lenvatinib and AEOSI for everolimus by category 
x Incidence and Time to First Onset of CSAEs for lenvatinib and AEOSI for 
everolimus  
 
The following tables will be provided only for subjects in Phase 1. 
x TEAEs in Cycle 1 in decreasing frequency of PT 
x TEAEs in Cycle 1 by SOC and PT 
x 7($(VLQ&\FOHZLWK&7&$(*UDGHVE\GHFUHDVLQJIUHTXHQF\RI37 
 
The following subject AE listings (treatment-emergent or otherwise) will be provided: 
x All AEs 
x All deaths for all enrolled subjects 
x All SAEs 
x All AEs leading to study drug discontinuation 
x All AEs leading to dose reduction and / or dose interruption 
x Subjects with Febrile Neutropenia 
x All CSAEs 
 


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The following subject listings will be provided only for subjects in Phase 1. 
x DLTs in Cycle 1 
x TEAEs in Cycle 1 
 
5.6.3 
Laboratory Values 
Laboratory values that are nonmissing and reported as “below the detectable limit” of an 
assay will be replaced by half the detectable limit in the summary tables.  Laboratory results 
will be summarized using Système International (SI) units.  Laboratory test results will be 
assigned a low/normal/high (LNH) classification according to whether the value was below 
(L), within (N), or above (H) the laboratory parameter’s reference range.  Abnormal 
laboratory values will be identified as those outside the normal range.  The abnormal values 
will be indicated in data listings. The CTCAE grade will also be included in the listing. 
 
Laboratory tests during treatment are defined as laboratory tests conducted from the start of 
treatment to no more than 28 days after the last dose of study drug.  Only laboratory 
parameters specified in the protocol will be summarized.  Other laboratory parameters 
collected for some individual subjects will be presented in listings only.  Baseline is defined 
as the last nonmissing result prior to the first administration of study drug. 
 
For quantitative parameters, the actual value and the change from Baseline to each 
postbaseline visit will be summarized by visit and dose level (Phase 1)/study cohort (Phase 2) 
using descriptive statistics. Qualitative parameters will be summarized using frequencies 
(number and percentage of subjects), and changes from baseline to the worst postbaseline 
will be reported using shift tables. Percentages will be based on the number of subjects with 
both nonmissing baseline and relevant postbaseline results. 
 
5.6.3.1 
Hematology and Clinical Chemistry 
Laboratory parameters will be reported using the following methods for hematology and 
clinical chemistry: 
x Descriptive summary statistics for all major hematology and clinical parameters and 
their changes from Baseline will be calculated (n, mean, SD, median, Q1, Q3, min, 
max) 
x Shifts from Baseline to worst postbaseline CTCAE grade (presented by each dose 
level in Phase 1 and overall, and each study cohort in Phase 2) for all clinical 
chemistry parameters and hematology parameters. 
 
All hematology and clinical chemistry laboratory parameters will be listed by subject and 
visit. 


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5.6.3.2 
Thyroid-Stimulating Hormone 
Thyroid-stimulating hormone values will be summarized separately at both Baseline and for 
worst postbaseline value LQFDWHJRULHV8/1DQG!8/1. 
 
5.6.3.3 
Urinalysis 
The shift of Baseline to worst postbaseline proteinuria will be summarized. All urinalysis 
parameters (RBCs/high-power-field [HPF], blood, glucose, and protein [dipstick], 24-hour 
urine protein) will be provided by subject listing at each visit. 
 
5.6.3.4 
Vital Signs  
Vital signs will be summarized by assessment time and dose level for Phase 1 or study cohort 
for Phase 2 for the actual value and change from Baseline. Baseline will be defined as the last 
nonmissing result prior to the first administration of study drug. 
 
Vital sign values will be evaluated on an individual basis by subject. Descriptive statistics for 
vital sign parameters (systolic [SBP] and diastolic [DBP] blood pressure (subjects <18 years 
old SUHVHQWHGDVSHUFHQWLOHRWKHUVXEMHFWV18 years old presented in mmHg), heart rate, 
respiratory rate, body temperature, height, weight and BSA), as well as changes from 
Baseline, will be presented for each cycle and day. 
 
Percentiles for height measurements will also be summarized using a shift table of lowest 
postbaseline from Baseline measurement by categories (5th, 10th, 25th, 50th, 75th, 90th, 95th). 
 
Percentiles for BP values (only for subjects <18 years old [see Protocol Appendix 7 and 8]) 
will also be summarized using a shift table of worst postbaseline from Baseline measurement 
by categories (<90th percentile, 90th to 95th percentile, 95th to <99th percentile, SBP or 
DBP 99th percentile). The overall percentile is taken as the worse of SBP/DBP percentiles.  
 
5.6.3.5 
Electrocardiograms 
Descriptive statistics for electrocardiogram parameters (HR, PR, QRS, QT, QTcB, QTcF and 
RR) and changes from Baseline will be presented by visit. ECG findings will be summarized. 
A shift table of worst postbaseline values from Baseline for ECG findings will be provided. 
A subject data listing will also be provided. 
 
In addition, the number (percentage) of subjects with at least 1 postbaseline ECG result in 
QTc Bazett and QTc Fridericia during the treatment will be summarized. ECG results in QTc 
Bazett and QTc Fridericia will be categorized as follows: 


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x For subjects with Baseline and postbaseline data, maximum increase from Baseline 
PVHFRI!WRDQG! 
x 0D[LPXPSRVWEDVHOLQHYDOXHPVHFRI!WR!WRDQG
! 
5.6.4 
Other Safety Analyses 
Descriptive statistics and changes from baseline for left ventricular shortening fraction 
assessed on echocardiogram and LVEF assessed on echocardiogram or MUGA scans will be 
presented. Percent reduction from baseline will also be summarized. 
 
Lansky play scores or Karnofsky performance scores (KPS) scores will be summarized by 
shifts from Baseline to worst postbaseline. A subject listing of Lansky play scores or KPS 
scores, will be provided.  
 
In addition, Radiographic findings of proximal tibial growth plates and dental examination 
will also be summarized. 
 
5.7 
Other Analyses 
 
5.8 
Exploratory Analyses 
See Section 5.4.3 for Exploratory Efficacy Analyses. 
6 
INTERIM ANALYSES 
For each disease cohort (Ewing sarcoma/pPNET, rhabdomyosarcoma and HGG) in Phase 2, 
there will be 1 futility analysis: this is planned for after the first 10 evaluable subjects have 
completed at least 4 treatment cycles and, if applicable, a confirmatory scan has been 
performed (in case of a PR or CR at week 16), or have discontinued study drug early (before 
Week 16). At the futility analysis, if there are no responders (CR/PR), then the enrollment for 
that cohort will be discontinued for lack of efficacy. If 1 or more responses are observed, the 
accrual will continue.  
7 
CHANGES IN THE PLANNED ANALYSES 
There is no change from the planned analyses defined in protocol.  


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8 
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING 
8.1 
Visit Windows 
Visit windows will be defined to be upper and lower bounds of 1 day of the scheduled visit, 
following the protocol, which states that efforts should be made to conduct laboratory 
assessments and administer treatment on the day scheduled (±1 day). 
In Phase 1, tumor assessments for efficacy analysis are to be performed at Week 4 during 
Treatment Phase, and at Week 12, Week 24 and every 12 weeks thereafter or as clinically 
indicated in the Extension Phase. In Phase 2, tumor assessments for efficacy analysis are to 
be performed at Week 8 and Week 16 during Treatment Phase, and at Week 24 and every 12 
weeks thereafter or as clinically indicated in the Extension Phase. All responses are to be 
confirmed at a follow-XSH[DPLQDWLRQDIWHUGD\VIROORZLQJWKHLQLWLDOLQGLFDWLRQRI
response. Efforts should be made to conduct tumor assessments on the day scheduled (±7 
days). 
In the calculation of descriptive statistics for laboratory values and vital signs, if a visit has 
multiple observations, the observation closest in date and time to the target visit day will be 
used in the analysis. If 2 or more observations have the same distance to the target visit day, 
the one that has the highest CTCAE grade or is farthest outside the normal range will be 
used. The purpose of this windowing is to provide a single record per subject per visit for the 
calculation of descriptive statistics and change from Baseline per visit. Other safety analyses 
(e.g., worst grade for laboratory results) will include all observations. All by-visit analyses 
will be performed using assessments at corresponding scheduled visits recorded in the eCRF. 
Data from all postbaseline assessments including those at scheduled and unscheduled visits 
will be used in the shift tables. 
8.2 
Safety and Efficacy Data Handling  
8.2.1 
Partial dates 
Partial dates for AE and prior/concomitant medication, laboratory values, vital signs, and 
ECGs will not be imputed. 
8.2.1.1 
Diagnosis date 
x If only the day of the month is missing, the 15th of the month will be used to replace 
the missing day 
x If both the day and the month are missing, "July 1" will be used to replace the missing 
information 
8.2.1.2 
Date of Death 
x If only the day of the month is missing, the 1st of the month will be used to replace 
the missing day 


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x If both the day and the month are missing, "Jan 1" will be used to replace the missing 
information 
x If the entire date is missing, the date of death will be imputed as the last known date 
the subject was known to be alive + 1 day 
8.2.1.3 
Date of Progression 
x If only the day of the month is missing, the 1st of the month will be used to replace 
the missing day 
x If the day and month are missing or a date is completely missing, it will be considered 
as missing and no date will be imputed 
In case the date of death is present (complete date), the imputed progression date will be 
compared with the date of death. The earlier date of imputed progression date and date of 
death will be considered as the date of progression. 
8.2.1.4 
Date of Last Tumor Assessment 
x If only the day of the month is missing, the 1st of the month will be used to replace 
the missing day 
x If the day and month are missing or a date is completely missing, it will be considered 
as missing and no date will be imputed 
In case the date of death is present (complete date), the imputed date for tumor assessment 
parameters will be compared with the date of death. The earlier date of the imputed date and 
date of death will be considered as the date of last tumor assessment. 
8.2.1.5 
Date of Start of Subsequent Anticancer Therapy 
x When the day is missing, it is assumed that the subsequent therapy started on the first 
day of the given month if this day is later than the last date of drug administration. 
Otherwise, it is assumed that the subsequent therapy started on the day following the 
last date of drug administration. 
x When the day and the month are missing, it is assumed that the subsequent therapy 
started on the first day of the given year if this day is later than the last date of drug 
administration. Otherwise, it is assumed that the subsequent therapy started on the 
day following the last date of drug administration. 
8.2.1.6 
Date of Previous Radiotherapy 
x If only the start day of the month is missing, the 1st of the month will be used to 
replace the missing day 


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x If both the start day and month are missing, "Jan 1" will be used to replace the 
missing information 
x If only the stop day of the month is missing, the latest possible day of the month will 
be used to replace the missing day 
x If both the stop day and month are missing, "Dec 31" will be used to replace the 
missing information 
In case the date of treatment start day is present (complete date), the imputed radiotherapy 
stop date will be compared with the date of treatment start day. The earlier date of imputed 
radiotherapy stop date and date of treatment start day will be considered as the stop date of 
radiotherapy. 
 
8.3 
Definitions, Derived Variables, and Data Sets 
8.3.1 
Baseline 
Baseline value is defined as the predose value on Cycle 1 Day 1 or the last observation 
before start of drug if the predose value on Cycle 1 Day 1 is missing. 
8.3.2 
Date/Time Definitions 
The following factors will be used to convert days to months: 
1 month = 30.4375 days 
x Time from first diagnosis to first dose (months) is: 
(Date of first dose – Date of first diagnosis) / 30.4375 
x Time from first metastatic diagnosis to first dose (months) is: 
(Date of first dose – Date of first metastatic diagnosis) / 30.4375 
x Time from last medication to first dose (months) is: 
(Date of first dose – End date of last medication) / 30.4375 
x Time from last anthracycline therapy to first dose (months) is: 
(Date of first dose – Start date of the last anthracycline therapy) /30.4375 
x Time from last radiotherapy to first dose (months) is: 
(Date of first dose – End date of the last radiotherapy) / 30.4375 
8.3.3 
Creatinine Clearance 
The pediatric Schwartz equation for creatinine clearance is: 


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x GFR (mL/min/1.73 m2) = (0.41 x Height) / Scr, where Scr is serum/plasma creatinine 
in mg/dL 
8.3.4 
Last Known Alive Date 
The last date the subject was known to be alive should be derived from survival follow-up 
date or the latest date among last treatment date, last radiologic follow-up date, last 
laboratory assessment date, last AE date, last concomitant medication date, or last vital sign 
measurement date. 
8.4 
Pharmacokinetics/Pharmacodynamics Data Handling 
8.4.1 
Lower Limit of Quantification of Lenvatinib Plasma Concentration 
The lower limit of quantification (LLOQ) of lenvatinib plasma concentration is 0.25 ng/mL. 
The LLOQ of everolimus whole blood concentration is 0.300 ng/mL. 
8.4.2 
BLQ Handling for Developing Concentration-Time Profiles 
When calculating the mean or median value for the concentration at a given time point, the 
BLQ values will be assigned as zero. If the proportion of values reported as BLQ is more 
than 50%, no summary statistics should be represented at that time point, and the value will 
be treated as missing in mean or median concentration profiles. 
9 
PROGRAMMING SPECIFICATIONS 
The rules for programming derivations and dataset specifications are provided in separate 
documents. 
10 STATISTICAL SOFTWARE 
Statistical programming and analyses will be performed using SAS® (SAS Institute, Inc., 
Cary, NC, USA), version 9 or higher, and/or other validated statistical software as required. 
11 MOCK TABLES, LISTINGS, AND GRAPHS 
The study TLG shells will be provided in a separate document, which will show the content 
and format of all tables, listings, and graphs in detail. 
12 REFERENCES 
1. Brookmeyer, R. and Crowley, JJ. A confidence interval for the median survival time. 
Biometrics. 1982; 38: 29-41. 
2. Cancer Therapy Evaluation Program, Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0 [published 28 May 2009 (v4.03: June 14, 2010)].  Available from: 


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https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03/CTCAE_4.03_2010-06-
14_QuickReference_5x7.pdf. 
3. Clopper, CJ and Pearson, ES. The Use of Confidence or Fiducial Limits Illustrated in the 
Case of the Binomial. Biometrika. 1934; 26: 404–413. 
4. Eisenhauer EA, Therasse P, Bogaerts J et al. New response evaluation criteria in solid 
tumours: Revised RECIST guideline (version 1.1). European Journal of Cancer 
2009 Jan; 45 (2): 228-247.  
5. Kaplan, E. and Meier, P. Nonparametric Estimation from Incomplete Observations. J Am 
Stat Assoc. 1958; 53: 457-481.  
6. Simon R. Optimal two-stage designs for phase II clinical trials. Controlled Clinical 
Trials. 1989; 10: 1-10. 
7. Skolnik JM, Barrett JS, Jayaraman B, Patal D, Adamson PC. Shortening the timeline of 
pediatric phase 2 trials: the rolling 6 design. J Clin Oncol. 2008; 26: 190-5 . 
8. Study Protocol Number: E7080-A001-216: A Phase 1/2 Study of Lenvatinib in 
Combination With Everolimus in Recurrent and Refractory Pediatric Solid Tumors, 
Including CNS Tumors (Amendment 03, 16 August 2021). 
9. Wen P, Macdonald DR, Reardon DA, Cloughesy TF, Sorenson AG, Galanis E, et al. 
Updated response assessment criteria for high-grade gliomas: Response Assessment in 
Neuro-Oncology Working Group. J Clin Oncol. 2010; 28: 1963-72. 
 


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13 APPENDICES 
13.1 Summary of Efficacy Analyses of Phase 1 
Efficacy 
Variable 
Analysis Set 
Statistical Method 
Tumor 
Assessments 
ORR at 
data cutoff 
Safety Analysis Set  
Number (percentage) of subjects 
(with PR + CR) at data cutoff and its 
exact 95% CI using method of 
Clopper and Pearson. 
Investigator 
DOR 
Safety Analysis Set 
Median, Q1, and Q3 DOR will be 
presented (KM method), with 2-sided 
95% CIs (Brookmeyer and Crowley, 
1982). 
Investigator 
DCR 
Safety Analysis Set 
Number (percentage) of subjects 
(measurable disease with CR + PR + 
VWDEOHGLVHDVH>6'@ZHHNV
evaluable disease with CR + Non-
CR/Non-PD for RECIST1.1 or 
IR/SD  weeks for RANO) and its 
exact 95% CI using method of 
Clopper and Pearson. 
Investigator 
CBR 
Safety Analysis Set 
Number (percentage) of subjects 
(measurable disease with CR+ PR + 
6'ZHHNVHYDOXDEOHGLVHDVHZLWK
CR + Non-CR/Non-PD for 
RECIST1.1 or IR/SD ZHHNV for 
RANO) and its exact 95% CI using 
method of Clopper and Pearson. 
Investigator 
 
 
 


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13.2 Summary of Efficacy Analyses of Phase 2 
Efficacy 
Variable 
Analysis Set 
Statistical Method 
Tumor 
Assessments 
ORR at 
Week 16  
Evaluable Analysis 
Set  
Number (percentage) of subjects 
(with PR + CR) at Week 16 and its 
exact 95% CI using method of 
Clopper and Pearson. 
Investigator 
ORR at 
data cutoff  
Evaluable Analysis 
Set  
Number (percentage) of subjects 
(with PR + CR) at data cutoff and its 
exact 95% CI using method of 
Clopper and Pearson. 
Investigator 
DOR 
Evaluable Analysis 
Set  
Median, Q1, and Q3 DOR will be 
presented (KM method), with 2-sided 
95% CIs (Brookmeyer and Crowley, 
1982). 
Investigator 
DCR 
Evaluable Analysis 
Set 
Number (percentage) of subjects 
(measurable disease with CR + PR + 
VWDEOHGLVHDVH>6'@ZHHNVDQGLWV
exact 95% CI using method of 
Clopper and Pearson. 
Investigator 
CBR 
Evaluable Analysis 
Set 
Number (percentage) of subjects 
(measurable disease with CR+ PR + 
6'ZHHNVDQGLWV exact 95% CI 
using method of Clopper and 
Pearson. 
Investigator 
 
 


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SIGNATURE PAGE 
Author:   
 
 
 
 
 
Oncology, DHBL, Eisai Inc. 
 
Date 
Approval: 
 
  
 
 
Oncology, DHBL, Eisai Ltd. 
 
Date 
 
 
 
 
  
Oncology, DHBL, Eisai Inc. 
Date 

9/22/2022
9/26/2022
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PPD
PPD
PPD
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PPD
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