Clinical trial NCT02432274
Conditions: Tumors Solid Malignant Tumors Osteosarcoma Differentiated Thyroid Cancer (DTC)
Keywords: E7080 Lenvatinib Solid malignancies Osteosarcoma Differentiated Thyroid Cancer
Sponsor: Eisai Limited
Start date: 2014-12-29; Completion date: 2022-07-20
Enrollment: 117 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a phase 1/2 study evaluating safety, tolerability, and efficacy of lenvatinib as single-agent, and in combination with chemotherapy (ifosfamide and etoposide) in children and adolescents with refractory or relapsed solid malignancies including differentiated thyroid carcinoma (single agent lenvatinib) and osteosarcoma (single agent and combination lenvatinib).

Detailed description:
The study consists of 5 cohorts:

Cohort 1 (Single-Agent Dose-Finding) dose-escalation to find the recommended dose (RD) of lenvatinib using time-to-event continual reassessment method (TiTE-CRM) in children and adolescents with relapsed or refractory solid malignant tumors. When the RD is identified, Cohorts 2A, 2B, and 3A will enroll in parallel.

Cohort 2 (Single-Agent Expansion) will evaluate the efficacy of lenvatinib at the RD in children, adolescents, and young adults with

1. 131 iodine-refractory differentiated thyroid cancer (DTC) \[Cohort 2A\] or
2. Relapsed or refractory osteosarcoma \[Cohort 2B\]

Cohort 3A (Combination Dose-Finding) will determine the RD of lenvatinib in combination with ifosfamide and etoposide in children, adolescents, and young adults with relapsed or refractory osteosarcoma.

Cohort 3B (Combination Expansion) will evaluate the efficacy of lenvatinib at the RD from Cohort 3A in combination with ifosfamide and etoposide in children, adolescents, and young adults with relapsed or refractory osteosarcoma. Participants with osteosarcoma who have enrolled into Cohort 1 or 2B and experienced progressive disease will also be candidates for enrollment in Cohort 3B.

Lenvatinib will be provided as hard capsules containing 1, 4, or 10 mg lenvatinib. Lenvatinib capsules should be dissolved in water or apple juice for those who are unable to swallow capsules.

Arms: arm 1: Children and adolescents with relapsed or refractory solid malignant tumors. arm 2: Children and adolescents with 131 iodine-refractory DTC. arm 3: Participants with relapsed or refractory osteosarcoma. arm 4: Participants with relapsed or refractory osteosarcoma will receive lenvatinib in combination with ifosfamide and etoposide. arm 5: Participants with relapsed or refractory osteosarcoma will receive lenvatinib in combination with ifosfamide and etoposide.
Interventions: intervention 1: Lenvatinib intervention 2: Lenvatinib intervention 3: Lenvatinib intervention 4: Lenvatinib intervention 5: Lenvatinib intervention 6: Ifosfamide intervention 7: Etoposide intervention 8: Ifosfamide intervention 9: Etoposide
Intervention descriptions: intervention 1: Cohort 1: Lenvatinib will be administered orally, once daily on Days 1 to 28 of each 28-day cycle at a starting dose of 11 mg/m2. Dose can be de-escalated to 9 mg/m2 or escalated to 14 and 17 mg/m2. intervention 2: Cohort 2A: Lenvatinib (RD determined in Cohort 1) will be administered orally, once daily on Days 1 to 28 of each 28-day cycle. intervention 3: Cohort 2B: Lenvatinib (RD determined in Cohort 1) will be administered orally, once daily on Days 1 to 28 of each 28-day cycle. intervention 4: Cohort 3A: Lenvatinib will be administered orally, once daily on Days 1 to 21 of each 21-day cycle at 20% lower than RD determined in Cohort 1 (starting dose). Lenvatinib dose can be escalated to the RD from Cohort 1 or de-escalated to 40 and 60% lower than the RD from Cohort 1. intervention 5: Cohort 3B: Lenvatinib will be administered orally, once daily on Days 1 to 21 of each 21-day cycle at the RD as determined in Cohort 3A. intervention 6: Ifosfamide 3000 mg/m2/day (starting dose) will be administered on Days 1 to 3 of each 21-day cycle for a total of 5 cycles. Ifosfamide dose can be de-escalated to 2400 mg/m2/day and 1800 mg/m2/day. intervention 7: Etoposide 100 mg/m2/day (starting dose) will be administered on Days 1 to 3 of each 21-day cycle for a total of 5 cycles. Etoposide dose can be de-escalated to 80 mg/m2/day and 60 mg/m2/day. intervention 8: Ifosfamide dose identified in Cohort 3A will be administered on Days 1 to 3 of each 21-day cycle for a total of 5 cycles. intervention 9: Etoposide dose identified in Cohort 3A will be administered on Days 1 to 3 of each 21-day cycle for a total of 5 cycles.

Protocol documents:
Prot_002.pdf: 
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1 
TITLE PAGE 
 
Clinical Study Protocol 
Study Protocol 
Number: 
E7080-G000-207 
Study Protocol 
Title: 
Phase 1/2 Study of Lenvatinib in Children and Adolescents With 
Refractory or Relapsed Solid Malignancies and Young Adults with 
Osteosarcoma   
Sponsor:  
Eisai Inc. 
300 Tice Boulevard 
Woodcliff Lake 
New Jersey 07677 
USA 
Eisai Ltd. 
Mosquito Way 
Hatfield, Hertfordshire, 
AL10 9SN 
United Kingdom 
Investigational 
Product Name: 
Lenvatinib 
Indication: 
Refractory or relapsed solid malignancies in children and adolescents 
Phase: 
1/2 
Approval Date: 
V1.0 
08 May 2014 (original protocol) 
 
V2.0 
12 Sep 2014 (Amendment 1) 
 
V3.0 
12 Sep 2014 minor editorial corrections (Amendment 1) 
 
 
14 Apr 2015 (Amendment 2) 
 
 
01 Sep 2016 (Amendment 3) 
 
 
22 Nov 2019 (Amendment 4) 
IND Number: 
113656 
EudraCT Number: 2013-005534-38  
GCP Statement: 
This study is to be performed in full compliance with International 
Council for Harmonization 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 
This document is confidential.  It contains proprietary information of 


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Statement: 
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. 


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Revision History  
Revisions per Amendment 04 
Date: 22 Nov 2019  
 
Change 
Rationale 
Affected Protocol 
Sections 
Updated abbreviation for ICH as per 
current definition. 
Administrative change 
• 
Title page 
• 
Section 4 
• 
Section 5.2 
• 
Investigator Signature page 
The objective “Evaluate the efficacy of 
lenvatinib as assessed by overall survival” 
was updated as a secondary objective 
(previously exploratory objective).  
Corresponding changes were also made in 
the endpoints and statistical analyses 
sections. 
Update made to align with 
lenvatinib paediatric 
investigation plan. 
• 
Synopsis: Objectives, 
Endpoints, Statistical 
Analyses 
• 
Section 8 
• 
Section 9.7.1.1 
• 
Section 9.7.1.5 
Clarified that for subjects continuing study 
treatment at the time of the data cutoff 
date for the primary analysis, the study 
drugs will be ordered and dispensed 
manually, and IxRS dispensing will be 
closed out once the procedure for 
reconciliation of study drugs is complete 
for the purpose of the clinical study report. 
Procedure for procurement 
of study drugs after data 
cutoff date for primary 
analysis was clarified. 
• 
Section 9.4.10 
Clarified that in subjects ongoing in the 
study at the time of data cut off date for 
the primary analysis, the biomarker 
samples will be collected at the 
Off-Treatment visit. 
Schedule of biomarkers was 
updated to minimize sample 
collection after data cutoff 
date for primary analysis. 
• 
Synopsis: 
Pharmacodynamic 
Assessments 
• 
Section 9.5.1.4 
• 
Section 9.5.2.1 (Table 7, 
Table 8, Table 9 
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 
instructions 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 the nasogastric 
tubing with undissolved 
granules.  
• 
Appendix 12 


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2 
CLINICAL PROTOCOL SYNOPSIS 
Compound No.:  E7080 
Name of Active Ingredient:  Lenvatinib 
Study Protocol Title 
Phase 1/2 Study of Lenvatinib in Children and Adolescents With Refractory or Relapsed 
Solid Malignancies and Young Adults with Osteosarcoma   
Investigators 
Principal Investigator:  Nathalie Gaspar 
Sites 
Approximately 12 sites in Europe and US 
Study Period and Phase of Development 
Approximately 36 months 
Phase 1/2 
Objectives 
Primary Objectives 
Cohort 1 (Single-Agent Dose-Finding) 
• Identify the recommended dose (RD) of lenvatinib as a single agent in children and 
adolescents with relapsed or refractory solid malignant tumors 
Cohort 2 (Single-Agent Expansion) 
• Evaluate the activity of lenvatinib in 2 separate malignancy groups: 
o Cohort 2A:  131I-refractory differentiated thyroid cancer:  by objective 
response rate (ORR) for subjects with measurable disease and by best overall 
response (BOR) for all subjects. 
o Cohort 2B:  Relapsed or refractory osteosarcoma:  by progression-free 
survival  at 4 months (PFS-4) 
Note:  The tumor types under study in the Single-Agent Expansion portion of the study may 
be modified based on preliminary efficacy and safety signals observed in Cohort 1 of the 
study. 
Cohort 3 (Combination Dose-Finding and Expansion) 
• Cohort 3A (Combination Dose-Finding) 
o To identify the RD of lenvatinib in combination with ifosfamide and 
etoposide in osteosarcoma subjects 


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• Cohort 3B (Combination Expansion) 
o Evaluate the activity of lenvatinib in combination with ifosfamide and 
etoposide in osteosarcoma subjects by PFS-4 
Secondary Objectives 
Cohort 1 (Single-Agent Dose-Finding) 
• Assess the safety and toxicity profile of lenvatinib in children and adolescents 
• Evaluate the activity of lenvatinib as assessed by best overall response (BOR), 
objective response rate (ORR), duration of response (DOR), progression free survival 
(PFS), time to progression (TTP), based on RECIST 1.1 (Appendix 1), disease 
control rate (DCR), and clinical benefit rate (CBR) 
• Evaluate the efficacy of lenvatinib as assessed by overall survival (OS)  
• Examine blood and tumor biomarkers and correlate with clinical response to 
lenvatinib 
• Determine population-based pharmacokinetic (PK) parameters of lenvatinib 
• Assess the palatability and acceptability of the suspension formulation of lenvatinib 
Cohort 2 (Single-Agent Expansion) 
• Assess the safety and toxicity profile of lenvatinib in children and adolescents, and 
young adults with relapsed or refractory osteosarcoma 
• Evaluate the efficacy of lenvatinib as assessed by BOR(osteosarcoma only), ORR 
(osteosarcoma only), DOR (measurable DTC and osteosarcoma only), PFS, TTP, 
DCR and CBR  
• Evaluate the efficacy of lenvatinib as assessed by OS 
• Examine blood and tumor biomarkers and correlate with clinical response to 
lenvatinib 
• Determine population-based PK parameters of lenvatinib  
• Assess the palatability and acceptability of the suspension formulation of lenvatinib 
Cohort 3 (Combination Dose-Finding and Expansion)  
• Assess the safety and toxicity of lenvatinib in combination with ifosfamide and 
etoposide in children and adolescents, and young adults with relapsed or refractory 
osteosarcoma  
• Evaluate the efficacy of lenvatinib as assessed by BOR, ORR, DOR, PFS, TTP, DCR 
and CBR 
• Evaluate the efficacy of lenvatinib as assessed by OS 
• Examine blood and tumor biomarkers and correlate with clinical response to 
lenvatinib 
• Determine population-based PK parameters of lenvatinib 
• Assess the palatability and acceptability of the suspension formulation of lenvatinib 


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Exploratory Objective 
• Explore the relationship of lenvatinib exposure to clinical response in children and 
adolescents (assessed during Cohort 1 [Single-Agent Dose-Finding] and Cohort 2 
[Single-Agent Expansion]) 
Study Design 
This is a Phase 1/2, multicenter, open-label, study.  The study will Need to update : 
Cohort 1 (Single-Agent Dose-Finding):  Dose-escalation to find the RD of lenvatinib using 
a Time to Event continual reassessment (TiTE-CRM) design in children and adolescents with 
relapsed or refractory solid malignant tumors (see Study Treatment below for dose-
escalation scheme) (Doussau, et al., 2012).  When the RD is identified, Cohorts 2A, 2B, and 
Cohort 3A will start in parallel.  After the RD is determined in Cohort 1, subsequent 
osteosarcoma subjects will be assigned to either Cohort 2B (Single-Agent Expansion) or 
Cohort 3A (Combination Dose-Finding), depending on whether the subject is deemed by the 
investigator to be a candidate for ifosfamide and etoposide. (If not, the subject would only be 
assigned to Cohort 2B). 


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Cohort 2 (Single-Agent Expansion):  To test the efficacy of lenvatinib in children and 
adolescents with 131I-refractory DTC (Cohort 2A), or subjects with relapsed or refractory 
osteosarcoma (Cohort 2B).  Cohort 2A and Cohort 2B will be open for enrollment in parallel 
with Cohort 3A (Combination Dose-Finding).  
Cohort 3 
Cohort 3A (Combination Dose-Finding): To define the RD of lenvatinib in combination 
with ifosfamide and etoposide in subjects with relapsed or refractory osteosarcoma.  This 
cohort will be open for enrollment in parallel with Cohort 2 (Single-Agent Expansion).   
After defining the RD of lenvatinib in combination with chemotherapy in Cohort 3A, 
subsequent osteosarcoma subjects will be assigned to either Cohort 2B (Single-Agent 
Expansion) or Cohort 3B (Combination Expansion), depending on whether the subject is 
deemed by the investigator to be a candidate for ifosfamide and etoposide ( If not, the subject 
would only be assigned to Cohort 2B).  
Cohort 3B (Combination Expansion):  To test the efficacy of lenvatinib in combination 
with ifosfamide and etoposide in subjects with relapsed or refractory osteosarcoma. 
Subjects with osteosarcoma who have enrolled into Cohort 1 or 2B and experienced 
progressive disease on lenvatinib as well as lenvatinib-naïve subjects with relapsed or 
refractory osteosarcoma will be candidates for enrollment in Cohort 3B. 
The study will include 3 phases:  Pretreatment (screening), Treatment (includes a Run-In 
Period for Cohort 1), and Posttreatment Follow-up. 
Pretreatment Phase:  Subjects will undergo screening evaluations to determine eligibility. 
Treatment Phase:  
In all cohorts, lenvatinib will be administered orally once daily (QD).  One treatment cycle is 
defined as a 28-day period for Cohorts 1, 2A, and 2B and a 21-day period for Cohorts 3A and 
3B.  A new treatment cycle is started after every 28 day period for Single-Agent Cohorts 1, 
2A, and 2B or after a 21-day period for Combination-Treatment Cohorts 3A and 3B, 
irrespective of dose interruptions.   
Cohort 1 (Single-Agent Dose-Finding):     
Dose-Escalation in Cohort 1 Cycle 1:  
Subjects 6 to <18 years will enroll in Cohort 1 prior to subjects 2 to <6 years of age. The 
lenvatinib starting dose is 11 mg/m2 QD (approximately 80% of the adult RD of 24 mg QD).  
If the 11 mg/m2 dose is not safe and tolerable, the dose will be de-escalated to 9 mg/m2 (Dose 
Level -1).  Doses of study drug administered during Cohort 1 of the study are displayed in 
the figure above.  Dose-limiting toxicities (DLTs) that occur during Cycle 1 will be 
evaluated.  A TiTE-CRM design will be used to drive dose-escalation and to determine the 


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RD of lenvatinib (Cheung and Chappell, 2000).  Dose-limiting toxicities (DLTs) are defined 
in a table below.  The RD in this study will be defined as the dose that has a DLT rate closest 
to the targeted 20% rate.  The TiTE-CRM design allows continuous accrual throughout the 
study while using the 4 week toxicity endpoint as the basis for dose-escalation.  At least 2 
subjects should receive the full 4-week study treatment or report a DLT (at the starting dose) 
and complete evaluations before escalation to the next dose level.  No intra-subject dose 
escalation will be allowed.  Subjects who discontinue the study before the end of Cycle 1 
(Cycle 1 Day 1 – Cycle 1 Day 28) due to reasons other than DLT will be replaced.  Refer to 
the figure above for the study design. 
Table 1:  Lenvatinib Doses for Single-Agent Dose-Finding (Cohort 
1) 
Dose Level 
Lenvatinib Once-Daily 
-1 
9 mg/m2 
1 (starting dose) 
11 mg/m2 
2 
14 mg/m2 
3 
17 mg/m2 
Intrasubject dose-escalation prior to determining the RD will be allowed only for subjects 2 
to <6 years of age from the Run-In Period to Cohort 1 Cycle 1 as described below. 
Dose-escalation for Subjects 2 to <6 years old: 
Run-In Period:  All subjects 2 to <6 years of age should complete Screening and Baseline 
assessments.  Eligible subjects will first enter a 21-day Run-In Period prior to entering 
Cohort 1.  During the Run-In Period the subject will receive single-agent lenvatinib at 5 
mg/m2/day for 21 days and will be evaluated for DLTs, along with PSC as needed. 
If a subject 2 to <6 years of age experiences a DLT during the Run-In Period, that subject 
will discontinue from the study without entering Cohort 1 Cycle 1.  The DLT data from that 
subject will be used for all subsequent TiTE-CRM calculations and the dose level for that 
subject in all subsequent calculations will be considered as Cohort 1 Dose Level -1 
(9 mg/m2), as 9 mg/m2 is the lowest dose in the Cycle 1 single-agent lenvatinib dose-finding 
cohort.  
Subjects 2 to <6 years of age can enter Cohort 1 Cycle 1 (following the completion of the 
Run-In Period without any DLT) only after: (1) at least 6 subjects 6 to <18 years of age have 
either completed 4 weeks of treatment in Cycle 1 or reported DLTs during Cycle 1, and (2) 
single-agent lenvatinib has been evaluated and considered by PSC to be safe based on the 
DLT data from all the previous subjects, including subjects 6 to <18 years of age.  When a 
subject 2 to < 6 years of age enters Cohort 1 Cycle 1, the subject will receive a dose that is 
either (1) one level below what is calculated from TiTE-CRM if calculated dose is greater 
than 9 mg/m2, based on the DLT data from all previous subjects from 2 to <18 years of age, 
or (2) 9 mg/m2 if the TiTE-CRM calculated dose is 9 mg/m2.  Consequently, that subject’s 


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DLT data in Cycle 1 will be included in all subsequent TiTE-CRM calculations. 
Cohort 2 (Single-Agent Expansion):   
The efficacy of lenvatinib in children and adolescents,and young adults with osteosarcoma 
will be evaluated in 2 malignancy groups separately:  DTC (Cohort 2A) and osteosarcoma 
(Cohort 2B).  Subjects will be treated at the RD identified in Cohort 1.  The primary efficacy 
endpoint in the DTC group is ORR (complete response [CR] plus partial response [PR]) for 
subjects with measurable disease and BOR for all subjects based on RECIST 1.1.  The 
primary efficacy endpoint in the osteosarcoma group is PFS, assessed at 4 months based on 
RECIST 1.1. 
Cohort 3A (Combination Dose-Finding):   
Lenvatinib will be administered orally QD in combination with ifosfamide and etoposide 
from Day 1 to Day 3 of each cycle for a total of 5 cycles to osteosarcoma subjects as 
described below and in Table 2.  Refer to Section 9.4.3 for dosing details. 
Table 2:  Lenvatinib and Chemotherapy Doses for Combination Dose-Finding (Cohort 3A) 
Dose Modification of Lenvatinib 
 
Dose -Escalation 
Starting Dose 
De-escalation 1 
De-escalation 2 
Lenvatinib 
RD (from Cohort 1) 
20% lower than 
RD from Cohort 1 
40% lower than 
RD from Cohort 1 
60% lower than RD 
from Cohort 1 
 
Dose Modification of Ifosfamide and Etoposide 
 
No Dose 
Escalation 
Starting Dose 
De-escalation 
1* 
De-escalation 2* 
Ifosfamide 
 
3000 mg/m2/day 
IV for 3 days 
2400 mg/m2/day 
IV for 3 days 
1800 mg/m2/day IV 
for 3 days 
Etoposide 
 
100 mg/m2/day IV 
for 3 days 
80 mg/m2/day IV 
for 3 days 
60 mg/m2/day IV for 3 
days 
RD = recommended dose, *each De-escalation dose level is 20% lower than the starting dose. 
The chemotherapy cycles will be repeated every 21 days. 
Six subjects with osteosarcoma (who have not received prior lenvatinib) will be enrolled first 
to Cohort 3A at the starting dose of lenvatinib (20% below the Single-Agent RD in Cohort 1) 
in combination with ifosfamide 3000 mg/m2/day for 3 days (ifosfamide total dose 9 g/m2) 
and etoposide 100 mg/m2/day for 3 days (etoposide total dose 300 mg/m2).  Subjects with 
lenvatinib dose capped after BSA adjustment (dose must not exceed 24 mg daily) actually 
take lower dose level than assigned.  If a subject with capped dose experiences a DLT, the 
DLT data from that subject will be counted to determine the RD of the combination 
treatment.  A subject with capped dose who does not experience a DLT will be replaced for 
the purpose of determining the RD.  


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DLTs occurring during Cycle 1 will be evaluated, and the next 6 subjects will be assigned a 
dose based on the rules for Dose Escalation and De-Escalation as follows:  
a. If ≤1 out of 6 subjects experiences a DLT at the starting dose during Cycle 1 (Day 1 to 
Day 21), then assign 6 more subjects to the next higher dose level of lenvatinib (RD 
from Cohort 1) and keep the chemotherapy dose the same (starting dose).  
b. If ≥2 out of 6 subjects experience a DLT at the starting dose during Cycle 1 (Day 1 to 
Day 21), then follow the instructions below; 
i. If ≥2 subjects experience hematologic DLT and ≤1 subject experiences non-
hematologic DLT, then assign 6 more subjects to 20% lower doses (De-
escalation 1) of ifosfamide and etoposide and keep the lenvatinib dose the same; 
or 
ii. If ≥2 subjects experience nonhematologic DLTs and ≤1 subject experiences a 
hematologic DLT, then assign 6 more subjects to a 20% lower dose of lenvatinib 
(De-escalation 1) and keep the ifosfamide and etoposide doses the same; or 
iii. If ≥2 subjects experience hematologic DLTs and ≥2 subjects experience 
nonhematologic DLTs, then assign 6 more subjects to 20% lower doses of 
lenvatinib, ifosfamide, and etoposide each (De-escalation 1); or 
iv. If only 1 subject experiences a hematologic DLT and only 1 subject experiences 
a nonhematologic DLT, then assign 6 more subjects to the same dose level of 
lenvatinib, ifosfamide, and etoposide each.  
c. Continue the above processes until the combination dose of lenvatinib, ifosfamide, and 
etoposide results in ≤1 DLT per 6 subjects, or only 1 subject experiences a 
hematologic DLT and only 1 subject experiences a nonhematologic DLT per 6 
subjects upon repeating the same dose level.  This dose will be considered the RD of 
the combination treatment. 
This dose of lenvatinib will be used to treat additional subjects with osteosarcoma in 
Cohort 3B. Further dose de-escalation of lenvatinib or the chemotherapy dose may be 
considered (pending discussion with the Protocol Steering Committee [PSC]), if needed.   
Cohort 3B (Combination Expansion):   
Subjects with either lenvatinib-naïve relapsed osteosarcoma or osteosarcoma subjects who 
progress on single-agent lenvatinib in Cohorts 1 or 2B (optional enrollment) will receive the 
combination RD from Cohort 3A, provided the combination of lenvatinib, ifosfamide, and 
etoposide in Cohort 3A (Combination Dose-Finding) is judged to be safe and tolerable.  
Approximately 18 lenvatinib-naïve subjects will be enrolled in Cohort 3B, along with some 


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subjects from Cohorts 1 and 2B. 
Osteosarcoma subjects who experience PD in Cohorts 1 or 2B and choose to receive the 
combination therapy of lenvatinib with ifosfamide and etoposide should meet only inclusion 
Criteria Numbers 6 through 17 and all the exclusion criteria except Criterion Number 6.  For 
osteosarcoma subjects who experience PD in Cohort 2B and choose to receive the 
combination therapy of lenvatinib with ifosfamide and etoposide, prior to entering Cohort 3B 
(Combination Expansion), baseline tumor assessments by computed tomography/magnetic 
resonance imaging (CT/MRI) must be repeated on new images, unless the images confirming 
disease progression were performed within 28 days of Cycle 1 Day 1 in Cohort 3B.  Subjects 
will undergo assessments as per the Schedule of Assessments provided for the combination 
treatment. 
Subjects in Cohorts 3A and 3B will receive ifosfamide and etoposide for a maximum of 5 
cycles. Subjects who discontinue ifosfamide and etoposide (eg, due to toxicity) prior to 
completing 5 cycles may continue on single-agent lenvatinib if they are benefiting from the 
treatment at the discretion of the investigator.  Subjects who discontinue lenvatinib prior to 
completing 5 cycles may continue on ifosfamide and etoposide, at the investigator’s 
discretion, for 5 cycles.  
Subjects benefiting from the study treatment, in the opinion of the investigator, will continue 
to receive treatment until disease progression, intolerable toxicity, subject noncompliance 
with safety or efficacy assessments, initiation of another anticancer therapy, voluntary 
discontinuation by the subject at any time, or study termination by the sponsor, whichever 
occurs first. 
Dose-Limiting Toxicity  
Dose-limiting toxicity (DLT) in subjects treated with lenvatinib will be assessed according 
to Common Terminology Criteria for Adverse Events (CTCAE) v4.03 (Appendix 2) and is 
defined as any of the following toxicities related to lenvatinib or chemotherapy drugs 
(ifosfamide and/or etoposide) occurring during Cycle 1 (Day 1 to Day 28) for Cohort 1 and 
during Cycle 1 (Day 1 to Day 21) for Cohort 3A. 
Hematologic Toxicity 
o Grade 4 neutropenia for ≥7 days (≥10 days for Cohort 3A) 
o Grade ≥3 thrombocytopenia with bleeding, or lasting >7 days (≥10 days for 
Cohort 3A) 
o Grade ≥3 febrile neutropenia (lasting ≥7 days for Cohort 3A) 
o Next course of chemotherapy delayed for ≥7 days (Cohort 3A) 
Non-Hematologic Toxicity 
o Grade ≥3 nonhematological toxicity persisting more than 7 days despite 
optimal supportive care.  Isolated laboratory abnormalities that resolve within 
a week, allergic reactions, and symptoms related to tumor progression will be 
excluded. 


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o Grade 4 hypertension, confirmed systolic or diastolic blood pressure more 
than 25 mmHg above the 95th percentile for age, or an elevated diastolic 
blood pressure (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 two antihypertensive ingredient medications will 
count as one antihypertensive medication. 
o Grade 3 proteinuria 
o Any recurrent Grade 2 nonhematological toxicity requiring ≥2 interruptions 
and dose reductions 
• Any dose interruption or reduction due to toxicity which results in administration of 
less than 75% of the planned dosage of lenvatinib. 
• Any other Grade ≥3 toxicity (hematologic and nonhematologic) assessed as related to 
lenvatinib treatment, and which in the opinion of the PSC and medical monitor 
constitutes 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 Eisai Medical Monitor in 
consultation with the PSC, as needed.  Subjects who discontinue the study treatment for any 
reason other than DLT during Cycle 1 (Day 1 to Day 28) for Cohort 1 and Cycle 1 (Day 
1 to Day 21) for Cohort 3A will be replaced. 
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 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.  
Each cohort will have its own cut-off date for the final analysis for the CSR reporting 
purpose. 
Cohorts 1 and 3A:  
For purposes of the final analysis, data cutoff will occur when the RD is determined and the 
last enrolled subject completes 6 cycles of treatment or discontinues before the end of Cycle 
6, whichever occurs first or pending discussion with the PSC. 
Cohorts 2A, 2B, and 3B:  
For DTC and osteosarcoma subjects, the cutoff will be after the completion of 6 cycles by the 
last subject enrolled in each cohort or early discontinuation before the end of Cycle 6, 
whichever occurs first (see figure above). 
Number of Subjects 
Approximately 69 to 108 subjects ages 2 to <18 years (≤25 years for osteosarcoma subjects) 


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are planned to be enrolled in this study.  
Cohort 1 (Single-Agent Dose-Finding):  Approximately 12 to 24 subjects with relapsed or 
refractory solid malignancies 
Cohort 2 (Single-Agent Expansion):  Approximately 27 to 42 subjects divided into 2 
malignancy-type groups:   
Cohort 2A:  DTC group (approximately 12 subjects) and  
Cohort 2B:  Osteosarcoma group (15 to 30 subjects) 
Cohort3A (Combination Dose-Finding):  Approximately 12 to 24 subjects with osteosarcoma 
Cohort 3B (Combination Expansion):  Approximately 18 lenvatinib-naïve subjects with 
osteosarcoma (along with some subjects from Cohorts 1 and 2B after experiencing PD) 
Inclusion Criteria 
1. Histologically or cytologically confirmed diagnosis of solid malignant tumor 
a. Cohort 1:  Any solid malignant tumor 
b. Cohort 2A:  DTC with one of the following histologic subtypes:  
a. Papillary thyroid cancer (PTC) 
1. Follicular variant 
2. Other variants (including, but not limited to, tall cell, columnar cell, 
cribriform-morular, solid, oxyphil, Warthin’s-like, trabecular, tumor 
with nodular fasciitis-like stroma, Hürthle cell variant of papillary 
carcinoma, or poorly differentiated carcinomas) 
b. Follicular thyroid cancer (FTC) 
1. Hürthle cell 
2. Clear cell 
3. Insular 
c. Cohort 2B, 3A, and 3B:  Relapsed or refractory osteosarcoma 
 
2. Relapsed or refractory solid tumor malignancy that has progressed on standard 
anticancer therapy with no available curative options.  (Note: Osteosarcoma subjects 
must be in first or subsequent relapse [≥ first relapse]).  Only the osteosarcoma 
subjects enrolled to Cohorts 3A and 3B must be deemed candidates for ifosfamide 
and etoposide chemotherapy).  
3. Evaluable or measurable disease that meets the following criteria  
a. Subjects must have evaluable or measurable disease based on RECIST 1.1 using 
computed tomography/magnetic resonance imaging (CT/MRI) (Appendix 1) 
b. Lesions that have had external beam radiotherapy (EBRT) or locoregional 
therapies such as radiofrequency (RF) ablation must have subsequently grown 


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unequivocally to be deemed a target lesion 
4. DTC subjects must be 131I-refractory/relapsed as defined by at least one of the 
following: 
a. One or more evaluable or measurable lesions that do not demonstrate iodine 
uptake on any radioiodine scan OR 
b. One or more evaluable or measurable lesions that have progressed based on 
RECIST 1.1, within 12 months of 131I therapy, despite demonstration of 
radioiodine avidity at the time of that treatment by pre- or post-treatment scanning.  
These subjects must not be eligible for possible curative surgery OR 
c. Cumulative activity of 131I >400 millicuries (mCi) or 14.8 gigabecquerels (GBq), 
with the last dose administered at least 6 months prior to study entry 
5. Subjects with DTC must be receiving thyroxine suppression therapy and levels of 
thyroid stimulating hormone (TSH) should not be elevated (TSH should be 
≤5.50 mU/L).  When tolerated by the subject, thyroxine dose should be changed to 
achieve TSH suppression (TSH <0.50 mU/L) 
6. Subjects with known central nervous system (CNS) primary tumors or  metastases 
who have completed brain therapy (such as radiotherapy, stereotactic radiosurgery, or 
surgical resection) and have remained clinically stable, asymptomatic, and off of 
steroids for 2 weeks prior to Cycle 1 Day 1 will be eligible 
7. Male or female subjects age 2 years to <18 years (≤25 years for osteosarcoma 
subjects) at the time of informed consent 
8. Lansky play score ≥50% or Karnofsky Performance Status score ≥50% (see 
Appendix 4 and Appendix 5, respectively).  Use Karnofsky for subjects ≥16 years of 
age and Lansky for subjects <16 years of age 
9. Life expectancy ≥ 3 months 
10. Adequate bone marrow function as evidenced by: 
a. absolute neutrophil count (ANC) ≥1.0 × 109/L (for Cohorts 3A and 3B leucocyte 
count ≥2 × 109/L; subjects with bone marrow involvement should have ANC ≥0.8 
× 109/L and leucocyte count ≥1 × 109/L) 
b. hemoglobin ≥8.0 g/dL (a hemoglobin <8.0 g/dL is acceptable if it is corrected by 
growth factor or transfusion before starting lenvatinib) 
c. platelet count ≥ 75 × 109/L  
11. Adequate liver function as evidenced by: 
a. bilirubin ≤ 1.5 times the upper limit of normal (ULN) 
b. alkaline phosphatase, alanine aminotransferase (ALT), and aspartate 
aminotransferase (AST) ≤3 × ULN (in the case of liver metastases ≤5 × ULN), 
unless there are bone metastases or bone primary tumor, in which case liver 


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specific alkaline phosphatase must be separated from the total and used to assess 
the liver function instead of the total alkaline phosphatase 
12. Adequate  renal function as evidenced by: 
a. Serum creatinine based on age/gender as below.  If serum creatinine is greater than 
maximum serum creatinine for age/gender as shown in the table below, then 
creatinine clearance (or radioisotope glomerular filtration rate [GFR]) must be >70 
mL/min/1.73 m2 (Appendix 6). 
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 (Schwartz, 
et al., 1985) using child length and stature data published by the CDC. 
 
b. 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) 
c. No clinical evidence of nephrotic syndrome 
13. Adequate cardiac function as evidenced by left ventricular ejection fraction (LVEF) 
≥50%) at baseline as determined by echocardiography 
14. Adequately controlled blood pressure (BP) with or without antihypertensive 
medications, defined as: 
a. BP <95th percentile for sex, age, and height/length at screening (as per National 
Heart Lung and Blood Institute [NHLBI] guidelines; see Appendix 7 and 
Appendix 8) and no change in antihypertensive medications within 1 week prior to 
Cycle 1 Day 1.  Osteosarcoma subjects 18 to 25 years should have BP ≤150/90 
mm Hg at screening and no change in antihypertensive therapy within 1 week prior 
to Cycle 1/Day 1. 
15. Washout of 3 weeks in case of prior chemotherapy, 6 weeks if treatment included 
nitrosoureas; 4 weeks for definitive radiotherapy, and 2 weeks for palliative 
radiotherapy; 3 months from high-dose chemotherapy and stem cell rescue; 3 weeks 


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from major surgery.  Subjects must have recovered from the acute toxic effects of all 
prior anticancer therapy before enrollment into the study 
16. Written and signed informed consent from the parent(s) or legal representative 
(guardian) and assent from the minor subject. Written informed consent from subjects 
≥18 years. 
17. Willing and able to comply with the protocol, scheduled follow-up, and management 
of toxicity as judged by the Investigator 
Cohort 3B (Combination Expansion): Osteosarcoma subjects who progressed in 
Cohorts 1 or 2B and opt to receive combination therapy:  
18. Osteosarcoma subjects receiving combination therapy of lenvatinib with ifosfamide 
and etoposide only need to meet Inclusion Criteria Numbers 7 6 through 17 (after 
progression in Cohort 2B) 
Exclusion Criteria 
1. Any active infection or infectious illness unless fully recovered prior to dosing 
2. Any medical or other condition that in the opinion of the investigator(s) would preclude 
the subject’s participation in a clinical study 
3. Other organ toxicity due to prior anticancer therapy (investigational agent, chemotherapy, 
or radiation therapy) except alopecia, and ototoxicity due to cisplatin not already covered 
in the inclusion/exclusion criteria, which has not recovered to Grade <2 per CTCAE 
v4.03  
4. Known hypersensitivity to any component of the product (lenvatinib or ingredients) 
5. Concurrent administration of any other antitumor therapy 
6. Previous treatment with lenvatinib (except for subjects previously enrolled into Cohorts 1 
or 2B of this study) 
7. Two or more prior VEGF/VEGFR-targeted therapies  
8. Currently receiving any investigational drug or device in another clinical trial or within 
30 days preceding informed consent 
9. A clinically significant ECG abnormality, including a marked baseline prolonged QT or 
QTc interval (eg, a repeated demonstration of a QTc interval >480 msec) 
10. Gastrointestinal malabsorption or any other condition that in the opinion of the 
investigator might affect the absorption of lenvatinib 
11. Gastrointestinal bleeding or active hemoptysis (bright red blood of at least ½ teaspoon) 


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within 3 weeks prior to the first dose of study drug 
12. Active second malignancy within 2 years prior to enrollment (in addition to the primary 
tumor types specified by cohort in Inclusion Criterion Number 1), but not including 
definitively treated superficial melanoma, carcinoma in-situ, basal or squamous cell 
carcinoma of the skin) 
13. Previous treatment with ifosfamide  and grade ≥3 nephrotoxicity or encephalopathy 
(Cohorts 3A and 3B) 
14. Females who are breastfeeding or pregnant at Screening or Baseline (as documented by a 
positive beta-human chorionic gonadotropin [ß-hCG] (human chorionic gonadotropin 
[hCG]) test with a minimum sensitivity of 25 IU/L or equivalent units of ß-hCG [ 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. 
Females of childbearing potential who: 
• 
Within 28 days before study entry, did not use a highly effective method of 
contraception, which includes any of the following: 
o total abstinence (if it is their preferred and usual lifestyle) 
o an intrauterine device or intrauterine hormone-releasing system (IUS) 
o an oral contraceptive (Subject must be on a stable dose of the same oral 
contraceptive product for at least 28 days before dosing and throughout the 
study and for 6 months after study drug discontinuation.) .  
o have a vasectomized partner with confirmed azoospermia. 
• 
Do not agree to use a highly effective method of contraception (as described above) 
throughout the entire study period and for 6 months after study drug discontinuation. 
 
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. 
 
NOTE:  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). 
Males who have not had a successful vasectomy (confirmed azoospermia) or 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 5 times the 
half-life of the study drug plus 90 days after study drug discontinuation).  No sperm 
donation is allowed during the study period and for 5 times the half-life of the study drug 
plus 90 days after study drug discontinuation. 


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Males who have not had a successful vasectomy (confirmed azoospermia) or 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 6 months 
after study drug discontinuation).  If the female partner is pregnant, then males who do 
not agree to use condoms throughout the study period and for 6 months after study drug 
discontinuation.  No sperm donation is allowed during the study period and for 6 months 
after study drug discontinuation. 
Cohort 3B (Combination Expansion): Osteosarcoma subjects who progressed in 
Cohorts 1 or 2B and opt to receive combination therapy:  
15. Osteosarcoma subjects receiving combination therapy of lenvatinib with ifosfamide and 
etoposide should meet all the exclusion criteria, with the exception of Criterion Number 6 
Study Treatment 
Additional details are provided in the Study Design section under Treatment Phase. 
Test drug:  Lenvatinib 
Lenvatinib will be provided as hard capsules containing 1, 4, or 10 mg lenvatinib.  
Lenvatinib will be administered orally QD.  The maximum dose administered during the 
study should not exceed 24 mg QD in any of the cohorts.  An extemporaneous suspension of 
lenvatinib capsules should be used for children unable to swallow capsules, as detailed in 
Appendix 12. 
Cohort 1 (Single-Agent Dose-Finding) 
Subjects 6 to <18 years: Lenvatinib will be administered orally QD.  Study drug doses for 
Cohort 1 are displayed in the table below.  The starting dose is 11 mg/m2 QD, which is 80% 
of the adult RD of 24 mg QD.  The 80% starting dose is based on consensus reached for 
pediatric Phase 1 trials (Smith, et al., 1998; Lee, et al., 2005).  If the dose of 11 mg/m2 (Dose 
Level 1) is not safe and tolerable, subjects will receive lenvatinib at the lower de-escalation 
dose of 9 mg/m2 (Dose Level -1).   
Lenvatinib Doses for Single-Agent Dose-Finding (Cohort 1) 
Dose Level 
Lenvatinib Once-Daily 
-1 
9 mg/m2 
1 (starting dose) 
11 mg/m2 
2 
14 mg/m2 
3 
17 mg/m2 
Body surface area (BSA) must be calculated on Day 1 of each cycle based on the subject’s 
current height and body weight.  BSA will be used to determine the amount of lenvatinib for 


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each subject.  The dose should be rounded to the nearest whole number.   
Subjects 2 to <6 years: Subjects will receive 5 mg/m2 during the 21-day Run-In Period. If 
these subjects do not experience any DLT, they will enter Cohort 1 Cycle 1 Day 1 and 
intrasubject dose escalation will take place as detailed in the Study Design section 
(Treatment Phase: Cohort 1).  
Cohorts 2A and 2B (Single-Agent Expansion) 
Lenvatinib will be administered orally QD at the RD. The RD of Single-Agent lenvatinib 
determined in Cohort 1 is 14 mg/m2 as recommended by TiTE-CRM and confirmed by PSC.  
Subjects in Cohorts 2A and 2B will receive 14 mg/m2 lenvatinib (equivalent to 24 mg QD, 
adult daily dose).  After adjustment for BSA, the daily dose should not exceed 24 mg QD.    
Cohort 3A (Combination Dose Finding) 
Lenvatinib will be administered in combination with ifosfamide and etoposide to 
osteosarcoma subjects as described in the Study Design section (Treatment Phase: Cohort 
3A).  Lower doses may be administered depending on the safety information. 
Cohort 3B (Combination Expansion) 
Subjects will receive lenvatinib at the RD determined to be safe and tolerable in Cohort 3A 
(Combination Dose-Finding) in combination with ifosfamide and etoposide.   
The chemotherapy cycles in Cohorts 3A and 3B will be repeated every 21 days. 
Lenvatinib Dose Reduction and Interruption Instructions 
Dose adjustments will be made for subjects who experience treatment-related toxicity 
according to the guidelines provided in the table below.  Doses in the Dose Adjustment 
column are based on a presumed starting dose of 11 mg/m2. 
Dose reductions will occur in succession based on the previous dose level.  Each dose level 
reduction is a 20% reduction from the previous dose.  Once the dose has been reduced, it 
cannot be increased at a later date. 
 
Criteria for Temporary Discontinuation of Study Drug, Dose Reduction, and 
Resumption of Treatment 
Treatment-Related Toxicitya,b 
including hepatic injury and 
thromboembolic events 
Management 
Dose Adjustment 
Grade 1 
 
Continue treatment 
No change 
Intolerable Grade 2c or Grade 3e 


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Blood Pressure 
For children, blood pressure varies by sex and age of the child and is closely related to height 
and weight.  Blood pressure will be assessed in terms of percentile for sex, age, and 
height/length.  Guidelines to sex, age, and height-specific percentiles of blood pressure are 
provided in Appendix 7 and Appendix 8.  Blood pressure that is consistently above the 95th 
[for subjects age 18-25 years BP >150/90 mm Hg] percentile for age and height/length 
requires further evaluation.  A referral to a cardiologist is recommended for patients 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 blood pressure in children of 
approximately the same age and body build should be expected and serial measurements 
should always be obtained when evaluating a patient with hypertension.  BP values for 
management of hypertension for subjects 18 to 25 years of age are included in 
parenthesis. 
Management of Hypertension  
First occurrence 
Interrupt until resolved to Grade 0-
1 or baseline 
8.8 mg/m2 (or 20% reduction of 
the starting dose) orally once daily 
(QD) (one-level reduction) 
Second occurrence (same toxicity 
or new toxicity) 
Interrupt until resolved to Grade 0-
1 or baseline 
7.0 mg/m2 (or 20% reduction of 
the previous dose) orally QD (one-
level reduction) 
Third occurrence (same toxicity or 
new toxicity) 
Interrupt until resolved to Grade 0-
1 or baseline 
5.6 mg/m2 (or 20% reduction of 
the previous dose) orally QD (one-
level reduction) 
Fourth occurrence (same toxicity 
or new toxicity) 
Interrupt until resolved to Grade 0-
1 or baseline 
Discuss with sponsor 
Grade 4d:  Discontinue Study Treatment 
Note:  For grading see Common Terminology Criteria for Adverse Events version 4.0 (Appendix 2).  Collect 
all CTC grades of adverse events, decreasing and increasing grade. 
a:  Interruption of lenvatinib treatment for more than 28 days (due to lenvatinib-related toxicities) will require 
a discussion with the sponsor before treatment can be resumed. 
b:  Initiate optimal medical management for nausea, vomiting, and/or diarrhea prior to any study treatment, 
interruption, or dose reduction. 
c:  Applicable only to Grade 2 toxicities judged by the subject and/or physician to be intolerable. Not 
applicable to abnormal clinical laboratory values that are not clinically relevant based on the judgment of 
the investigator. 
d:  Excluding laboratory abnormalities judged to be non-life-threatening, in which case manage as Grade 3. 
e.  Obese subjects with weight loss do not need to return to baseline or Grade 1 weight loss to restart 
lenvatinib. There should be no weight loss for at least 1 week, and subjects should be started at the lower 
dose and normal Body Mass Index (BMI) should be used for future dose reductions. Obesity is defined as 
body mass index (BMI) percentiles corresponding to 30 kg/m², related to the age of the children. (Cole 
TJ., et al 2000) or BMI  ≥ the 95th percentile for children and teens of the same age and sex. (Ogden CL 
et al, 2002) (Appendix 9 and 10).   
 


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Hypertension is a recognized side-effect of treatment with drugs inhibiting vascular 
endothelial growth factor (VEGF) signaling.  Investigators should therefore ensure that 
subjects enrolled to receive treatment with lenvatinib have BP <95th percentile [BP ≤150/90 
mm Hg] for sex, age, and height/length at the time of study entry and, if known to be 
hypertensive, have been on a stable dose of antihypertensive therapy for at least 1 week 
before Cycle 1 Day 1.  Early detection and effective management of hypertension are 
important to minimize the need for lenvatinib dose interruptions and reductions.  
Antihypertensive agents should be started as soon as elevated BP (systolic BP ≥95th 
percentile or diastolic BP ≥95th percentile [BP ≥140 mm Hg or diastolic BP ≥90 mm Hg]) 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 mm Hg] or diastolic BP ≥95th percentile [BP ≥90 mm Hg] 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.  
 
Lenvatinib should be withheld in any instances where a subject is at imminent risk to 
develop a hypertensive crisis or has significant risk factors for severe complications of 
uncontrolled hypertension (eg, BP ≥99th percentile [BP ≥160/100 mm Hg], 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, lenvatinib should be resumed as 
described below.  
During the Treatment Period, subjects with systolic BP ≥99th percentile [BP ≥160 mm Hg] 
or diastolic BP ≥99th percentile [BP ≥100 mm Hg] 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 mm Hg] and diastolic BP has been <95th percentile [≤ 95 mm Hg] for 3 
consecutive months.  If a new event of systolic BP ≥99th percentile [BP ≥160 mm Hg] or 
diastolic BP ≥99th percentile [BP ≥100 mm Hg] occurs, the subject must resume the Day 15 
evaluation until systolic BP has been <95th percentile [≤150 mm Hg] and diastolic BP has 
been <95th percentile [≤ 95 mm Hg] for 3 consecutive months.  
The following guidelines should be followed for the management of systolic BP ≥99th 
percentile [BP ≥160 mm Hg] or diastolic BP ≥99th percentile [BP ≥100 mm Hg] confirmed 
on repeat measurements after an hour:  
• Continue lenvatinib and institute antihypertensive therapy for subjects not already 
receiving antihypertensive medication.  


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• 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 mm Hg] or diastolic BP ≥99th percentile 
[BP ≥100 mm Hg] persists despite maximal antihypertensive therapy, then lenvatinib 
administration should be interrupted and restarted at a lower dose QD (one dose level 
reduction [20%] as specified in the table above) only when systolic BP <95th 
percentile [≤150 mm Hg] and diastolic BP <95th percentile [BP ≤95 mm Hg] 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 mm Hg] or diastolic BP ≥99th percentile 
[BP ≥100 mm Hg] recurs despite optimal management of hypertension with 
antihypertensive medications (either by dose increase or the addition of a different 
class of antihypertensive), then lenvatinib administration should be interrupted 
and restarted at a lower dose QD (one dose level reduction [20%] as specified in 
the table above) only when systolic BP <95th percentile [BP ≤ 150 mm Hg] and 
diastolic BP <95th percentile [BP ≤95 mm Hg] 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 mm Hg] or diastolic BP ≥99th percentile 
[BP ≥100 mm Hg] recurs despite optimal management of hypertension with 
antihypertensive medications (either by dose increase or the addition of a different 
class of antihypertensive), then lenvatinib administration should be interrupted 
and a restart of lenvatinib should be discussed with the sponsor.  
The following guidelines should be followed for the management of Grade 4 hypertension 
(life-threatening consequences):  
• Institute appropriate medical management  
• Discontinue  lenvatinib  
Management of Posterior Reversible Leukoencephalopathy Syndrome (PRES) 
A thorough medical history and a comprehensive physical examination, including a 
neurological examination, should be conducted as detailed in the Schedule of Assessments 
(Table 7, Table 8, and Table 9) and as clinically indicated.  
 
Any subject with signs or symptoms of headache, confusion, seizure, or visual change 
combined with hypertension (usually but not always severe) should be immediately 
evaluated with brain MRI to evaluate the possibility of posterior reversible 
leukoencephalopathy syndrome (PRES), a Grade 4 hypertension adverse event per CTCAE 
v4.03.  In subjects with suspected PRES, lenvatinib should be immediately withheld, and if 
the condition is confirmed by MRI, lenvatinib must be permanently discontinued (see 
Table 3).  Appropriate measures should be taken to control blood pressure (see Section 
9.4.1.4), and neurologic consultation is advised.  


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Management of Proteinuria  
Regular assessment for proteinuria should be conducted as detailed in the Schedule of 
Assessments.  Guidelines for assessment and management of proteinuria are summarized as 
follows:  
• Initial episode of proteinuria: If proteinuria ≥2+ is detected on urine dipstick testing, 
study drug will be continued and a spot protein-creatinine ratio test and if possible a 
24-hour urine collection for total protein will be obtained as soon as possible within 
72 hours to verify the grade of proteinuria.  Grading according to CTCAE v4.03 
(Appendix 2) will be based on the protein-creatinine ratio, and whenever possible, 
also on the 24-hour urinary protein result per investigators discretion.  Management 
of lenvatinib administration will be based on the grade of proteinuria according to the 
Treatment Related Toxicity table.  
• During the Treatment Period, urine dipstick testing for subjects with proteinuria ≥2+ 
should be performed every 2 weeks (on Day 15 or more frequently as clinically 
indicated) until the results have been 1+ or negative for 3 consecutive months.  Any 
subsequent increases in the level of proteinuria ≥2+ on urine dipstick testing must be 
confirmed with a spot protein-creatinine ratio test, and if possible a 24-hour urinary 
protein test as per investigators discretion, which will be assessed and graded and 
managed according to the dose reduction and interruption instructions provided in the 
table above.  If a new event of proteinuria ≥2+ occurs, the subject must resume the 
Day 15 urine dipstick testing for evaluation of proteinuria until results are 1+ or 
negative for 3 consecutive months.  
Management of Hepatotoxicity 
Regular monitoring of liver function tests (alanine transaminase [ALT], aspartate 
transaminase [AST], bilirubin levels) should be conducted as detailed in the Schedule of 
Assessments 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, “Study Treatment Dose Reduction and Interruption Instructions.”  Appropriate 
supportive care should be provided together with close monitoring.  If hepatic failure occurs, 
the study drug must be discontinued. 
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 (DVT) 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 treating physician.  If a thromboembolic event is confirmed, instructions contained in the 
table for dose reduction and interruptions of the protocol should be followed, “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 drug must be 
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Management of Hypocalcemia 
Serum calcium should be monitored monthly per the Schedule of Assessments.  
Hypocalcemia should be treated per institutional guidelines (eg, using appropriate calcium, 
magnesium, and Vitamin D supplementation) until resolution. 
 
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 adverse events of abdominal pain believed to be related to lenvatinib or more specific 
adverse events felt related to lenvatinib that result in the symptom of abdominal pain, 
instructions contained in the table Study Treatment Dose Reduction and Interruption 
instructions should be followed.  For Grade 4 adverse events that result in abdominal pain, 
study drug must be discontinued. 
Gastrointestinal (GI) 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, per investigator’s discretion.  
All GI symptoms should be recorded in the diary provided. 
For additional information please refer to the current Investigator’s Brochure (Lenvatinib 
Investigator’s Brochure).  
Management of Ifosfamide-Etoposide Associated Toxicity 
All sites participating in this trial have had considerable experience with these 
chemotherapeutic agents.  Blood counts should be closely monitored during and prior to the 
next cycle of chemotherapy.  Chemotherapy-associated myelosuppression should be 
managed by G-CSF.  It is recommended that pegylated G-CSF or G-CSF be administered at 
least 24 to 72 hours after completion of ifosfamide-etoposide chemotherapy; use of G-CSF is 
recommended until WBC counts are ≥1 × 109/L.  Guidelines for dose modification for 
ifosfamide- and etoposide-associated toxicities are provided below.  
• 
Neutropenia (Grade 4): Monitor ANC counts every 3 days until resolved to <Grade 3 
• 
Febrile neutropenia (Grade 4): Reduce the next dose of ifosfamide and etoposide by 
20% each 
• 
Mucositis (repeated Grade 3 or Grade 4): Reduce etoposide by 20% 
• 
Renal Toxicity: If serum creatinine >1.5 - 3 × ULN - interrupt ifosfamide and 
etoposide for 1 week  
• 
Hematuria: Interrupt ifosfamide and etoposide if hematuria >50 RBC/high power 
field (hpf) 


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• 
Neurological Toxicity: Interrupt and reduce ifosfamide and etoposide each by 20% of 
the previous dose. After 2 dose reductions, the subject must discontinue the 
chemotherapy drugs, but if there is benefit, the subject can continue on single-agent 
lenvatinib at the investigator’s discretion 
 
Details of ifosfamide and etoposide dose interruption and reduction as well as management 
of toxicity can be found in the Summary of Product Characteristics (SmPC), and should be 
followed according to local and institutional guidelines.  The SmPC will be provided to the 
study sites in the Investigator and Pharmacy files in the relevant local language.  For 
additional information, investigators may refer to the SmPC or Euramos-1 protocol 
(ISRCTN67613327 EudraCT no. 2004-000242-20).  
Duration of Treatment 
Subjects benefiting from study treatment in the opinion of the investigator will continue to 
receive treatment until disease progression, intolerable toxicity, subject noncompliance with 
safety or efficacy assessments, initiation of another anticancer therapy, voluntary 
discontinuation by the subject at any time, or study termination by the sponsor, whichever 
occurs first.   
Concomitant Drug/Therapy 
Prophylactic use of granulocyte colony-stimulating factors (G-CSFs) is not permitted during 
this study in Cohorts 1, 2A, and 2B. G-CSF use is recommended for Cohorts 3A and 3B to 
mitigate the toxicity of ifosfamide and etoposide). 
The following concomitant treatments/procedures are allowed: 
a. Removal of existing (not new) osteosarcoma metastatic lesion (surgical, 
radiofrequency ablation, etc) is allowed only: 
• After completion of the first 4 months of the Treatment Period without 
progression, and 
• Before the first 4 months of the Treatment Period only if there is disease 
progression assessed by the investigator and the subject will discontinue the 
study for progression 
b. Palliative radiotherapy in Cohorts 2 and 3B is allowed for ≤2 significantly 
symptomatic nontarget lesions. For Cohorts 1 and 3A, palliative radiotherapy will be 
allowed after the RD is determined. 
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 
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• 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.  
 
Any additional procedural or patient specific particularities should be discussed with the 
sponsor.    
Assessments 
Efficacy Assessments 
Tumor assessments will be performed based on RECIST 1.1 (Appendix 1).  Investigator-
determined response assessments at each assessment time point will be entered onto the 
appropriate case report form (CRF). 
At Screening 
CT scans of the brain, neck (DTC only) chest, abdomen, pelvis, and other known sites of 
disease (bone metastases) plus any areas of newly suspected disease, will be performed at the 
Screening Visit.  MRI may be used for brain, neck, abdomen, pelvis, and other sites of 
disease, but chest may only be evaluated with CT. 
During Treatment Phase 
For Cohort 1 only, CT/MRI scans of neck (DTC only), chest, abdomen, pelvis, and other 
known sites of disease plus any areas of newly suspected disease will be performed using the 
same methodology as at screening every 6 or 8 weeks per the appropriate tumor assessment 
schedule, or sooner if clinically indicated, beginning from the date of the first treatment dose, 
continuing during treatment cycles until documentation of disease progression.  
For subjects with DTC (Cohort 2A) CT/MRI of the neck and other known sites of the disease 
plus any areas of newly suspected disease and CT chest will be performed.  For osteosarcoma 
(Cohorts 2B, 3A and 3B), CT chest, and CT/MRI of other known sites of disease plus any 
areas of newly suspected disease will be performed.  Tumor assessments should be 
performed using the same methodology as at screening every 6 or 8 weeks per the 
appropriate tumor assessment schedule, or sooner if clinically indicated, beginning from the 
date of the first treatment dose, continuing during treatment cycles until documentation of 
disease progression.  
Brain scans should be performed at screening and during the study if clinically indicated.  If 
protocol eligible brain metastases are present at screening, a CT/MRI of the brain must be 
performed at all tumor assessment time points.  An initial assessment of CR or PR according 
to RECIST 1.1 must be confirmed not less than 4 weeks after the initial response.  In subjects 
2 to <6 years of age, CT/MRI scans must be performed at screening, Cycle 1 Day 1 
(following the Run-In Period at investigator’s discretion), and every 8 weeks during the 
Treatment Period as indicated in Table 7.  For Cohorts 3A and 3B, CT/MRI scans should be 


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performed as indicated in Table 9. 
During Post-treatment Follow-up  
Subjects who discontinue treatment without disease progression will have tumor assessments 
performed every 6 or 8 weeks (per the appropriate tumor assessment schedule) for 
documented disease progression up to 1 year, or sooner if clinically indicated, or until 
another anticancer therapy is initiated whichever occurs first.  All subjects will be followed 
for survival for 1 year or until death, whichever occurs first unless the study is terminated.  
After data cutoff, tumor assessments may be performed as clinically indicated using the 
investigator’s discretion, following the prevailing local standard of care.   
Palatability and Acceptability of Lenvatinib Suspension Formulation 
The palatability and acceptability of lenvatinib suspension formulation will be assessed using 
the Palatability Questionnaire (see Appendix 13).  All subjects who receive suspension 
formulation must complete the questionnaire according to the Schedule of Assessments.  If 
the subject is unable to complete the questionnaire, this must be done by a parent or legal 
guardian.  Measurement of palatability will be assessed using the Hedonic scale (Guinard, 
2001) which is a Visual Analog Scale (VAS). 
Pharmacokinetic Assessments 
Blood samples for PK profiling of lenvatinib will be collected on Day 1 and Day 15 (single 
agent cohorts only-see Table 5) of Cycle 1 and on Day 1 of Cycle 2.  For Cohort 1, Run-In 
Period blood samples will be collected on Day 15 (predose).  PK blood samples for 
lenvatinib will also be drawn pretreatment on the day of tumor assessment.  Exposure 
parameters such as area under the concentration × time curve (AUC) will be derived from 
posterior estimates of the PK parameters from the final population PK model. 
Pharmacodynamic Assessments 
Blood serum samples from study subjects will be collected at Baseline, Day 8 of Cycle 1 
(Combination-Agent cohorts), Day 15 of Cycle 1 (Single-Agent cohorts), Day 1 of all 
subsequent cycles, and at the Off-treatment Visit.  For subjects ongoing after the data cutoff 
date for the primary analysis, blood samples will be collected at the Off-Treatment Visit.  For 
subjects 2 to <6 years, a blood serum sample will be collected in Cohort 1 at Day 1 of Cycle 
1 (predose).  Blood serum samples may be analyzed using global proteomic methods, 
enzyme-linked immunosorbent assay (ELISA), multiplex bead-based immunoassay, or other 
assays/methods and new technology in an effort to identify biomarkers.  In addition, 
biomarkers identified in other lenvatinib clinical studies may also be assessed in samples 
collected from subjects enrolled in this study.  Blood biomarker samples may be used for 
exploratory analysis for evaluation of response-related outcomes as well as for potential use 
in diagnostic development. 
Pharmacogenomic/Pharmacogenetic Assessments 


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Archived, fixed tumor tissue will be collected (if available) for assessment of mutations and 
other genetic alterations or proteins that may be important in the development and 
progression of cancer as well as for potential use in diagnostic development. 
A blood sample will be collected for pharmacogenomic analysis.  The DNA may be analyzed 
for genes associated with lenvatinib absorption, distribution, metabolism, excretion (ADME) 
and to validate mutations suspected of functional relevance (using in silico prediction) to 
determine exclusivity to tumor sample.  The DNA will not be used to determine or predict 
risks for diseases that an individual subject does not currently have. 
Data obtained from the PD and PG samples will be used for research.  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 to assist in any research scientific questions related to lenvatinib and for 
potential diagnostic development.  If the subject reaches 18 years of age prior to the date of 
final sample analyses they will be reconsented.  No further analyses will be performed on 
these collected samples from subjects who either do not reconsent after their 18th birthday or 
cannot be reached for reconsenting and the sample will be destroyed. 
When the subject reaches the age of 18 years (or 16 years in the UK) while on the study, and 
becomes competent to give informed consent, his/her consent will be obtained using separate 
ICFs to continue on the study. 
Safety Assessments 
Safety assessments will consist of monitoring and recording all adverse events (AEs) and 
serious adverse events (SAEs); regular laboratory evaluation for hematology, blood 
chemistry, and urine values; periodic measurement of vital signs; 12-lead ECGs; Lansky play 
score or Karnofsky performance status score; physical examinations; and height assessments.  
A diary will be provided to each subject to capture any abnormal gastrointestinal symptoms 
(e.g., diarrhea, abdominal discomfort, cramps, etc) experienced during the study.  Fecal 
occult blood will be monitored regularly during the study. 
Skeletal bone growth will be assessed by height measurements at the Baseline Visit, 
thereafter Day 1 of each cycle during the Treatment Phase for Cohort 1 (and Day 1 of every 3 
cycles for cohorts 2A, 2B, 3A and 3B); at the Off-treatment Visit, and every 3 months during 
the Post-treatment Follow-up.  Proximal tibial growth plates x-rays will be done at baseline 
and at the off-treatment visit.  Postbaseline, only open growth plates will be further assessed.  
Clinical and laboratory toxicities/symptomatology will be graded according to Common 
Terminology Criteria for Adverse Events (CTCAE) v4.03 (Appendix 2).  Adverse events that 
are not reported in the CTCAE will be graded on a 4-point scale (mild, moderate, severe, and 
life-threatening). 
Protocol Steering Committee 
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along with the Protocol Steering Committee (PSC) as needed.  The PSC may review 
available relevant data:  DLT and safety data including laboratory assessments, 12-lead 
ECGs, dose administration, etc.  
Bioanalytical Methods 
Lenvatinib will be quantified using a validated liquid chromatography/mass 
spectrometry/mass spectrometry (LC/MS/MS) method.  Pharmacodynamic biomarker 
analysis will be performed as described in the separate analysis plan.  Clinical laboratory 
tests will be performed at qualified local laboratories. 
Statistical Methods 
Cohort 1 (Single-Agent Dose-Finding) 
Primary Endpoint 
RD based on the TiTE-CRM design.  
Secondary Endpoints 
• Efficacy 
o BOR over the treatment period 
o ORR  
o DOR 
o Disease Control Rate (DCR) defined as the percentage of subjects with measurable 
disease who have a BOR of CR or PR or stable disease (SD) or subjects with 
evaluable disease who have a BOR of CR or Non-CR/Non-PD.  To be assigned a 
best overall response of SD or Non-CR/Non-PD, the time from the first 
administration of study drug until the date of documented SD or Non-CR/Non-PD 
should be ≥7 weeks. 
o Clinical Benefit Rate (CBR) defined as the percentage of subjects with measurable 
disease who have a BOR of CR or PR or durable SD lasting ≥23 weeks or subjects 
with evaluable disease who have a BOR of CR or durable Non-CR/Non-PD lasting 
≥23 weeks   
o PFS defined as the time from the date of the first administration of study drug until 
the date of first documentation of PD or death (whichever occurs first) 
o TTP defined as the time from the date of the first administration of study drug until 
the date of first documentation of disease progression  
o OS defined as the time from the date of the first administration of study drug until 
the date of death from any cause.  Subjects who are lost to follow-up and those who 
are alive at the date of data cutoff will be censored at the date the subject was last 
known to be alive (or the data cutoff date). 
• 
Safety 
o AEs, SAEs, clinical laboratory values, vital signs, 12-lead ECG, urine dipstick, 


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occult blood in stool, Lansky Play Scores or Karnofsky performance status scores, 
physical examination findings, and height and closure of proximal tibial plates 
during treatment and follow-up 
• 
Plasma lenvatinib exposure 
• 
Assessment of blood or tumor biomarkers that correlate with clinical response to 
lenvatinib treatment or AEs associated with lenvatinib treatment 
 
• 
Palatibility and acceptability of the suspension formulation of lenvatinib  
Cohort 2 
Primary Endpoints 
• 
Cohort 2A:  DTC:  ORR (CR + PR) for subjects with measurable disease and BOR 
for all subjects based on RECIST 1.1 
• 
Cohort 2B:  Osteosarcoma:  PFS-4, ie, the percentage of subjects who are alive and 
free of disease progression at 4 months after the first dose based on RECIST 1.1 
Secondary Endpoints  
• 
Efficacy 
o BOR over the treatment period (osteosarcoma group) 
o ORR (measurable osteosarcoma group) 
o DOR (measurable DTC and osteosarcoma group) 
o Disease Control Rate (DCR) defined as the percentage of subjects with measurable 
disease who have a BOR of CR or PR or stable disease (SD) or subjects with 
evaluable disease who have a BOR of CR or Non-CR/Non-PD.  To be assigned a 
best overall response of SD or Non-CR/Non-PD, the time from the first 
administration of study drug until the date of documented SD or Non-CR/Non-PD 
should be ≥7 weeks. 
o  Clinical Benefit Rate (CBR) defined as the percentage of subjects with measurable 
disease who have a BOR of CR or PR or durable SD lasting ≥23 weeks or subjects 
with evaluable disease who have a BOR of CR or durable Non-CR/Non-PD lasting 
≥23 weeks   
o  PFS defined as the time from the date of first administration of study drug to the 
date of first documentation of disease progression or date of death, whichever 
occurs first 
o TTP defined as the time from the date of the first administration of study drug until 
the date of first documentation of disease progression  
o OS defined as the time from the date of the first administration of study drug until 
the date of death from any cause.  Subjects who are lost to follow-up and those who 
are alive at the date of data cutoff will be censored at the date the subject was last 


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known to be alive (or the data cutoff date). 
• 
Safety 
o AEs, SAEs, clinical laboratory values, vital signs, 12-lead ECGs, urine dipstick, 
occult blood in stool, Lansky play scores or Karnofsky performance status scores, 
physical examination findings, and height and closure of proximal tibial plates 
during treatment and follow-up  
• 
Plasma lenvatinib exposure parameters 
• 
Assessment of blood or tumor biomarkers that correlate with clinical response to 
lenvatinib treatment or AEs associated with lenvatinib treatment 
• 
Palatibility and acceptability of the suspension formulation of lenvatinib  
Cohort 3  
Primary Endpoint 
• 
Cohort 3A:  RD of the combination treatment (lenvatinib + etoposide + ifosfamide) 
• 
Cohort 3B:  PFS-4, ie, the percentage of subjects who are alive and free of disease 
progression 4 months after the first dose based on RECIST 1.1 
Cohorts 3A and 3B  
Secondary Endpoints 
• 
Efficacy 
o BOR over the treatment period 
o ORR (measurable osteosarcoma group) 
o DOR 
o Disease Control Rate (DCR) defined as the percentage of subjects with measurable 
disease who have a BOR of CR or PR or stable disease (SD) or subjects with 
evaluable disease who have a BOR of CR or Non-CR/Non-PD.  To be assigned a 
best overall response of SD or Non-CR/Non-PD, the time from the first 
administration of study drug until the date of documented SD or Non-CR/Non-PD 
should be ≥7 weeks. 
o Clinical Benefit Rate (CBR) defined as the percentage of subjects with measurable 
disease who have a BOR of CR or PR or durable SD lasting ≥23 weeks or subjects 
with evaluable disease who have a BOR of CR or durable Non-CR/Non-PD lasting 
≥23 weeks   
o PFS defined as the time from the date of first administration of study drug to the 
date of first documentation of disease progression or date of death, whichever 
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o TTP defined as the time from the date of the first administration of study drug until 
the date of first documentation of disease progression  
o OS defined as the time from the date of the first administration of study drug until 
the date of death from any cause.  Subjects who are lost to follow-up and those who 
are alive at the date of data cutoff will be censored at the date the subject was last 
known to be alive (or the data cutoff date). 
• 
Safety 
o AEs, SAEs, clinical laboratory values, vital signs, 12-lead ECGs, urine dipstick, 
occult blood in stool, Lansky play scores or Karnofsky performance status scores, 
physical examination findings, and height and closure of proximal tibial plates 
during treatment and follow-up 
• 
Plasma lenvatinib exposure parameters 
• 
Assessment of blood or tumor biomarkers that correlate with clinical response to 
lenvatinib treatment or AEs associated with lenvatinib treatment 
• 
Palatability and acceptability of the suspension formulation of lenvatinib  
Analysis Sets 
The Safety Analysis Set is defined as subjects who receive any study drug. 
The Pharmacokinetic Analysis Set is defined as subjects in Safety Analysis Set who have at 
least 1 measurable postdose plasma concentration with an adequately documented dosing 
history. 
Statistical Analyses 
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, and range 
(minimum and maximum) unless otherwise specified.  Pharmacokinetic data will be 
summarized using n, mean, standard deviation, coefficient of variation (% CV), geometric 
mean, median, minimum and maximum.  Survival data (PFS and OS) will be estimated using 
Kaplan-Meier methods.  
Efficacy will be evaluated based on the as-treated population (Safety Analysis Set).  Safety 
data will be evaluated using the Safety Analysis Set.  Pharmacokinetic data will be evaluated 
using the Pharmacokinetic Analysis Set on pooled data from both Cohort 1 and Cohort 2.  
Other study results for Cohort 1 and Cohort 2 will be reported separately. 
Primary Endpoint Analyses 


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Cohort 1 (Single-Agent Dose-Finding) 
Cohort 1 will be a lenvatinib single-agent dose-finding study including up to 24 subjects.  A 
TiTE-CRM design will be used to determine the RD of lenvatinib and to increase the 
flexibility by allowing continuous accrual with no trial suspensions, which are typically 
needed when the toxicity assessment of subjects previously recruited, is not completed 
(Smith, et al., 1998; Cheung, 2009).  Using the TiTE-CRM design, an eligible subject can be 
included in the trial at any time, without waiting for the completion of prior subjects 
(Doussau, et al., 2012).  The model will be re-estimated considering all the toxicity 
observations currently available.  The subject will be treated at the best current estimate of 
the RD.  Individual subjects on long-term treatment may be treated at a dose below the dose 
recommended by the model for safety reasons. 
The RD will be defined as the dose that has a DLT rate closest to the targeted 20% rate.  
Four experimental doses may be investigated in Cohort 1:  Dose -1 (9 mg/m2), Dose 1 
(11 mg/m2), Dose 2 (14 mg/m2), and Dose 3 (17 mg/m2).  The starting dose will be Dose 1. 
A one-parameter empirical power model will be used to assess the relation between the dose 
level and the probability of DLT: 
)
exp(
)
,
(
α
α
d
p
d
F
=
 where F(d,α) is the estimated probability 
of DLT at dose-level d, pd is the prior probability of DLT at dose level d, and α is the 
unknown parameter to be estimated by the model.  The vector {p0d} represents the initial 
guesses of toxicity probabilities, reflecting the clinicians’ prior impression.  The skeleton of 
initial guesses of toxicity probabilities {p0d} is numerically calibrated using the approach of 
(Lee, et al., 2005; Cheung, 2009) and using the “getprior” function of R, ensuring good 
design operating characteristics.  Based on consultation with the clinicians, the delta (half of 
the width of the CI) defining the indifference interval was set at 0.06 (indifference interval: 
0.14 to 0.26) and the prior maximum tolerated dose (MTD0) at Dose 2, (14 mg/m²) is likely 
to be the RD (same as in adults).  This yields a vector of prior probabilities {p0k} equal to 
0.03, 0.10, 0.20, and 0.33, for the doses 9 mg/m2, 11 mg/m2, 14 mg/m2, and 17 mg/m2, 
respectively, that was found reasonable by the clinicians.  
A noninformative prior distribution Normal (0, 1.34) has been assigned for α in the Bayesian 
computation.  
The simulation study confirmed that the operating characteristics of the model defined with 
these parameters were reasonable, with more than 50% correct selection of the RD in 3 
contrasted scenarios.  
Starting with Dose 1, the prior distribution of the parameter α will be updated by the 
accruing data on DLTs each time a subject completes evaluation for toxicity in Cycle 1.  
Additional subjects will be allocated to the dose associated with the posterior probability of 
DLT closest to the target.  At least 2 subjects will be required to complete 4-week treatment 
in Cycle 1 or report a DLT in Cycle 1 (at the starting dose) before a subject can be treated at 
the next dose level.  It is further specified that dose levels cannot be skipped when escalating.  
The RD will be determined either when approximately 18 subjects have been tested, or when 


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futility is declared or when 10 subjects have been treated at the same dose.  Futility is defined 
as having a low probability that any of the doses is safe.  
Cohort 2 (Single-Agent Expansion) 
DTC and osteosarcoma groups will be evaluated separately. 
Cohort 2A:  DTC  
The primary efficacy endpoint is ORR for subjects with measurable disease and BOR for all 
subjects.  All ORR or BOR will be based on RECIST 1.1 assessed every 8 weeks.   
The analyses will be descriptively performed on the Safety Analysis Set.  
Cohort 2B:  Osteosarcoma  
The primary efficacy endpoint is PFS-4 based on RECIST 1.1.   
The null hypothesis that PFS-4 is ≤25% will be tested against the alternative hypothesis of a 
PFS-4 ≥45%, using the 1-sample exact test of a single proportion, at the 1-sided 0.1 level.  
PFS-4 will be presented with corresponding 2-sided, exact binomial 80% and 95% CIs.  This 
analysis will be performed on the Safety Analysis Set. 
Cohort 3:  Combination Dose-Finding and Expansion) 
Cohort 3A: Osteosarcoma Combination Dose-Finding  
As in Cohort 1, the DLT will be assessed to determine the RD of lenvatinib in combination 
with chemotherapy (ifosfamide and etoposide).  DLTs occurring during Cycle 1 will be 
evaluated and the subjects will be assigned a dose based on the rules for Dose-Escalation and 
De-Escalation (refer to Section Study Design Treatment Phase: Cohort 3A). 
Cohort 3B:  Osteosarcoma Combination Expansion 
The primary efficacy endpoint is PFS-4 based on RECIST 1.1.   
The null hypothesis that PFS-4 is ≤25% will be tested against the alternative hypothesis of a 
PFS-4 ≥50%, using the 1-sample exact test of a single proportion, at the 1-sided 0.1 level. 
PFS-4 will be presented with corresponding 2-sided, exact binomial 80% and 95% CIs.  This 
analysis will be performed on the lenvatinib-naïve subjects in Safety Analysis Set, while 
subjects enrolled from Cohorts 1 and 2B will only be summarized as appropriate. 
Secondary Endpoint Analyses  
The secondary endpoints of PFS and TTP will be analyzed using Kaplan-Meier product-limit 
estimates.  Median PFS, and the cumulative probability of PFS at 4 and 12 months will be 
presented with 2-sided, 95% CIs when an adequate number of at risk subjects at those time 


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points warrant the estimate.  The cumulative PFS and TTP probabilities will be plotted over 
time as appropriate. 
The secondary endpoints of ORR, DCR, and CBRwill be calculated with exact binomial 95% 
CIs. 
The endpoint of OS will be analyzed using Kaplan-Meier product-limit estimates.  Median 
OS and the cumulative probability of OS at 12 months will be presented with 2-sided, 95% 
CIs when an adequate number of at risk subjects at those time points warrant the estimate.   
The above analyses will be based on the lenvatinib-naïve subjects in Safety Analysis Set, 
while other subjects enrolled from Cohorts 1 and 2B will be summarized for these endpoints 
as appropriate. 
Pharmacokinetic, Pharmacodynamic, and Pharmacogenomic/Pharmacogenetic 
Analyses 
Plasma concentrations of lenvatinib versus time data will be listed.  Plasma concentrations of 
lenvatinib versus time data will be analyzed using a population PK approach to estimate 
population PK parameters.  The analysis will be detailed in an analysis plan at a later date. 
Correlation between clinical response to lenvatinib treatment and blood or tumor biomarkers 
may be examined using descriptive statistics and graphic displays as appropriate.  If 
conducted, a detailed analysis plan will be provided in a separate document. 
Exploratory/graphical analyses will be conducted for PK/PD evaluations, and may be 
followed by model based analyses.  If conducted, a detailed analysis plan will be provided in 
a separate document at a later date. 
Safety Analyses 
The incidence of treatment-emergent adverse events (TEAEs) and SAEs will be summarized 
by study cohort, dose-level, and group.  Laboratory test data, vital signs, 12-lead ECGs, urine 
dipstick, occult blood in stool, Lansky play scores or Karnofsky performance scores, physical 
examination, height, and proximal tibial growth plates at scheduled time points and their 
changes from baseline will be summarized by study cohort and group using descriptive 
statistics, as appropriate.  Abnormal values will be flagged.  Prior and concomitant 
medications, medical/surgical history, and subject demographics will be summarized and 
listed by study cohort and group.  
Other Analyses 
Measurement of palatability will be assessed using the Hedonic scale (Guinard, 2001) which 
is a Visual Analog Scale (VAS). 
 


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Interim Analyses 
Interim analyses may be performed after consultation with the PSC. 
The sponsor will closely evaluate the risks and benefits of the study throughout its conduct, 
along with the PSC as needed. 
Sample Size Rationale 
Approximately 69 to 108 subjects are planned for this study. 
Cohort 1 (Single-Agent Dose-Finding) 
Approximately 12 to 24 subjects based on TiTE-CRM algorithm (Cheung and Chappell, 
2000).  
Cohort 2 (Single-Agent Expansion) 
Approximately 27 to 42 subjects:  DTC group (12 subjects) and osteosarcoma group (15 to 
30 subjects). 
Cohort 2A:  DTC Group 
Approximately 12 subjects with evaluable or measurable disease are planned to be enrolled 
in Cohort 2A due to limited number of pediatric patients with DTC.   
Cohort 2B:  Osteosarcoma Group 
A minimum of 15 PFS-4 evaluable subjects will be assessed in cohort 2B.  The sample size 
estimates were based on Simon’s Optimal Two-Stage Design (Simon, 1989).  If fewer than 5 
subjects who are alive and free of disease progression at 4 months after first dose date are 
observed among the 15 evaluable subjects in Stage I, accrual in the cohort will be suspended.  
Otherwise, if at any time during Stage I of the cohort, at least 5 subjects who are alive and 
free of disease progression at 4 months after first dose date are recorded among the 15 
evaluable subjects, enrollment in the cohort will continue seamlessly for a total of 
approximately 27 evaluable subjects.  If, at the end of the second stage for the cohort, at least 
10 subjects who are alive and free of disease progression at 4 months are recorded among the 
27 subjects in the cohort, study drug will be considered active in the population. 
The above sample size estimates are based on the following assumptions:  the null hypothesis 
PFS-4 (H0) is ≤ 25%, and the alternative hypothesis PFS-4 (H1) is ≥ 45%.  One-sided Type I 
error (α) = 0.1, and power = 80%.  To account for nonevaluable subjects, a total of 15-30 
osteosarcoma subjects will be enrolled for Cohort 2B. 
Cohort 3 (Combination Dose-Finding and Expansion) 
Cohort 3A (Combination Dose-Finding) 
Approxinately 12 to 24 osteosarcoma subjects for whom ifosfamide and etoposide are 


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considered a treatment option 
Cohort 3B (Combination Expansion) 
With the following assumptions:  p0=25%, p1=50%, 1-sided α=10%, β=20%, where p0 is an 
unacceptable rate of PFS, p1 is the target rate of PFS, α is the probability of declaring 
lenvatinib effective when the true rate is p0, and β is the probability of declaring lenvatinib 
not effective if the true rate is p1, a sample size of 15 subjects will provide a statistical power 
of 80%.  To account for nonevaluable subjects, a total of 18 lenvatinib-naïve subjects will be 
enrolled for Cohort 3B, along with some subjects enrolled from Cohorts 1 and 2B.   


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3 
TABLE OF CONTENTS 
1 
TITLE PAGE .....................................................................................................................1 
2 
CLINICAL PROTOCOL SYNOPSIS ...............................................................................4 
3 
TABLE OF CONTENTS .................................................................................................38 
4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..................................43 
5 
ETHICS............................................................................................................................48 
5.1 
Institutional Review Boards/Independent Ethics Committees ..............................48 
5.2 
Ethical Conduct of the Study .................................................................................48 
5.3 
Subject Information and Informed Consent ...........................................................49 
6 
INVESTIGATORS AND STUDY PERSONNEL ..........................................................50 
7 
INTRODUCTION ...........................................................................................................50 
7.1 
Pediatric Cancers ...................................................................................................50 
7.1.1 
Epidemiology and Etiology of Pediatric Thyroid Cancer ............................50 
7.1.2 
Epidemiology and Etiology of Pediatric Osteosarcoma ..............................51 
7.1.3 
Current Therapeutic Options........................................................................52 
7.1.3.1 
Angiogenesis and Pediatric Tumors - Mechanism of Action ............54 
7.1.3.2 
Clinical Experience with Lenvatinib .................................................56 
7.1.3.3 
Lenvatinib Clinical Experience in Thyroid Cancer ...........................57 
7.1.3.4 
Pediatric Studies.................................................................................58 
7.2 
Study Rationale ......................................................................................................58 
8 
STUDY OBJECTIVES ....................................................................................................58 
8.1 
Primary Objective(s) ..............................................................................................58 
8.2 
Secondary Objective(s) ..........................................................................................59 
8.3 
Exploratory Objective ............................................................................................60 
9 
INVESTIGATIONAL PLAN ..........................................................................................60 
9.1 
Overall Study Design and Plan ..............................................................................60 
9.1.1 
Pretreatment Phase (All Cohorts) ................................................................62 
9.1.1.1 
Screening (All Cohorts) .....................................................................62 
9.1.1.2 
Baseline (All Cohorts) .......................................................................63 
9.1.2 
Treatment Phase ...........................................................................................63 
9.1.2.1 
Cohort 1 (Single-Agent Dose-Finding) .............................................63 
9.1.2.2 
Cohort 2 (Single-Agent Expansion)...................................................65 
9.1.2.3 
Cohort 3A: Combination Dose-Finding.............................................65 
9.1.2.4 
Cohort 3B (Combination Expansion) ................................................67 
9.1.3 
Post-treatment (All Cohorts) ........................................................................67 
9.2 
Discussion of Study Design, Including Choice of Control Groups .......................68 
9.3 
Selection of Study Population ................................................................................69 
9.3.1 
Inclusion Criteria .........................................................................................69 


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9.3.2 
Exclusion Criteria ........................................................................................72 
9.3.3 
Removal of Subjects from Therapy or Assessment .....................................74 
9.4 
Treatment ...............................................................................................................75 
9.4.1 
Treatment(s) Administered ..........................................................................75 
9.4.1.1 
Dose-Limiting Toxicity .....................................................................75 
9.4.1.2 
Lenvatinib Dose Reduction and Interruption Instructions .................76 
9.4.1.3 
Blood Pressure ...................................................................................79 
9.4.1.4 
Management of Hypertension ............................................................79 
9.4.1.5 
Management of Posterior Reversible Leukoencephalopathy 
Syndrome (PRES) ..............................................................................81 
9.4.1.6 
Management of Proteinuria ................................................................82 
9.4.1.7 
Management of Hepatotoxicity..........................................................82 
9.4.1.8 
Management of Thromboembolic Events ..........................................82 
9.4.1.9 
Management of Hypocalcemia ..........................................................83 
9.4.1.10 
Management of Gastrointestinal Symptoms and Acute Abdominal 
Pain ....................................................................................................83 
9.4.1.11 
For additional information please refer to the current 
Investigator’s Brochure (Lenvatinib Investigator’s Brochure). 
Management of Ifosfamide-Etoposide Associated Toxicity ..............83 
9.4.2 
Identity of Investigational Product(s) ..........................................................84 
9.4.2.1 
Chemical Name, Structural Formula of Lenvatinib ...........................84 
9.4.2.2 
Comparator Drug ...............................................................................85 
9.4.3 
Cytotoxic Chemotherapy:  Ifosfamide and Etoposide .................................85 
9.4.3.1 
Labeling for Study Drug ....................................................................85 
9.4.3.2 
Storage Conditions .............................................................................86 
9.4.4 
Method of Assigning Subjects to Treatment Groups ...................................86 
9.4.5 
Selection of Doses in the Study ...................................................................87 
9.4.6 
Selection and Timing of Lenvatinib Dose for Each Subject ........................87 
9.4.7 
Blinding........................................................................................................87 
9.4.8 
Prior and Concomitant Therapy ...................................................................87 
9.4.8.1 
Drug-Drug Interactions ......................................................................88 
9.4.8.2 
Prohibited Concomitant Therapies and Drugs ...................................88 
9.4.8.3 
Permitted Concomitant Treatment/Procedures ..................................89 
9.4.9 
Any additional procedural or patient specific particularities should be 
discussed with the investigator and the sponsor.  Treatment Compliance ..89 
9.4.10 
Drug Supplies and Accountability ...............................................................89 
9.5 
Study Assessments .................................................................................................91 
9.5.1 
Assessments .................................................................................................91 
9.5.1.1 
Demography .......................................................................................91 
9.5.1.2 
Baseline Assessments ........................................................................91 
9.5.1.3 
Efficacy Assessments.........................................................................92 


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9.5.1.4 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Assessments ...........................................................94 
9.5.1.5 
Safety Assessments ............................................................................96 
9.5.2 
Schedule of Assessments ...........................................................................102 
9.5.2.1 
Schedule of Assessments .................................................................102 
9.5.3 
Appropriateness of Measurements .............................................................115 
9.5.4 
Reporting of Serious Adverse Events, Pregnancy, and Events 
Associated with Special Situations ............................................................115 
9.5.4.1 
Reporting of Serious Adverse Events ..............................................115 
9.5.4.2 
Reporting of Pregnancy and Exposure to Study Drug Through 
Breastfeeding ...................................................................................116 
9.5.4.3 
Reporting of Events Associated with Special Situations .................116 
9.5.4.4 
Expedited Reporting ........................................................................118 
9.5.4.5 
Breaking the Blind ...........................................................................118 
9.5.4.6 
Regulatory Reporting of Adverse Events ........................................118 
9.5.5 
Completion/Discontinuation of Subjects ...................................................118 
9.5.6 
Abuse or Diversion of Study Drug ............................................................119 
9.5.7 
Confirmation of Medical Care by Another Physician ...............................119 
9.6 
Data Quality Assurance .......................................................................................119 
9.6.1 
Data Collection ..........................................................................................119 
9.6.2 
Clinical Data Management ........................................................................119 
9.7 
Statistical Methods ...............................................................................................120 
9.7.1 
Statistical and Analytical Plans ..................................................................120 
9.7.1.1 
Study Endpoints ...............................................................................120 
9.7.1.2 
Definitions of Analysis Sets.............................................................123 
9.7.1.3 
Demographic and Other Baseline Characteristics ...........................123 
9.7.1.4 
Prior and Concomitant Therapy .......................................................123 
9.7.1.5 
Efficacy Analyses ............................................................................124 
9.7.1.6 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Analyses ...............................................................127 
9.7.1.7 
Safety Analyses ................................................................................127 
9.7.1.8 
Other Analyses .................................................................................129 
9.7.2 
Determination of Sample Size ...................................................................129 
9.7.3 
Interim Analysis .........................................................................................130 
9.7.4 
Other Statistical/Analytical Issues .............................................................130 
9.7.5 
Procedure for Revising the Statistical Analysis Plan .................................130 
10 REFERENCE LIST .......................................................................................................131 
11 PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE PROCEDURES) .....137 
11.1 
Changes to the Protocol .......................................................................................137 
11.2 
Adherence to the Protocol ....................................................................................137 
11.3 
Monitoring Procedures.........................................................................................137 


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11.4 
Recording of Data ................................................................................................138 
11.5 
Identification of Source Data ...............................................................................138 
11.6 
Retention of Records............................................................................................138 
11.7 
Auditing Procedures and Inspection ....................................................................139 
11.8 
Handling of Study Drug .......................................................................................139 
11.9 
Publication of Results ..........................................................................................139 
11.10 Disclosure and Confidentiality ............................................................................140 
11.11 Discontinuation of Study .....................................................................................140 
11.12 Subject Insurance and Indemnity .........................................................................140 
12 APPENDICES ...............................................................................................................141 
 
LIST OF IN-TEXT TABLES 
Table 1 
Lenvatinib Doses for Dose-Finding (Cohort 1) .........................................63 
Table 2 
Lenvatinib and Chemotherapy Doses for Combination Dose-Finding 
(Cohort 3A) ..................................................................................................................65 
Table 3 
Criteria for Temporary Discontinuation of Study Drug, Dose 
Reduction, and Resumption of Treatment ...................................................................78 
Table 4 
Criteria for Dose Modification of Chemotherapy Dose ............................84 
Table 5 
Lenvatinib Pharmacokinetic Sampling Time Points..................................95 
Table 6 
Clinical Laboratory Tests .........................................................................100 
Table 7 
Schedule of Assessments – Cohort 1 .......................................................103 
Table 8 
Schedule of Assessments – Cohort 2A – Differentiated Thyroid 
Cancer and Cohort 2B - Osteosarcoma ......................................................................107 
Table 9 
Schedule of Assessments – Cohorts 3A and 3B – Osteosarcoma ...........111 
 
LIST OF IN-TEXT FIGURES 
Figure 1 
Overall Study Design .................................................................................61 
Figure 2 
Management of Hypertension ....................................................................81 
 
LIST OF APPENDICES 
Appendix 1 
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 ................141 
Appendix 2 
Common Terminology Criteria for Adverse Events (v4.0) .....................142 
Appendix 3 
Papillary or Follicular Thyroid Carcinoma Staging .................................143 
Appendix 4 
Lansky Score ............................................................................................144 
Appendix 5 
Karnofsky Performance Status Scale Definitions Rating (%) Criteria ....145 


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Appendix 6 
Schwartz Formula ....................................................................................146 
Appendix 7 
Blood Pressure Levels for Boys by Age and Height Percentile ..............147 
Appendix 8 
Blood Pressure Levels for Girls by Age and Height Percentile...............149 
Appendix 9 
Body Mass Index-For-Age Percentiles ....................................................151 
Appendix 10 Body Mass Index-For-Age Percentiles ....................................................152 
Appendix 11 Pharmacodynamic, Pharmacogenomic, and Other Biomarker Research 153 
Appendix 12 Preparation of Lenvatinib Suspension .....................................................156 
Appendix 13 Palatability Questionnaire ........................................................................162 


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4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Term 
131I 
radioiodine 
ACE 
angiotensin converting enzyme 
ADME 
absorption, distribution, metabolism, excretion 
AE 
adverse event 
ALT 
alanine aminotransferase 
AJCC 
American Joint Committee on Cancer 
AST 
aspartate aminotransferase 
ANC 
absolute neutrophil count 
ATC 
Anatomical-Therapeutic-Chemical 
AUC 
area under the concentration x time curve 
bFGF 
basic fibroblast growth factor 
β-hCG 
beta-human chorionic gonadotropin 
BID 
twice daily 
BMI 
body mass index 
BOR 
best overall response 
BP 
blood pressure 
BSA 
body surface area 
BUN 
blood urea nitrogen 
CA 
competent authorities 
CBR 
clinical benefit rate 
CEP 
circulating endothelial progenitor cell 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CK 
creatine kinase 
Cmax 
maximum drug or metabolite concentration 
CPM 
cyclophosphamide 
CR 
complete response 
CRA 
Clinical Research Associate 
CRF 
case report form 


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CRM 
continual reassessment method 
CRO 
Clinical Research Organization 
CSR 
clinical study report 
CT 
computerized tomography 
CTC 
Common Toxicity Criteria 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
curriculum vitae/coefficient of variation 
CYP/CYP3A4 
Cytochrome P450/cytochrome P4503A4 
DCR 
disease control rate 
DLT 
dose limiting toxicity 
DNA 
deoxyribonucleic acid 
DOR 
duration of response 
DTC 
differentiated thyroid cancer 
EBRT 
external bean radiotherapy 
EC 
European Communities 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EDC 
Electronic Data Capture 
EEG 
electroencephalogram 
ELISA 
enzyme-linked immunosorbent assay 
EU 
European Union 
FDA 
Food and Drug Administration 
FGFR 
fibroblast growth factor receptor 
FGF 
fibroblast growth factor 
Flt-1 
fms-like tyrosine kinase-1 
FS 
fractional shortening 
FTC 
follicular thyroid cancer 
GBq 
Gigabequerels 
GCP 
Good Clinical Practice 
h 
Hour 
HIV 
human immunodeficiency virus 
HR 
hazard ratio/heart rate 


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IC50 
half maximal inhibitory concentration 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use 
ID 
identification 
IEC 
Independent Ethics Committee 
IHC 
immunohistochemical 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
IUD 
intrauterine device 
IVRS/IWRS 
interactive voice/web response system 
KDR 
kinase insert domain receptor 
KM 
Kaplan-Meier 
LC/MS/MS 
liquid chromatography/mass spectrometry/mass spectrometry 
LDH 
lactate dehydrogenase 
LVEF 
left ventricular ejection fraction 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MEN 
multiple endocrine neoplasia 
MRI 
magnetic resonance imaging 
MTC 
medullary thyroid cancer 
MTD 
maximum tolerated dose 
MTD0 
prior maximum tolerated dose 
N/n 
number 
NA 
not applicable 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NE 
not evaluable 
NYHA 
New York Heart Association 


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ORR 
objective response rate 
OS 
overall survival 
PBMC 
peripheral blood mononuclear cells 
PD 
pharmacodynamics(s) or progressive disease 
PDGFR 
platelet-derived growth factor receptor 
PDGFRβ 
platelet-derived growth factor receptor beta 
PFS 
progression-free survival 
PFS-4 
progression free survival at 4 months 
PI 
principal investigator 
PK 
pharmacokinetic(s) 
pNET 
primitive neuroectodermal tumors 
PR 
partial response 
PRES  
Posterior Reversible Leukoencephalopathy Syndrome  
PSC 
Protocol Steering Committee 
PT 
preferred term 
PTC 
papillary thyroid cancer 
QD 
once daily 
RBC 
red blood cell (count) 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RD 
recommended dose 
RET 
rearranged during transfection 
RF 
radiofrequency 
RR 
respiratory rate 
RTK 
receptor tyrosine kinase 
QTc 
QT interval corrected for heart rate 
SAE 
serious adverse event 
SD 
stable disease 
SEER 
Surveillance Epidemiology and End Result 
SmPC 
summary of product characteristics 
SOC 
system organ class 
SOP 
standard operating procedure 


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SUSARs 
suspected unexpected serious adverse reactions 
99m-Tc 
99m-technetium 
t1/2 
terminal elimination half-life 
T4 
thyroxine 
TEAEs 
treatment-emergent adverse events 
TiTE-CRM 
Time To Event-Continual Reassessment Method 
TEAV 
treatment-emergent abnormal laboratory value 
Tmax 
time to reach maximum (peak) concentration following 
administration 
TNM 
tumor-node metastasis 
TSH 
thyroid stimulating hormone 
TTP 
time to progression 
UK 
United Kingdom 
ULN 
upper limit of normal 
US/USA 
United States of America 
VEGF 
vascular endothelial growth factor  
VEGFR 
vascular endothelial growth factor receptor 
WBC 
white blood cell (count) 
WHO DD 
World Health Organization Drug Dictionary 


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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 ICH E6 (Good Clinical 
Practice), Section 3, and any local regulations (eg, European Union [EU] Clinical Trials 
Directive 2001/20/EC or Code of Federal Regulations, Title 21 CFR Part 56).  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 [CRA], 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 
(CA) within 90 days.  The definition for end of the study is the time of data cutoff for the 
final analysis or the time of last subject/last treatment, whichever occurs later.  It is estimated 
that the study duration will be 36 months. 
In the case of early termination/temporary halt of the study, the investigator should notify the 
IEC and competent authority (CA) within 15 days and a detailed written explanation of the 
reasons for the termination/halt should be given. 
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, 2008 


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• 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 
Harmonization 
of 
Technical 
Requirements 
for 
Pharmaceuticals for Human Use 
• US 21 CFR, including parts 50 and 56 concerning Informed Patient Consent and IRB 
regulations, and applicable sections of US 21 CFR Part 312 
All studies that are conducted within any EU country will comply with the European Clinical 
Trial Directive 2001/20/EC.  All SUSARs will be reported, as required, to the CA 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 and the 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 will be given by means of a standard written statement, written in 
nontechnical language.  The subject 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.   
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, EU Clinical 
Trials Directive 2001/20/EC or Code of Federal Regulations, Title 21, CFR Part 50) and 
provided to the sponsor.  Each subject and the subject’s parent(s) or legally acceptable 


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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 (or 16 years in the UK) while on study, and 
becomes competent to give informed consent, his/her consent will be obtained using separate 
ICFs to continue on the study. 
6 
INVESTIGATORS AND STUDY PERSONNEL 
This study will be conducted by qualified investigators under the sponsorship of Eisai (the 
sponsor) at approximately 12 investigational site(s) in the European Union (EU) and the US. 
The name and telephone and fax numbers of the Eisai Medical Monitor and other contact 
personnel at the sponsor will be listed in the Regulatory Binder provided to each site. 
7 
INTRODUCTION 
7.1 
Pediatric Cancers  
Cancer occurs rarely in children and adolescents (incidence of 10 to 15 cases per 100,000 
individuals <19 years of age) and the incidence is comprised mainly of leukemias 
(approximately 30% of all cases) and solid tumors (Ries, et al., 1999).  Current treatments for 
malignant solid tumors in pediatric patients involve a combination of chemotherapy, surgery, 
and in certain cases, radiotherapy.  This multidisciplinary treatment approach leads to an 
overall cure rate of 80%.  Nevertheless, cancer mortality remains the leading cause of 
disease-related death in children and adolescents between 1 and 19 years of age.  This 
mortality rate is due to diseases with a poor prognosis (3-year overall survival <30%), such 
as metastatic neuroblastoma, multi-metastatic bone sarcomas (osteosarcomas and Ewing’s 
sarcomas), metastatic medulloblastomas, and refractory disease and relapses of most of the 
pediatric solid tumors.   
7.1.1 
Epidemiology and Etiology of Pediatric Thyroid Cancer 
Pediatric thyroid cancer is rare, with less than 15% of differentiated thyroid cancer (DTC) 
cases diagnosed at age <18 years.  However, it does account for approximately 10% of 
malignant tumors and approximately 35% of carcinomas in children (Bernstein and Gurney, 
1999).  In the US, approximately 350 people younger than 20 years of age are diagnosed with 
thyroid carcinoma each year (Bernstein and Gurney, 1999).  In Europe, annual numbers of 
new pediatric cases are similar to the US with the exception of the geographic areas close to 


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the 1986 nuclear plant accident in Chernobyl, where much higher incidence rates are 
observed (Steliarova-Foucher, et al., 2006).  
Differentiated thyroid cancer comprises 90% to 95% of all childhood thyroid cancers.  
Medullary thyroid cancer (MTC) is diagnosed in 5% to 8% of childhood thyroid cancer 
patients (Bernstein and Gurney, 1999; Harach and Williams, 1995).  Undifferentiated thyroid 
tumors, ie, insular and anaplastic cancers, are extremely rare in the pediatric population 
(Hassoun, et al., 1997).  Juvenile DTC is classified as sporadic or radiation induced.  These 2 
forms do not appear to have major clinical differences (Samaan, et al., 1987).   
Juvenile DTC appears to have several notable differences when compared to DTC in adults.  
DTC in childhood is often more advanced at presentation and there is a higher risk of disease 
recurrence.  In addition, a higher propensity for lymph node and distant lung metastases is 
observed in childhood DTC.  
In papillary thyroid cancer (PTC), which constitutes the main histologic type of DTC 
diagnosed in children, there are 2 major initiating events, rearranged transformation/papillary 
thyroid carcinoma (RET/PTC) and BRAF point mutation T1799A, both activating the 
mitogen activated protein kinase (MAPK) signaling pathway (Santoro, et al., 2006).  
RET/PTC is a chimeric gene generated by the fusion of the tyrosine kinase domain of the 
rearranged during transfection gene (RET) to the 5′terminal region of genes that are 
constitutively expressed in thyroid follicular cells and result in constitutively active tyrosine 
kinase.  There are at least 10 different types of RET/PTC of which RET/PTC1 and 
RET/PTC3 are the most common types, accounting for >90% of all rearrangements (Xing, 
2005).   The frequency of RET/PTC rearrangement differs substantially in various 
populations, the most important factor seems to be age:  RET/PTC rearrangements are much 
more frequent in younger patients (aged 6 to 21 years of age) with PTC and especially in 
children <8 years of age.  The T1799A BRAF point mutation is the more common mutation 
in sporadic papillary carcinomas seen in adult patients.  It occurs in approximately 40% to 
60% of all cases (Kumagai, et al., 2004).  In contrast to adult papillary carcinomas, pediatric 
tumors (both sporadic and radiation-induced) have a low (0% to 12%) prevalence of BRAF 
mutations (Giordano, et al., 2005).  
7.1.2 
Epidemiology and Etiology of Pediatric Osteosarcoma 
Osteosarcoma is the most commonly diagnosed primary malignancy of the bone, particularly 
in children and adolescents.  Malignancies of the bone, with an average annual incidence rate 
of 8.7 per million children younger than 20 years of age, comprise about 6% of childhood 
cancers reported by the Surveillance, Epidemiology, and End Results (SEER) program area 
from 1975 to 1995 (Gurney, et al., 1997).  In the US, between 650 and700 children and 
adolescents younger than 20 years of age are diagnosed with bone tumor each year of which 
approximately 400 are osteosarcomas and 200 are Ewing’s sarcomas (Gurney, et al., 1997).  
There is a bimodal age distribution of osteosarcoma incidence.  A primary peak in 
osteosarcoma incidence occurs in children and adolescents ages 0 to 24 years, the incidence 
plateaus for ages 25 to 59 years, with a second peak in the elderly (ages 60 to >85).  Current 


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treatment utilizes multi-agent chemotherapy and surgical resection of all clinically detectable 
disease.   
An extensive list of genetic abnormalities and environmental exposures, including vascular 
endothelial growth factor receptor (VEGFR) platelet-derived growth factor receptor 
(PDGFR) overexpression, c-fos overexpression, and radiation exposure, has been associated 
with the development of osteosarcoma in laboratory models as well as humans (Gorlick and 
Khanna, 2010).  A single recurrent genetic event does not seem to define this cancer.  The 
vast majority of abnormal oncogenes and tumor-suppressor genes associated with 
osteosarcoma are also common in the most prevalent cancers (Gorlick and Khanna, 2010).  
The use of ionizing radiation for the treatment of childhood solid tumors has been well 
implicated in the development of a second malignancy, with osteosarcoma being the most 
likely to develop within the first 2 decades following treatment (Le Vu, et al., 1988).   
7.1.3 
Current Therapeutic Options 
Recurrent Pediatric DTC Which is Refractory/Resistant to Radioiodine 
The current standard management of pediatric DTC is total or near total thyroidectomy (often 
with central lymph node dissection) followed by radioiodine (131I) ablation and then thyroid 
hormone treatment, with further surgery and ablation for recurrences.  Despite pediatric cases 
having large initial tumors, common involvement of cervical lymph node at presentation, and 
high recurrence rates, this approach is highly successful with a 5 year survival rate of 96% to 
100% and a 20 year survival rate of over 90%. 
A subset of these pediatric/adolescent patients with recurrent relapsed DTC may become 
refractory and/or resistant to radioiodine. 
Cytotoxic chemotherapy in the setting of 131I-refractory/resistant DTC in any patient age 
group offers little to no benefit and is associated with significant toxicity.  In fact, the 2012 
ESMO Clinical Practice Guidelines for thyroid cancer state that “chemotherapy is no longer 
indicated [for treatment of advanced 131I-refractory DTC] because of lack of effective results 
and should be replaced by enrollment of the patients in experimental trials with targeted 
therapy (Pacini, et al., 2014).”  
Recurrent Pediatric and Adolescent Osteosarcoma  
About 30% of patients with localized disease and 80% of those presenting with metastatic 
disease will relapse (NCCN Bone Cancer Guidelines, 2014).  Complete removal of all sites 
of metastases must be attempted as the disease is otherwise almost universally fatal (ESMO, 
2012).  
The role of second-line chemotherapy for recurrent osteosarcoma is much less well defined 
that of surgery and there is no accepted standard regimen (ESMO, 2012).  Choice may take 
into account the prior disease-free interval, and often includes ifosfamide +/- etoposide +/- 
carboplatin, and other active drugs (ESMO, 2012).  In the two largest reported series, the use 
of second-line chemotherapy correlated with limited prolongation of survival in patients with 


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inoperable metastatic recurrences, while a positive correlation in operable disease was 
observed in only one of the two (Ferrari, et al., 2003; Kempf-Bielack, et al., 2005).  
The combination of etoposide with cyclophosphamide (CPM) or ifosfamide has been 
evaluated in at least 2 clinical trials of >20 patients (Berger, et al., 2009; Gentet, et al., 1997).  
The French Society of Paediatric Oncology conducted a Phase 2 trial of high-dose ifosfamide 
and moderate-dose etoposide in 27 patients with relapsed or refractory childhood 
osteosarcoma (Gentet, et al., 1997).  The chemotherapy regimen was 2 courses (3-4 weeks 
apart) of ifosfamide 3 g/m2/day and etoposide 75 mg/m2/day, each given daily for 4 days 
with mesna uroprotection.  The response rate was 48% (95% confidence interval, 29-67%).  
Response rate was equivalent in the sub-group of 22 patients who had previously received 
ifosfamide (4 CR, 6 PR).   
In another Phase II trial by Italian investigators led by Berger (Berger, et al., 2009), the 
activity of 2 courses of cyclophosphamide and etoposide was evaluated in 26 relapsed high-
risk osteosarcoma patients with a median age of 18.5 years.  The chemotherapy regimen 
consisted of cyclophosphamide 4 g/m2 IV over 3 hours on Day 1 and etoposide 100 mg/m2 
IV over 1 hour twice daily for 3 days on Days 2, 3, and 4 (total dose: 600 mg/m2) with mesna 
uroprotection.  This resulted in a 19% response rate (2 CR, 3 PR).  Progression-free survival 
at 4 months (PFS-4) was 42%.  
In a smaller Phase 2 study reported by Rodríguez-Galindo, 14 children with refractory 
osteosarcoma were given fractionated cyclophosphamide (500 mg/m2/day for 5 days) and 
etoposide (100 mg/m2/day for 5 days) with granulocyte colony-stimulating factor every 21 to 
28 days (Rodriguez-Galindo, et al., 2002).   A total of 47 courses were given (median 3 per 
patient [range: 1 to 12]).  The response rate was 28.5% (1 CR, 3 PR, in 11 evaluable 
subjects). 
In general, despite second-line treatment, the prognosis of recurrent disease in osteosarcoma 
has remained poor, with long-term post-relapse survival of <20% (NCCN Bone Cancer 
Guidelines, 2014).  
In light of this, the use of newer targeted therapies either alone or in combination with 
chemotherapy for bone sarcoma subjects is an area under intensive study in clinical trials.  
Gaspar, Di Giannatale, Geoerger, and colleagues have published a detailed review 
summarizing these efforts (Gaspar, et al., 2012).  
One published Phase 2 trial conducted by the Italian Sarcoma Group explored the activity of 
the multikinase inhibitor sorafenib as single-agent therapy (400-mg dose twice daily) in 35 
patients aged >14 years with relapsed and unresectable osteosarcoma (Grignani, et al., 2012).  
The PFS-4 (primary endpoint) was 46% with a median follow-up of 3.6 months.  The 
objective response rate was 9% (3 PR, no CR).  Based on these results, the 2014 NCCN Bone 
Cancer Guidelines have included sorafenib as a systemic therapy option for osteosarcoma 
patients with relapsed disease (NCCN Bone Cancer Guidelines, 2014).  
 


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Lenvatinib 
Lenvatinib is an oral, multiple receptor tyrosine kinase (RTK) inhibitor that selectively 
inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors 
VEGFR1 (FLT1), VEGFR2 (kinase domain receptor [KDR]), and VEGFR3 (FLT4), in 
addition to other proangiogenic and oncogenic pathway-related RTKs including fibroblast 
growth factor (FGF) receptors FGFR1, 2, 3, and 4; the platelet derived growth factor (PDGF) 
receptor PDGFRα; KIT; and RET.  Lenvatinib inhibits VEGF-driven KDR phosphorylation 
and suppresses proliferation and tube formation in human umbilical vein endothelial cell 
(HUVEC) models.  It has demonstrated antiangiogenic activity and has shown antitumor 
effects against various human cancer xenograft models in mice (Lenvatinib Investigator’s 
Brochure, 2014).  In combination with paclitaxel or platinum-based anticancer agents, it 
showed enhanced antitumor activity in gastric cancer, non-small cell lung cancer, and 
melanoma xenografts in athymic mice (Lenvatinib Investigator’s Brochure, 2014).  In view 
of these properties, it is being developed as an anticancer therapy as a single agent or in 
combination with other anticancer agents.  It has exhibited anti-tumor activity in Phase 1 and 
2 clinical trials in adults; based on which, several Phase 3 clinical trials were initiated.  
Preliminary data have shown promising results in DTC patients in a Phase 2 trial and a Phase 
3 trial in adult DTC patients (Schlumberger M, et al. 2015).  
7.1.3.1 
Angiogenesis and Pediatric Tumors - Mechanism of Action 
Angiogenesis and Vasculogenesis in Pediatric Solid Tumors 
Pediatric tumors are highly vascularized.  As with normal tissue, the growing tumor requires 
an extensive network of capillaries to provide the necessary nutrients and oxygen.  Moreover, 
the new intratumor blood vessels offer a way for tumor cells to enter the circulation and 
metastasize to distant organs and thus play an indispensable role in solid tumor growth and 
metastasis.  Angiogenesis, which is the growth of new capillaries from pre-existing blood 
vessels, and vasculogenesis, which is the differentiation of precursor cells into endothelial 
cells, are the fundamental processes by which new blood vessels are formed.  Angiogenesis 
is the result of a dynamic balance between proangiogenic factors, VEGF and platelet-derived 
growth factor (PDGF), and factors that inhibit angiogenesis such as thrombospondin-1 and 
angiostatin (Bid and Houghton, 2011).  VEGF, through its binding to the RTK vascular 
endothelial growth factor receptor 2 (VEGFR2), is the most potent and specific promoter of 
angiogenesis known.  The PDGFR and their cognate RTK PDGFR have potent implications 
in modulating endothelial cell proliferation and angiogenesis in solid tumors (Geoerger, et 
al., 2003).  Vasculogenesis is mainly dependent on VEGFA/VEGFR2 for migration of the 
bone marrow-derived progenitor cells and Notch signaling (DLL4) for their differentiation 
into pericytes and vascular smooth muscle cells (Stewart and Kleinerman, 2011).  
Growth Factor Receptors in Pediatric Solid Tumors 
VEGF receptor signaling plays a regulatory role in pediatric cancer angiogenesis via both a 
paracrine mechanism through 2 specific tyrosine kinase VEGF receptors, VEGFR1 (or Flt-1) 
and VEGFR2 (or KDR) at the surface of the endothelial cells, and a VEGF autocrine loop 


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involved in pediatric tumor growth (mainly rhabdomyosarcomas [RMS] (Gee, et al., 2005) 
and high-grade gliomas [HGG]) (Tuettenberg, et al., 2006).  Both angiogenesis and 
vasculogenesis appeared to be correlated with metastatic status of the disease and poor 
outcome.  VEGFR plays a significant role in osteosarcoma, a highly vascularized tumor, and 
in DTC.  VEGF expression and serum levels correlated with increased tumor vascularity, 
metastatic potential and poorer prognosis (Bid and Houghton, 2011).  These results advocate 
a role for inhibition of tumor angiogenesis using anti-VEGF methods. 
Fibroblast growth factors (especially FGF2), FGF3, and vascular endothelial growth factor 
(VEGF) are some of the genes acting in multistep bone development.  Fibroblast growth 
factor receptors (FGFR1, 2, 3, and 4) seem to play a major role, the latter particularly in 
RMS (Cao, et al., 2010; Hirotsu, et al., 2009; Taylor, et al., 2009).  FGFR1 is upregulated in 
70 % of human osteosarcomas and involved in the malignant transformation (Guagnano and 
Kauffmann, 2012).  FGF2/FGFR1 activation has been shown to induce growth inhibition, 
neuronal differentiation, and apoptosis in primitive neuroectodermal tumors [PNET] and 
Ewing’s sarcoma (Sturla, et al., 2000; Kim, et al., 2004).  Basic fibroblast growth factor 
(bFGF)/FGFR1 strongly induced the motility and invasion of Ewing’s sarcoma cells 
(Kamura, et al., 2010).  Embryonal RMS patient biopsy specimens were found to over-
express FGFR3 (Bodo, et al., 2002).  An autocrine role of βFGF endogenous release 
controlled the different osteosarcoma phenotypes (Bodo, et al., 2002).  
High expression of the PDGFR and its ligands PDGFα and PDGFβ highlight the role of the 
PDGF pathway in several pediatric tumors (eg., osteosarcoma, [Kubo, 2008] glioma, [Mauro, 
et al., 1991] diffuse pontine glioma, [Zarghooni, et al., 2010] nephroblastoma, [Ghanem, et 
al., 2010] Ewing sarcoma [Schaefer, et al., 2008]).  PDGFR expression is associated with 
clinical stage (nephroblastoma [Ghanem, et al., 2010]), with the metastatic status (eg., 
Ewing’s sarcomas, [Schaefer, et al., 2008] medulloblastoma), and correlates with event-free 
survival (eg., osteosarcoma [Kubo, et al., 2008]). 
The RET protooncogene, a member of the cadherin superfamily, encodes an RTK with a 
crucial role in neural crest development.  Different activating mutations in the RET gene are 
associated with disorders like multiple endocrine neoplasia (MEN) type 2A (MEN2A is 
characterized by MTC, pheochromocytoma, and primary hyperparathyroidism), MEN type 
2B (MEN2B is characterized by clinically aggressive MTC, pheochromocytoma, a 
Marfanoid body habitus, mucosal and other neuromas, and intestinal tumors mostly 
ganglioneuromas), Hirschsprung disease, and MTC. 
Antiangiogenic Therapies in Pediatric Solid Tumors 
Inhibition of single or multiple angiogenic factors have demonstrated antitumor efficacy in 
nonclinical pediatric tumor models (eg, NB [Pacini, et al., 2012; NCCN Bone Cancer 
Guidelines, 2014], 3ES [ESMO, 2012], HGG [Tuettenberg, et al., 2006]).  Vascular 
normalization allows reoxygenation and hence increased radiation sensitivity or increased 
uptake of drugs into tumor tissue, including brain tumors (Tuettenberg, et al., 2006).  Drugs 
such as cediranib (Ferrari, et al., 2003), sorafenib (Kempf-Bielack, et al., 2005), and sunitinib 
(Berger, et al., 2009), exhibited growth inhibitory activity, inducing significant prolongation 


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of the time to event in pediatric solid tumor models.  Complete responses were rare in soft 
tissue sarcoma, Ewing's sarcoma, osteosarcoma, Wilms' tumor, hepatoblastoma, 
ependymoma, and high- and low-grade glioma (Gentet, et al., 1997).  
Tyrosine kinase inhibitor (TKI) class toxicity has been similar to adults, with an apparent 
lower incidence of hypertension in the pediatric population and fewer than anticipated reports 
of growth plate toxicity.  
Inhibition of multiple angiogenic related factors by multitargeted RTK inhibitors:   
RTK inhibitors suppress several angiogenic factors but also other TK proto-oncogenes 
involved in tumor growth and might be useful in tumors with complex genetic abnormalities 
such as osteosarcoma.  Several molecules are available and are currently in early clinical 
trials in children and adolescents with relapsed or refractory cancer.  Phase 1 trials have been 
completed for sunitinib (inhibitor of PDGFR, VEGFR1-3, c-kit, RET, CSF1R, Flt3) with 
observed cardiac toxicity (shortened ejection fraction) for pediatric patients with solid tumors  
with prior anthracycline or radiation exposure, (Rodriguez-Galindo, et al., 2002) and for 
pazopanib (inhibitor of VEGFR1-3, PDGFRα/β, c kit) with 1 partial response in 
hepatoblastoma and 3 stable disease (Zarghooni, et al., 2010).  A pediatric Phase 2 trial is 
ongoing for sorafenib (inhibitor of VEGFR1-3, PDGFR, RET, BRAF, c-kit; NCT01445080), 
that has demonstrated clinical activity in an osteosarcoma Phase 3 study in adults (Ghanem, 
et al., 2010).  A vandetanib (inhibitor of VEGFR2-3, EGFR, RET) Phase 1/2 trial in children 
and adolescents with hereditary medullary thyroid carcinoma started recruiting in 2007 and is 
expected to continue recruiting up to 2014 (Schaefer, et al., 2008).  
All these molecules are well tolerated with a similar toxicity profile (eg, arterial 
hypertension, proteinuria, fatigue, gastrointestinal discomfort) due to VEGF pathway 
inhibition. 
7.1.3.2 
Clinical Experience with Lenvatinib 
As of 27 Apr 2013, 13 studies in Phase 1/1b have been completed in the adult population; 5 
in healthy volunteers, 1 bioavailability, 1 QTc effect, 1 food effect, 2 drug-drug interaction 
(DDI), 2 studies in renally or hepatically impaired subjects, and a mass balance study.  
Lenvatinib is rapidly absorbed with tmax typically from 1 to 4 hours postdose.  The capsule 
form of lenvatinib is about 10% to 14% less bioavailable than the tablet (E7080-A001-001).  
The terminal elimination half-life (t½) of lenvatinib is about 28 hours for both the tablet and 
the capsule.  Serum protein binding of lenvatinib is high (96.6% to 98.2%) and is almost 
constant in the concentration range of 26 ng/mL to 574 ng/mL (Study E7080-J081-103).  
Systemic exposure of lenvatinib increases slightly (15% to 19%) upon coadministration with 
ketoconazole; a CYP3A4 and P glycoprotein inhibitor (P-gp) (E7080-A001-004).  Food did 
not have any significant effect on absorption, indicating that lenvatinib may be administered 
with or without food (E7080-A001-003). A bioavailability study was conducted in adult 
healthy volunteers to evaluate the relative bioavailability and palatability of a lenvatinib 
suspension compared to the capsule formulation (E7080-A001-009). 


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Pharmacokinetic analysis demonstrated that lenvatinib is rapidly absorbed with maximum 
concentrations observed from 1 to 3 hours postdose.  Exposure to lenvatinib, as measured by 
AUC and Cmax, increased proportionally with increasing lenvatinib.  Steady-state plasma 
concentrations were achieved within 5 days.  Lenvatinib elimination occurred with a bi-
exponential decline composed of an initial rapid decline followed by a slower decline.  The 
terminal half-life is approximately 30 hours and steady state is achieved within 5 days.  A 
dose dependent increase in soluble VEGF, consistent with an anti-angiogenic effect was 
observed during 2 weeks of continuous dosing. 
Lenvatinib does not exert a clinically relevant effect on QTcF.  Hepatic impairment did not 
impact the excretion of lenvatinib in urine.  Continuous lenvatinib administration at 25 mg 
once daily (QD) allowed the targeting of higher exposures compared to 10 mg BID and was 
recommended for ongoing and future studies. 
Eight ongoing Phase 2 studies are exploring the safety and efficacy of lenvatinib in subjects 
with DTC and MTC (E7080-G000-201), HCC (E7080-J081-202), malignant glioma (E7080-
G000-203), endometrial cancer (E7080-G000-204), melanoma (E7080-G000-206), thyroid 
cancer (E7080-J081-208), adenocarcinoma of the lung (E7080-G000-209), and NSCLC 
(E7080-703) (O’Day, et al., 2013; Funahashi, et al., 2013; Vergote, et al., 2013).  
Hypertension and proteinuria were the most common dose-limiting toxicities (DLTs).  A 
dose of 25 mg QD was found to be the maximum tolerated dose (MTD) for the QD 
continuous dosing schedule.   
There are 2 ongoing Phase 3 studies, E7080-G000-303, comparing the PFS of subjects 
treated with lenvatinib versus placebo who have 131I-refractory DTC and E7080-G000-304 
comparing the efficacy and safety of lenvatinib versus sorafenib as a first-line systemic 
treatment in subjects with unresectable HCC. 
7.1.3.3 
Lenvatinib Clinical Experience in Thyroid Cancer 
The most common DLTs reported in the Phase 1b studies were hypertension (31%) and 
proteinuria (25%).  TEAEs commonly reported during Phase 1/1b studies included diarrhea, 
nausea, hypertension, fatigue, anorexia, constipation, vomiting, proteinuria, and stomatitis.  
In general, it appears that the incidence of TEAEs increased with increasing doses.  The 
majority of events were ≤Grade 3.  In the Phase 2 program, overall, 97% of subjects 
experienced at least 1 TEAE.  The most frequently reported TEAEs included hypertension, 
fatigue, diarrhea, nausea, and decreased appetite.  More than half of the TEAEs were 
Common Terminology Criteria for Solid Tumors (CTCAE) Grade 3 events, with some 
CTCAE Grade 4 or Grade 5 events.   
As of 27 Apr 2013, 1046 serious adverse events (SAEs) have been reported, including 
deaths.  Of these reported SAEs, 444 were reported as related to test drug and 602 were 
reported as unrelated to test drug.  Of the 187 deaths, 34 (18.2%) were considered related to 
study drug and 153 (81.8%) were considered not related to study drug.  These 187 deaths 
represent the entire lenvatinib program and include ongoing, blinded studies, which may 
include deaths in subjects randomized to placebo. 


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In the randomized, double-blind, placebo-controlled, Phase 3 study that compares the safety 
and efficacy of lenvatinib in subjects with 131I-refractory DTC, a total of 354 SAEs have been 
reported (includes active and blinded arms, excludes placebo arm) of which 151 SAEs 
(42.7%) were reported as related to study drug and 203 SAEs (57.3%) were not related to 
study drug.  The most frequently reported SAEs were hypertension, cerebral vascular 
accident, pneumonia, dehydration, pulmonary embolism, and vomiting. 
For additional information please refer to the current Investigator’s Brochure (Lenvatinib 
Investigator’s Brochure).  
7.1.3.4 
Pediatric Studies 
There is no prior experience with lenvatinib in children. 
7.2 
Study Rationale 
Although DTC is rare in children, subjects with DTC have a higher frequency of relapse and 
their tumors are generally aggressive and advanced at initial presentation.  Chemotherapy in 
the setting of radio-resistant cases offers little or no benefit.  Novel therapies, like lenvatinib, 
with its antiangiogenic activity via the VEGF pathway, may potentially offer therapeutic 
benefit.  However, one of the challenges is that pediatric DTC is rare and it is rarer still to 
find radio-iodine refractory DTC patients.  Osteosarcoma is another pediatric malignancy 
that uses the VEGF regulatory pathway and merits further exploration of new treatment 
options.  Lenvatinib in combination with conventional chemotherapy for pediatric 
osteosarcoma potentially could improve clinical results and warrants clinical study. 
8 
STUDY OBJECTIVES 
8.1 
Primary Objective(s) 
The primary objectives of this study are to: 
Cohort 1 (Single-Agent Dose-Finding) 
• Identify the recommended dose (RD) of lenvatinib as a single agent in children and 
adolescents with relapsed or refractory solid malignant tumors 
Cohort 2 (Single-Agent Expansion) 
• Evaluate the activity of lenvatinib in 2 separate malignancy groups: 
o Cohort 2A:  131I- refractory differentiated thyroid cancer:  by objective 
response rate (ORR) for subjects with measurable disease and best overall 
response (BOR) for all subjects 
o Cohort 2B:  Relapsed or refractory osteosarcoma: by progression-free survival 
at 4 months (PFS-4)  


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Note:  The tumors types under study in the Single-Agent Expansion portion of the study 
may be modified based on preliminary efficacy and safety signals observed in Cohort 1 
of the study. 
Cohort 3 (Combination Dose-Finding and Expansion) 
• Cohort 3A (Combination Dose-Finding) 
o To identify the RD of lenvatinib in combination with ifosfamide and 
etoposide in osteosarcoma subjects 
• Cohort 3B (Combination Expansion) 
o Evaluate the activity of lenvatinib in combination with ifosfamide and 
etoposide in osteosarcoma subjects by PFS-4 
8.2 
Secondary Objective(s) 
The secondary objectives of this study are to: 
Cohort 1 (Single-Agent Dose-Finding) 
• Assess the safety and toxicity profile of lenvatinib in children and adolescents 
• Evaluate the activity of lenvatinib as assessed by best overall response (BOR), ORR, 
duration of response (DOR), progression-free survival (PFS), time to progression 
(TTP), based on RECIST 1.1, disease control rate (DCR), and clinical benefit rate 
(CBR)  
• Evaluate the efficacy of lenvatinib as assessed by overall survival (OS) 
• Examine blood and tumor biomarkers and correlate with clinical response to 
lenvatinib 
• Determine population-based pharmacokinetic (PK) parameters of lenvatinib 
• Assess the palatability and acceptability of the suspension formulation of lenvatinib 
Cohort 2 (Single-Agent Expansion) 
• Assess the safety and toxicity profile of lenvatinib in children and adolescents, and 
young adults with relapsed or refractory osteosarcoma 
• Evaluate the efficacy of lenvatinib as assessed by BOR (osteosarcoma only), ORR 
(osteosarcoma only), DOR (measurable DTC and osteosarcoma only), PFS, TTP , 
DCR and CBR 
• Evaluate the efficacy of lenvatinib as assessed by OS 
• Examine blood and tumor biomarkers and correlate with clinical response to 
lenvatinib 
• Determine population-based PK parameters of lenvatinib 
• Assess the palatability and acceptability of the suspension formulation of lenvatinib  


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Cohort 3 (Combination Dose-Finding and Expansion)  
• Assess the safety and toxicity of lenvatinib in combination with  ifosfamide and 
etoposide in children and adolescents, and young adults with relapsed or refractory 
osteosarcoma  
• Evaluate the efficacy of lenvatinib as assessed by BOR, ORR, DOR, PFS, TTP, DCR 
and CBR 
• Evaluate the efficacy of lenvatinib as assessed by OS 
• Examine blood and tumor biomarkers and correlate with clinical response to 
lenvatinib 
• Determine population-based PK parameters of lenvatinib 
• Assess the palatability and acceptability of the suspension formulation of lenvatinib  
8.3 
Exploratory Objective 
The exploratory objective of this study is to: 
• Explore the relationship of lenvatinib exposure to clinical response in children and 
adolescents (assessed during Cohort 1 [Single-Agent Dose-Finding] and Cohort 2 
[Single-Agent Expansion]) 
9 
INVESTIGATIONAL PLAN 
9.1 
Overall Study Design and Plan 
This is a Phase 1/2, multicenter, open-label, study.  The study will be conducted in 5 cohorts: 


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Figure 1 
Overall Study Design 
Cohort 1 (Single-Agent Dose-Finding):  Dose-escalation to find the RD of lenvatinib using 
a TiTE-CRM design in children and adolescents with relapsed or refractory solid malignant 
tumors (see Study Treatment for dose-escalation scheme; Section 9.1.2.1) (Doussau et al, 
2012).  When the RD is identified, Cohorts 2A, 2B, and Cohort 3A will start in parallel.  
After the RD is determined in Cohort 1, subsequent osteosarcoma subjects will be assigned 
to either Cohort 2B (Single-Agent Expansion) or Cohort 3A (Combination Dose-Finding), 
depending on whether the subject is deemed by the investigator to be a candidate for 
ifosfamide and etoposide. (If not, the subject would only be assigned to Cohort 2B).  
Cohorts 2 (Single-Agent Expansion):  To test the efficacy of lenvatinib in children and 
adolescents with 131I-refractory DTC (Cohort 2A), or subjects with relapsed or refractory 
osteosarcoma (Cohort 2B).  Osteosarcoma subjects will be assigned to either Cohort 2B 
(Single-Agent Expansion) or Cohort 3A (Combination Dose-Finding), depending on whether 
the subject is deemed by the investigator to be a candidate for ifosfamide and etoposide.  If 
not, the subject would only be assigned to Cohort 2B.  Cohort 2A and Cohort 2B will be 
enrolled in parallel with Cohort 3A (Combination Dose-Finding).  


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Cohort 3 
Cohort 3A (Combination Dose-Finding): To define the RD of lenvatinib in combination 
with ifosfamide and etoposide in subjects with relapsed or refractory osteosarcoma.  This 
cohort will be open for enrollment in parallel with Cohort 2 (Single-Agent Expansion).   
After defining the RD of lenvatinib in combination with chemotherapy in Cohort 3A, 
subsequent osteosarcoma subjects will be assigned to either Cohort 2B (Single-Agent 
Expansion) or Cohort 3B (Combination Expansion), depending on whether the subject is 
deemed by the investigator to be a candidate for ifosfamide and etoposide.  If not, the subject 
would only be assigned to Cohort 2B.  
Cohort 3B (Combination Expansion):  To test the efficacy of lenvatinib in combination 
with ifosfamide and etoposide in subjects with relapsed or refractory osteosarcoma. 
Subjects with osteosarcoma who have enrolled into Cohorts 1 or 2B and experienced 
progressive disease on lenvatinib (optional enrollment for subjects in Cohorts 1 and 2B) as 
well as lenvatinib-naïve subjects with relapsed or refractory osteosarcoma will be candidates 
for enrollment in Cohort 3B.  The efficacy analyses will be based on lenvatinib-naïve 
subjects, while subjects from Cohorts 1 and 2B will only be summarized as appropriate. 
The study will include 3 phases:  Pretreatment (screening and baseline), Treatment (includes 
a Run-In Period for Cohort 1), and Post-treatment follow-up.   
9.1.1 
Pretreatment Phase (All Cohorts) 
The pretreatment phase will last no longer than 28 days and will include a Screening Period 
and a Baseline Period. 
9.1.1.1 
Screening (All Cohorts) 
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 prior to the conduct of any screening procedures or assessments.  (Procedures to be 
followed when obtaining informed consent are detailed in Section 5.3.) 
Subjects in Cohort 1 must have a histologically or cytologically confirmed diagnosis of solid 
malignant tumor.  Subjects in Cohort 2 or Cohort 3 must have a histologically or 
cytologically confirmed diagnosis of either osteosarcoma or DTC meeting the criteria for 
being 131I-refractory (either papillary thyroid cancer [PTC] or follicular thyroid cancer 
[FTC]) as detailed in the Inclusion Criteria (Section 9.3.1). 
The Screening Disposition case report form (CRF) page must be completed to indicate 
whether the subject is eligible to participate in the study and to provide reasons for screen 
failure, if applicable. 


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9.1.1.2 
Baseline (All Cohorts) 
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 drug (Cycle 1 Day 1).  
Baseline assessments may be performed on Day -1 or on Cycle 1 Day 1 prior to dosing.  
Clinical laboratory tests (Table 6), including a pregnancy test (where applicable), should be 
performed within 72 hours prior to the first dose of study drug. 
 
Subjects who complete the Baseline Period and continue to meet the criteria for 
inclusion/exclusion (as detailed in Section 9.3.1 and Section 9.3.2) will begin the Treatment 
Phase of this study. 
9.1.2 
Treatment Phase 
In all the cohorts, lenvatinib is administered daily (QD) and 1 treatment cycle is defined as a 
28-day period for Cohorts 1, 2A, and 2B and a 21-day period for Cohorts 3A and 3B.  A new 
treatment cycle begins every 28 days for Single-Agent Cohorts 1, 2A, and 2B or 21-day 
period for Combination-Treatment Cohorts 3A and 3B, irrespective of dose interruptions.  
See Section 9.4.1 for rules regarding the calculation of lenvatinib dose based on body surface 
area (BSA). 
9.1.2.1 
Cohort 1 (Single-Agent Dose-Finding) 
This cohort will identify the RD of lenvatinib as a single agent in children and adolescents 
with relapsed or refractory solid malignant tumors.  The RD in this study will be defined as 
the dose that has a DLT rate closest to the targeted 20% rate. 
Dose-Escalation in Cohort 1 Cycle 1:  
Subjects 6 to <18 years, will enroll in Cohort 1 prior to subjects 2 to <6 years of age.  Each 
subject will be assigned a dose in accordance with the rules of the TiTE-CRM design as 
detailed in Statistical Methods, Section 9.7.1.5.  The TiTE-CRM design is an accepted 
adaptive design used in Phase 1 trials and allows continuous accrual throughout the study 
while using the 4-week toxicity endpoint as the basis for dose-escalation.  Four experimental 
doses of lenvatinib may be investigated in Cohort 1 as displayed in Table 1. 
Table 1 
Lenvatinib Doses for Dose-Finding (Cohort 1) 
Dose Level 
Lenvatinib (QD) 
-1 
9 mg/m2 
1 (starting dose) 
11 mg/m2 
2 
14 mg/m2 
3 
17 mg/m2 
QD = once daily. 
 


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The starting dose (Dose Level 1) of lenvatinib for this cohort is 11 mg/m2 QD 
(approximately 80% of the adult RD of 24 mg QD).  The maximum daily dose should not 
exceed 24 mg.  If the 11 mg/m2 dose is not safe and tolerable, the dose will be de-escalated to 
9 mg/m2 (Dose Level -1). 
Determination as to whether a subject has experienced a DLT will be made by the principal 
investigator and the sponsor according to the DLT definition in Section 9.4.1.1, and as 
needed with the Protocol Steering Committee (PSC).  At least 2 subjects should receive the 
full 4-week study treatment or report a DLT (at the starting dose) and complete the DLT 
evaluations before escalation to the next dose level. Intra-subject dose escalation will not be 
allowed. Subjects who discontinue the study during Cycle 1 (Cycle 1 Day 1 to Cycle 1 Day 
28) for any reason other than DLT will be replaced.  
Intrasubject dose-escalation prior to determining the RD will be allowed only for subjects 2 
to <6 years who can escalate lenvatinib dose when they enter Cohort 1 Cycle 1 from the Run-
In Period as described below. 
Dose-escalation for Subjects 2 to <6 years old: 
Run-In Period:  All subjects 2 to <6 years of age should complete Screening and Baseline 
assessments.  Eligible subjects will first enter a 21-day Run-In Period prior to entering 
Cohort 1.  During the Run-In Period the subject will receive single-agent lenvatinib at 5 
mg/m2/day for 21 days and will be evaluated for DLTs, along with PSC as needed. 
If a subject 2 to <6 years of age experiences a DLT during the Run-In Period, that subject 
will discontinue from the study without entering Cohort 1 Cycle 1, but the DLT data from 
that subject will be used for all subsequent TiTE-CRM calculations and the dose level for 
that subject in all subsequent calculations will be considered as Cohort 1 Dose Level -1 
(9 mg/m2), as 9 mg/m2 is the lowest dose in the Cycle 1 single-agent lenvatinib dose-finding 
cohort.  
Subjects 2 to <6 years of age can enter Cohort 1 Cycle 1 (following the completion of the 
Run-In Period without any DLT) only after:  (1) at least 6 subjects 6 to <18 years of age have 
either completed 4 weeks of treatment in Cycle 1 or reported DLTs during Cycle 1, and (2) 
single-agent lenvatinib has been evaluated and considered by the PSC to be safe based on the 
DLT data from all the previous subjects including subjects 6 to <18 years of age.  When a 
subject 2 to < 6 years of age enters Cohort 1 Cycle 1, the subject will receive a dose that is 
either (1) one level below what is calculated from TiTE-CRM if the calculated dose is greater 
than 9 mg/m2, based on the DLT data from all previous subjects from 2 to <18 years of age, 
or (2) 9 mg/m2 if the TiTE-CRM calculated dose is 9 mg/m2.  Consequently, that subject’s 
DLT data in Cycle 1 will be included in all subsequent TiTE-CRM calculations. 
Once the RD has been determined, subjects treated at a lower dose level should continue to 
be treated at that dose level.   


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9.1.2.2 
Cohort 2 (Single-Agent Expansion) 
Cohort 2 will begin enrollment after the RD of lenvatinib is identified in Cohort 1.  The 
efficacy of lenvatinib will be evaluated in 2 malignancy groups separately:  DTC (Cohort 
2A) and osteosarcoma (Cohort 2B).  Subjects will be treated at the RD identified in Cohort 1.  
The RD of Single-Agent lenvatinib determined in Cohort 1 is 14 mg/m2 as recommended by 
TiTE-CRM and confirmed by PSC.  Subjects in Cohorts 2A and 2B will receive 14 mg/m2 
lenvatinib (equivalent to 24 mg QD, adult daily dose).  After adjustment for BSA, the daily 
dose should not exceed 24 mg QD. 
9.1.2.3 
Cohort 3A: Combination Dose-Finding 
Lenvatinib will be administered orally QD in combination with ifosfamide and etoposide 
from Day 1 to Day 3 of each cycle for a total of 5 cycles to subjects with relapsed or 
refractory osteosarcoma as described below and in Table 2.  See Section 9.4.3 for additional 
details on cytotoxic chemotherapy. 
Table 2 
Lenvatinib and Chemotherapy Doses for Combination Dose-Finding 
(Cohort 3A) 
Dose Modification of Lenvatinib 
 
Dose -
Escalation 
Starting Dose 
De-escalation 1 
De-escalation 2 
Lenvatinib 
RD (from Cohort 
1) 
20% lower than 
RD from Cohort 
1 
40% lower than RD 
from Cohort 1 
60% lower than RD 
from Cohort 1 
 
Dose Modification of Ifosfamide and Etoposide 
 
No Dose 
Escalation 
Starting Dose 
De-escalation 1* 
De-escalation 2* 
Ifosfamide  
3000 mg/m2/day 
IV for 3 days 
2400 mg/m2/day IV 
for 3 days 
1800 mg/m2/day IV for 3 
days 
Etoposide 
 
100 mg/m2/day 
IV for 3 days 
80 mg/m2/day IV 
for 3 days 
60 mg/m2/day IV for 3 
days 
RD = recommended dose, *each De-escalation dose level is 20% lower than the Starting Dose. 
The chemotherapy cycles will be repeated every 21 days. 


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Lenvatinib is administered daily as a QD dose, and ifosfamide and etoposide will be 
administered on Days 1 to 3 of each cycle for a total of 5 cycles.  Each Chemotherapy cycle 
is repeated every 21 days.  Six subjects with osteosarcoma (who have not received prior 
lenvatinib) will be enrolled first to Cohort 3A at the Starting Dose of lenvatinib (20% below 
the Single-Agent RD in Cohort 1) in combination with ifosfamide 3000 mg/m2/day for 3 
days (ifosfamide total dose 9 g/m2) and etoposide 100 mg/m2/day for 3 days (etoposide total 
dose 300 mg/m2).  Subjects with lenvatinib dose capped after BSA adjustment (dose must not 
exceed 24 mg daily) actually take lower dose level than assigned.  If a subject with capped 
dose experiences a DLT, the DLT data from that subject will be counted to determine the RD 
of the combination treatment.  A subject with capped dose who does not experience a DLT 
will be replaced for the purpose of determining the RD.  
DLTs occurring during Cycle 1 will be evaluated and the next 6 subjects will be assigned a 
dose based on the rules for Dose Escalation and Dose De-Escalation as follows:  
a. If ≤1 out of 6 subjects experiences a DLT at the starting dose during Cycle 1 (Day 
1 to Day 21), then assign 6 more subjects to the next higher dose level of 
lenvatinib (RD from Cohort 1) and keep the chemotherapy dose the same (starting 
dose).  
b. If ≥2 out of 6 subjects experience a DLT at the starting dose during Cycle 1 (Day 
1 to Day 21), then follow the instructions below; 
i. If ≥2 subjects experience hematologic DLT and ≤1 subject experiences non-
hematologic DLT, then assign 6 more subjects to 20% lower doses (De-
escalation 1) of ifosfamide and etoposide and keep the lenvatinib dose the 
same; or 
ii. If ≥2 subjects experience non-hematologic DLT and ≤1 subject experiences 
a hematologic DLT, then assign 6 more subjects to a 20% lower dose of 
lenvatinib (De-escalation 1) and keep the ifosfamide and etoposide doses the 
same; or 
iii. If ≥2 subjects experience hematologic DLTs and ≥2 subjects experiences 
non-hematologic DLTs, then assign 6 more subjects to 20% lower doses of 
lenvatinib, ifosfamide, and etoposide each (De-escalation 1); or 
iv. If only 1 subject experiences a hematologic DLT and only 1 subject 
experiences a non-hematologic DLT, then assign 6 more subjects to the 
same dose level  of lenvatinib, ifosfamide and etoposide each.  


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c. Continue the above processes until the combination dose of lenvatinib, ifosfamide 
and etoposide results in ≤1 DLT per 6 subjects or only 1 subject experiences a 
hematologic DLT and only 1 subject experiences a nonhematologic DLT per 6 
subjects upon repeating the same dose level.  This dose will be considered as the 
RD of the combination treatment.  
Once the RD has been determined, subjects treated at a lower dose level should continue to 
be treated at that dose level.  Intrasubject dose-escalation is not permitted.  Further dose de-
escalation of lenvatinib or the chemotherapy dose may be considered (pending discussion 
with the Protocol Steering Committee [PSC]), if needed.    
9.1.2.4 
Cohort 3B (Combination Expansion) 
Subjects with either lenvatinib-naïve relapsed or refractory osteosarcoma or osteosarcoma 
subjects who progress on single-agent lenvatinib in Cohorts 1 or 2B (optional enrollment) 
will receive lenvatinib (at the RD identified from Cohort 3A) in combination with ifosfamide 
and etoposide, provided the combination of lenvatinib, ifosfamide, and etoposide in Cohort 
3A (Combination Dose-Finding) is determined to be safe and tolerable.  
Osteosarcoma subjects who experience progressive disease in Cohorts 1 or 2B and choose to 
receive the combination therapy of lenvatinib with ifosfamide and etoposide should meet 
only inclusion criteria numbers 6 through 17 and all the exclusion criteria except Criterion 
Number 6.   
Subjects in Cohorts 3A and 3B will receive ifosfamide and etoposide for a maximum of 5 
cycles.  Subjects who discontinue ifosfamide and etoposide in Cohorts 3A and 3B (e.g., due 
to toxicity) prior to completing 5 cycles may continue on single-agent lenvatinib if they are 
benefiting from the treatment at the discretion of the investigator.  Subjects who discontinue 
lenvatinib prior to completing 5 cycles may continue on ifosfamide and etoposide at the 
investigator’s discretion for 5 cycles.   
9.1.3 
Post-treatment (All Cohorts) 
The Post-treatment Follow-up begins when the subject discontinues treatment.  After subject 
discontinues treatment, an Off-Treatment Visit and the procedures noted in the Schedule of 
Assessments Tables (Table 7, Table 8, and Table 9) should be completed within 30 days after 
the last dose of drug.  Subjects will be followed for survival every 3 months until death or for 
1 year, whichever occurs first, unless the study is terminated or the subject discontinues due 
to withdrawal of consent or is lost to follow-up (see Section 9.3.3).  
Subjects who discontinue treatment without disease progression will have tumor assessments 
performed every 6 or 8 weeks (per the appropriate tumor assessment schedule) for up to 1 
year, or sooner if clinically indicated, for documented disease progression or until another 
anticancer therapy is initiated whichever occurs first.  After data cutoff, tumor assessments 
may be performed as clinically indicated using the institutional guidelines, following the 
prevailing local standard of care. 


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As required by some regulatory agencies, the following estimates are provided:  
• The study will begin in December 2014 and will end on or before December 2017. 
• The maximum estimated period for the study is anticipated to be approximately 
36 months.  However, subjects will continue to receive study treatment as long as they 
demonstrate clinical benefit.  Subjects benefiting from study treatment in the opinion of 
the investigator will continue to receive treatment until disease progression, intolerable 
toxicity, subject noncompliance with safety or efficacy assessments, initiation of another 
anticancer therapy, voluntary discontinuation by the subject at any time, or study 
termination by the sponsor, whichever occurs first. 
9.2 
Discussion of Study Design, Including Choice of Control Groups 
This study is the first study of lenvatinib in the pediatric population.  The primary objective 
is to identify the RD, and evaluate the activity of lenvatinib as single-agent or in combination 
with chemotherapy (ifosfamide and etoposide).  The study will be conducted in 5 cohorts:   
• Cohort 1, a single-agent dose-finding study of lenvatinib in children and adolescents with 
relapsed or refractory solid tumors to determine the RD;  
• Cohort 2, an assessment of the efficacy of lenvatinib at the RD in subjects with either  
o 
131I-refractory DTC (Cohort 2A) or  
o relapsed or refractory osteosarcoma (Cohort 2B);  
• Cohort 3A, a combination dose-finding study of lenvatinib in combination with 
ifosfamide and etoposide in subjects with osteosarcoma to determine the RD of the 
combination; and  
• Cohort 3B, a combination expansion study with lenvatinib at the RD, in combination 
with ifosfamide and etoposide in subjects with osteosarcoma who had either disease 
progression on lenvatinib (from Cohorts 1 or 2B) or who are lenvatinib-naïve.   
In Cohort 1, the Time-to-Event Continuous Reassessment Method (TiTE-CRM [Cheung and 
Chappell, 2000]) will be used to identify the RD of lenvatinib.  TiTE-CRM is an accepted 
adaptive design that is statistically robust to evaluate RD in most dose-escalation Phase 1 
studies (Doussau, et al., 2012).  Single agent lenvatinib will be administered at the RD in 
Cohort 2 of the study. The 80% starting dose is based on consensus reached for pediatric 
Phase 1 trials (Smith, et al., 1998).  
Cohort 2 will evaluate the efficacy of lenvatinib in subjects (1) with relapsed or 
131I refractory DTC (Cohort 2A) based upon ORR for subjects with measurable disease and 
BOR for all subjects as assessed by RECIST 1.1; and (2) with osteosarcoma (Cohort 2B) 
based upon PFS-4, as assessed by RECIST 1.1.  Tumors under study in Cohort 2 may be 
modified based on preliminary safety and efficacy signals observed in Cohort 1 of the study.   


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Cohort 3A will determine the RD and safety and toxicity of the combination of lenvatinib, 
ifosfamide, and etoposide. 
Osteosarcoma subjects receiving combination treatment in Cohort 3B will be evaluated for 
efficacy based upon PFS-4, as assessed by RECIST 1.1.   
Secondary objectives of the study will assess safety, toxicity, and tumor response (BOR 
(osteosarcoma), DOR (measurable DTC and osteosarcoma), PFS, TTP, ORR [osteosarcoma 
only], DCR and CBR), determine and PK parameters and palatability and acceptability of the 
suspension formulation. 
The study will also collect blood and tumor biomarkers to correlate PK and 
pharmacodynamics (PD) biomarkers with tumor response or AEs associated with lenvatinib 
treatment.  Dose-limiting toxicities are defined based on known lenvatinib and chemotherapy 
drug toxicities, but also include any unexpected toxicities. 
9.3 
Selection of Study Population 
Approximately 69 to 108 subjects between 2 and <18 years of age (≤25 years for 
osteosarcoma subjects) will be enrolled at approximately 12 sites in Europe and US.  
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 drug. 
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 solid malignant tumor 
a. Cohort 1: Any solid malignant tumor 
b. Cohort 2A: DTC with one of the following histological subtypes: 
b.Papillary thyroid cancer (PTC) 
1. Follicular variant 
2. Other variants (including but not limited to tall cell, columnar cell, 
cribriform-morular, solid, oxyphil, Warthin’s-like, trabecular, 
tumor with nodular fasciitis-like stroma, Hürthle cell variant of 
papillary carcinoma, or poorly differentiated carcinomas) 
c. Follicular thyroid cancer (FTC) 
1. Hürthle cell 
2. Clear cell 
3. Insular 
c. Cohort 2B, 3A, and 3B: Relapsed or refractory osteosarcoma 
2. Relapsed or refractory solid tumor malignancy that has progressed on standard anticancer 
therapy with no available curative options.  (Note: Osteosarcoma subjects must be in first 


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or subsequent relapse [≥ first relapse]).  Only the osteosarcoma subjects enrolled to 
Cohorts 3A and 3B must be deemed candidates for ifosfamide and etoposide 
chemotherapy). 
3. Evaluable or measurable disease per RECIST 1.1 that meets the following criteria 
a. Subjects must have evaluable or measurable disease based on RECIST 1.1 using 
computed tomography/magnetic resonance imaging (CT/MRI) (Appendix 1) 
b. Lesions that have had external beam radiotherapy (EBRT) or locoregional 
therapies such as radiofrequency (RF) ablation must have subsequently grown 
unequivocally to be deemed a target lesion  
4. DTC subjects must have 131I-non-avid/refractory progressive disease and no effective 
anticancer therapy options available.  
a. One or more evaluable or measurable lesions that do not demonstrate iodine 
uptake on any radioiodine scan OR 
b. One or more evaluable or measurable lesions that have progressed based on 
RECIST 1.1, within 12 months of 131I therapy, despite demonstration of 
radioiodine avidity at the time of that treatment by pre- or post-treatment 
scanning.  These subjects must not be eligible for possible curative surgery OR 
c. Cumulative activity of 131I >400 millicuries (mCi) or 14.8 gigabecquerels (GBq), 
with the last dose administered at least 6 months prior to study entry 
5. Subjects with DTC must be receiving thyroxine suppression therapy and levels of thyroid 
stimulating hormone (TSH) should not be elevated (TSH should be ≤5.50 mU/L).  When 
tolerated by the subject, thyroxine dose should be changed to achieve TSH suppression 
(TSH <0.50 mU/L) 
6. Subjects with known central nervous system (CNS) primary tumors or metastases who 
have completed brain therapy (such as radiotherapy, stereotactic radiosurgery or surgical 
resection), and have remained clinically stable, asymptomatic and off of steroids for 2 
weeks prior to Cycle 1 Day 1 will be eligible 
7. Male or female subjects age 2 years to <18, (≤25 years for osteosarcoma subjects) at the 
time of informed consent 
8. Lansky play score ≥50% or Karnofsky Performance Status score ≥50% (Appendix 4 and 
Appendix 5, respectively).  Use Karnofsky for subjects ≥16 years of age and Lansky for 
subjects <16 years of age 
9. Life expectancy ≥3 months 
10. Adequate bone marrow function as evidenced by: 
a. absolute neutrophil count (ANC) ≥1.0 × 109/L 


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b. (for Cohorts 3A and 3B leucocyte count ≥2 × 109/L; subjects with bone marrow 
involvement should have ANC ≥ 0.8 × 109/L and leucocyte count ≥1 ×x 109/L) 
c. hemoglobin ≥8.0 g/dL (a hemoglobin <8.0 g/dL is acceptable if it is corrected by 
growth factor or transfusion before starting lenvatinib) 
d. platelet count ≥75 × 109/L  
11. Adequate liver function as evidenced by: 
a. bilirubin ≤1.5 times the upper limit of normal (ULN) 
b. alkaline 
phosphatase, 
alanine 
aminotransferase 
(ALT), 
and 
aspartate 
aminotransferase (AST) ≤3 × ULN (in the case of liver metastases ≤5 × ULN), 
unless there are bone metastases or bone primary tumor, in which case liver 
specific alkaline phosphatase must be separated from the total and used to assess 
the liver function instead of the total alkaline phosphatase 
12. Adequate  renal function as evidenced by: 
a. Serum creatinine based on age/gender as below.  If serum creatinine is greater 
than maximum serum creatinine for age/gender as shown in the table below, then 
creatinine clearance (or radioisotope glomerular filtration rate [GFR]) must be 
>70 mL/min/1.73 m2 (Appendix 6). 
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 (Schwartz, et al., 1985) using child length and stature data published by the CDC. 
b. Urine dipstick <2+ for proteinuria.  Subjects who have ≥2+ proteinuria on 
dipstick urinalysis should undergo a spot protein-creatinine (P/C) ratio test 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) 
c. No clinical evidence of nephrotic syndrome  
13. Adequate cardiac function as evidenced by left ventricular ejection fraction ≥50%) at 
baseline as determined by echocardiography 
14. Adequately controlled blood pressure (BP) with or without antihypertensive medications, 
 
defined as: 


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BP <95th percentile for sex, age, and height/length at screening (as per National Heart 
Lung and Blood Institute guidelines; see Appendix 7 and Appendix 8) and no change in 
antihypertensive medications within 1 week prior to Cycle 1/Day 1.  Osteosarcoma 
subjects age 18 to 25 years should have BP ≤150/90 mm Hg at screening and no change 
in antihypertensive therapy within 1 week prior to Cycle 1 Day 1. 
 
15. Washout of 3 weeks in case of prior chemotherapy, 6 weeks if treatment included 
nitrosoureas; 4 weeks for definitive radiotherapy, and 2 weeks for palliative radiotherapy; 
3 months from high-dose chemotherapy and stem cell rescue; 3 weeks from major 
surgery.  Subjects must have recovered from the acute toxic effects of all prior anticancer 
therapy before enrollment into the study 
16. Written and signed informed consent from the parent(s) or legal guardian and assent from 
the minor subject.  Written informed consent from subjects ≥18 years. 
17. Willing and able to comply with the protocol, scheduled follow-up, and management of 
toxicity as judged by the Investigator 
Cohort 3B (Combination Expansion): Osteosarcoma subjects who progressed in 
Cohorts 1 or 2B and opt to receive combination therapy:  
18. Osteosarcoma subjects receiving combination therapy of lenvatinib with ifosfamide and 
etoposide should meet only Inclusion Criteria Numbers 7 6 through 17 (after progression 
in Cohort 2B) 
9.3.2 
Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from this study: 
1. Any active infection or infectious illness unless fully recovered prior to dosing 
2. Any medical or other condition that in the opinion of the investigator(s) would preclude 
the subject’s participation in a clinical study 
3. Other organ toxicity due to prior anticancer therapy (investigational agent, chemotherapy, 
or radiation therapy) except alopecia, and ototoxicity due to cisplatin not already covered 
in the inclusion/exclusion criteria, which has not recovered to Grade <2 per CTCAE 
v4.03  
4. Known hypersensitivity to any component of the product (lenvatinib or ingredients) 
5. Concurrent administration of any other antitumor therapy 
6. Previous treatment with lenvatinib (except for subjects previously enrolled into Cohorts 1 
or 2B of this study) 


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7. Two or more prior VEGF/VEGFR-targeted therapies  
8. Currently receiving any investigational drug or device in another clinical trial or within 
30 days preceding informed consent 
9. A clinically significant ECG abnormality, including a marked baseline prolonged QT or 
QTc interval (eg, a repeated demonstration of a QTc interval >480 msec). 
10. Gastrointestinal malabsorption or any other condition that in the opinion of the 
investigator might affect the absorption of lenvatinib. 
11. Gastrointestinal bleeding or active hemoptysis (bright red blood of at least ½ teaspoon) 
within 3 weeks prior to the first dose of study drug. 
12. Active second malignancy within 2 years prior to enrollment ([in addition to the primary 
tumor types specified by cohort in Inclusion Criterion Number 1], but not including 
definitively treated superficial melanoma, in-situ, basal or squamous cell carcinoma of 
the skin). 
13. Previous treatment with ifosfamide and grade ≥3 nephrotoxicity or encephalopathy 
(Cohorts 3A and 3B). 
14. Females who are breastfeeding or pregnant at Screening or Baseline (as documented by a 
positive beta-human chorionic gonadotropin [ß-hCG], human chorionic gonadotropin 
[hCG] test with a minimum sensitivity of 25 IU/L or equivalent units of ß-hCG / 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. 
Females of childbearing potential who: 
• 
Within 28 days before study entry, did not use a highly effective method of 
contraception, which includes any of the following: 
o total abstinence (if it is their preferred and usual lifestyle) 
o an intrauterine device or intrauterine hormone-releasing system (IUS) 
o an oral contraceptive.  Subject must be on a stable dose of the same oral 
contraceptive product for at least 28 days before dosing and throughout the 
study and for 6 months after study drug discontinuation.) .  
o have a vasectomized partner with confirmed azoospermia. 
• 
Do not agree to use a highly effective method of contraception (as described above) 
throughout the entire study period and for 6 months after study drug discontinuation. 
 
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. 
 


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NOTE:  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). 
Males who have not had a successful vasectomy (confirmed azoospermia) or 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 5 times the 
half-life of the study drug plus 90 days after study drug discontinuation).  No sperm 
donation is allowed during the study period and for 5 times the half-life of the study drug 
plus 90 days after study drug discontinuation. 
Males who have not had a successful vasectomy (confirmed azoospermia) or 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 6 months 
after study drug discontinuation).  If the female partner is pregnant, then males who do 
not agree to use condoms throughout the study period and for 6 months after study drug 
discontinuation.  No sperm donation is allowed during the study period and for 6 months 
after study drug discontinuation. 
Cohort 3B (Combination Expansion):  Osteosarcoma subjects who progressed in 
Cohorts 1 or 2B and opt to receive combination therapy:  
15. Osteosarcoma subjects receiving combination therapy of lenvatinib with etoposide and 
ifosfamide should meet all the exclusion criteria, with the exception of Criterion 
Number 6 
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.  
The reason for discontinuation will be documented.  If a subject discontinues study 
treatment, the subject will enter the Post-treatment Follow-up Period and complete protocol-
specified off-treatment visits, procedures, and 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 
Discontinuation From Treatment, case report form (CRF) page 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 Drug Dosing CRF page. 
During the Follow-Up Period, subjects who discontinue study treatment without progression 
should have tumor assessments every 6 or 8 weeks (per the appropriate tumor assessment 
schedule) for up to 1 year or sooner if clinically indicated, until disease progression is 


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documented or until another anticancer therapy is initiated.  After data cutoff, tumor 
assessments may be performed as clinically indicated per institutional guidelines, following 
the prevailing local standard of care. 
All subjects will be followed for survival for 1 year or until death, except where a subject 
withdraws consent or the sponsor chooses to halt survival follow-up after completion of the 
primary study analysis. 
9.4 
Treatment 
9.4.1 
Treatment(s) Administered 
Lenvatinib will be provided by Eisai as hard capsules containing 1, 4, or 10 mg lenvatinib.  
An extemporaneous suspension of lenvatinib capsules should be used for children unable to 
swallow capsules, as detailed in Appendix 12. 
Cohort 1 (Single-Agent Dose-Finding):  Lenvatinib will be administered orally QD on Days 
1 to 28 of each 28-day cycle (Table 1).   
Cohort 2 (Single-Agent Expansion):  Lenvatinib will be administered orally QD at the 
Single-Agent RD (identified in Cohort 1) on Days 1 to 28 of each 28-day cycle. 
Cohort 3A (Combination Dose-Finding):  Lenvatinib will be administered orally QD on Days 
1 to 21 of each 21-day cycle (Table 2) 
Cohort 3B (Combination Expansion):  Lenvatinib will be administered orally QD at the RD 
(identified in Cohort 3A) on Days 1 to 21 of each 21-day cycle.  Ifosfamide and etoposide 
will be administered on Days 1 to 3 of each 21-day cycle.  
Before dose administration on Day 1 of each cycle and prior to a change in dose due to dose 
reduction, the amount of lenvatinib needed for each subject must be calculated as follows:   
 
Scheduled dose (mg/m2) x body surface area (BSA) (m2) = lenvatinib dose (mg) 
BSA will be calculated using the method that is accepted and customarily used by the clinical 
site.  BSA must be calculated on Day 1 of each cycle based on the subject’s current height 
and body weight.  BSA will be used to determine the amount of lenvatinib for each subject.  
BSA should not be corrected for amputation.  The dose should be rounded to the nearest 
whole number.  After adjustment for BSA, the daily dose of lenvatinib should not exceed 24 
mg daily.  
9.4.1.1 
Dose-Limiting Toxicity 
Dose-limiting toxicity (DLT) in subjects treated with lenvatinib will be assessed according to 
CTCAE v4.03 (Appendix 2) and is defined as any of the following toxicities related to 
lenvatinib or chemotherapy drugs (ifosfamide and/or etoposide) occurring during Cycle 1 
(Day 1 to Day 28) for Cohort 1, and Cycle 1 (Day 1 to Day 21) for Cohort 3A. 


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Hematologic Toxicity 
o Grade 4 neutropenia for ≥7 days (≥10 days for Cohort 3A) 
 
o Grade ≥3 thrombocytopenia with bleeding, or lasting >7 days (≥10 days for 
Cohort 3A) 
o Grade ≥3 febrile neutropenia.(lasting ≥7 days for Cohort 3A) 
o Next course of chemotherapy delayed for ≥7 days (Cohort 3A) 
 
Non-Hematologic Toxicity 
o Grade ≥3 nonhematological toxicity persisting more than 7 days despite 
optimal supportive care.  Isolated laboratory abnormalities that resolve within 
a week, allergic reactions, and symptoms related to tumor progression will be 
excluded. 
o Grade 4 hypertension, confirmed systolic or diastolic blood pressure more 
than 25 mmHg above the 95th percentile for age, or an elevated diastolic 
blood pressure (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 two antihypertensive ingredient medications will 
count as one antihypertensive medication. 
o Grade 3 proteinuria 
o Any recurrent Grade 2 nonhematological toxicity requiring ≥2 interruption 
and dose reductions 
• 
Any dose interruption or reduction due to toxicity which results in administration 
of less than 75% of the planned dosage of lenvatinib. 
• 
Any other Grade ≥3 toxicity (hematologic and nonhematologic) assessed as 
related to lenvatinib treatment, and which in the opinion of the principal 
investigator and Eisai medical monitor constitutes a dose-limiting toxicity 
All DLTs must be reported to the Eisai medical monitor 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 during Cycle 1 (Day 1 through Day 28 for Cohort 1, and Day 
1 through Day 21 for Cohort 3A) will be replaced.   
9.4.1.2 
Lenvatinib Dose Reduction and Interruption Instructions 
Dose adjustments will be made for subjects who experience treatment-related toxicity 
according to the instructions provided in the Table 3.  Doses in the Dose Adjustment column 
are based on a presumed starting dose of 11 mg/m2. 


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Dose reductions occur in succession based on the previous dose level.  Each dose level 
reduction is a 20% reduction from the previous dose.  Once the dose has been reduced, it 
cannot be increased at a later date.   


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Table 3 Criteria for Temporary Discontinuation of Study Drug, Dose Reduction, and 
Resumption of Treatment  
Lenvatinib Related Toxicitya, b 
including hepatic injury and 
thromboembolic events 
Management 
Dose Adjustment 
Grade 1 
 
Continue treatment 
No change 
 
Intolerable Grade 2c or Grade 3e 
First occurrence 
Interrupt until resolved to Grade 
0 - 1 or baseline 
8.8 mg/m2 (or 20% reduction of the 
starting dose) orally QD (one-level 
reduction) 
Second occurrence 
 
 
(same toxicity or new toxicity) 
Interrupt until resolved to Grade 
0 - 1 or baseline 
7.0 mg/m2 (or 20% reduction of the 
previous dose) orally QD (one-
level reduction) 
Third occurrence 
 
 
(same toxicity or new toxicity) 
Interrupt until resolved to Grade 
0 - 1 or baseline 
5.6 mg/m2 (or 20% reduction of the 
previous dose) orally QD (one-
level reduction) 
Fourth occurrence 
 
 
(same toxicity or new toxicity) 
Interrupt until resolved to Grade 
0 - 1 or baseline 
Discuss with sponsor 
 
Grade 4d: Discontinue Study Treatment 
For grading, see Common Terminology Criteria for Adverse Events (CTCAE v4.03) (Appendix 2). Collect all 
CTC grades of adverse events, decreasing and increasing grade. 
a. Interruption of lenvatinib treatment for more than 28 days (due to lenvatinib-related toxicities) will require 
a discussion with the sponsor before treatment can be resumed. 
b. Initiate optimal medical management for nausea, vomiting, and/or diarrhea before any lenvatinib 
interruption or dose reduction.  
c. Applicable only to those Grade 2 toxicities judged by the subject and physician to be intolerable. Not 
applicable to abnormal clinical laboratory values that are not clinically relevant based on the judgment of 
the investigator.  
d. Excluding laboratory abnormalities judged to be non-life-threatening, in which case manage as Grade 3. 
e. Obese subjects with weight loss do not need to return to baseline or Grade 1 weight loss to restart 
lenvatinib. There should be no weight loss for at least 1 week, and subjects should be started at the lower 
dose and normal BMI should be used for future dose reductions. Obesity is defined as body mass index 
(BMI) percentiles corresponding to 30 kg/m², related to the age of the children. (Cole T.J., et al 2000) or 
BMI ≥ the 95th percentile for children and teens of the same age and sex (Ogden CL et al, 2002)(Appendix 
9 and 10).     
 
 


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9.4.1.3 
Blood Pressure 
For children, blood pressure varies by the sex and age of the child and it is closely related to 
height and weight.  Blood pressure will be assessed in terms of percentile for sex, age and 
height/length.  Guidelines to sex, age, and height-specific percentiles of blood pressure is 
provided in Appendix 7 and Appendix 8.  Blood pressure that is consistently above the 95th 
percentile [for subjects age 18-25 years BP ≤140/90 mm Hg] for age and height/length 
requires further evaluation.  A referral to a cardiologist is recommended for patients 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 blood pressure in children of 
approximately the same age and body build should be expected and serial measurements 
should always be obtained when evaluating a patient with hypertension.  BP values for 
management of hypertension for subjects 18 to 25 years of age are included in 
parenthesis. 
9.4.1.4 
Management of Hypertension 
Hypertension is a recognized side-effect of treatment with drugs inhibiting vascular 
endothelial growth factor (VEGF) signaling.  Investigators should therefore ensure that 
subjects enrolled to receive treatment with lenvatinib have BP <95th percentile [BP ≤150/90 
mm Hg] for sex, age, and height/length at the time of study entry and, if known to be 
hypertensive, have been on a stable dose of antihypertensive therapy for at least 1 week 
before Cycle 1 Day 1.  Early detection and effective management of hypertension are 
important to minimize the need for lenvatinib dose interruptions and reductions.  
Antihypertensive agents should be started as soon as elevated BP (systolic BP ≥95th 
percentile [BP ≥140 mm Hg] or diastolic BP ≥95th percentile [BP ≥90 mm Hg]) is confirmed 
on 2 assessments obtained 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 mm Hg] or 
diastolic BP ≥95th percentile [BP ≥90 mm Hg] 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.  
Lenvatinib should be withheld in any instances where a subject is at imminent risk to develop 
a hypertensive crisis or has significant risk factors for severe complications of uncontrolled 
hypertension (eg, BP ≥99th percentile [BP ≥160/100 mm Hg], 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, lenvatinib should be resumed as described below.  


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During the Treatment Period, subjects with systolic BP ≥99th percentile [BP ≥160 mm Hg] 
or diastolic BP ≥99th percentile [BP ≥100 mm Hg] 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 mm Hg] and diastolic BP has been <95th percentile [≤ 95 mm Hg] for 3 
consecutive months.  If a new event of systolic BP ≥99th percentile [BP ≥160 mm Hg] or 
diastolic BP ≥99th percentile [BP ≥100 mm Hg] occurs, the subject must resume the Day 15 
evaluation until systolic BP has been <95th percentile [≤ 150 mm Hg] and diastolic BP has 
been <95th percentile [≤ 95 mm Hg]  for 3 consecutive months.  
The following guidelines should be followed for the management of systolic BP ≥99th 
percentile [BP ≥160 mm Hg] or diastolic BP ≥99th percentile [BP ≥100 mm Hg] confirmed 
on repeat measurements after an hour:  
• Continue lenvatinib 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 mm Hg] or diastolic BP ≥99th percentile 
[BP ≥100 mm Hg] persists despite maximal antihypertensive therapy, then lenvatinib 
administration should be interrupted and restarted at a lower dose QD (one dose level 
reduction [20%] as specified in Table 2) only when systolic BP <95th percentile [BP 
≤150 mm Hg] and diastolic BP <95th percentile [BP ≤95 mm Hg] 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 mm Hg] or diastolic BP ≥99th 
percentile [BP ≥100 mm Hg] recurs despite optimal management of 
hypertension with antihypertensive medications (either by dose increase or the 
addition of a different class of antihypertensive), then lenvatinib 
administration should be interrupted and restarted at a lower dose QD (one 
dose level reduction [20%] as specified in the table above) only when systolic 
BP <95th percentile [BP ≤150 mm Hg] and diastolic BP <95th percentile [BP 
≤ 95 mm Hg] 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 mm Hg] or diastolic BP ≥99th 
percentile [BP ≥100 mm Hg] recurs despite optimal management of 
hypertension with antihypertensive medications (either by dose increase or the 
addition of a different class of antihypertensive), then lenvatinib 
administration should be interrupted and a restart of lenvatinib should be 
discussed with the sponsor.  
The following guidelines should be followed for the management of Grade 4 hypertension 
(life-threatening consequences):  


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• Institute appropriate medical management  
• Discontinue lenvatinib 
Figure 2 shows the procedures associated with the management of hypertension. 
 
Figure 2 
Management of Hypertension 
BP = blood pressure, HTN = hypertension, Tx = treatment. 
9.4.1.5 
Management of Posterior Reversible Leukoencephalopathy Syndrome (PRES) 
A thorough medical history and a comprehensive physical examination, including a 
neurological examination, should be conducted as detailed in the Schedule of Assessments 
(Table 7, Table 8, and Table 9) and as clinically indicated.  
Any subject with signs or symptoms of headache, confusion, seizure, or visual change 
combined with hypertension (usually but not always severe) should be immediately 
evaluated with brain MRI to evaluate the possibility of posterior reversible 
leukoencephalopathy syndrome (PRES), a Grade 4 hypertension adverse event per CTCAE 
v4.03.  In subjects with suspected PRES, lenvatinib should be immediately withheld, and if 
the condition is confirmed by MRI, lenvatinib must be permanently discontinued (see 


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Table 3).  Appropriate measures should be taken to control blood pressure (see Section 
9.4.1.4), and neurologic consultation is advised.  
9.4.1.6 
Management of Proteinuria 
Regular assessment for proteinuria should be conducted as detailed in the Schedule of 
Assessments (Table 7, Table 8, and Table 9).  Guidelines for assessment and management of 
proteinuria are summarized as follows:  
• Initial episode of proteinuria:  If proteinuria ≥ 2+ is detected on urine dipstick testing, 
study drug will be continued and a spot protein-creatinine ratio test and if possible a 
24-hour urine collection for total protein will be obtained as soon as possible within 
72 hours to verify the grade of proteinuria.  Grading according to CTCAE v4.03 
(Appendix 2) will be based on the protein-creatinine ratio.  And wherever possible 
also on the 24-hour urinary protein result per investigators discretion.  Management 
of lenvatinib administration will be based on the grade of proteinuria according to 
Table 3.  
• During the Treatment Period, urine dipstick testing for subjects with proteinuria ≥ 2+ 
should be performed every 2 weeks (on Day 15 or more frequently as clinically 
indicated) until the results have been 1+ or negative for 3 consecutive months.  Any 
subsequent increases in the level of proteinuria ≥ 2+ on urine dipstick testing must be 
confirmed with a spot protein-creatinine ratio test and if possible a 24-hour urinary 
protein test per investigators discretion which will be assessed and graded and 
managed according to the dose reduction and interruption instructions provided in the 
table above.  If a new event of proteinuria ≥ 2+ occurs, the subject must resume the 
Day 15 urine dipstick testing for evaluation of proteinuria until results are 1+ or 
negative for 3 consecutive months. 
9.4.1.7 
Management of Hepatotoxicity 
Regular monitoring of liver function tests (alanine transaminase [ALT], aspartate 
transaminase [AST], bilirubin levels) should be conducted as detailed in the Schedule of 
Assessments (Table 7, Table 8, and Table 9) 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 3), for Study Treatment Dose 
Reduction and Interruption Instructions).  Appropriate supportive care should be provided 
together with close monitoring.  If hepatic failure occurs the study drug must be 
discontinued. 
9.4.1.8 
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 3), 
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 
drug must be discontinued. 
9.4.1.9 
Management of Hypocalcemia 
Serum calcium should be monitored monthly per the Schedule of Assessments. 
Hypocalcemia should be treated per institutional guidelines (eg, using appropriate calcium, 
magnesium, and Vitamin D supplementation) until resolution. 
 
9.4.1.10 
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 adverse events of abdominal pain believed related to lenvatinib or more specific adverse 
events believed related to lenvatinib that result in the symptom of abdominal pain, 
instructions contained in Table 3 regarding study treatment dose reduction and interruption 
instructions.  For Grade 4 adverse events that result in abdominal pain, study drug must be 
discontinued. 
Gastrointestinal (GI) 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.  
All GI symptoms should be recorded in the diary provided. 
9.4.1.11 
For additional information please refer to the current Investigator’s Brochure 
(Lenvatinib Investigator’s Brochure). Management of Ifosfamide-Etoposide 
Associated Toxicity 
All sites participating in this trial have had considerable experience with these 
chemotherapeutic agents.  Blood counts should be closely monitored during and prior to the 
next cycle of chemotherapy.  Chemotherapy-associated myelosuppression should be 
managed by G-CSF.  It is recommended that pegylated G-CSF or G-CSF be administered at 
least 24 to 72 hours after completion of ifosfamide-etoposide chemotherapy; use of G-CSF is 
recommended until WBC counts are ≥1 × 109/L.  Guidelines for dose modification for 
ifosfamide and etoposide associated toxicities are provided in the Table 4 below.  


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Details of ifosfamide and etoposide dose interruption and reduction as well as management 
of toxicity can be found in the Summary of Product Characteristics (SmPC), and may be 
followed as per local and institutional guidelines.  The SmPC will be provided to the study 
sites in the Investigator and Pharmacy files in the relevant local language.  For additional 
information investigators may refer to the SmPC or Euramos-1 protocol (ISRCTN67613327 
EudraCT no. 2004-000242-20).  
Table 4 
Criteria for Dose Modification of Chemotherapy Dose  
Toxicity 
Grade 
Action 
Neutropenia 
Grade 4 
Monitor ANC counts every 3 days until 
resolved to < Grade 3 
Febrile neutropenia 
Grade 4 
Reduce the next dose of ifosfamide and 
etoposide by 20% 
Mucositis 
Repeated grade 3 or Grade 4 
Reduce etoposide by 20% 
Renal Toxicity 
Serum creatinine is 1.5 – 3 × 
ULN  maximum serum 
creatinine for age and gender 
Interrupt ifosfamide and etoposide for 1 
week 
Hematuria 
>50 RBC/ high power field 
(hpf) 
Interrupt ifosfamide for 1 week 
Neurological Toxicity ≥ Grade 2 
Interrupt and reduce ifosfamide and 
etoposide each by 20% of the previous 
dose. After 2 dose reductions subject must 
discontinue the chemotherapy drugs, but 
if benefiting, can continue on single-agent 
lenvatinib at the investigator’s discretion 
9.4.2 
Identity of Investigational Product(s) 
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.   
9.4.2.1 
Chemical Name, Structural Formula of Lenvatinib 
• Study drug code:  E7080 


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• 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:   
N
H3CO
H2N
O
O
Cl
N
H
N
H
O
H3C SO3H
 
9.4.2.2 
Comparator Drug 
Not applicable. 
9.4.3 
Cytotoxic Chemotherapy:  Ifosfamide and Etoposide 
The cytotoxic chemotherapy drugs (used in combination with lenvatinib) in this study will be 
ifosfamide and etoposide.  These chemotherapy drugs will be provided by the sponsor.  The 
administration procedure should follow the approved prescribing information in each 
country/region.  The chemotherapy regimen schedule and dosing details are provided below. 
The chemotherapy regimen schedule will consist of ifosfamide 3000 mg/m2/day IV infusion 
over 30 minutes for 3 consecutive days (Day 1 to Day 3 of each cycle) and etoposide 
100 mg/m2/day IV infusion for 3 consecutive days (Day 1 to Day 3 of each cycle).  
Chemotherapy administration should be accompanied by vigorous hydration and 
administration of mesna according to the institutional guidelines.  Each chemotherapy cycle 
will be 21 days for a total of 5 cycles. 
Pegylated G-CSF or G-CSF will be administered at least 24 to 72 hours after completion of 
ifosfamide-etoposide chemotherapy until WBC counts are ≥1 × 109/L or at the investigator’s 
discretion.  
9.4.3.1 
Labeling for Study Drug 
Lenvatinib and the combination chemotherapy drugs, ifosfamide and etoposide, will be 
labeled centrally for all countries except for Germany and US 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.   
The following information will be provided (but not limited to): 
• For clinical trial use only 


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• Name and address of the sponsor 
• Chemical name / drug identifier 
• Lot number/Batch number 
• Storage conditions, expiration date if necessary 
9.4.3.2 
Storage Conditions 
Lenvatinib will be stored in accordance with the labeled storage conditions.  The expiry date 
for lenvatinib will be established based on the date that manufacturing/packing is completed 
or will be based on formulation testing, and will therefore be described in the “Procedures for 
Handling Investigational Drug.”  The sponsor will prepare the “Procedures for Handling 
Investigational Drug," which will be provided to the investigator and the designated 
pharmacist. 
Ifosfamide and etoposide 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 (or if 
regionally required, the head of the medical institution) 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 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. 
9.4.4 
Method of Assigning Subjects to Treatment Groups 
This is an open-label study.  All subjects who provide signed informed consent and/or assent 
to participate in this study and satisfy all eligibility requirements (see Section 9.3) will be 
assigned to 1 of 5 dosing cohorts.  Enrollment will start with Cohort 1.  Approximately 12 to 
24 subjects with solid tumors will be enrolled.   
After identifying the Single-Agent RD of lenvatinib in Cohort 1, Cohorts 2A, 2B, and 3A 
will begin enrollment in parallel.  Osteosarcoma subjects will be assigned to either Cohort 2B 
or Cohort 3A.  Approximately 27 to 42 subjects divided into the 2 malignancy groups 
(approximately 12 subjects with 131I refractory DTC and 15 to 30 subjects with 
osteosarcoma) will be enrolled in Cohort 2.  Approximately 12 to 24 subjects with 
osteosarcoma will be enrolled in Cohort 3A (Dose-Finding combination).   
Enrollment in Cohort 3B will start after Combination RD of lenvatinib is identified in Cohort 
3A.  After defining the RD of lenvatinib in combination with chemotherapy (ifosfamide and 
etoposide) in Cohort 3A, subsequent osteosarcoma subjects will be assigned to either Cohort 
2B (Single-Agent Expansion) or Cohort 3B (Combination Expansion), depending on whether 
the subject is deemed by the investigator to be a candidate for ifosfamide and etoposide.  If 
not, the subject would only be assigned to Cohort 2B. 


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Cohort 3B will enroll approximately 18 lenvatinib–naïve subjects with osteosarcoma, along 
with some subjects who progressed in Cohorts 1 or 2B. 
9.4.5 
Selection of Doses in the Study 
The starting dose of lenvatinib for Cohort 1 is 11 mg/m2 QD, which is 80% of the adult RD 
of 24 mg QD.  The 80% starting dose is based on the consensus reached for pediatric Phase 1 
trials (Smith, et al., 1998).  The starting dose of lenvatinib used in Cohort 3A will be 20% 
lower than the RD of lenvatinib identified in Cohort 1.  
9.4.6 
Selection and Timing of Lenvatinib Dose for Each Subject 
Lenvatinib capsules are to be taken orally once a day at approximately the same time in the 
morning without regard to food intake for 28 days from Cycle 1 onward.  If a subject misses 
a dose, it may be taken within the 12 hours following the usual time of the morning 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 morning.  In the event a subject vomits after study 
drug administration, the subject should not take another dose until the next scheduled dose.   
Study drug(s) 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. 
9.4.7 
Blinding 
Not applicable. 
9.4.8 
Prior and Concomitant Therapy 
All prior medications (including over-the-counter medications) administered 30 days before 
the first dose of study drug and any concomitant therapy administered to the subject during 
the course of the study (starting at the date of informed consent) until 30 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 lenvatinib may be continued during the study. 
Drugs that are not prohibited for concomitant use include drugs used to treat complications or 
adverse events or drugs used to ameliorate symptoms (including blood products, blood 
transfusions, fluid transfusions, antibiotics, and antidiarrheal drugs), may be given at the 
discretion of the investigator, unless it is expected to interfere with the evaluation of (or to 
interact with) lenvatinib. 
Aspirin, nonsteroidal antiinflammatory 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), 


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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 (RBC) counts. 
If concomitant medication/therapy is administered for an adverse event, investigators will 
record that AE on the Adverse Events CRF. 
9.4.8.1 
Drug-Drug Interactions 
The weak inhibitory effect on CYP enzymes (in vitro) exhibited by lenvatinib suggests a low 
risk of lenvatinib interference with the PK of other drugs co-administered in usual clinical 
practice.  Simultaneous CYP3A4/P-gp inhibitions by ketoconazole slightly (15% – 19%) 
increased systemic exposure to lenvatinib after oral administration as measured by AUC and 
Cmax in humans.  Since no change was observed in half-life, tmax, or tlag, the slight increase in 
systemic exposure is probably related to a decrease in first pass metabolism.  However, since 
the magnitude of the change is small, coadministration of lenvatinib with CYP3A4/P-gp 
inhibitors is not of clinical concern.  Similarly, PK data did not suggest any major effects of 
rifampin on the exposure or disposition of lenvatinib.  Following administration of a single 
dose of lenvatinib with a single dose of rifampin, lenvatinib exposure increased about 31%.  
In contrast, following administration of multiple doses of rifampin, free lenvatinib exposure 
was reduced about 9% and about 18% for total lenvatinib.  These findings suggest that there 
is no clinically meaningful influence of either P-gp inhibition (single dose of rifampin) or 
simultaneous P-gp and CYP3A4 induction (multiple doses of rifampin) on lenvatinib PK. 
 
The locally approved product label or applicable SmPC for ifosfamide and etoposide should 
be referenced for any concomitant therapy use with ifosfamide and etoposide. 
9.4.8.2 
Prohibited Concomitant Therapies and Drugs 
Subjects should not receive other antitumor therapies while on study.  If subjects receive 
additional antitumor therapies, such as chemotherapy, hormone therapy with well-known 
direct antitumor activity against the subject’s malignancy, palliative radiotherapy (other than 
as described below), or immunotherapy, 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 Post-treatment 
Follow-Up. 
Prophylactic use of G-CSF is not permitted during this study for Cohorts 1, 2A, and 2B.  
G-CSF is recommended for Cohorts 3A and 3B to mitigate the toxicity of ifosfamide and 
etoposide). 


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9.4.8.3 
Permitted Concomitant Treatment/Procedures 
The following concomitant treatments/procedures are allowed: 
a. Removal of existing (not new) osteosarcoma metastatic lesion (surgical, radiofrequency 
ablation, etc) as follows: 
• After the completion of first 4 months of the Treatment Period without progression, 
and 
• Before the first 4 months of the Treatment Period only if there is disease progression 
assessed by the investigator and the subject will discontinue the study for progression 
b. Palliative radiotherapy in Cohort 2 and 3B is allowed for ≤2 significantly symptomatic 
nontarget lesions.  For Cohorts 1 and 3A, it will be allowed after the RD is determined. 
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.  
 
9.4.9 
Any additional procedural or patient specific particularities should be 
discussed with the investigator and the sponsor.  Treatment Compliance 
Records of treatment compliance for each subject will be kept during the study.  Clinical 
research associates (CRAs) will review treatment compliance during site visits and at the 
completion of the study. 
9.4.10 
Drug Supplies and Accountability 
In compliance with local regulatory requirements, drug supplies will not be sent to the 
investigator 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 


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• 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 Food and Drug Administration (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, study staff, and the designated pharmacist will be responsible for the 
accountability of all study drugs/study supplies (dispensing, inventory, and record keeping) 
following the sponsor’s instructions and adherence to Good Clinical Practice (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 
study subject.   
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 the site but not dispensed to the 
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 
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 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 


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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. 
For subjects continuing study treatment at the time of the data cutoff date for the primary 
analysis, the study drugs will be ordered and dispensed manually, and IxRS dispensing will 
be closed out once the procedure for reconciliation of study drugs is complete for the purpose 
of the clinical study report. 
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, race/ethnicity (recorded in accordance with 
prevailing regulations). 
9.5.1.2 
Baseline Assessments 
Baseline assessments will be performed at Day -1 or at Cycle 1 Day 1 prior to treatment.  
Assessments will include confirmation of subject eligibility with the inclusion and exclusion 
criteria, medical and surgical history, prior medications and procedures, pregnancy test 
(serum or urine) within 72 hours of the first dose of study medication), Lansky play score 
(see Appendix 4) or Karnofsky performance status score (see Appendix 5), TNM Staging (at 
initial diagnosis of the disease), vital signs, clinical chemistry and hematology, urine dipstick 
testing, height, hand/wrist x-ray, proximal tibial growth plates, guaiac fecal occult blood test, 
guaiac fecal occult blood test, PD biomarkers and optional biomarkers, and blood sample 
collection for pharmacogenomics (PG) analysis. 
A comprehensive physical examination, including a neurological examination, will be 
performed at baseline if the screening physical examination was performed >7 days prior to 
Cycle 1 Day 1.  Subjects 2 to <6 years of age must complete Screening/ Baseline assessments 
and all the assessments during the Run-In Period as indicated in Table 7 from Day 1 to Day 
21 of Cycle 1 prior to entering Cycle 1. 


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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, Table 8, and Table 9).  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.  
A urogenital examination will only be required in the presence of clinical symptoms related 
to this region.  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 
TUMOR RESPONSE ASSESSMENTS 
Tumor assessment will be performed based on RECIST 1.1 (Appendix 1).  Investigator-
determined response assessments at each assessment time point will be entered onto the 
appropriate CRF.  Subjects must have evaluable disease or measurable disease based on 
RECIST 1.1. 
At Screening 
CT/MRI scans of the brain, neck (DTC only) chest, abdomen, pelvis, and other known sites 
of disease (bone), plus any areas of newly suspected disease will be performed at screening.  
Historical scans (within prior 28 days) that do not follow the guidelines completely may be 
used to demonstrate eligibility.  For subjects with 131I refractory DTC, historical scans 
(within prior 12 months) that do not follow the guidelines completely may be used to 
demonstrate eligibility. 
During Treatment Phase 
For Cohort 1 only, CT/MRI scans of neck (DTC only), chest, abdomen, pelvis, and other 
known sites of disease plus any areas of newly suspected disease will be performed using the 
same methodology as at screening every 8 weeks per the appropriate tumor assessment 
schedule, or sooner if clinically indicated, beginning from the date of the first treatment dose, 
continuing during treatment cycles until documentation of disease progression.  
For subjects with DTC (Cohort 2A) CT/MRI of the neck and other known sites of the disease 
and CT chest plus any areas of newly suspected disease will be performed. For subjects with 
osteosarcoma (Cohorts 2B, 3A and 3B), CT chest, and CT/MRI of other known sites of 
disease plus any areas of newly suspected disease will be performed.  Tumor assessments 


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will be performed based on RECIST 1.1 every 6 or 8 weeks per the appropriate tumor 
assessment schedule (or sooner, if clinically indicated) beginning from the date of the first 
treatment dose, continuing during treatment cycles until documentation of disease 
progression.  
In subjects 2 to <6 years of age, CT/MRI scans must be performed at screening, Cycle 1 Day 
1 (following the Run-In Period at investigator’s discretion) and every 8 weeks during the 
Treatment Period as indicated in Table 7. For Cohorts 3A and 3B CT/MRI scans should be 
performed every 6 weeks.  This schedule for tumor assessments will be maintained 
irrespective of treatment delays.  
An initial assessment of CR or PR according to RECIST 1.1 must be confirmed not less than 
4 weeks after the initial response.  The same methodology (CT or MRI) and scan acquisition 
techniques (including use or nonuse of IV 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 8 weeks (for Single-Agent Cohorts) or 6 
weeks (for Combination-Cohorts) until documentation of progression or start of a new 
anticancer agent.  Screening CT scans should be performed with oral and iodinated IV 
contrast and 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 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 
neck, 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 assessable by both clinical 
and radiographic techniques, the radiographic (CT/MRI) technique should be used for the 
assessment of target and non-target lesions. 


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Brain scans by MRI with and without contrast enhancement or CT with contrast 
enhancement will be performed at screening, and as clinically indicated.  If protocol eligible 
brain metastases are present at screening, a CT/MRI of the brain must be performed at all 
tumor assessment time points (eg, every 6 or 8 weeks).   
During Post-treatment Follow-up  
Subjects who discontinue treatment without disease progression will have tumor assessments 
performed every 6 or 8 weeks (per the appropriate tumor assessment schedule) for up to 1 
year, or sooner if clinically indicated, for documented disease progression or until another 
anticancer therapy is initiated, whichever occurs first.  
For osteosarcoma subjects who experience PD in Cohort 2B and choose to receive the 
combination therapy of lenvatinib with ifosfamide and etoposide, prior to entering Cohort 3B 
(Combination Expansion), baseline tumor assessments must be re-established on new images 
(unless the images confirming disease progression were performed within 28 days of Cycle 1 
Day 1 in Cohort 3B).  Subjects will undergo assessments as per the Schedule of Assessments 
provided for the combination treatment.  After data cutoff, tumor assessments may be 
performed as clinically indicated as per the institutional guidelines, following the prevailing 
local standard of care.  All subjects will be followed for survival for 1 year or until death, 
unless the study is terminated. 
PALATABILITY AND ACCEPTABILITY OF LENVATINIB SUSPENSION FORMULATION 
The palatability and acceptability of lenvatinib suspension formulation will be assessed using 
the Palatability Questionnaire (see Appendix 13).  All subjects who receive suspension 
formulation must complete the questionnaire according to the Schedule of Assessments.  If 
the subject is unable to complete the questionnaire, this must be done by a parent or legal 
guardian.  Measurement of palatability will be assessed using the Hedonic scale (Guinard, 
2001) which is a Visual Analog Scale (VAS). 
9.5.1.4 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Assessments 
PHARMACOKINETIC ASSESSMENTS 
Blood samples (2 mL each) will be collected from all subjects at the time points shown in 
Table 5.  PK blood samples will also be drawn pretreatment on the day of tumor assessment 
as described in the Table 5.  Actual time and date of PK blood collection as well as time of 
drug administration will be recorded on the appropriate page of the CRF.  Exposure 
parameters such as area under the concentration × time curve (AUC) will be derived from 
posterior estimates of the PK parameters from the final population PK model.  For the time 
points shown in Table 5, subjects or their parents will be instructed not to take the dose of 
lenvatinib prior to arriving at the study site.  Lenvatinib capsule administration will be 
recorded in the eCRF.  The Cycle 1 Day 1 and Day 15 (single agent cohorts only), and Cycle 
2 Day 1 doses of lenvatinib will be administered at the study site at approximately the same 
time of day as the Cycle 1 Day 1 dose was administered in order to accommodate PK sample 


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collection timing.  Instructions for the collection, handling, and shipping procedures of PK 
samples will be provided in a separate Laboratory Manual. 
Table 5 
Lenvatinib Pharmacokinetic Sampling Time Points 
Time Pointa 
Time (h) 
Run-In Day 15 
Predoseb 
Cycle 1 Day 1 
Postdose:  0.5-4 and 6-10 
Cycle 1 Day 15c 
Predose 
Postdose: 0.5-4 and 6-10 
Cycle 2 Day 1 
Predose 
Postdose:  2-12 
Note:  PK blood samples should be drawn on day of tumor assessments (predose).  If the tumor 
assessments fall on the same day as study treatment PK samples, they need not be collected again to avoid 
duplicate samples. 
h = hour(s). 
a. If dose interruption is necessary in these time points, only predose sample should be collected, if 
possible. 
b. Sample to be collected during the Run-in Period (Cohort 1). 
c. Samples not required for Cohorts 3A and 3B 
 
Only the samples from all subjects receiving active treatment will be analyzed.  Lenvatinib 
will be quantified using a validated liquid chromatography/mass spectrometry/mass 
spectrometry (LC/MS/MS) method. 
PHARMACODYNAMIC ASSESSMENTS 
Blood serum samples from study subjects will be collected at Baseline, Day 8 of Cycle 1 
(Combination-Agent cohorts 3A and 3B), Day 15 of Cycle 1 (Single-Agent cohorts), Day 1 
of all subsequent cycles, and at the Off-Treatment Visit.  For subjects ongoing after the data 
cutoff date for the primary analysis, blood samples will be collected at the Off-Treatment 
Visit.  For subjects 2 to <6 years, blood serum sample will be collected in Cohort 1 at Cycle 
1 Day 1 (predose).  Blood serum samples may be analyzed using global proteomic methods, 
enzyme-linked immunosorbent assay (ELISA), multiplex bead-based immunoassay, or other 
assays/methods and new technology in an effort to identify biomarkers.  In addition, 
biomarkers identified in other lenvatinib clinical studies may also be assessed in samples 
collected from subjects enrolled in this study.  Blood biomarker samples may be used for 
exploratory analysis for evaluation of response-related and/or safety-related outcomes as well 
as for potential use in diagnostic development. (see Appendix 11) 
Pharmacodynamic biomarker analysis will be performed as described in an analysis plan 
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PHARMACOGENOMIC/PHARMACOGENETIC ASSESSMENTS 
Archived, fixed tumor tissue will be collected (if available) for assessment of mutations and 
other genetic alterations or proteins that may be important in the development and 
progression of cancer as well as for potential use in diagnostic development. 
A blood sample will be collected for pharmacogenomic analysis.  The DNA may be analyzed 
for genes associated with lenvatinib absorption, distribution, metabolism, excretion (ADME) 
and to validate mutations suspected of functional relevance (using in silico prediction) to 
determine exclusivity to tumor sample.  The DNA will not be used to determine or predict 
risks for diseases that an individual subject does not currently have. 
Data obtained from the PD and PG samples will be used for research.  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 to assist in any research scientific questions related to lenvatinib and for 
potential diagnostic development.  If the subject reaches 18 years of age prior to the date of 
final sample analyses they will be reconsented.  No further analyses will be performed on 
these collected samples from subjects who either do not reconsent after their 18th birthday or 
cannot be reached for reconsenting and the sample will be destroyed. 
Instructions for the processing, storage, and shipping of samples will be provided in the 
Laboratory Manual. 
When the subject reaches the age of 18 years (or 16 years in the UK) while on the study, and 
becomes competent to give informed consent, his/her consent will be obtained using separate 
ICFs to continue the study. 
9.5.1.5 
Safety Assessments 
Safety assessments will consist of monitoring and recording all AEs, including all Common 
Terminology Criteria for Adverse Events (CTCAE) v4.03 grades (for both increasing and 
decreasing severity), and serious adverse events (SAEs); regular laboratory evaluation of 
hematology, blood chemistry, and urine values; periodic measurement of vital signs and 12-
lead ECGs; and echocardiograms, Lansky play score or Karnofsky performance status score, 
physical examinations, and height assessments as detailed in the Schedule of Assessments 
(Table 7, Table 8, and Table 9).  A diary will be provided to each subject to capture any 
abnormal gastrointestinal symptoms (eg, diarrhea, abdominal discomfort, cramps) 
experienced during the study. Fecal occult blood will be monitored regularly during the 
study. 
Skeletal bone growth will be assessed by height measurements at the Baseline Visit, 
thereafter at Day 1 of each cycle during the Treatment Phase for Cohort 1 (and Day 1 of 
every 3 cycles for cohorts 2A, 2B, 3A and 3B), at the Off-treatment Visit, and every 3 months 
during the Post-treatment Follow-up for 1 year.  Proximal tibial growth plate x-rays will be 
done at Baseline and at the Off-treatment Visit. Postbaseline, only open growth plates will be 
further assessed.  


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Clinical and laboratory toxicities/symptomatology will be graded according to Common 
Terminology Criteria for Adverse Events (CTCAE) v4.03 (see Appendix 2).  
ADVERSE EVENTS AND OTHER EVENTS OF INTEREST 
An adverse event (AE) is any untoward medical occurrence in a subject or clinical 
investigation in a subject administered an investigational product.  An AE does not 
necessarily have a causal relationship with the medicinal product.  For this study, the study 
drug(s) are lenvatinib, etoposide, and ifosfamide.  
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 
• 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, whether prescribed in the 
protocol or not. 
A laboratory result should be considered by the investigator to be an AE if it: 
• Results in the withdrawal of study drug 
• Results in withholding of study drug pending some investigational outcome 
• Results in an intervention, based on medical evaluation (eg, potassium supplement for 
hypokalemia) 
• Is an out-of-range laboratory value that in the investigator’s judgment fulfills the 
definitions of an AE with regard to the subject’s medical profile 
 
All AEs observed during the clinical 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 informed consent form until 30 days after the last dose of study 
treatment.  Subjects who fail screening primarily due to AE(s) must have the AE(s) leading 
to screen failure reported on the Screening Disposition CRF.   
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.  Any laboratory abnormality 


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considered to constitute an AE should be reported on the Adverse Event CRF.  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.   
Abnormal ECG (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 >480 or a QTc 
increase of ≥60 msec from baseline.  Any ECG abnormality that the investigator considers as 
an AE should be reported as such. 
Progression of malignant disease under study should not be recorded as an AE in studies 
where it is included as an endpoint for underlying disease.  Signs and symptoms clearly 
related to the progression of disease should not be captured as an AE.  If the progression 
leads to an untoward medical occurrence, then this medical occurrence should be recorded as 
an AE. 
All AEs, regardless of relationship to study drug or procedure, should be collected beginning 
from the time the subject signs the study consent through the last visit and for 30 days 
following study drug discontinuation. 
All AEs must be followed for 30 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. 
Assessing Severity of Adverse Events 
Adverse events will be graded according to Common Terminology Criteria for Adverse 
Event (CTCAE v4.03) (Appendix 2).     
Investigators will report CTCAE grades for all AEs (for both increasing and decreasing 
severity).  All adverse events reported using CTCAE classification and graded as 4 or 5 are 
to be considered serious.  Adverse events that are not reported in the CTCAE will be graded 
on a 4-point scale (mild, moderate, severe, and life-threatening). 
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 


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• 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 
Not Related: A causal relationship between the study treatment and the AE is not a 
reasonable possibility 
Related: 
A causal relationship between the study treatment and the AE is a reasonable 
possibility.  The investigator must further qualify the degree of certainty as “possible” or 
“probable.” 
Serious Adverse Events and Other Events of Interest 
A serious adverse event (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 adverse 
event 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) 
Other important medical events should also be considered SAEs.  These events 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.  Medical and scientific 
judgment should be exercised in deciding whether expedited reporting is appropriate in such 
situations.  
In addition to the above, other events of interest include pregnancy overdose, misuse, abuse, 
or medication error; and any treatment-emergent significant laboratory abnormality (TEAV).  
These events of interest 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 events of 
interest 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  


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• 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 
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, Table 8, and Table 9) shows the visits 
and time points at which blood for clinical laboratory tests and urine for urinalysis will be 
collected in the study. 
Table 6 
Clinical Laboratory Tests 
Category 
Parameters 
Hematology 
Hematocrit, hemoglobin, platelets, RBC count, and WBC count 
with differential (bands, basophils, eosinophils, lymphocytes, 
monocytes, neutrophils), MCH, MCHC, MCV 
Chemistry 
 
 
Electrolytes 
Bicarbonate, chloride, potassium, sodium  
 
Liver function tests 
ALT, alkaline phosphatase, aspartate AST,  conjugated (direct) 
bilirubina, total bilirubin 
 
Renal function tests 
BUN or urea, creatinine 
 
Other chemistries 
Albumin, amylase, calcium, glucose, LDH, lipase, magnesium, 
phosphorus, total protein, uric acid, Guaiac fecal occult blood test 
(FOBT) 
Urinalysis for microscopyb 
RBCs/high-power-field (HPF) 
Urine dipstick testingb,c 
Blood, protein, glucose 
Other 
Pregnancy test (serum or urine β–hCG), TSH, free T4 levels, 
thyroglobulind 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; β hCG = beta-human chorionic 
gonadotropin; LDH = lactate dehydrogenase; MCH = mean corpuscular hemoglobin; MCHC = mean corpuscular hemoglobin 
concentration; MCV = mean corpuscular volume; RBC = red blood cells; T4 = thyroxine; TSH = thyroid stimulating hormone; WBC = 
white blood cells. 
a: Direct bilirubin should be assessed if total bilirubin is elevated. 
b: 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 
c:  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.  
d:  For DTC subjects, TSH, free T4, and thyroglobulin should be tested. TSH should be assessed for all subjects. 
 
All clinical laboratory tests during the study will be performed by local laboratories.  All 
hematology, blood chemistry (including pregnancy test, as applicable), and urinalysis 


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samples are to be obtained prior to study drug administration and sent to the local laboratory 
on the day of collection unless otherwise instructed.  
Clinical chemistry and hematology results must be reviewed prior to administration of study 
drug on Cycle 1 Day 1 and within 48 hours after 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).  Refer to Study Drug 
Dose Reduction and Interruption Instructions, Table 3 for the management of clinically 
significant laboratory abnormalities.  Every effort should be made to collect samples for 
analysis at the local laboratory at the same time.   
A laboratory abnormality may meet the criteria to qualify as an AE as described in this 
protocol (see Section 9.5.1.5) and the CRF Completion Guidelines.  In these instances, the 
AE corresponding to the laboratory abnormality will be recorded on the Adverse Event CRF. 
For laboratory abnormalities meeting the criteria of SAEs (Section 9.5.1.5), 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. 
VITAL SIGNS AND WEIGHT MEASUREMENTS 
Vital sign measurements (ie, systolic and diastolic blood pressure [BP] [mmHg], pulse [beats 
per minute], respiratory rate [per minute]), body temperature (in centigrade), weight [kg]), 
and height (cm) will be obtained at the visits designated in the Schedule of Assessments 
(Table 7, Table 8, and Table 9) by a validated method.  Blood pressure and pulse 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.   
PHYSICAL EXAMINATIONS 
Physical examinations will be performed as designated in the Schedule of Assessments 
(Table 7, Table 8, and Table 9).  A comprehensive physical examination (including a 
neurological examination) will be performed at Screening, Baseline (only if screening 
physical examination was performed >7 days prior to Cycle 1 Day 1), Cycle 1 Day 8 
(Cohorts 3A and 3B), Cycle 1 Day 15 (Single-Agent), Day 1 of each subsequent cycle, and at 
the off-treatment assessment.  A symptom-directed physical examination will be performed 
on Cycle 1 Day 1 and at any time during the study, as clinically indicated.  Documentation of 
the physical examination will be included in the source documentation at the site.  Only 


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changes from screening physical examination findings that meet the definition of an AE will 
be recorded on the Adverse Events CRF. 
ELECTROCARDIOGRAMS 
Electrocardiograms will be obtained as designated in the Schedule of Assessments (Table 7, 
Table 8 and Table 9).  Complete, standardized, 12-lead ECG recordings that permit all 12 
leads to be displayed on a single page with an accompanying lead II rhythm strip below the 
customary 3 × 4 lead format are to be used.  In addition to a rhythm strip, a minimum of 3 
full complexes should be recorded from each lead simultaneously.  Subjects must be in the 
recumbent position 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) and the CRF Completion Guidelines.  In these instances, the AE 
corresponding to the ECG abnormality will be recorded on the Adverse Events CRF. 
For ECG abnormalities meeting criteria of an SAE (see Serious Adverse Events and Other 
Events of Interest), the study site must fax the SAE report including the ECG report to the 
number indicated in the Investigator File using the SAE reporting form (see Section 9.5.4.1). 
OTHER SAFETY ASSESSMENTS 
Pregnancy Test 
A serum β-hCG test will be performed for females of childbearing potential (see definition 
included in the Inclusion/Exclusion criteria, Sections 9.3.1and 9.3.2).  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) and at the Off-treatment Visit in women of childbearing 
potential.  Blood and urine samples will be taken at designated time points as specified in the 
Schedule of Assessments Table 7, Table 8, and Table 9). 
Echocardiogram 
An echocardiogram to assess left ventricular ejection fraction (LVEF) will be performed 
during the screening phase, every 16 weeks following the first dose of study drug while the 
subject is on treatment or sooner, if clinically indicated, and at (or within 1 week following) 
the off-treatment assessment.  LVEFs as assessed by the institution will be entered onto the 
CRF.  Investigator assessment will be based upon institutional reports. 
9.5.2 
Schedule of Assessments 
9.5.2.1 
Schedule of Assessments 
Table 7, Table 8, and Table 9 present the Schedules of Assessments for the cohorts in this 
study. 


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Table 7 
Schedule of Assessments – Cohort 1 
Phase 
Pretreatment  
 
Treatmenta 
(All cycles are 28 days in duration) 
 
Post-
Tx 
Period 
Screen-
ingb 
Baselinec Run-In 
Period 
Treatment Phased 
 
Off-
Tx 
Follo
w-upe 
Visit  
1 
2 
3-5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23, 
etc 
99 
 
Cycle 
 
 
21 Days 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 - 
Last 
 
 
Day 
-28 to -2 
-1 
1 8 15 1 
8 
15 
22 
1 
8 
15 
22 
1 
8 
15 
22 
1 
8 
15 
22 
1 
15 
 
 
Procedures/Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/surgical history 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior 
medication/procedures 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy testf 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Lansky play score/ 
Karnofsky PSg 
X 
X 
 
 
 
Xg 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
TNM Staging 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examinationh 
X 
X 
 
 
 
Xh 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
Vital signsi 
X 
X 
 
 X Xi 
 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X  
12-lead ECGj 
X 
 
 
 
 
Xj 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
Echocardiogramk 
X 
 
 
 X 
Performed every 16 weeks following the first dose of study drug or sooner, if clinically indicated 
X 
 
Clinical chemistry and 
hematologyl 
X 
X 
 
 X Xl 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
X 
 
Guaiac Fecal occult blood 
testl 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
Urine dipstick testingm 
X 
X 
 
 X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
 
PK blood samplesn 
 
 
 
 X 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study treatment 
 
 
Once Daily (lenvatinib) [based on BSA calculations at Day 1 of each Cycle] 
 
 
Palatability Questionnaire 
 
 
 
  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
  
Xo CT/MRI of neck, chest, abdomen, pelvis, and other areas of known disease at Screening plus any 
X 
 


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Table 7 
Schedule of Assessments – Cohort 1 
Phase 
Pretreatment  
 
Treatmenta 
(All cycles are 28 days in duration) 
 
Post-
Tx 
Period 
Screen-
ingb 
Baselinec Run-In 
Period 
Treatment Phased 
 
Off-
Tx 
Follo
w-upe 
Visit  
1 
2 
3-5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23, 
etc 
99 
 
Cycle 
 
 
21 Days 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 - 
Last 
 
 
Day 
-28 to -2 
-1 
1 8 15 1 
8 
15 
22 
1 
8 
15 
22 
1 
8 
15 
22 
1 
8 
15 
22 
1 
15 
 
 
 
Tumor assessments: 
CT/MRIo 
areas of newly suspected disease should be performed every 8 weeks (during week 8) or sooner if 
clinically indicated until documentation of disease progression 
Brain CT/MRIp 
X 
 
 
  
 
Brain scans will be performed at screening and, if clinically indicated during treatment.  For 
subjects with protocol-eligible, treated brain metastases at screening, brain scans should be 
performed at all tumor assessment time points. 
 
 
Heightq 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
X 
Proximal Tibial growth 
plates x-rayq 
 
X 
 
 
 
 
 
X 
 
Pharmacodynamic 
biomarkersr 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
Archival tumor block or 
slidess 
 
X 
 
Blood sample for 
pharmacogenetic/ 
pharmacogenomic analysist 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Survivalu 
 
 
 
X 
X 
Concomitant medicationsv 
 
 
Throughout 
X 
AEs/SAEsw 
 
 
Throughout 
X 
Safety Monitoring (call at 
C1D8) 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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, PK =pharmacokinetics, PR = partial response, PS = 
performance score, RECIST 1.1 = Response Evaluation Criteria in Solid Tumors, version 1.1, RR = respiratory rate, SAE = serious adverse event, TNM = tumor-node-
metastasis, Tx = treatment. Note: Subjects 2 to <6 years of age must complete Screening/ Baseline assessments, all the assessments during the Run-In period, and all the cycles as 
indicated in Table 7.  All subjects who receive suspension formulation must complete the Palatability Questionnaire according to the Schedule of Assessments. If 
the subject is unable to complete the questionnaire, this must be done by a parent or legal guardian (Appendix 13).   


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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. 
Subjects benefiting from study treatment in the opinion of the investigator will continue treatment until disease progression, intolerable toxicity, subject noncompliance 
with safety or efficacy assessments, initiation of another anticancer therapy, voluntary discontinuation by the subject at any time, or study termination by the sponsor, 
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 Screening and Baseline (or within 72 hours prior to the first dose of study medication) and at the off visit in women of 
childbearing potential. 
g. 
A Lansky play score or Karnofsky performance status score will be obtained at the screening, baseline, C1D1 (subjects 2 to <6 years), Cycle 2 Day 1 visits, and every 
subsequent cycle visit thereafter. 
h. 
A comprehensive physical examination (including a neurological examination) will be performed at the screening, baseline (only if screening physical examination was 
performed > 7 days prior to C1D1), C1D1 (subjects 2 to <6 years), C1D15, and Day 1 visits of each subsequent cycle, and at the Off-treatment visits.  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.  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 Section 9.4.1.3 and Figure 2 in the protocol. Vitals should also be performed 
at Run-In Period D15, C1D1 and C1D22 for subjects 2 to <6 years. 
j. 
Single 12-lead ECG. Subjects must be in the recumbent position for a period of 5 minutes prior to the ECG. It should also be performed at C1D1 for subjects 2 to <6 years. 
k. 
An echocardiogram is performed during screening, every 16 weeks, and at the end of treatment visit, or sooner if clinically indicated. 
l. 
Clinical chemistry and hematology results must be reviewed prior to administration of study drug on C1D1 (should be performed for subjects 2 to <6 years) and within 48 
hours after 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). Guaiac fecal occult blood test (FOBT) should 
be performed. TSH should be assessed for all subjects, free T4 and thyroglobulin should be assessed only for RR-DTC subjects. See Table 6.  
m. Urine dipstick testing should be performed on Days 1, 8, 15, and 22 for Cycles 1-3, bi-weekly thereafter, or more frequently as clinically indicated. and at the Off-treatment 
Visit. For subjects with history of proteinuria ≥2+, urine dipstick testing should be performed until the results have been 1+ or negative for 3 consecutive months.  If a new 
event of proteinuria ≥2+ occurs, the subject must resume the Day 15 urine dipstick testing for evaluation of proteinuria until results are 1+ or negative for 3 consecutive 
months.  Subjects who have ≥2+ proteinuria on dipstick urinalysis should perform a spot P/C test and if possible undergo a 24-hour urine collection. Please refer to the 
guidelines in the protocol. Urine glucose should be performed as shown in Table 7 as part of urine dipstick. Also, see Table 6. 
n. 
PK blood samples drawn 0.5-4 hours and 6-10 hours postdose on C1D1 and predose, 0.5-4 hours and 6-10 hours postdose on C1D15 and predose and 2-12 hours postdose 
on C2D1. A PK sample should also be collected during the Run-In Period of D15 (predose), for subjects 2 to <6 years. Study Treatment PK blood samples should be 
drawn also on the day of tumor assessment (predose).  If the tumor assessments fall on the same day as study treatment PK samples, they need not be collected again to 
avoid duplicate samples. If dose interruption is necessary at these time points, only a predose sample should be collected, if possible. 
o. 
Screening:  Tumor assessments using CT of the neck (DTC only)/chest/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. CT scans should be performed with oral and iodinated IV contrast and MRI scans should be performed with IV gadolinium chelate.  
Treatment Phase:  Tumor assessments of the neck (DTC only)/chest/abdomen/pelvis and other areas of known disease at Screening or newly suspected disease should be 
performed every 8 weeks (within week 8) from C1D1 during the Treatment Phase (or sooner if there is evidence of progressive disease) and should utilize 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.  For subjects 2 to <6 years tumor assessment must also be performed at C1D1 at the investigator’s discretion. Any CR or PR must be 


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confirmed not less than 4 weeks after initial achievement of the response.  After treatment discontinuation, tumor assessments should continue to be performed every 8 
weeks until documentation of progression for 1 year or start of a new anticancer agent (refer to Section 9.5.1.3). 
p. 
Brain CT with contrast or MRI pre- and post- gadolinium contrast will be performed at the Screening Visit, and as clinically indicated.  For subjects with protocol-eligible 
treated brain metastases, brain CT/MRI will be performed at all tumor assessment time points. 
q. 
Height will be assessed at the Baseline Visit, Day 1 of each cycle during the Treatment Phase, at the Off-treatment Visit and every 3 months during the Post-treatment 
Follow-up.  Proximal tibial growth plates x-rays should be conducted at baseline and at the Off-treatment Visit. 
r. 
Blood samples will be collected at the Baseline Visit, C1D1 (predose for subjects 2 to <6 years), C1D15, Day 1 of all subsequent cycles, and at the Off-treatment Visit for 
assessment for blood serum sample to measure factors implicated in angiogenesis.  For subjects ongoing after the data cutoff date for the primary analysis, blood samples 
will be collected at the Off-Treatment Visit.     
s. 
An archival tumor sample from the most recent surgery or biopsy for identification of predictive biomarkers and pathology review may be collected at any time during the 
study, unless no such material is available.  
t. 
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.  Pharmacogenetic markers of drug metabolism and drug transport may be assessed. 
u. 
Survival data will be collected every 3 months until death or 1 year as per the protocol.  All anticancer therapies will be collected. 
v. 
Concomitant medications will be recorded throughout the study and for 30 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 30 days after the last dose.  SAEs irrespective of relationship to study 
treatment must be reported as soon as possible but not later than 24 hours. A diary will be provided to the subject to capture any abnormal gastrointestinal symptoms (eg, 
diarrhea, abdominal discomfort, cramps) experienced during the study. 
 
 


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Table 8 
Schedule of Assessments – Cohort 2A – Differentiated Thyroid Cancer and Cohort 2B - Osteosarcoma 
Phase 
Pretreatment 
Treatmenta 
(All cycles are 28 days in duration) 
Post-
Treatment 
Period 
Screening
b 
Baselinec 
Treatmentd 
Off-
Tx 
Follow-upe 
Visit  
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
99 
 
Cycle 
 
 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5-
Last 
 
 
Day 
-28 to -2 
-1 
1 
8 
15 
22 
1 
8 
15 
22 
1 
8 
15 
22 
1 
8 
15 
22 
1 
15 
 
 
Procedures/Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/surgical history 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior medication/ procedures 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy testf 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Lansky play score/ 
Karnofsky  PSg 
X 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
TNM Staging 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examinationh 
X 
X 
 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
Vital signsi 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
 
12-lead ECGj 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
Echocardiogramk 
X 
Performed every 16 weeks following the first dose of study drug or sooner, if clinically indicated 
X 
 
Clinical chemistry and 
hematologyl 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
X 
 
Guaiac Fecal occult blood testl 
X 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
Urine dipstick testingm 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
 
PK blood samplesn 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study treatment 
 
 
Once Daily (lenvatinib) [based on BSA calculations at Day 1 of each Cycle] 
 
 
Palatability Questionnaire 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor assessments:  CT/MRIo 
X 
 
CT chest, CT/MRI of neck (DTC only), and other areas of known disease at Screening plus any areas 
of newly suspected disease should be performed every 8 weeks (during week 8) or sooner if clinically 
indicated until documentation of disease progression 
X 
 


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Table 8 
Schedule of Assessments – Cohort 2A – Differentiated Thyroid Cancer and Cohort 2B - Osteosarcoma 
Phase 
Pretreatment 
Treatmenta 
(All cycles are 28 days in duration) 
Post-
Treatment 
Period 
Screening
b 
Baselinec 
Treatmentd 
Off-
Tx 
Follow-upe 
Visit  
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
99 
 
Cycle 
 
 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5-
Last 
 
 
Day 
-28 to -2 
-1 
1 
8 
15 
22 
1 
8 
15 
22 
1 
8 
15 
22 
1 
8 
15 
22 
1 
15 
 
 
Brain CT/MRIp 
X 
 
Brain scans will be performed at screening and, if clinically indicated during treatment.  For subjects 
with protocol-eligible, treated brain metastases at screening, brain scans should be performed at all 
tumor assessment time points. 
 
 
Heightq 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
Proximal Tibial growth plates 
x-rayq 
 
X 
 
X 
 
Pharmacodynamic biomarkersr 
 
X 
 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
Archival tumor block or slidess 
X 
 
Blood sample for 
pharmacogenomic analysist 
 
X 
 
 
Survivalu 
 
 
X 
X 
Concomitant medicationsv 
Throughout 
X 
AEs/SAEsw 
Throughout 
X 
Safety Monitoring (call at 
C1D8) 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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, PK = pharmacokinetics, PR = partial response, PS = 
performance score, RECIST 1.1 = Response Evaluation Criteria in Solid Tumors, version 1.1, RR = respiratory rate, SAE = serious adverse event, TNM = tumor-node-metastasis, 
Tx = treatment. Note: All subjects who receive suspension formulation must complete the Palatability Questionnaire according to the Schedule of Assessments. If the subject is 
unable to complete the questionnaire, this must be done by a parent or legal guardian (Appendix 13). 
 
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. Subjects benefiting from study treatment in the opinion of the investigator will continue treatment until disease progression, intolerable toxicity, subject noncompliance with 
safety or efficacy assessments, initiation of another anticancer therapy, voluntary discontinuation by the subject at any time, or study termination by the sponsor, whichever 
occurs first.   


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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) and at the off visit in 
women of childbearing potential. 
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. 
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. 
i. Assessments will include vital signs (resting BP, HR, RR, and body temperature, and weight. 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 Section 9.4.1.3 and Figure 2 in the protocol. 
j. Single 12-lead ECG.  Subject must be in the recumbent position for a period of 5 minutes prior to the ECG. 
k. An echocardiogram is performed during screening, every 16 weeks, and at end of treatment visit, or sooner if clinically indicated. 
l. Clinical chemistry and hematology results must be reviewed prior to administration of study drug on C1D1 and within 48 hours after 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).  Guaiac fecal occult blood test (FOBT) should be performed. TSH should be assessed for all subjects, free 
T4 and thyroglobulin should be assessed only for RR-DTC subjects. See Table 6. 
m. Urine dipstick testing should be performed every on Day 1, 8, 15 and 22 for cycles 1-3, bi-weekly thereafter or more frequently as clinically indicated and at the off-treatment 
visit. For subjects with history of proteinuria ≥2+, urine dipstick testing should be performed until the results have been 1+ or negative for 3 consecutive months.  If a new 
event of proteinuria ≥2+ occurs, the subject must resume the Day 15 urine dipstick testing for evaluation of proteinuria until results are 1+ or negative for 3 consecutive 
months.  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 shown in Table 8 as part of urine dipstick. Also see Table 6. 
n. PK blood samples drawn 0.5-4 hours and 6-10 hours postdose on C1D1 and predose, 0.5-4 hours and 6-10 hours postdose on C1D15 and predose and 2-12 hours postdose on 
C2D1. Study Treatment PK blood samples drawn also on the day of tumor assessment (Predose). If the tumor assessments fall on the same day as study treatment PK samples, 
they need not be collected again to avoid duplicate samples. If dose interruption is necessary at these time points, only a predose sample should be collected, if possible. 
o. Screening:  Tumor assessments using CT/MRI of the neck (DTC only), CT chest, 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. CT scans should be performed with oral and iodinated IV contrast and MRI scans should be performed with IV gadolinium chelate.   
Treatment Phase:  Tumor assessments of the neck (DTC only), chest, and other areas of known disease at Screening or newly suspected disease should be performed every 8 
weeks (within week 8) from C1D1 during the Treatment Phase (or sooner if there is evidence of progressive disease) and should use 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. 
An initial assessment of CR or PR must be confirmed not less than 4 weeks after achievement of the initial response.  After treatment discontinuation, tumor assessment should 
continue to be performed every 8 weeks until documentation of progression for 1 year or start of a new anticancer agent (refer to Section 9.5.1.3). 
p. Brain CT with contrast or MRI pre- and post- gadolinium contrast will be performed at the Screening Visit, and as clinically indicated.  For subjects with protocol-eligible 
treated brain metastases, brain CT/MRI will be performed at all tumor assessment time points. 
q. Height will be assessed at the Baseline Visit, Day 1 of every 3 cycles during the Treatment Phase, at the Off-treatment Visit, and every 3 months during the Post-treatment 
Follow-up.  Proximal tibial growth plates x-rays should be conducted at baseline, and at the Off-treatment visit.  
r. 
Blood samples will be collected at the Baseline Visit, C1D15, Day 1 of all subsequent cycles, at the Off-treatment Visit for blood serum sample to measure factors 
implicated in angiogenesis.  For subjects ongoing after the data cutoff date for the primary analysis, blood samples will be collected at the Off-Treatment Visit. 
s. An archival tumor sample from the most recent surgery or biopsy for identification of predictive biomarkers and pathology review may be collected at any time during the 
study, unless no such material is available. 
t. 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. 
u. Survival data will be collected every 3 months until death or 1 year as per the protocol.  All anticancer therapies will be collected. 


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v. Concomitant medications will be recorded throughout the study and for 30 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 30 days after last dose.  SAEs irrespective of relationship to study treatment must 
be reported as soon as possible but not later than 24 hours. A diary will be provided to the subject to capture any abnormal gastrointestinal symptoms (e.g., diarrhea, abdominal 
discomfort, cramps, etc) experienced during the study. 


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Table 9 
Schedule of Assessments – Cohorts 3A and 3B – Osteosarcoma  
Phase 
Pretreatment 
Treatmenta 
(All cycles are 21 days in duration) 
Post-
Treatment 
Period 
Screeningb Baselinec 
Treatmentd 
Off-Tx Follow-upe 
Visit  
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
99 
 
Cycle 
 
 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
 
 
Day 
-28 to -2 
-1 
1 
8 
15 
1 
8 
15 
1 
8 
15 
1 
8 
15 
1 
8 
15 
 
 
Procedures/Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/surgical history 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior medication/ procedures 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy testf 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Lansky play score/ 
Karnofsky PSg 
X 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
TNM Staging 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examinationh 
X 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Vital signsi 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
12-lead ECGj 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Echocardiogramk 
X 
Performed every 16 weeks following the first dose of study drug or sooner, if clinically indicated. 
 
 
Clinical chemistry and 
hematologyl 
X 
X 
 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Guaiac Fecal occult blood testl 
X 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Urine dipstick testingm 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
PK blood samplesn 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study treatment 
 
 
Combination of lenvatinib (QD) + ifosfamide + etoposide (Days 1-3 of Cycles 1-5 only)  
[based on BSA calculations at Day 1 of each Cycle]  
 
 
Palatability Questionnaire 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor assessments: CT/MRIo 
X 
 
CT chest and CT/MRI of  other areas of known disease at Screening plus any areas of newly 
suspected disease should be performed every 6 weeks (during Week 6) or sooner if clinically 
indicated until documentation of disease progression. 
X 
 
Brain CT/MRIp 
X 
 
Brain scans will be performed at screening and, if clinically indicated during treatment.  For subjects 
 
 


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Table 9 
Schedule of Assessments – Cohorts 3A and 3B – Osteosarcoma  
Phase 
Pretreatment 
Treatmenta 
(All cycles are 21 days in duration) 
Post-
Treatment 
Period 
Screeningb Baselinec 
Treatmentd 
Off-Tx Follow-upe 
Visit  
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
99 
 
Cycle 
 
 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
 
 
Day 
-28 to -2 
-1 
1 
8 
15 
1 
8 
15 
1 
8 
15 
1 
8 
15 
1 
8 
15 
 
 
with protocol-eligible, treated brain metastases at screening, brain scans should be performed at all 
tumor assessment time points. 
Heightq 
 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
Proximal Tibial growth plates 
x-ray  
 
X 
 
X 
 
Pharmacodynamic 
biomarkersr 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
Archival tumor block or 
slidess 
X 
 
Blood sample for 
pharmacogenetic/ 
pharmacogenomic analysist 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Survivalu 
 
 
X 
X 
Concomitant medicationsv 
Throughout 
X 
AEs/SAEsw 
Throughout 
X 
Safety Monitoring (call at 
C1D8) 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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, PBMC = peripheral blood mononuclear cells, PK = 
pharmacokinetics, PR = partial response, PS = performance score, RECIST 1.1 = Response Evaluation Criteria in Solid Tumors, version 1.1, RR = respiratory rate, SAE = serious 
adverse event, TNM = tumor-node-metastasis, Tx = treatment.  All subjects who receive suspension formulation must complete the Palatability Questionnaire according to the 
Schedule of Assessments. If the subject is unable to complete the questionnaire this must be done by their parents or their legal guardian (Appendix 13).   
 


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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. Subjects benefiting from study treatment in the opinion of the investigator will continue treatment until disease progression, intolerable toxicity, subject noncompliance with 
safety or efficacy assessments, initiation of another anticancer therapy, voluntary discontinuation by the subject at any time, or study termination by the sponsor, whichever 
occurs first. 
e. Subjects will be followed every 3 months for 1 year or until death 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) and at the Off-treatment 
Visit in women of childbearing potential. 
g. A Lansky play score or Karnofsky performance status score will be obtained at the Screening, Baseline, and Cycle 2 Day 1 Visits, and Day 1 of every subsequent cycle visit 
thereafter. 
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), C1D8, and 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. 
i. Assessments will include vital signs (resting BP, HR, RR, and body temperature), and weight.  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 Section 9.4.1.3 and Figure 2 in the protocol. 
j. Single 12-lead ECG.  Subjects must be in the recumbent position for a period of 5 minutes prior to the ECG. 
k. An echocardiogram is performed during screening, every 16 weeks, and at end of treatment visit, or sooner if clinically indicated. 
l. Clinical chemistry and hematology results must be reviewed prior to administration of study drug on C1D1 and within 48 hours after 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). Guaiac fecal occult blood test (FOBT) should be performed. TSH should be assessed for all subjects, See 
Table 6. 
m. Urine dipstick testing should be performed on Day 1 or more frequently as clinically indicated for 4 cycles, biweekly thereafter, and at the Off-treatment Visit. For subjects 
with a history of proteinuria ≥2+, urine dipstick testing should be performed until the results have been 1+ or negative for 3 consecutive months.  If a new event of proteinuria 
≥2+ occurs, the subject must resume the Day 15 urine dipstick testing for evaluation of proteinuria until results are 1+ or negative for 3 consecutive months.  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 shown in 
Table 9 as part of the urine dipstick.  Also, see Table 6. 
n. Study Treatment PK blood samples drawn 0.5-4 hours and 6-10 hours postdose on C1D1, and predose and 2-12 hours postdose on C2D1.  Study Treatment PK blood samples 
drawn also on the day of tumor assessment (predose). If the tumor assessments fall on the same day as study treatment PK samples, they need not be collected again to avoid 
duplicate samples. If dose interruption is necessary at these time points, only a predose sample should be collected, if possible. 
o. Screening:  Tumor assessments of the chest, 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.  CT scans should be 
performed with oral and iodinated IV contrast and MRI scans should be performed with IV gadolinium chelate  
Treatment Phase:  Tumor assessments of the chest, and other areas of known disease at Screening or newly suspected disease should be performed every 6 weeks (within 
Week 6) from C1D1 during the Treatment Phase (or sooner if there is evidence of progressive disease) and should utilize 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. 
Subjects who discontinue must complete the off-treatment tumor assessment. Any CR or PR must be confirmed not less than 4 weeks following the initial achievement of the 
response.  After treatment discontinuation, tumor assessment should continue to be performed every 6 weeks until documentation of progression for 1 year or start of a new 
anticancer agent (refer to Section 9.5.1.3). 
p. Brain CT with contrast or MRI pre- and post- gadolinium contrast will be performed at the Screening Visit, and as clinically indicated.  For subjects with protocol-eligible 
treated brain metastases, brain CT/MRI will be performed at all tumor assessment time points. 


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q. Height will be assessed at the Baseline Visit, Day 1 of every 3 cycles during the Treatment Phase, at the Off-treatment Visit and every 3 months during the Post-treatment 
Follow-up for 1 year.  Proximal tibial growth plates x-rays should be conducted at baseline and at the Off-treatment Visit. Hand and wrist x-rays and tibial growth plate x-rays 
will be optional for Germany. 
r. Blood samples will be collected at the Baseline Visit, C1D8, Day 1 of all subsequent cycles, and at the Off-Treatment assessment for blood serum sample to measure factors 
implicated in angiogenesis.  For subjects ongoing after the data cutoff data for the primary analysis, blood samples will be collected at the Off-Treatment Visit. 
s. An archival tumor sample from the most recent surgery or biopsy for identification of predictive biomarkers and pathology review may be collected at any time during the 
study, unless no such material is available. 
t. 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.  Pharmacogenetic markers of drug metabolism and drug transport may be assessed. 
u. Survival data will be collected every 3 months until death or 1 year as per the protocol.  All anticancer therapies will be collected. 
v. Concomitant medications will be recorded throughout the study and for 30 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 30 days after last dose.  SAEs irrespective of relationship to study treatment must 
be reported as soon as possible but not later than 24 hours. A diary will be provided to the subject to capture any abnormal gastrointestinal symptoms (eg, diarrhea, abdominal 
discomfort, cramps) experienced during the study. 


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9.5.3 
Appropriateness of Measurements 
All clinical assessments are standard measurements commonly used in studies of relapsed 
or refractory solid tumors. 
The safety assessments to be performed in this study, including hematology analyses, 
blood chemistry tests, urinalysis, radiologic studies, 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 24 hours from the time the investigator becomes aware of 
the event. 
Deaths and life-threatening events should be reported immediately by telephone.  
The immediate report should be followed up within 24 hours by emailing or faxing 
the completed SAE form. 
Serious adverse events, regardless of causality assessment, must be collected through the 
last visit and for 30 days after the subject’s last dose, whichever occurs first.  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 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 24 hours 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 should notify his/her IRB/IEC of the occurrence of the SAE, in writing, 
in accordance with local requirements.  A copy of this communication must be forwarded 
to the sponsor and/or the designated CRO monitor and filed in the 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 30 days of last study treatment, or any exposure to study drug through 
breastfeeding during study treatment or within 30 days of last study treatment, must be 
reported. 
If an adverse outcome of a pregnancy is suspected to be related to study drug, 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 24 hours from the time 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 24 hours from the time 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 
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. 
REPORTING OF SIGNIFICANT LABORATORY ABNORMALITY 
Any significant treatment-emergent laboratory abnormality that  meets the criteria 
described below and is observed during the clinical study should be entered on the 
Adverse Event CRF and reported using the procedures detailed in Reporting of Serious 
Adverse Events (Section 9.5.4.1), even if the laboratory abnormality does not meet 
serious criteria.  If the significant laboratory abnormality 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. 
A laboratory result should be considered a treatment-emergent significant abnormality if 
the result: 
• Is within normal limits at baseline and has increased in severity to meet the sponsor’s 
grading criteria for laboratory values of Grade 3 or above 
• Is outside normal limits at baseline and increases in severity to the sponsor’s grading 
criteria for laboratory values of Grade 4 or above.  These abnormalities are 
automatically considered to be serious, with the exception of expected and 
reproducible hematologic abnormalities. 
• Is otherwise considered by the investigator to meet serious criteria as defined in 
Section 9.5.1.5 
Significant laboratory abnormalities should not be listed as separate AEs or SAEs if they 
are considered to be part of the clinical syndrome that is being reported as an AE or SAE. 
REPORTING OF STUDY-SPECIFIC EVENTS 
Study-specific events should be entered on the Adverse Event CRF and reported using 
the procedures detailed in Reporting of Serious Adverse Events (Section 9.5.4.1), even if 
the study-specific event does not meet serious criteria.  If the event 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. 


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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 study drug at any 
time for safety, medical, or personal reasons.  Subjects who choose to discontinue study 
drug prior to disease progression will be followed in the post-study treatment follow-up 
period and continue to undergo regularly scheduled disease assessment until 
documentation of disease progression or start of an alternative anticancer treatment.  All 
subjects who discontinue study drug will be followed for overall survival and all post 
progression cancer treatments administered will be recorded.  Subjects may at any time 
withdraw consent for further study participation.  No further data will be collected on 
subjects once consent has been withdrawn.  All subjects who discontinue the study are to 
complete the study’s early discontinuation procedures indicated in the Schedule of 
Assessments (Table 7, Table 8, and Table 9).  
The investigator will promptly explain to the subject (or subject’s parent or guardian) 
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 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 administrative/other.  In addition to 


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the primary reason, the subject may indicate 1 or more secondary reason(s) for 
discontinuation.  Study disposition information will be collected on the Subject 
Disposition CRF. 
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 to inform site personnel when they are planning to 
receive medical care by another physician.  At each visit, the investigator will ask the 
subject whether he/she 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, 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, 
standard operating procedures (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 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. 
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 


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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 data 
cut-off 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 
The statistical analyses of the study data are described in this section.  Further details of 
the analytical plan will be provided in the SAP, which will be finalized before database 
lock. 
9.7.1.1 
Study Endpoints 
PRIMARY ENDPOINT(S) 
Cohort 1 (Single-Agent Dose-Finding) 
• RD based on the TiTE-CRM design. 
Cohort 2 (Single-Agent Expansion) 
• Cohort 2A:  DTC Group:  ORR (CR + PR) for subjects with measurable disease 
and BOR for all subjects  based on RECIST 1.1 
• Cohort 2B:  Osteosarcoma Group:  PFS-4, ie, the percentage of subjects who are 
alive and free of disease progression 4 months after the first dose based on 
RECIST 1.1 
Cohort 3A (Combination Dose-Finding) 
• RD of the combination treatment (lenvatinib + ifosfamide + etoposide) 
Cohort 3B (Combination Expansion) 
• PFS-4, ie, the percentage of subjects who are alive and free of disease progression 
4 months after the first dose based on RECIST 1.1 
SECONDARY ENDPOINTS 
Cohort 1 (Single-Agent Dose-Finding) 
• Efficacy 
o BOR over the treatment period 


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o ORR  
o DOR 
o Disease Control Rate (DCR) defined as the percentage of subjects with 
measurable disease who have a BOR of CR or PR or stable disease (SD) or 
subjects with evaluable disease who have a BOR of CR or Non-CR/Non-PD.  
To be assigned a best overall response of SD or Non-CR/Non-PD, the time 
from the first administration of study drug until the date of documented SD or 
Non-CR/Non-PD should be ≥7 weeks. 
o Clinical Benefit Rate (CBR) defined as the percentage of subjects with 
measurable disease who have a BOR of CR or PR or durable SD lasting ≥23 
weeks or subjects with evaluable disease who have a BOR of CR or durable 
Non-CR/Non-PD lasting ≥23 weeks 
o PFS defined as the time from the date of the first administration of study drug 
to the date of first documentation of disease progression or date of death, 
whichever occurs first 
o  TTP defined as the time from the date of the first administration of study drug 
until the date of first documentation of disease progression  
o OS defined as the time from the date of the first administration of study drug 
until the date of death from any cause.  Subjects who are lost to follow-up and 
those who are alive at the date of data cutoff will be censored at the date the 
subject was last known to be alive (or the data cutoff date). 
• Safety 
o AEs, SAEs, clinical laboratory values, vital signs, 12-lead ECG, urine 
dipstick, occult blood in stool, Lansky play scores or Karnofsky performance 
scores, physical examination findings, and height and closure of proximal 
tibial plates during treatment and follow-up 
• Plasma lenvatinib exposure parameters 
• Assessment of blood or tumor biomarkers that correlate with clinical response to 
lenvatinib treatment or AEs associated with lenvatinib treatment 
Cohorts 2A and 2B 
• Efficacy 
o 
BOR over the treatment period (osteosarcoma group) 
o 
ORR (measurable osteosarcoma group) 
o 
DOR (measurable DTC and osteosarcoma group) 
o 
Disease Control Rate (DCR) defined as the percentage of subjects with 
measurable disease who have a BOR of CR or PR or stable disease (SD) or 
subjects with evaluable disease who have a BOR of CR or Non-CR/Non-PD.  
To be assigned a best overall response of SD or Non-CR/Non-PD, the time 


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from the first administration of study drug until the date of documented SD 
or Non-CR/Non-PD should be ≥7 weeks.  
o 
Clinical Benefit Rate (CBR) defined as the percentage of subjects with 
measurable disease who have a BOR of CR or PR or durable SD lasting ≥23 
weeks or subjects with evaluable disease who have a BOR of CR or durable 
Non-CR/Non-PD lasting ≥23 weeks 
o 
PFS defined as the time from the date of the first administration of study drug 
to the date of first documentation of disease progression or date of death, 
whichever occurs first 
o 
TTP defined as the time from the date of the first administration of study 
drug until the date of first documentation of disease progression  
o 
OS defined as the time from the date of the first administration of study drug 
until the date of death from any cause.  Subjects who are lost to follow-up 
and those who are alive at the date of data cutoff will be censored at the date 
the subject was last known to be alive (or the data cutoff date). 
• Safety 
o AEs, SAEs, clinical laboratory values, vital signs, 12-lead ECGs, urine 
dipstick, occult blood in stool, Lansky play scores or Karnofsky performance 
scores, physical examination findings, and height and closure of proximal 
tibial plates during treatment and follow-up  
• 
Plasma lenvatinib exposure parameters  
• 
Assessment of blood or tumor biomarkers that correlate with clinical response to 
lenvatinib treatment or AEs associated with lenvatinib treatment 
Cohorts 3A and 3B 
• Efficacy 
o BOR over the treatment period 
o ORR (osteosarcoma group) 
o DOR 
o Disease Control Rate (DCR) defined as the percentage of subjects with 
measurable disease who have a BOR of CR or PR or stable disease (SD) or 
subjects with evaluable disease who have a BOR of CR or Non-CR/Non-PD.  
To be assigned a best overall response of SD or Non-CR/Non-PD, the time 
from the first administration of study drug until the date of documented SD or 
Non-CR/Non-PD should be ≥7 weeks.  
o Clinical Benefit Rate (CBR) defined as the percentage of subjects with 
measurable disease who have a BOR of CR or PR or durable SD lasting ≥23 
weeks or subjects with evaluable disease who have a BOR of CR or durable 
Non-CR/Non-PD lasting ≥23 weeks 


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o PFS defined as the time from the date of the first administration of study drug 
to the date of first documentation of disease progression or date of death, 
whichever occurs first 
o TTP defined as the time from the date of the first administration of study drug 
until the date of first documentation of disease progression 
o OS defined as the time from the date of the first administration of study drug 
until the date of death from any cause.  Subjects who are lost to follow-up and 
those who are alive at the date of data cutoff will be censored at the date the 
subject was last known to be alive (or the data cutoff date). 
• Safety 
o AEs, SAEs, clinical laboratory values, vital signs, 12-lead ECGs, urine 
dipstick, occult blood in stool, Lansky play scores or ECOG performance 
scores, physical examination findings, and height and closure of proximal 
tibial plates during treatment and follow-up  
• Plasma lenvatinib exposure parameters 
• Assessment of blood or tumor biomarkers that correlate with clinical response to 
lenvatinib treatment or AEs associated with lenvatinib treatment  
9.7.1.2 
Definitions of Analysis Sets 
The Safety Analysis Set is defined as all subjects who received any study drug and had at 
least one post-baseline safety evaluation. 
The Pharmacokinetic Analysis Set is defined as all subjects who received any study drug 
and have evaluable PK data. 
9.7.1.3 
Demographic and Other Baseline Characteristics 
Demographic and other baseline characteristics for the safety analysis set will be 
summarized using descriptive statistics.  Continuous demographic and baseline variables 
include age, sex, race, height, and weight will be summarized using n (number of subjects 
with available data), mean, standard deviation (SD), median, and range (minimum and 
maximum) unless otherwise specified.  Categorical variables will be summarized by 
number and percentage.  
9.7.1.4 
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).  Concomitant 
medications will be further coded to the appropriate Anatomical Therapeutic Chemical 
(ATC) class indicating therapeutic classification.  Prior medications will be defined as 
medications that stopped 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 


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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 up to 30 days after the subject’s last dose.  All medications 
will be will be summarized and listed by drug and drug class and by cohort. 
9.7.1.5 
Efficacy Analyses 
Efficacy will be evaluated based on the as-treated population (Safety Analysis Set).  
Each cohort will have its own cutoff date for the final analysis for CSR reporting 
purpose. 
Cohorts 1 and 3A: For purposes of the final analysis, data cutoff will occur when the RD 
is determined and the last enrolled subject completes 6 cycles of treatment or discontinue 
before the end of Cycle 6, whichever occurs first or pending discussion with the PSC. 
Cohorts 2A, 2B, and 3B: For DTC and osteosarcoma subjects, the cutoff will be after the 
completion of 6 cycles by the last subject enrolled in each cohort or early discontinuation 
before the end of Cycle 6, whichever occurs first. 
PRIMARY EFFICACY ANALYSIS 
Primary Endpoint Analyses 
Cohort 1 (Single-Agent Dose-Finding) 
Cohort 1 will be a lenvatinib single-agent dose-finding study including up to 24 subjects.  
A TiTE-CRM design will be used to determine the RD of lenvatinib and to increase the 
flexibility by allowing continuous accrual with no trial suspensions, which are typically 
needed when the toxicity assessment of subjects previously recruited, is not completed 
(Smith, et al., 1998; Cheung, 2009).  Using this TiTE-CRM design, an eligible subject 
can be included in the trial at any time, without waiting for the completion of prior 
subjects (Doussau, et al, 2012).  The model will be re-estimated considering all the 
toxicity observations currently available.  The subject will be treated at the best current 
estimate of the RD.  Individual subjects on long-term treatment may be treated at a dose 
below the dose recommended by the model for safety reasons. 
The RD will be defined as the dose that has DLT rate closest to the targeted a 20% rate.  
Four experimental doses may be investigated in Cohort 1:  Dose -1 (9 mg/m2), Dose 1 
(11 mg/m2), Dose 2 (14 mg/m2), and Dose 3 (17 mg/m2).  The starting dose will be Dose 
1. 
A one-parameter empirical power model will be used to assess the relation between the 
dose level and the probability of DLT: 
 where F(d,α) is the estimated 
probability of DLT at dose-level d, pd is the prior probability of DLT at dose level d, and 
α is the unknown parameter to be estimated by the model.  The vector {p0d} represents 
the initial guesses of toxicity probabilities, reflecting the clinicians’ prior impression.  
)
exp(
)
,
(
α
α
d
p
d
F
=


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The skeleton of initial guesses of toxicity probabilities {p0d} is numerically calibrated 
using the approach of Lee et al. (2005) and Cheung (2009) and using the “getprior” 
function of R, ensuring good design operating characteristics.  Based on consultation with 
the clinicians, the delta (half of the width of the CI) defining the indifference interval was 
set at 0.06 (indifference interval: 0.14 to 0.26) and the prior maximum tolerated dose 
(MTD0) at Dose 2, (14 mg/m²) is likely to be the RD (same as in adults).  This yields a 
vector of prior probabilities {p0k} equal to 0.03, 0.10, 0.20, and 0.33, for the doses 9 
mg/m2, 11 mg/m2, 14 mg/m2, and 17 mg/m2, respectively, that was found reasonable by 
the clinicians.  
A noninformative prior distribution Normal (0, 1.34) has been assigned for α in the 
Bayesian computation.  
The simulation study confirmed that the operating characteristics of the model defined 
with these parameters were reasonable, with more than 50% correct selection of the RD 
in 3 contrasted scenarios.  
Starting with Dose 1, the prior distribution of the parameter α will be updated by the 
accruing data on DLTs each time a subject completes evaluation for toxicity in Cycle 1.  
Additional subjects will be allocated to the dose associated with the posterior probability 
of DLT closest to the target (ie, having a DLT rate closest to 20%).  A least 2 subjects 
will be required to complete 4 weeks of treatment in Cycle 1 or report a DLT during 
Cycle 1 (at the starting dose) before a subject can be treated at the next dose level (dose-
escalation).  It is further specified that dose levels cannot be skipped when escalating.  
The RD will be determined either when approximately 18 subjects have been tested, or 
when futility is declared or when 10 subjects have been treated at the same dose.  Futility 
is defined as having <25% probability that any of the doses is safe.  
Cohort 2 (Single-Agent Expansion) 
DTC and osteosarcoma groups will be evaluated separately. 
Cohort 2A: DTC 
The primary efficacy endpoint is ORR for subjects with measurable disease and BOR for 
all subjects.  All ORR or BOR will be based on RECIST 1.1 assessed every 8 weeks.   
The analyses will be descriptively performed on the Safety Analysis Set.  
Cohort 2B: Osteosarcoma 
The primary efficacy endpoint is PFS-4 based on RECIST 1.1.   
The null hypothesis that PFS-4 is ≤25% will be tested against the alternative hypothesis 
of a PFS-4 ≥45%, using the 1-sample exact test of a single proportion, at the 1-sided 0.1 
level. PFS-4 will be presented with corresponding 2-sided, exact binomial 80% and 95% 
CIs. This analysis will be performed on the Safety Analysis Set. 


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Cohort 3 (Combination Dose-Finding and Expansion) 
Cohort 3A: Osteosarcoma Combination Dose-Finding 
As in Cohort 1, the DLT will be assessed to determine the RD of lenvatinib in 
combination with ifosfamide plus etoposide.    DLTs occurring during Cycle 1 will be 
evaluated and the subjects will be assigned a dose based on the rules for dose escalation 
and de-escalation (see Section 9.1.2.3 Treatment Phase: Cohort 3A).  
This dose of lenvatinib will be used to treat additional osteosarcoma subjects in Cohort 
3B. 
Cohort 3B (Osteosarcoma Combination Expansion) 
The primary efficacy endpoint is PFS-4 based on RECIST 1.1.   
The null hypothesis that PFS-4 is ≤25% will be tested against the alternative hypothesis 
of a PFS-4 ≥50%, using the 1-sample exact test of a single proportion, at the 1-sided 0.1 
level. PFS-4 will be presented with corresponding 2-sided, exact binomial 80% and 95% 
CIs.  This analysis will be performed on the lenvatinib-naïve subject in Safety Analysis 
Set, while subjects enrolled from Cohorts 1 and 2B will be summarized only as 
appropriate. 
SECONDARY EFFICACY ANALYSES 
Secondary endpoints PFS and TTPwill be analyzed using Kaplan-Meier product-limit 
estimates.  Median PFS and the cumulative probability of PFS at 4, and 12 months will 
be presented with 2-sided, 95% CIs when an adequate number of at risk subjects at those 
time points warrant the estimate.  The cumulative PFS and TTP probabilities will be 
plotted over time as appropriate. 
Secondary endpoints ORR, DCR, and CBRwill be calculated with exact binomial 95% 
CIs. 
The endpoint of OS will be analyzed using Kaplan-Meier product-limit estimates.  
Median OS and the cumulative probability of OS at 12 months will be presented with 2-
sided, 95% CIs when an adequate number of at risk subjects at those time points warrant 
the estimate. 
The above analyses will be based on the lenvatinib-naïve subjects in the Safety Analysis 
Set, while subjects enrolled from Cohorts 1 and 2B will be summarized only as 
appropriate.  


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9.7.1.6 
Pharmacokinetic, 
Pharmacodynamic, 
Pharmacogenomic, 
and 
Other 
Biomarker Analyses 
PHARMACOKINETIC ANALYSES 
Plasma concentration of lenvatinib versus time data will be listed.  Plasma concentration 
of lenvatinib versus time data from all cohorts will be pooled and analyzed using a 
population PK approach to estimate population PK parameters.  The analysis will be 
detailed in an analysis plan at a later date. 
Pharmacokinetic data will be summarized using n, mean, SD, percent coefficient of 
variation (% CV), geometric mean, median, minimum and maximum.  Survival data (PFS 
and OS) will be estimated using Kaplan-Meier methods. 
PHARMACODYNAMIC, PHARMACOGENOMIC, AND OTHER BIOMARKER ANALYSES 
Correlation between clinical response to lenvatinib treatment or AEs associated with 
lenvatinib treatment and blood or tumor biomarkers may be examined using descriptive 
statistics and graphic displays as appropriate.   
Exploratory/graphical analyses will be conducted for PK/PD evaluations, and may be 
followed by model based analyses.  If conducted, a detailed analysis plan will be 
provided in a separate document at a later date. 
9.7.1.7 
Safety Analyses 
All safety analyses will be performed on the Safety Analysis Set.  The incidence of 
treatment-emergent adverse events (TEAEs) and SAEs will be summarized by study 
cohort, and dose-level, if appropriate.  Laboratory test data, vital signs, 12-lead ECGs, 
urine dipstick, occult blood in stool, Lansky play scores or Karnofsky performance 
scores, physical examination, height, and closure of proximal tibial plates at scheduled 
time points and their changes from baseline will be summarized by study cohort and 
group using descriptive statistics, as appropriate.  Abnormal values will be flagged.  Prior 
and concomitant medications, medical/surgical history and subject demographics will be 
summarized and listed by study cohort and group.  
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 adverse events will be summarized. 
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 (Version 16.1 or higher) 


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lower level term (LLT) closest to the verbatim term.  The linked MedDRA preferred term 
(PT) and primary system organ class (SOC) will also be captured in the database. 
A treatment-emergent adverse event (TEAE) is defined as an AE that emerges during 
treatment (and within 30 days of the last study 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. 
An overview table, including the incidence of and the number of subjects with treatment-
emergent adverse events (TEAEs), SAEs, deaths, and TEAEs that led to discontinuation, 
dose modification, or dose interruption will be provided. 
The TEAEs will be summarized by study cohort and dose level, as appropriate.  The 
incidence of TEAEs will be reported as the number (percentage) of subjects with TEAEs 
by SOC and PT.     
LABORATORY VALUES 
Laboratory results will be summarized using Système International (SI) units, as 
appropriate.  For quantitative parameters, the actual value and the change from baseline 
to each postbaseline visit and to the end of treatment (defined as the last on-treatment 
value) will be summarized by visit and cohort using descriptive statistics.  Qualitative 
parameters will be summarized using frequencies (number and percentage of subjects), 
and changes from baseline to the worst postbaseline visit and to end of treatment will be 
reported using shift tables.  Percentages will be based on the number of subjects with 
both nonmissing baseline and relevant postbaseline results. 
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.  Shift tables for baseline CTC grade to worst post-baseline grade may  be 
provided. 
VITAL SIGNS 
Descriptive statistics for vital signs parameters (ie, systolic and diastolic BP, pulse, 
respiratory rate, temperature, weight, height) and changes from baseline will be presented 
by study cohort and group.  Descriptive summary statistics for vital sign parameters and 
their changes from baseline will be calculated. 


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ELECTROCARDIOGRAMS AND ECHOCARDIOGRAMS 
ECG results will be evaluated on an individual basis by subject.  Abnormal readings will 
be identified as those outside (above or below) the reference range.  ECG findings will be 
summarized. 
Echocardiograms (including LVEFs) will be summarized using descriptive statistics. 
9.7.1.8 
Other Analyses 
Palatability and Acceptability Questionnaire 
Measurement of palatability will be assessed using the Hedonic scale (Guinard, 2001) 
which is a Visual Analog Scale (VAS).  
Expansion Phase Analyses 
Safety data for Cohort 3B (Combination Expansion) will be reported at a later date. 
9.7.2 
Determination of Sample Size 
Approximately 69 to 108 subjects are planned for this study as follows: 
Cohort 1 (Single-Agent Dose-Finding):  Approximately 12 to 24 subjects based on TiTE-
CRM algorithm.   
Cohort 2 (Single-Agent Expansion):  Approximately 27 to 42 subjects:  Cohort 2A:  DTC 
group (12 subjects) and Cohort 2B:  osteosarcoma group (15 to 30 subjects). 
Cohort 2A:  DTC Group 
Approximately 12 subjects with evaluable or measurable disease are planned to be 
enrolled in Cohort 2A due to limited number of pediatric patients with DTC.  
Cohort 2B: Osteosarcoma Group 
A minimum of 15 PFS-4 evaluable subjects will be assessed in cohort 2B.  The sample 
size estimates were based on Simon’s Optimal Two-Stage Design (Simon, 1989).  If 
fewer than 5 subjects who are alive and free of disease progression at 4 months after first 
dose date are observed among the first 15 evaluable subjects in Stage I, accrual in the 
cohort will be suspended.  Otherwise, if at any time during Stage I of the cohort, at least 5 
subjects who are alive and free of disease progression at 4 months after first dose date are 
recorded among the first 15 evaluable subjects, enrollment in the cohort will continue 
seamlessly for a total of approximately 27 evaluable subjects.  If, at the end of the second 
stage for the cohort, at least 10 subjects who are alive and free of disease progression at 4 
months are recorded among the 27 subjects in the cohort, study drug will be considered 
active in the population. 


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The above sample size estimates are based on the following assumptions: the null 
hypothesis PFS-4 (H0) is ≤ 25%, and the alternative hypothesis PFS-4 (H1) is ≥ 45%. 
One-sided Type I error (α) = 0.1, and power = 80%.  To account for nonevaluable 
subjects, a total of 15-30 osteosarcoma subjects will be enrolled for Cohort 2B. 
 Cohort 3A (Combination Dose-Finding) 
Approximately 12 to 24 osteosarcoma subjects for whom ifosfamide and etoposide are 
considered a treatment option 
Cohort 3B (Combination Expansion) 
With the following assumptions:  p0=25%, p1=50%, 1-sided α=10%, β=20%, where p0 is 
an unacceptable rate of PFS, p1 is the target rate of PFS, α is the probability of declaring 
lenvatinib effective when the true rate is p0, and β is the probability of declaring 
lenvatinib not effective if the true rate is p1, a sample size of 15 subjects will provide a 
statistical power of 80%.  To account for nonevaluable subjects, a total of 18 lenvatinib-
naïve subjects will be enrolled for Cohort 3B, along with some subjects from Cohorts 1 
and 2B. 
9.7.3 
Interim Analysis 
Interim analyses may be performed after consultation with the PSC.   
The sponsor will closely evaluate the risks and benefits of the study throughout its 
conduct, along with the PSC as needed. 
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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11 PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE 
PROCEDURES) 
11.1 Changes to the Protocol 
There are to be no changes to the protocol without written approval from the sponsor.  
Protocols will be followed as written. 
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 and the IRB/IEC for the site must be notified immediately.  
The sponsor must notify the health or regulatory authority as required by local 
regulations. Per 21 CFR 312.30, a protocol change intended to eliminate an immediate 
hazard may be implemented immediately, provided FDA is subsequently notified by 
protocol amendment. 
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 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 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 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. 


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In accordance with ICH E6, Section 1.52, source documents include, but are not limited 
to, the following: 
• Clinic, office, or hospital charts 
• 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, EEGs, 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 
11.5 Identification of Source Data 
Not applicable. 
All data to be recorded on the CRF must reflect the corresponding source documents.  
11.6 Retention of Records 
The circumstances of completion or termination of the study notwithstanding, the 
investigator 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 2 years 


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after the last approval of a marketing application in an ICH region and until there are no 
pending or contemplated marketing applications in an ICH region or at least 3 years have 
elapsed since the formal discontinuation of clinical development of the investigational 
product. 
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 
Lenvatinib will be supplied to the principal investigator (or a designated pharmacist) by 
the sponsor.  Ifosfamide and etoposide will be supplied by the study sites from 
commercially available sources.  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, when approval is given by the sponsor, 
will destroy supplies and containers at the site. 
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 


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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. 
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. 
 


Clinical Study Protocol 
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incorporating Amendment 04 
 
 
 
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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: 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03  [Accessed 11 Jan 2015] 
 
 


Clinical Study Protocol 
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incorporating Amendment 04 
 
 
 
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FINAL:  22 Nov 2019 
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Appendix 3 
Papillary or Follicular Thyroid Carcinoma Staging 
Papillary or Follicular Carcinoma 
Stage Groupa 
T Stage 
N Stage 
M Stage 
Under 45 Years 
I 
Any T 
Any N 
M0 
II 
Any T 
Any N 
M1 
a. Separate stage groupings are recommended for papillary or follicular, medullary, and 
anaplastic (undifferentiated) carcinoma. 
Adapted from AJCC:  Thyroid. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging 
Manual. 7th ed. New York, NY: Springer, 2010, pp 87-96. 
 


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FINAL:  22 Nov 2019 
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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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incorporating Amendment 04 
 
 
 
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FINAL:  22 Nov 2019 
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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. 
 
 
 


Clinical Study Protocol 
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incorporating Amendment 04 
 
 
 
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FINAL:  22 Nov 2019 
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Page 146 of 165  
 
Appendix 6 
Schwartz Formula 
The pediatric Schwartz equation is: 
 
GFR (mL/min/1.73 m2) = (0.41 x Height) / Scr were Scr is serum/plasma creatinine in mg/dL 
Related references 
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: 989–996. 
See more at: http://nkdep.nih.gov/lab-evaluation/gfr-calculators/children-conventional-
unit.asp#sthash.FRfNtBFs.dpuf. 
Francis at al: Management Guidelines for Children with Thyroid Nodules and Differentiated Thyroid Cancer; The 
American Thyroid Association Guidelines Task Force on Pediatric Thyroid Cancer. THYROID, Volume 25, Number 7, 
2015. 
and 
Kumagai at al: Childhood thyroid cancers and radioactive iodine therapy: necessity of precautious radiation health risk 
management. Endocr J. 2007 Dec;54(6):839-47. 


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incorporating Amendment 04 
 
 
 
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FINAL:  22 Nov 2019 
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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) 
Ð 
5th 
10th 
25th 
50th 
75th 
90th 
95th 
5th 
10th 
25th 
50th 
75th 
90th 
95th 
1 
50th 
80 
81 
83 
85 
87 
88 
89 
34 
35 
36 
37 
38 
39 
39 
90th 
94 
95 
97 
99 
100 
102 
103 
49 
50 
51 
52 
53 
53 
54 
95th 
98 
99 
101 
103 
104 
106 
106 
54 
54 
55 
56 
57 
58 
58 
99th 
105 
106 
108 
110 
112 
113 
114 
61 
62 
63 
64 
65 
66 
66 
2 
50th 
84 
85 
87 
88 
90 
92 
92 
39 
40 
41 
42 
43 
44 
44 
90th 
97 
99 
100 
102 
104 
105 
106 
54 
55 
56 
57 
58 
58 
59 
95th 
101 
102 
104 
106 
108 
109 
110 
59 
59 
60 
61 
62 
63 
63 
99th 
109 
110 
111 
113 
115 
117 
117 
66 
67 
68 
69 
70 
71 
71 
3 
50th 
86 
87 
89 
91 
93 
94 
95 
44 
44 
45 
46 
47 
48 
48 
90th 
100 
101 
103 
105 
107 
108 
109 
59 
59 
60 
61 
62 
63 
63 
95th 
104 
105 
107 
109 
110 
112 
113 
63 
63 
64 
65 
66 
67 
67 
99th 
111 
112 
114 
116 
118 
119 
120 
71 
71 
72 
73 
74 
75 
75 
4 
50th 
88 
89 
91 
93 
95 
96 
97 
47 
48 
49 
50 
51 
51 
52 
90th 
102 
103 
105 
107 
109 
110 
111 
62 
63 
64 
65 
66 
66 
67 
95th 
106 
107 
109 
111 
112 
114 
115 
66 
67 
68 
69 
70 
71 
71 
99th 
113 
114 
116 
118 
120 
121 
122 
74 
75 
76 
77 
78 
78 
79 
5 
50th 
90 
91 
93 
95 
96 
98 
98 
50 
51 
52 
53 
54 
55 
55 
90th 
104 
105 
106 
108 
110 
111 
112 
65 
66 
67 
68 
69 
69 
70 
95th 
108 
109 
110 
112 
114 
115 
116 
69 
70 
71 
72 
73 
74 
74 
99th 
115 
116 
118 
120 
121 
123 
123 
77 
78 
79 
80 
81 
81 
82 
6 
50th 
91 
92 
94 
96 
98 
99 
100 
53 
53 
54 
55 
56 
57 
57 
90th 
105 
106 
108 
110 
111 
113 
113 
68 
68 
69 
70 
71 
72 
72 
95th 
109 
110 
112 
114 
115 
117 
117 
72 
72 
73 
74 
75 
76 
76 
99th 
116 
117 
119 
121 
123 
124 
125 
80 
80 
81 
82 
83 
84 
84 
7 
50th 
92 
94 
95 
97 
99 
100 
101 
55 
55 
56 
57 
58 
59 
59 
90th 
106 
107 
109 
111 
113 
114 
115 
70 
70 
71 
72 
73 
74 
74 
95th 
110 
111 
113 
115 
117 
118 
119 
74 
74 
75 
76 
77 
78 
78 
99th 
117 
118 
120 
122 
124 
125 
126 
82 
82 
83 
84 
85 
86 
86 
8 
50th 
94 
95 
97 
99 
100 
102 
102 
56 
57 
58 
59 
60 
60 
61 
90th 
107 
109 
110 
112 
114 
115 
116 
71 
72 
72 
73 
74 
75 
76 
95th 
111 
112 
114 
116 
118 
119 
120 
75 
76 
77 
78 
79 
79 
80 
99th 
119 
120 
122 
123 
125 
127 
127 
83 
84 
85 
86 
87 
87 
88 
9 
50th 
95 
96 
98 
100 
102 
103 
104 
57 
58 
59 
60 
61 
61 
62 
90th 
109 
110 
112 
114 
115 
117 
118 
72 
73 
74 
75 
76 
76 
77 
95th 
113 
114 
116 
118 
119 
121 
121 
76 
77 
78 
79 
80 
81 
81 
99th 
120 
121 
123 
125 
127 
128 
129 
84 
85 
86 
87 
88 
88 
89 
10 
50th 
97 
98 
100 
102 
103 
105 
106 
58 
59 
60 
61 
61 
62 
63 


Clinical Study Protocol 
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incorporating Amendment 04 
 
 
 
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FINAL:  22 Nov 2019 
Confidential 
Page 148 of 165  
 
 
BP 
Systolic BP (mmHg) 
Diastolic BP (mmHg) 
AGE 
Percentile 
Percentile of Height 
Percentile of Height 
(Year) 
Ð 
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/guidelines/hypertension/child_tbl.htm. 
 
 
 
 


Clinical Study Protocol 
E7080-G000-207 
incorporating Amendment 04 
 
 
 
Eisai 
FINAL:  22 Nov 2019 
Confidential 
Page 149 of 165  
 
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) 
Ð 
5th 
10th 
25th 
50th 
75th 
90th 
95th 
5th 
10th 
25th 
50th 
75th 
90th 
95th 
l 
50th 
83 
84 
85 
86 
88 
89 
90 
38 
39 
39 
40 
41 
41 
42 
90th 
97 
97 
98 
100 
101 
102 
103 
52 
53 
53 
54 
55 
55 
56 
95th 
100 
101 
102 
104 
105 
106 
107 
56 
57 
57 
58 
59 
59 
60 
99th 
108 
108 
109 
111 
112 
113 
114 
64 
64 
65 
65 
66 
67 
67 
2 
50th 
85 
85 
87 
88 
89 
91 
91 
43 
44 
44 
45 
46 
46 
47 
90th 
98 
99 
100 
101 
103 
104 
105 
57 
58 
58 
59 
60 
61 
61 
95th 
102 
103 
104 
105 
107 
108 
109 
61 
62 
62 
63 
64 
65 
65 
99th 
109 
110 
111 
112 
114 
115 
116 
69 
69 
70 
70 
71 
72 
72 
3 
50th 
86 
87 
88 
89 
91 
92 
93 
47 
48 
48 
49 
50 
50 
51 
90th 
100 
100 
102 
103 
104 
106 
106 
61 
62 
62 
63 
64 
64 
65 
95th 
104 
104 
105 
107 
108 
109 
110 
65 
66 
66 
67 
68 
68 
69 
99th 
111 
111 
113 
114 
115 
116 
117 
73 
73 
74 
74 
75 
76 
76 
4 
50th 
88 
88 
90 
91 
92 
94 
94 
50 
50 
51 
52 
52 
53 
54 
90th 
101 
102 
103 
104 
106 
107 
108 
64 
64 
65 
66 
67 
67 
68 
95th 
105 
106 
107 
108 
110 
111 
112 
68 
68 
69 
70 
71 
71 
72 
99th 
112 
113 
114 
115 
117 
118 
119 
76 
76 
76 
77 
78 
79 
79 
5 
50th 
89 
90 
91 
93 
94 
95 
96 
52 
53 
53 
54 
55 
55 
56 
90th 
103 
103 
105 
106 
107 
109 
109 
66 
67 
67 
68 
69 
69 
70 
95th 
107 
107 
108 
110 
111 
112 
113 
70 
71 
71 
72 
73 
73 
74 
99th 
114 
114 
116 
117 
118 
120 
120 
78 
78 
79 
79 
80 
81 
81 
6 
50th 
91 
92 
93 
94 
96 
97 
98 
54 
54 
55 
56 
56 
57 
58 
90th 
104 
105 
106 
108 
109 
110 
111 
68 
68 
69 
70 
70 
71 
72 
95th 
108 
109 
110 
111 
113 
114 
115 
72 
72 
73 
74 
74 
75 
76 
99th 
115 
116 
117 
119 
120 
121 
122 
80 
80 
80 
81 
82 
83 
83 
7 
50th 
93 
93 
95 
96 
97 
99 
99 
55 
56 
56 
57 
58 
58 
59 
90th 
106 
107 
108 
109 
111 
112 
113 
69 
70 
70 
71 
72 
72 
73 
95th 
110 
111 
112 
113 
115 
116 
116 
73 
74 
74 
75 
76 
76 
77 
99th 
117 
118 
119 
120 
122 
123 
124 
81 
81 
82 
82 
83 
84 
84 
8 
50th 
95 
95 
96 
98 
99 
100 
101 
57 
57 
57 
58 
59 
60 
60 
90th 
108 
109 
110 
111 
113 
114 
114 
71 
71 
71 
72 
73 
74 
74 
95th 
112 
112 
114 
115 
116 
118 
118 
75 
75 
75 
76 
77 
78 
78 
99th 
119 
120 
121 
122 
123 
125 
125 
82 
82 
83 
83 
84 
85 
86 
9 
50th 
96 
97 
98 
100 
101 
102 
103 
58 
58 
58 
59 
60 
61 
61 
90th 
110 
110 
112 
113 
114 
116 
116 
72 
72 
72 
73 
74 
75 
75 
95th 
114 
114 
115 
117 
118 
119 
120 
76 
76 
76 
77 
78 
79 
79 
99th 
121 
121 
123 
124 
125 
127 
127 
83 
83 
84 
84 
85 
86 
87 
10 
50th 
98 
99 
100 
102 
103 
104 
105 
59 
59 
59 
60 
61 
62 
62 
90th 
112 
112 
114 
115 
116 
118 
118 
73 
73 
73 
74 
75 
76 
76 
95th 
116 
116 
117 
119 
120 
121 
122 
77 
77 
77 
78 
79 
80 
80 
99th 
123 
123 
125 
126 
127 
129 
129 
84 
84 
85 
86 
86 
87 
88 


Clinical Study Protocol 
E7080-G000-207 
incorporating Amendment 04 
 
 
 
Eisai 
FINAL:  22 Nov 2019 
Confidential 
Page 150 of 165  
 
 
BP 
Systolic BP (mmHg) 
Diastolic BP (mmHg) 
AGE 
Percentile 
Percentile of Height 
Percentile of Height 
(Year) 
Ð 
5th 
10th 
25th 
50th 
75th 
90th 
95th 
5th 
10th 
25th 
50th 
75th 
90th 
95th 
11 
50th 
100 
101 
102 
103 
105 
106 
107 
60 
60 
60 
61 
62 
63 
63 
90th 
114 
114 
116 
117 
118 
119 
120 
74 
74 
74 
75 
76 
77 
77 
95th 
118 
118 
119 
121 
122 
123 
124 
78 
78 
78 
79 
80 
81 
81 
99th 
125 
125 
126 
128 
129 
130 
131 
85 
85 
86 
87 
87 
88 
89 
12 
50th 
102 
103 
104 
105 
107 
108 
109 
61 
61 
61 
62 
63 
64 
64 
90th 
116 
116 
117 
119 
120 
121 
122 
75 
75 
75 
76 
77 
78 
78 
95th 
119 
120 
121 
123 
124 
125 
126 
79 
79 
79 
80 
81 
82 
82 
99th 
127 
127 
128 
130 
131 
132 
133 
86 
86 
87 
88 
88 
89 
90 
13 
50th 
104 
105 
106 
107 
109 
110 
110 
62 
62 
62 
63 
64 
65 
65 
90th 
117 
118 
119 
121 
122 
123 
124 
76 
76 
76 
77 
78 
79 
79 
95th 
121 
122 
123 
124 
126 
127 
128 
80 
80 
80 
81 
82 
83 
83 
99th 
128 
129 
130 
132 
133 
134 
135 
87 
87 
88 
89 
89 
90 
91 
14 
50th 
106 
106 
107 
109 
110 
111 
112 
63 
63 
63 
64 
65 
66 
66 
90th 
119 
120 
121 
122 
124 
125 
125 
77 
77 
77 
78 
79 
80 
80 
95th 
123 
123 
125 
126 
127 
129 
129 
81 
81 
81 
82 
83 
84 
84 
99th 
130 
131 
132 
133 
135 
136 
136 
88 
88 
89 
90 
90 
91 
92 
15 
50th 
107 
108 
109 
110 
111 
113 
113 
64 
64 
64 
65 
66 
67 
67 
90th 
120 
121 
122 
123 
125 
126 
127 
78 
78 
78 
79 
80 
81 
81 
95th 
124 
125 
126 
127 
129 
130 
131 
82 
82 
82 
83 
84 
85 
85 
99th 
131 
132 
133 
134 
136 
137 
138 
89 
89 
90 
91 
91 
92 
93 
16 
50th 
108 
108 
110 
111 
112 
114 
114 
64 
64 
65 
66 
66 
67 
68 
90th 
121 
122 
123 
124 
126 
127 
128 
78 
78 
79 
80 
81 
81 
82 
95th 
125 
126 
127 
128 
130 
131 
132 
82 
82 
83 
84 
85 
85 
86 
99th 
132 
133 
134 
135 
137 
138 
139 
90 
90 
90 
91 
92 
93 
93 
17 
50th 
108 
109 
110 
111 
113 
114 
115 
64 
65 
65 
66 
67 
67 
68 
90th 
122 
122 
123 
125 
126 
127 
128 
78 
79 
79 
80 
81 
81 
82 
95th 
125 
126 
127 
129 
130 
131 
132 
82 
83 
83 
84 
85 
85 
86 
99th 
133 
133 
134 
136 
137 
138 
139 
90 
90 
91 
91 
92 
93 
93 
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/guidelines/hypertension/child_tbl.htm. 
 
 


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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.htm.


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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 will be bound by the sample 
principles and processes outlined in the main study protocol.  Sample collection for PD, PG, 
and other biomarker analysis is required as per the study protocol unless the collection and 
use of the samples is prohibited by specific country laws. 
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 both 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 of 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 from 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 (NG) 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) 
 
 
 
 
 
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. 
 
 
 
 
 
 
 
 
 


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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 3mL of suspension into the 
mouth of the subject. 
 
 
 
 
 
 
Rinse step 
 
After the administration of the 3 mL suspension from the 
syringe, recap the syringe for reuse. 
 
 
 
 
 
 
 
 
 


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Draw up 2 mL of water or apple 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. 
 
 
 
 
 
 
 
 
 
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 (=3 mL for suspension + 2 mL of water of apple 
juice for rinse) for 1 to 5 capsules. 
 
 
 
 
 


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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. 
 
 
 
 
 
 
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). 
 
 
 
 
 
 
A
B
C
D
E


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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.. 
 
 
 
 
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 in a new 20 mL syringe 
and insert the liquid into the medication syringe. 
 
 
 
 
  


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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 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 
Palatability Questionnaire 
 
 
Treatment Dose: 
Visit Cycle: 
Date: 
Subject ID: 
 
 
 
(Please circle according to your experience)  
 
Taste 
Please provide reasons for your rating: 
………………………………………………… 
 
 
(Please circle according to your experience) 
 
Appearance 
Please provide reasons for your rating: 
………………………………………………… 
 
 
(Please circle according to your experience) 
Smell 
Study E7080-G000-207- Palatability Questionnaire 


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(Please circle according to your experience) 
Mouth Feel (how does it 
feel in your mouth?) 
 
 
(Please circle according to your experience) 
Overall Acceptability 
 


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PROTOCOL SIGNATURE PAGE 
Study Protocol Number: E7080-G000-207 
 
Study Protocol Title: 
Phase 1/2 Study of Lenvatinib in Children and Adolescents 
With Refractory or Relapsed Solid Malignancies and Young 
Adults with Osteosarcoma   
 
Investigational Product 
Name: 
Lenvatinib 
 
EudraCT Number: 
2013-005534-38 
 
 
SIGNATURES 
 
 
 
Authors: 
 
 
 
 
 
 
  
Oncology Business Group, Eisai Limited 
 
Date 
 
 
 
Date 
 
 
 
ai Inc. 
 
Date 
 
 
Director, Biostatistics 
Oncology Business Group, Eisai Inc. 
 
Date 
 
 
 
 
 
 
 
PPD
PPD
PPD
PPD


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INVESTIGATOR SIGNATURE PAGE 
Study Protocol Number: 
E7080-G000-207 
Study Protocol Title: 
Phase 1/2 Study of Lenvatinib in Children and Adolescents 
With Refractory or Relapsed Solid Malignancies and Young 
Adults with Osteosarcoma   
Investigational Product 
Name: 
Lenvatinib 
EudraCT Number: 
2013-005534-38 
 
 
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. 
 
 
Medical Institution 
 
 
  
  
Investigator 
 Signature 
 Date 
 
 

SAP_003.pdf: 
Statistical Analysis Plan– Final 1.0
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STATISTICAL ANALYSIS PLAN
Study Protocol 
Number:
E7080-G000-207
Study Protocol 
Title:
Phase 1/2 Study of Lenvatinib in Children and Adolescents With 
Refractory or Relapsed Solid Malignancies and Young Adults with 
Osteosarcoma
Date:
26 Mar 2019
Version:
Final 1.0 


Statistical Analysis Plan– Final 1.0
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1
TABLE OF CONTENTS
1
TABLE OF CONTENTS...................................................................................................2
2
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS....................................5
3
INTRODUCTION .............................................................................................................7
3.1
Study Objectives ......................................................................................................7
3.1.1
Primary Objectives.........................................................................................7
3.1.2
Secondary Objectives.....................................................................................7
3.2
Exploratory Objectives ............................................................................................8
3.3
Overall Study Design and Plan................................................................................9
3.3.1
Pretreatment Phase (All Cohorts) ................................................................11
3.3.2
Screening (All Cohorts)...............................................................................11
3.3.3
Baseline (All Cohorts) .................................................................................12
3.3.4
Treatment Phase...........................................................................................12
3.3.4.1
Cohort 1 (Single-Agent Dose-Finding) .............................................12
3.3.4.2
Cohort 2 (Single-Agent Expansion)...................................................13
3.3.4.3
Cohort 3A: Combination Dose-Finding.............................................14
3.3.4.4
Cohort 3B (Combination Expansion) ................................................15
3.3.5
Post-treatment (All Cohorts)........................................................................16
3.4
Doses for Cohorts 2A, 2B, 3A, and 3B..................................................................16
3.4.1
Doses for Cohorts 2A and 2B......................................................................16
3.4.2
Doses for Cohorts 3A and 3B......................................................................17
3.5
Toxicity Management ............................................................................................17
4
DETERMINATION OF SAMPLE SIZE........................................................................17
5
STATISTICAL METHODS............................................................................................18
5.1
Study Endpoints.....................................................................................................18
5.1.1
Primary Endpoints .......................................................................................18
5.1.2
Secondary Endpoints ...................................................................................18
5.1.3
Exploratory Endpoints .................................................................................19
5.2
Study Subjects........................................................................................................20
5.2.1
Definitions of Analysis Sets.........................................................................20
5.2.2
Subject Disposition......................................................................................20
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.................................................................................23
5.3
Data Analysis General Considerations ..................................................................23
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
5.4
Primary, Secondary and Exploratory Analyses .....................................................26
5.4.1
Primary Dose-Finding Analyses..................................................................26
5.4.1.1
Cohort 1: (Single-Agent Dose-Finding) ............................................26
5.4.1.2
Cohort 3A: Osteosarcoma Combination Dose-Finding.....................27
5.4.2
Efficacy Analyses ........................................................................................27
5.4.2.1
Primary Efficacy Analyses ................................................................27
5.4.2.2
Secondary Efficacy Analyses ............................................................29
5.4.3
Other Efficacy Analyses ..............................................................................34
5.4.3.1
Exploratory Efficacy Analyses ..........................................................34
5.5
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other 
Biomarker Analyses...............................................................................................34
5.5.1
Pharmacokinetic Analyses...........................................................................34
5.5.2
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Analyses ....35
5.6
Safety Analyses......................................................................................................35
5.6.1
Extent of Exposure.......................................................................................35
5.6.1.1
Extent of Exposure of Study Drug.....................................................35
5.6.1.2
Study Drug Administration................................................................35
5.6.1.3
Study Drug Dose Modifications ........................................................36
5.6.1.4
Dose Limiting Toxicity......................................................................36
5.6.2
Adverse Events ............................................................................................37
5.6.3
Laboratory Values........................................................................................40
5.6.3.1
Hematology and Clinical Chemistry..................................................40
5.6.3.2
Thyroid-Stimulating Hormone...........................................................41
5.6.3.3
Urinalysis ...........................................................................................41
5.6.4
Vital Signs....................................................................................................41
5.6.5
Other Safety Analyses..................................................................................41
5.6.5.1
Electrocardiograms ............................................................................41
5.6.5.2
Left Ventricular Ejection Fraction.....................................................42
5.6.5.3
Lansky Play Scores or Karnofsky Performance Status Scores..........42
5.6.5.4
Proximal Tibial Growth Plates...........................................................42
5.7
Other Analyses.......................................................................................................42
5.8
Exploratory Analyses.............................................................................................42
6
INTERIM ANALYSES...................................................................................................42
7
CHANGES IN THE PLANNED ANALYSES...............................................................42


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7.1
PFS-4 in Cohort 3A ...............................................................................................42
7.2
Analysis Sets..........................................................................................................43
7.3
Proximal Tibial Growth Plates and Palatability and Acceptability 
Questionnaire.........................................................................................................43
8
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING...............................43
8.1
Visit Windows .......................................................................................................43
8.2
Safety and Efficacy Data Handling........................................................................44
8.2.1
Partial dates..................................................................................................44
8.2.1.1
Diagnosis date....................................................................................44
8.2.1.2
Date of Death.....................................................................................44
8.2.1.3
Date of Progression............................................................................44
8.2.1.4
Date of Last Tumor Assessment........................................................44
8.2.1.5
Date of Start of Subsequent Anticancer Therapy ..............................45
8.3
Definitions, Derived Variables, and Data Sets ......................................................45
8.3.1
Baseline........................................................................................................45
8.3.2
Date/Time Definitions .................................................................................45
8.3.3
Radioiodine Therapy Conversions...............................................................45
8.3.4
Creatinine Clearance....................................................................................46
8.3.5
Last Known Alive Date ...............................................................................46
8.4
Pharmacokinetics/Pharmacodynamics Data Handling ..........................................46
8.4.1
Lower Limit of Quantification of Lenvatinib Plasma Concentration..........46
8.4.2
BLQ Handling for Developing Concentration-Time Profiles .....................46
9
PROGRAMMING SPECIFICATIONS ..........................................................................46
10
STATISTICAL SOFTWARE..........................................................................................46
11
MOCK TABLES, LISTINGS, AND GRAPHS ..............................................................46
12
REFERENCES ................................................................................................................46
13
APPENDICES .................................................................................................................48
13.1
Dose-Limiting Toxicities.......................................................................................48
13.2
Summary of Efficacy Analyses .............................................................................49
13.3
Common Terminology Criteria For Adverse Events (CTCAE) For 
Hematology & Clinical Chemistry ........................................................................52


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2
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term or Definition
AE
adverse event
AESI
adverse events of special interest
ATC
Anatomical Therapeutic Chemical classification
BLQ
below limit of quantification
BMI
body mass index
BOR
best overall response
BSA
body surface area
CBR
clinical benefit rate
CI
confidence interval
CR
complete response
CRF
case report form
CSAE
clinically significant adverse events
CSR
clinical study report
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
DTC
differentiated thyroid cancer
ECG
electrocardiogram
ECOG PS
Eastern Cooperative Oncology Group performance status
FDA
Food and Drug Administration 
eCRF
electronic case report form
KM
Kaplan-Meier
KPS
Karnofsy performance status
LLN
lower limit of normal
LVEF
left ventricular ejection fraction
MedDRA
Medical Dictionary for Regulatory Activities
NA
not applicable
NE
not evaluable
ORR
objective response rate
OS
overall survival
PD
progressive disease


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Abbreviation
Term or Definition
PFS-4
progression-free survival at 4 months
PK
pharmacokinetic
PR
partial response
PSC
Protocol Steering Committee
PT
preferred term
q6w
every 6 weeks
q8w
every 8 weeks
RECIST
Response Evaluation Criteria in Solid Tumors
RD
recommended dose
SAE
serious adverse event
SAP
statistical analysis plan
SBP
systolic blood pressure
SD
stable disease / standard deviation
SI
Système International
SOC
system organ class
TEAE
treatment-emergent adverse event
TiTE-CRM
time-to-event continual-reassessment method
TLG
Tables, Listings, and Graphs
TNM
tumor, node, metastasis staging system
TTP
time to progression
ULN
upper limit of normal
VEGF
vascular endothelial growth factor
VEGFR
vascular endothelial growth factor receptor
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 the results for Phases 1 and 2 of 
Eisai Study E7080-G000-207. This SAP is based on Protocol V3.0 Amendment 03 (dated 1 
Sep 2016) and final electronic Case Report Form (eCRF) (17 Oct 2018).
3.1
Study Objectives
3.1.1
Primary Objectives
The primary objectives of this study are to:
Cohort 1 (Single-Agent Dose-Finding)

Identify the recommended dose (RD) of lenvatinib as a single agent in children and 
adolescents with relapsed or refractory solid malignant tumors
Cohort 2 (Single-Agent Expansion)

Evaluate the activity of lenvatinib in 2 separate malignancy groups:
◦
Cohort 2A: 131I- refractory differentiated thyroid cancer: by objective response 
rate (ORR) for subjects with measurable disease and best overall response (BOR) 
for all subjects
◦
Cohort 2B: Relapsed or refractory osteosarcoma: by progression-free survival at 4 
months (PFS-4) 
Note: The tumors types under study in the Single-Agent Expansion portion of the study 
may be modified based on preliminary efficacy and safety signals observed in Cohort 1 
of the study.
Cohort 3 (Combination Dose-Finding and Expansion)

Cohort 3A (Combination Dose-Finding)
◦
To identify the RD of lenvatinib in combination with ifosfamide and etoposide in 
osteosarcoma subjects

Cohort 3B (Combination Expansion)
◦
Evaluate the activity of lenvatinib in combination with ifosfamide and etoposide 
in osteosarcoma subjects by PFS-4
3.1.2
Secondary Objectives
The secondary objectives of this study are to:
Cohort 1 (Single-Agent Dose-Finding)


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
Assess the safety and toxicity profile of lenvatinib in children and adolescents

Evaluate the activity of lenvatinib as assessed by best overall response (BOR), ORR, 
duration of response (DOR), progression-free survival (PFS), time to progression 
(TTP), based on RECIST 1.1 [Eisenhauer, 2009], disease control rate (DCR), and 
clinical benefit rate (CBR)

Examine blood and tumor biomarkers and correlate with clinical response to 
lenvatinib

Determine population-based pharmacokinetic (PK) parameters of lenvatinib

Assess the palatability and acceptability of the suspension formulation of lenvatinib
Cohort 2 (Single-Agent Expansion)

Assess the safety and toxicity profile of lenvatinib in children and adolescents, and 
young adults with relapsed or refractory osteosarcoma

Evaluate the efficacy of lenvatinib as assessed by BOR (osteosarcoma only), ORR 
(osteosarcoma only), DOR (measurable DTC and osteosarcoma only), PFS, TTP , 
DCR and CBR

Examine blood and tumor biomarkers and correlate with clinical response to 
lenvatinib

Determine population-based PK parameters of lenvatinib

Assess the palatability and acceptability of the suspension formulation of lenvatinib 
Cohort 3 (Combination Dose-Finding and Expansion) 
•
Assess the safety and toxicity of lenvatinib in combination with ifosfamide and 
etoposide in children and adolescents, and young adults with relapsed or refractory 
osteosarcoma

Evaluate the efficacy of lenvatinib as assessed by BOR, ORR, DOR, PFS, TTP, DCR 
and CBR

Examine blood and tumor biomarkers and correlate with clinical response to 
lenvatinib

Determine population-based PK parameters of lenvatinib

Assess the palatability and acceptability of the suspension formulation of lenvatinib
3.2
Exploratory Objectives
The exploratory objectives of this study are to:

Explore the relationship of lenvatinib exposure to clinical response in children and 
adolescents (assessed during Cohort 1 [Single-Agent Dose-Finding] and Cohort 2 
[Single-Agent Expansion])

Evaluate the efficacy of lenvatinib as assessed by overall survival (OS)


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3.3
Overall Study Design and Plan
This is a Phase 1/2, multicenter, open-label, study. The study will be conducted in 5 cohorts:


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Figure 1
Overall Study Design
Cohort 1 (Single-Agent Dose-Finding): Dose-escalation to find the RD of lenvatinib using 
a time-to-event continual-reassessment method (TiTE-CRM) design in children and 
adolescents with relapsed or refractory solid malignant tumors (Doussau et al, 2012). When 
the RD is identified, Cohorts 2A, 2B, and Cohort 3A will start in parallel. After the RD is 
determined in Cohort 1, subsequent osteosarcoma subjects will be assigned to either Cohort 
2B (Single-Agent Expansion) or Cohort 3A (Combination Dose-Finding), depending on 
whether the subject is deemed by the investigator to be a candidate for ifosfamide and 
etoposide. (If not, the subject would only be assigned to Cohort 2B).
Cohorts 2 (Single-Agent Expansion): To test the efficacy of lenvatinib in children and 
adolescents with 131I-refractory DTC (Cohort 2A), or subjects with relapsed or refractory 
osteosarcoma (Cohort 2B). Osteosarcoma subjects will be assigned to either Cohort 2B 
(Single-Agent Expansion) or Cohort 3A (Combination Dose-Finding), depending on whether
the subject is deemed by the investigator to be a candidate for ifosfamide and etoposide, If 
not, the subject would only be assigned to Cohort 2B. Cohort 2A and Cohort 2B will be 
enrolled in parallel with Cohort 3A (Combination Dose-Finding). 


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Cohort 3
Cohort 3A (Combination Dose-Finding): To define the RD of lenvatinib in combination 
with ifosfamide and etoposide in subjects with relapsed or refractory osteosarcoma. This 
cohort will be open for enrollment in parallel with Cohort 2 (Single-Agent Expansion).
After defining the RD of lenvatinib in combination with chemotherapy in Cohort 3A, 
subsequent osteosarcoma subjects will be assigned to either Cohort 2B (Single-Agent 
Expansion) or Cohort 3B (Combination Expansion), depending on whether the subject is 
deemed by the investigator to be a candidate for ifosfamide and etoposide, If not, the subject 
would only be assigned to Cohort 2B.
Cohort 3B (Combination Expansion): To test the efficacy of lenvatinib in combination 
with ifosfamide and etoposide in subjects with relapsed or refractory osteosarcoma.
Subjects with osteosarcoma who have enrolled into Cohorts 1 or 2B and experienced 
progressive disease on lenvatinib (optional enrollment for subjects in Cohorts 1 and 2B) as 
well as lenvatinib-naïve subjects with relapsed or refractory osteosarcoma will be candidates 
for enrollment in Cohort 3B. The efficacy analyses will be based on lenvatinib-naïve 
subjects, while subjects from Cohorts 1 and 2B will only be summarized as appropriate.
The study will include 3 phases: Pretreatment (screening and baseline), Treatment (includes a
Run-In Period for Cohort 1), and Post-treatment follow-up.
3.3.1
Pretreatment Phase (All Cohorts)
The pretreatment phase will last no longer than 28 days and will include a Screening Period 
and a Baseline Period.
3.3.2
Screening (All Cohorts)
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 prior to the conduct of any screening procedures or assessments.
Subjects in Cohort 1 must have a histologically or cytologically confirmed diagnosis of solid 
malignant tumor. Subjects in Cohort 2 or Cohort 3 must have a histologically or cytologically 
confirmed diagnosis of either osteosarcoma or DTC meeting the criteria for being 131I-
refractory (either papillary thyroid cancer [PTC] or follicular thyroid cancer [FTC]).
The Screening Disposition case report form (CRF) page must be completed to indicate 
whether the subject is eligible to participate in the study and to provide reasons for screen 
failure, if applicable.


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3.3.3
Baseline (All Cohorts)
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 drug (Cycle 1 Day 
1). Baseline assessments may be performed on Day 1 or on Cycle 1 Day 1 prior to dosing.
Clinical laboratory tests, including a pregnancy test (where applicable), should be performed 
within 72 hours prior to the first dose of study drug.
Subjects who complete the Baseline Period and continue to meet the criteria for 
inclusion/exclusion will begin the Treatment Phase of this study.
3.3.4
Treatment Phase
In all the cohorts, lenvatinib is administered daily (QD) and 1 treatment cycle is defined as a 
28-day period for Cohorts 1, 2A, and 2B and a 21-day period for Cohorts 3A and 3B. A new 
treatment cycle begins every 28 days for Single-Agent Cohorts 1, 2A, and 2B or 21-day 
period for Combination-Treatment Cohorts 3A and 3B, irrespective of dose interruptions.
See Protocol Section 9.4.1 for rules regarding the calculation of lenvatinib dose based on 
body surface area (BSA).
3.3.4.1
Cohort 1 (Single-Agent Dose-Finding)
This cohort will identify the RD of lenvatinib as a single agent in children and adolescents 
with relapsed or refractory solid malignant tumors. The RD in this study will be defined as 
the dose that has a DLT rate closest to the targeted 20% rate.
DOSE-ESCALATION IN COHORT 1 CYCLE 1:
Subjects 6 to <18 years, will enroll in Cohort 1 prior to subjects 2 to <6 years of age. Each 
subject will be assigned a dose in accordance with the rules of the TiTE-CRM design as 
detailed in SAP Section 5.4.1.1. The TiTE-CRM design is an accepted adaptive design used 
in Phase 1 trials and allows continuous accrual throughout the study while using the 4-week 
toxicity endpoint as the basis for dose-escalation. Four experimental doses of lenvatinib may 
be investigated in Cohort 1 as displayed in Table 1.
Table 1
Lenvatinib Doses for Dose-Finding (Cohort 1)
Dose Level
Lenvatinib (QD)
-1
9 mg/m2
1 (starting dose)
11 mg/m2
2
14 mg/m2
3
17 mg/m2
QD = once daily.
The starting dose (Dose Level 1) of lenvatinib for this cohort is 11 mg/m2 QD 
(approximately 80% of the adult RD of 24 mg QD). The maximum daily dose should not 


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exceed 24 mg. If the 11 mg/m2 dose is not safe and tolerable, the dose will be de-escalated to 
9 mg/m2 (Dose Level -1).
Determination as to whether a subject has experienced a DLT will be made by the principal 
investigator and the sponsor according to the DLT definition in Protocol Section 9.4.1.1, and 
as needed with the Protocol Steering Committee (PSC). At least 2 subjects should receive the 
full 4-week study treatment or report a DLT (at the starting dose) and complete the DLT 
evaluations before escalation to the next dose level. Intra-subject dose escalation will not be 
allowed. Subjects who discontinue the study during Cycle 1 (Cycle 1 Day 1 to Cycle 1 Day 
28) for any reason other than DLT will be replaced.
Intra-subject dose-escalation prior to determining the RD will be allowed only for subjects 2 
to <6 years who can escalate lenvatinib dose when they enter Cohort 1 Cycle 1 from the Run-
In Period as described below.
Dose-escalation for Subjects 2 to <6 years old:
Run-In Period: All subjects 2 to <6 years of age should complete Screening and Baseline 
assessments. Eligible subjects will first enter a 21-day Run-In Period prior to entering Cohort 
1. During the Run-In Period the subject will receive single-agent lenvatinib at 5 mg/m2/day 
for 21 days and will be evaluated for DLTs, along with PSC as needed.
If a subject 2 to <6 years of age experiences a DLT during the Run-In Period, that subject 
will discontinue from the study without entering Cohort 1 Cycle 1, but the DLT data from 
that subject will be used for all subsequent TiTE-CRM calculations and the dose level for 
that subject in all subsequent calculations will be considered as Cohort 1 Dose Level -1
(9 mg/m2), as 9 mg/m2 is the lowest dose in the Cycle 1 single-agent lenvatinib dose-finding 
cohort.
Subjects 2 to <6 years of age can enter Cohort 1 Cycle 1 (following the completion of the 
Run-In Period without any DLT) only after: (1) at least 6 subjects 6 to <18 years of age have 
either completed 4 weeks of treatment in Cycle 1 or reported DLTs during Cycle 1, and (2) 
single-agent lenvatinib has been evaluated and considered by the PSC to be safe based on the 
DLT data from all the previous subjects including subjects 6 to <18 years of age. When a 
subject 2 to < 6 years of age enters Cohort 1 Cycle 1, the subject will receive a dose that is 
either (1) one level below what is calculated from TiTE-CRM if the calculated dose is greater 
than 9 mg/m2, based on the DLT data from all previous subjects from 2 to <18 years of age, 
or (2) 9 mg/m2 if the TiTE-CRM calculated dose is 9 mg/m2. Consequently, that subject’s 
DLT data in Cycle 1 will be included in all subsequent TiTE-CRM calculations.
Once the RD has been determined, subjects treated at a lower dose level should continue to 
be treated at that dose level. 
3.3.4.2
Cohort 2 (Single-Agent Expansion)
Cohort 2 will begin enrollment after the RD of lenvatinib is identified in Cohort 1. The 
efficacy of lenvatinib will be evaluated in 2 malignancy groups separately: DTC (Cohort 2A) 


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and osteosarcoma (Cohort 2B). Subjects will be treated at the RD identified in Cohort 1.  The 
RD of Single-Agent lenvatinib determined in Cohort 1 is 14 mg/m2 as recommended by 
TiTE-CRM and confirmed by PSC. Subjects in Cohorts 2A and 2B will receive 14 mg/m2
lenvatinib (equivalent to 24 mg QD, adult daily dose). After adjustment for BSA, the daily 
dose should not exceed 24 mg QD.
3.3.4.3
Cohort 3A: Combination Dose-Finding
Lenvatinib will be administered orally QD in combination with ifosfamide and etoposide 
from Day 1 to Day 3 of each cycle for a total of 5 cycles to subjects with relapsed or 
refractory osteosarcoma as described below and in Table 2 See Protocol Section 9.4.3 for 
additional details on cytotoxic chemotherapy.
Table 2
Lenvatinib and Chemotherapy Doses for Combination Dose-Finding 
(Cohort 3A)
Dose Modification of Lenvatinib
Dose -
Escalation
Starting Dose
De-escalation 1
De-escalation 2
Lenvatinib
RD (from Cohort 
1)
20% lower than 
RD from Cohort 
1
40% lower than RD 
from Cohort 1
60% lower than RD 
from Cohort 1
Dose Modification of Ifosfamide and Etoposide
No Dose 
Escalation
Starting Dose
De-escalation 1*
De-escalation 2*
Ifosfamide
3000 mg/m2/day 
IV for 3 days
2400 mg/m2/day IV 
for 3 days
1800 mg/m2/day IV for 3 
days
Etoposide
100 mg/m2/day 
IV for 3 days
80 mg/m2/day IV 
for 3 days
60 mg/m2/day IV for 3 
days
RD = recommended dose, *each De-escalation dose level is 20% lower than the Starting Dose.
The chemotherapy cycles will be repeated every 21 days.
Lenvatinib is administered daily as a QD dose, and ifosfamide and etoposide will be 
administered on Days 1 to 3 of each cycle for a total of 5 cycles. Each Chemotherapy cycle is 
repeated every 21 days. Six subjects with osteosarcoma (who have not received prior 
lenvatinib) will be enrolled first to Cohort 3A at the Starting Dose of lenvatinib (20% below 
the Single-Agent RD in Cohort 1) in combination with ifosfamide 3000 mg/m2/day for 3 
days (ifosfamide total dose 9 g/m2) and etoposide 100 mg/m2/day for 3 days (etoposide total 
dose 300 mg/m2). Subjects with lenvatinib dose capped after BSA adjustment (dose must not 
exceed 24 mg daily) actually take lower dose level than assigned. If a subject with capped 
dose experiences a DLT, the DLT data from that subject will be counted to determine the RD 
of the combination treatment. A subject with capped dose who does not experience a DLT 
will be replaced for the purpose of determining the RD.


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DLTs occurring during Cycle 1 will be evaluated and the next 6 subjects will be assigned a 
dose based on the rules for Dose Escalation and Dose De-Escalation as follows: 
a.
If ≤1 out of 6 subjects experiences a DLT at the starting dose during Cycle 1 (Day 
1 to Day 21), then assign 6 more subjects to the next higher dose level of 
lenvatinib (RD from Cohort 1) and keep the chemotherapy dose the same (starting 
dose). 
b. If ≥2 out of 6 subjects experience a DLT at the starting dose during Cycle 1 (Day 
1 to Day 21), then follow the instructions below;
i. If ≥2 subjects experience hematologic DLT and ≤1 subject experiences non-
hematologic DLT, then assign 6 more subjects to 20% lower doses (De-
escalation 1) of ifosfamide and etoposide and keep the lenvatinib dose the 
same; or
ii. If ≥2 subjects experience non-hematologic DLT and ≤1 subject experiences 
a hematologic DLT, then assign 6 more subjects to a 20% lower dose of 
lenvatinib (De-escalation 1) and keep the ifosfamide and etoposide doses the 
same; or
iii. If ≥2 subjects experience hematologic DLTs and ≥2 subjects experiences 
non-hematologic DLTs, then assign 6 more subjects to 20% lower doses of 
lenvatinib, ifosfamide, and etoposide each (De-escalation 1); or
iv. If only 1 subject experiences a hematologic DLT and only 1 subject 
experiences a non-hematologic DLT, then assign 6 more subjects to the 
same dose level of lenvatinib, ifosfamide and etoposide each. 
c. Continue the above processes until the combination dose of lenvatinib, ifosfamide and 
etoposide results in ≤1 DLT per 6 subjects or only 1 subject experiences a hematologic 
DLT and only 1 subject experiences a nonhematologic DLT per 6 subjects upon 
repeating the same dose level. This dose will be considered as the RD of the combination 
treatment. 
Once the RD has been determined, subjects treated at a lower dose level should continue to 
be treated at that dose level. Intrasubject dose-escalation is not permitted. Further dose de-
escalation of lenvatinib or the chemotherapy dose may be considered (pending discussion 
with the Protocol Steering Committee [PSC]), if needed.
3.3.4.4
Cohort 3B (Combination Expansion)
Subjects with either lenvatinib-naïve relapsed or refractory osteosarcoma or osteosarcoma 
subjects who progress on single-agent lenvatinib in Cohorts 1 or 2B (optional enrollment) 
will receive lenvatinib (at the RD identified from Cohort 3A) in combination with ifosfamide 
and etoposide, provided the combination of lenvatinib, ifosfamide, and etoposide in Cohort 
3A (Combination Dose-Finding) is determined to be safe and tolerable.


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Osteosarcoma subjects who experience progressive disease in Cohorts 1 or 2B and choose to 
receive the combination therapy of lenvatinib with ifosfamide and etoposide should meet 
only inclusion criteria numbers 6 through 17 and all the exclusion criteria except Criterion 
Number 6.
Subjects in Cohorts 3A and 3B will receive ifosfamide and etoposide for a maximum of 5 
cycles. Subjects who discontinue ifosfamide and etoposide in Cohorts 3A and 3B (e.g., due 
to toxicity) prior to completing 5 cycles may continue on single-agent lenvatinib if they are 
benefiting from the treatment at the discretion of the investigator. Subjects who discontinue 
lenvatinib prior to completing 5 cycles may continue on ifosfamide and etoposide at the 
investigator’s discretion for 5 cycles.
3.3.5
Post-treatment (All Cohorts)
The Post-treatment Follow-up begins when the subject discontinues treatment. After subject 
discontinues treatment, an Off-Treatment Visit and the procedures noted in the Schedule of 
Assessments Tables (see Protocol Table 7, Table 8, and Table 9) should be completed within 
30 days after the last dose of drug. Subjects will be followed for survival every 3 months 
until death or for 1 year, whichever occurs first, unless the study is terminated or the subject 
discontinues due to withdrawal of consent or is lost to follow-up (see Protocol Section 9.3.3). 
Subjects who discontinue treatment without disease progression will have tumor assessments
performed every 6 or 8 weeks (per the appropriate tumor assessment schedule) for up to 1 
year, or sooner if clinically indicated, for documented disease progression or until another 
anticancer therapy is initiated whichever occurs first. 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 will begin in December 2014 and will end on or before December 2017
(revised estimate is April 202).
•
The maximum estimated period for the study is anticipated to be approximately 
36 months. However, subjects will continue to receive study treatment as long as they 
demonstrate clinical benefit. Subjects benefiting from study treatment in the opinion of 
the investigator will continue to receive treatment until disease progression, intolerable 
toxicity, subject noncompliance with safety or efficacy assessments, initiation of another 
anticancer therapy, voluntary discontinuation by the subject at any time, or study 
termination by the sponsor, whichever occurs first.
3.4
Doses for Cohorts 2A, 2B, 3A, and 3B
3.4.1
Doses for Cohorts 2A and 2B
The RD of single-agent lenvatinib determined in Cohort 1 is 14 mg/m2 as recommended by
the TiTE-CRM and confirmed by the PSC.


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Cohorts 2A and 2B will receive 14 mg/m2 lenvatinib (equivalent to 24 mg QD, the adult 
daily dose). After adjustment for BSA, the daily dose should not exceed 24 mg QD. 
3.4.2
Doses for Cohorts 3A and 3B
The RD of the combination with ifosfamide and etoposide determined in Cohort 3A is 
lenvatinib 14 mg/m2/day + ifosfamide 3000 mg/m2/day and etoposide 100 mg/m2/day as 
recommended by the above rules and confirmed by the PSC.
Cohort 3B will receive lenvatinib 14 mg/m2/day + ifosfamide 3000 mg/m2/day and etoposide 
100 mg/m2/day.
3.5
Toxicity Management
Toxicity will be managed by treatment interruption, dose reduction and/or treatment 
discontinuation. Dose reduction and interruption for subjects who experience lenvatinib-
related toxicity and ifosfamide/etoposide-associated toxicity will be in accordance with the 
protocol-specified dose reduction and interruption instructions (Sections 9.4.1.2 and 9.4.1.11 
of the Protocol).
4
DETERMINATION OF SAMPLE SIZE
Cohort 1: Approximately 12 to 24 subjects based on the TiTE-CRM algorithm in the single-
agent dose-finding cohort.
Cohort 3A: Approximately 12 to 24 subjects with osteosarcoma will be enrolled in 
combination dose-finding cohort.
Cohort 2A: Approximately 12 subjects with evaluable or measurable disease are planned to 
be enrolled in the DTC cohort.
Cohort 2B: A minimum of 15 PFS-4 evaluable subjects will be assessed in the osteosarcoma 
single-agent expansion. The sample size estimates were based on Simon’s Optimal Two-
Stage Design (Simon, 1989). If < 5 subjects achieve PFS-4 among the 15 evaluable subjects 
in Stage I, accrual in the cohort will be suspended. Otherwise, if at any time during Stage I of 
the cohort, ≥5 subjects achieve PFS-4 among the 15 evaluable subjects, enrollment in the 
cohort will continue for a total of approximately 27 evaluable subjects. If, at the end of the 
second stage for the cohort, ≥10 subjects achieve PFS-4 among the 27 subjects in the cohort, 
lenvatinib will be considered active in the population. The above sample size estimates are 
based on the following assumptions: the null hypothesis PFS-4 (H0) is ≤25%, and the 
alternative hypothesis PFS-4 (H1) is ≥45%. One-sided Type I error (α) = 0.1, and power = 
80%. To account for nonevaluable subjects, a total of 15-30 osteosarcoma subjects will be 
enrolled in Cohort 2B.
Cohort 3B: With the following assumptions: p0 = 25%, p1 = 50%, 1-sided α = 10%, β =
20%, where p0 is an unacceptable rate of PFS, p1 is the target rate of PFS, α is the probability 
of declaring lenvatinib effective when the true rate is p0, and β is the probability of declaring 


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lenvatinib not effective if the true rate is p1, a sample size of 15 subjects will provide a 
statistical power of 80%. To account for nonevaluable subjects, a total of 18 lenvatinib-naïve 
subjects will be enrolled in the combination expansion, along with some subjects from 
Cohorts 1 and 2B.
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 be included in the CSR.
Efficacy will be evaluated based on the Full Analysis Set (see SAP Sections 5.2.1 and 7.2).
Each cohort will have its own cutoff date for the final analysis for CSR reporting purposes.
For Cohorts 1 and 3A, the data cutoff will occur when the RD is determined and the last 
enrolled subject completes 6 cycles of treatment or discontinues before the end of Cycle 6, 
whichever occurs first or pending discussion with the PSC. For DTC and osteosarcoma 
subjects in Cohorts 2A, 2B, and 3B, the cutoff will be after all subjects enrolled have either 
completed 6 cycles or have discontinued treatment before the end of Cycle 6, whichever 
occurs first.
5.1
Study Endpoints
5.1.1
Primary Endpoints
For Cohort 1, the primary endpoint is RD of lenvatinib based on the TiTE-CRM design.
While for Cohort 3A, it is RD of the combination treatment (lenvatinib + etoposide + 
ifosfamide).
For the three Phase 2 cohorts, the primary endpoints are:
•
Cohort 2A (DTC): ORR, ie, the proportion of subjects who have a BOR of complete 
response (CR) or partial response (PR) for subjects with measurable disease and BOR 
for all subjects based on RECIST 1.1
•
Cohort 2B (Osteosarcoma): PFS-4, ie, the percentage of subjects evaluable for PFS-4
who are alive and without PD at 4 months from the first dose based on RECIST 1.1.
Subjects evaluable for PFS-4 includes those treated at least 4 months or those who 
died or radiologically progressed within 4 months after first dose.
•
Cohort 3B: PFS-4
5.1.2
Secondary Endpoints
•
Efficacy endpoints:


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◦
BOR over the treatment period (except for Cohort 2A): defined as the best 
response recorded from the start of study drug until 30 days after the last dose or 
until PD, whichever occurs earlier
◦
ORR (except for Cohort 2A): defined as the proportion of subjects who have 
BOR of CR or PR
◦
DOR: defined as the time from first documentation of tumor response (CR or PR) 
to PD
◦
Disease Control Rate (DCR): defined as the percentage of subjects with 
measurable disease who have a BOR of CR or PR or stable disease (SD) or 
subjects with evaluable disease who have a BOR of CR or Non-CR/Non-PD. To 
be assigned a BOR of SD or Non-CR/Non-PD, the time from the first 
administration of study drug until the date of documented SD or Non-CR/Non-PD 
should be ≥7 weeks
◦
Clinical Benefit Rate (CBR): defined as the percentage of subjects with 
measurable disease who have a BOR of CR or PR or durable SD lasting 
≥23 weeks or subjects with evaluable disease who have a BOR of CR or durable 
Non-CR/Non-PD lasting ≥23 weeks
◦
TTP: defined as the time from the date of the first administration of study drug 
until the date of first documentation of PD.
◦
PFS: defined as the time from first dose to documented date of PD or death 
(whichever occurs first)
•
Safety endpoints:
◦
Adverse events (AEs), serious AEs (SAEs), clinical laboratory values, vital signs, 
12-lead electrocardiograms (ECGs), urine dipstick, occult blood in stool, 
echocardiogram, Lansky play scores or Karnofsky performance status (KPS),
physical examination findings, and height, and closure of proximal tibial growth 
plates during treatment and follow-up.
•
Plasma lenvatinib exposure parameters
•
Assessment of blood or tumor biomarkers that correlate with clinical response to 
lenvatinib treatment or AEs associated with lenvatinib treatment
•
Palatability and acceptability of the suspension formulation of lenvatinib
5.1.3
Exploratory Endpoints 
•
Time to OS: defined as the time from first dose of study drug until the date of death 
from any cause. Subjects who are lost to follow-up and those who are alive at the date 
of data cutoff will be censored at the date the subject was last known to be alive (or 
the data cutoff date).
•
PFS-4 in Cohort 3A (see SAP Section 7.1).


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5.2
Study Subjects
5.2.1
Definitions of Analysis Sets
The following analysis sets will be defined:
•
Full Analysis Set includes all enrolled subjects who have not failed study screening.
Demographic and baseline characteristics, previous anticancer medications, prior and 
concomitant medications, procedures and radiotherapy, medical history, and efficacy 
analyses will primarily be based on the Full Analysis Set.
•
Per Protocol Analysis Set includes those subjects who (1) receive at least 1 dose of 
the assigned study drug; (2) have no major protocol deviations; (3) had both Baseline 
and at least 1 postbaseline tumor assessment. This will be the secondary analysis set 
for all tumor response-related efficacy endpoints.
•
Safety Analysis Set includes all subjects who received study drug. This will be the 
analysis set for all safety evaluations.
•
Palatability Analysis Set includes all subjects who received oral suspension of 
lenvatinib and answered at least 1 question in the Palatability Questionnaire CRF.
•
Pharmacokinetic (PK) Analysis Set includes all subjects who have received at least 
1 dose of any study drug and have evaluable lenvatinib concentration data.
This additional analysis set will be defined for Cohort 1:
•
DLT Analysis Set includes all subjects who either a) experience DLT during Run-in 
Period or Cycle 1 or b) receive all scheduled doses of study drug on their scheduled 
days during Cycle 1 and complete Cycle 1 observation period without a DLT.
This additional analysis set will be defined for Cohort 3A:
•
DLT Analysis Set includes all subjects who either a) experience DLT during Cycle 1 
or b) receive all scheduled doses of study drug on their scheduled days during Cycle 1 
and complete Cycle 1 observation period without a DLT.
See Section 7.2 explaining the analysis sets in addition to those listed in the protocol.
The number and percentage of subjects included in each analysis set will be presented by 
cohort and dose level in Phase 1 and by cohort in Phase 2. A listing will also be provided to 
identify subjects in each analysis set.
5.2.2
Subject Disposition
The number and percentage of enrolled and treated subjects who completed study drug and 
who discontinued study drug will be summarized according to the primary reason for 
discontinuation by cohort and dose level in Phase 1 and by cohort in Phase 2. Additionally, 


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the disposition of subjects who discontinued treatment or withdrew from the study will be 
summarized. For Cohorts 3A and 3B (combination therapy), reasons for prematurely 
discontinuing either lenvatinib or chemotherapy (etoposide + ifosfamide) will be summarized 
separately.
5.2.3
Protocol Deviations
All major protocol deviations will be determined and will be agreed upon after review of 
individual subject data prior to database lock. This review will be undertaken in collaboration 
between the Study Director, the Study Statistician, the Study Data Manager and the Study 
Clinical Operations Manager.
Major protocol deviations will be listed and summarized by cohort and dose level in Phase 1 
and by cohort in Phase 2.
5.2.4
Demographic and Other Baseline Characteristics
Demographic and baseline characteristics for the Full Analysis Set will be summarized by
cohort using descriptive statistics. Continuous demographic and baseline variables including 
age (year), height (cm), weight (kg), BMI (kg/m2) and BSA (m2), results will be summarized 
and presented as n, mean, standard deviation, median, Q1, Q3, minimum and maximum 
values. For categorical variables, the number and percentage of subjects will be used.
Demographics and Baseline categorical variables include age group (2 to <6 years, 6 to <18 
years, 6 to <12 years, 12 to <16 years, 16 to <18 years, 18 to ≤25 years [Cohorts 2B, 3A and 
3B only]), race (White, Black or African American, Asian [Japanese, Chinese, Other Asian], 
American Indian or Alaska Native, Native Hawaiian or other Pacific Islander, and Other), 
ethnicity (Hispanic or Latino, not Hispanic or Latino), pregnancy test (present, absent), KPS 
or Lansky play scores.
Previous anticancer therapy will be summarized by cohort and dose level in Phase 1 and by 
cohort in Phase 2 as follows:
•
Number of previous therapy regimens
•
Duration of last medication (months)
•
Best response for last anticancer medication (CR, PR, SD, PD, not evaluable, not 
applicable, unknown)
•
Time from end of last anticancer medication to first dose of study drug (months)
•
Previous anticancer medication (administered as adjuvant, therapeutic, neoadjuvant,
consolidation, maintenance, unknown)
•
Previous anticancer procedures (yes, no)
•
Time from prior anticancer procedures to first dose (months)
•
Prior anticancer medication preferred term


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Previous anti-VEGF/VEGFR (vascular endothelial growth factor/vascular endothelial growth 
factor receptor) therapy will be summarized by cohort and dose level in Phase 1 and by 
cohort in Phase 2 as follows:
•
Number of subjects with any previous VEGF/VEGFR-targeted therapy
•
Previous VEGF/VEGFR-targeted therapy (sunitinib, pazopanib, etc.)
•
Duration of most recent VEGF/VEGFR-targeted therapy (months)
•
Primary reason for discontinuation
•
Time from end of most recent VEGF/VEGFR-targeted therapy to first dose of study 
drug
Prior radiotherapy and radioiodine therapies will be summarized by cohort and dose level in 
Phase 1 and by cohort in Phase 2 as follows:
•
Subjects with any previous radiotherapy
•
Tumor lesion at the site progressed since radiotherapy (yes, no, not evaluated)
•
Time from last radiotherapy to first dose (months)
•
Number of subjects with any previous radioiodine therapy
•
Time from last radioiodine therapy to first dose (months)
•
Type of previous radioiodine therapy (curative, palliative or other)
Disease history and characteristics at study entry will be summarized by cohort and dose 
level in Phase 1 and by cohort in Phase 2 as follows:
•
Solid tumor diagnosis classification
•
DTC subtype classification (papillary, follicular) and histologic subtypes (Cohort 2A 
only)
•
Time since first diagnosis of solid tumor/DTC/osteosarcoma to date of first dose
(months)
•
Time since metastatic diagnosis to date of the first dose (months)
•
Time Since Last Progression to First Dose of Study Drug (months)
•
Age at diagnosis (in years)
•
TNM staging and grade at diagnosis
•
Target lesions (lymph node [yes/no], nonlymph node [yes/no]), and nontarget lesions
[yes/no] based on the measurable disease criteria at study entry (nonlymph node:
longest diameter ≥1.5 cm, lymph-node: short axis diameter ≥1.0 cm) based on 
RECIST version 1.1.


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Previous anticancer therapies, anti-VEGF/VEGFR therapy, radiotherapy and radioiodine 
therapies, 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.
Some items captured on the Previous Anti-Cancer Procedures CRF for Cohorts 1 and 2B are
excluded from the summary table of Previous Anti-Cancer Procedures because they are 
diagnostic procedures considered as Medical History and Current Medical Conditions. These 
items will be flagged in the listing of Previous Anti-Cancer Procedures.
5.2.5
Prior and Concomitant Therapy
All investigator terms for medications recorded on the CRF will be coded using the World 
Health Organization (WHO) Drug Dictionary using the 2018 B2 version. The number 
(percentage) of subjects who have taken prior and concomitant medications will be 
summarized on the Full Analysis Set, by Anatomical Therapeutic Chemical (ATC) 
Classification, WHO drug preferred term, and by cohort. Prior medications will be defined as 
medications that started prior to the first dose of study drug and discontinued prior to the start 
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 30 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).
The summary of prior and concomitant antihypertensive, antidiarrheal and other medications 
will be summarized by cohort and dose level in Phase 1 and by cohort in Phase 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.
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.


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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 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
•
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


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5.3.6
Other Considerations
Subjects in Cohort 1 will be assigned to the planned dose levels of 9 mg/m2, 11 mg/m2, 
14 mg/m2, and 17 mg/m2, respectively. The actual dose level could be different from the 
planned dose level due to the adjustment of BSA and capped dose. The actual dose level 
resulting from capping the dose will be set as:
•
17 mg/m2, if the rounded calculated dose level on Cycle 1 Day 1 ≥17 mg/m2
•
14 mg/m2, if 14 mg/m2 ≤the rounded calculated dose level on Cycle 1 Day 1 
<17 mg/m2
•
11 mg/m2, if 11 mg/m2 ≤the rounded calculated dose level on Cycle 1 Day 1
<14 mg/m2
•
9 mg/m2, if 9 mg/m2 ≤the rounded calculated dose level on Cycle 1 Day 1 <11 mg/m2
•
7 mg/m2, if 7 mg/m2 ≤the rounded calculated dose level on Cycle 1 Day 1 < 9 mg/m2
•
5 mg/m2, if the rounded calculated dose level on Cycle 1 Day 1 < 7mg/m2
Subjects in Cohort 3A (Combination Dose-Finding) will receive study drug as described in 
Table 2 of the Protocol. The actual dose level of lenvatinib could be different from the 
planned dose level due to the adjustment of BSA and capped dose. The actual dose level of 
lenvatinib resulted from capping the dose will be set as:
•
14 mg/m2, if the rounded calculated dose level on Cycle 1 Day 1 ≥14 mg/m2
•
11 mg/m2, if 11 mg/m2 ≤the rounded calculated dose level on Cycle 1 Day 1 
<14 mg/m2
•
9 mg/m2, if 9 mg/m2 ≤the rounded calculated dose level on Cycle 1 Day 1 
<11 mg/m2
•
7 mg/m2, if 7 mg/m2 ≤the rounded calculated dose level on Cycle 1 Day 1 <9 mg/m2
•
5 mg/m2, if the rounded calculated dose level on Cycle 1 Day 1 <7 mg/m2
The actual dose level of ifosfamide and etoposide that resulted from a BSA adjustment will 
be set as:
Ifosfamide:
•
3000 mg/m2 if the calculated dose level on Cycle 1 Day 1 ≥2700 mg/m2
•
2400 mg/m2 if 2100 mg/m2 ≤the calculated dose level on Cycle 1 Day 1<2700 mg/m2
•
1800 mg/m2 if 1500 mg/m2 ≤the calculated dose level on Cycle 1 Day 1<2100 mg/m2
Etoposide:


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•
100 mg/m2 if the calculated dose level on Cycle 1 Day 1 ≥90 mg/m2
•
80 mg/m2 if 70 mg/m2 ≤the calculated dose level on Cycle 1 Day 1< 90 mg/m2
•
60 mg/m2 if 50 mg/m2 ≤the calculated dose level on Cycle 1 Day 1< 70 mg/m2
For subjects in expansion cohorts (2A, 2B and 3B), the actual dose level will be set to the 
planned dose level regardless of capped dose.
The planned dose level is used in the Full Analysis Set and Per Protocol Analysis Set, while 
the actual dose level (BSA-adjusted dose level) will be used for the Safety Analysis Set, PK 
Analysis Set, and DLT Analysis Set. 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 12 the 3 treatment groups have 4, 3 
and 1 subjects, respectively, then Cycle 12 will be summarized for all treatment groups. If at 
Cycle 13, 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 13 
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 Dose-Finding Analyses
5.4.1.1
Cohort 1: (Single-Agent Dose-Finding)
Cohort 1, the lenvatinib single-agent dose-finding group, will enroll up to 24 subjects. A 
TiTE-CRM design will be used to determine the RD of lenvatinib and to increase the 
flexibility by allowing continuous accrual with no trial suspensions, which are typically 
needed when the toxicity assessment of subjects previously recruited is not completed 
(Smith, et al., 1998; Cheung, 2009). Using this TiTE-CRM design, an eligible subject can be 
included in the trial at any time, without waiting for the completion of prior subjects 
(Doussau, et al, 2012). The model will be re-estimated considering all the toxicity 
observations currently available. The subject will be treated at the best current estimate of the 
RD. Individual subjects on long-term treatment may be treated at a dose below the dose 
recommended by the model for safety reasons.
A 1-parameter empirical power model will be used to assess the relation between the dose 
level and the probability of DLT: 
(, ) = 
 () 
where F(d, α)is the estimated probability of DLT at dose-level d,  is the 
prior probability of DLT at dose level d, and α is the unknown parameter 
to be estimated by the model.


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The vector {p0d} represents the initial guesses of toxicity probabilities, reflecting the 
clinicians’ prior impression. The skeleton of initial guesses of toxicity probabilities {p0d} is 
numerically calibrated using the approach of Lee et al. (2005) and Cheung (2009) and using 
the “getprior” function of R, ensuring good design operating characteristics. Based on 
consultation with the clinicians, the delta (half of the width of the CI) defining the 
indifference interval was set at 0.06 (indifference interval: 0.14 to 0.26) and the prior 
maximum tolerated dose (MTD0) at Dose 2 (14 mg/m²) is likely to be the RD (same as in 
adults). This yields a vector of prior probabilities {p0k} equal to 0.03, 0.10, 0.20, and 0.33, 
for the doses 9 mg/m2, 11 mg/m2, 14 mg/m2, and 17 mg/m2, respectively, that was found 
reasonable by the clinicians. A noninformative prior distribution Normal (0, 1.34) has been 
assigned for α in the Bayesian computation.
The simulation study confirmed that the operating characteristics of the model defined with 
these parameters were reasonable, with more than 50% correct selection of the RD in 
3 contrasted scenarios. Starting with Dose 1, the prior distribution of the parameter α will be 
updated by the accruing data on DLTs each time a subject completes evaluation for toxicity 
in Cycle 1.
5.4.1.2
Cohort 3A: Osteosarcoma Combination Dose-Finding
The DLT will be assessed to determine the RD of lenvatinib in combination with ifosfamide 
and etoposide. DLTs occurring during Cycle 1 will be evaluated and the subjects will be 
assigned a dose based on the rules for dose escalation and de-escalation (see Section 3.3.4.3). 
The RD of lenvatinib in combination with ifosfamide and etoposide will be used to treat 
osteosarcoma subjects in Cohort 3B.
5.4.2
Efficacy Analyses
The tumor response data used in the primary analyses of the PFS-4 rate and ORR will be 
obtained from the 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. All the efficacy analyses will be performed on the Full Analysis Set, and the 
Per Protocol Analysis Set for all tumor response-related efficacy endpoints. A tabular 
summary of key features of the efficacy analyses is described in SAP Appendix 13.2 
(Summary of Efficacy Analyses).
5.4.2.1
Primary Efficacy Analyses
COHORT 2A: DTC
The primary efficacy endpoint is ORR for subjects with measurable disease and BOR for all 
subjects. Tumor response will be based on RECIST 1.1 and assessed every 8 weeks. The 
analysis will be descriptively performed on the Full Analysis Set.


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COHORT 2B: SINGLE-AGENT EXPANSION
The primary efficacy endpoint is the PFS-4 rate based on RECIST 1.1. This is the proportion 
of subjects free of progression at 4 months. The PFS-4 rate will be estimated using the 
binomial proportion and the corresponding 80% and 95% exact binomial distribution CIs
(Clopper and Pearson, 1934) will also be provided. The PFS-4 rate will also be tested using a 
null hypothesis that the PFS-4 rate is ≤25% tested against the alternative hypothesis of a 
PFS-4 rate ≥45%, using the 1-sample exact test of a single proportion, at the 1-sided 0.1 
level. These analyses will be performed on the lenvatinib-naïve subjects in the Full Analysis 
Set and the Per Protocol Analysis Set.
The PFS-4 rate will be calculated using PFS-4 evaluable subjects. These are defined as 
follows.
PFS-4 evaluable subjects:
•
includes subjects who were treated with study medication at least 16 weeks;
•
includes subjects who died or radiologically progressed within 16 weeks after the first 
administration of study medication. These subjects are not considered free of 
progression at 4 months;
•
includes subjects who received anticancer treatment within 16 weeks after the first 
administration of study medication. These subjects are not considered free of 
progression at 4 months;
•
excludes those who discontinue the study due to AE or reasons other than disease 
progression, death, or receiving anticancer treatment within 16 weeks after the first 
administration of study medication;
•
excludes subjects administered any study medication with no baseline or no 
postbaseline tumor assessments.
COHORT 3B: OSTEOSARCOMA COMBINATION EXPANSION
The primary efficacy endpoint is the PFS-4 rate based on RECIST 1.1. This is the proportion 
of subjects free of progression free at 4 months. The PFS-4 rate will be estimated using the 
binomial proportion along with the corresponding exact binomial 80% and 95% CIs. The 
PFS-4 rate will be tested using a null hypothesis that PFS-4 rate is ≤25% tested against the 
alternative hypothesis of a PFS-4 rate ≥50%, using the 1-sample exact test of a single 
proportion, at the 1-sided 0.1 level. This analysis will be performed on the lenvatinib-naïve 
subjects in Full Analysis Set and Per Protocol Analysis Set, while subjects enrolled from 
Cohorts 1 and 2B will be summarized only as appropriate.
The PFS-4 rate will be analyzed using PFS-4 evaluable subjects. These are defined as 
follows.


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PFS-4 evaluable subjects:
•
includes subjects who were treated with study medication at least 18 weeks
•
includes subjects who died or radiologically progressed within 18 weeks after the first 
administration of study medication. These subjects are not considered free of 
progression at 4 months.
•
includes subjects who received anticancer treatment within 18 weeks after the first 
administration of study medication. These subjects are not considered free of 
progression at 4 months.
•
excludes those who discontinue the study due to AE or other reasons than disease 
progression, death , or receiving anticancer treatment within 18 weeks after the first 
administration of study medication 
•
excludes subjects administered any study medication but had no baseline or no 
postbaseline tumor assessments.
SURGICALLY REMOVED LESIONS
For Cohorts 2B, 3A and 3B, removal of existing (not new) osteosarcoma metastatic lesion(s) 
is permitted after the completion of the first 4 months of the treatment period without PD.
The time points for tumor response assessment after tumor removal will be considered ‘Not 
Evaluable’ unless the tumor response is considered PD for the following reasons:
•
appearance of an unequivocal new lesion
•
unequivocal progression of non-target lesions or target lesions
Lesions removed before the first 4 months are permitted only in the case of PD.
5.4.2.2
Secondary Efficacy Analyses
The secondary efficacy endpoints include BOR over the treatment period (except for Cohort 
2A), ORR (except for Cohort 2A), DCR, and CBR, as well as DOR (measurable disease 
only). PFS and TTP are defined in SAP Section 5.1 and will be performed for subjects in the 
Full Analysis and Per Protocol Analysis Sets.
Subjects who do not have a tumor response assessment for any reason will be considered 
nonresponders and will be included in the denominator when calculating the response rate.
The count and percentage for ORR will be summarized by dose level for Cohorts 1 and 3A 
and by cohort for Cohorts 2B and 3B. ORR and corresponding 95% CI based on the exact 
binomial distribution will be estimated for all corresponding treatment cohorts.


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The count and percentage for both the DCR and CBR will be summarized for each treatment 
cohort, along with the exact 95% CI for.
The median and quartiles of DOR will be estimated by the Kaplan-Meier (KM) method
(Kaplan and Meier, 1958), and the 95% CI estimated with a generalized Brookmeyer and 
Crowley method (Brookmeyer and Crowley, 1982).
For PFS, if a subject has not experienced PD or death, then the subject’s data will be 
censored on the date of the last adequate radiologic assessment.
TTP will be calculated using data from all subjects in the Full Analysis Set. The calculation 
for TTP does not classify deaths as events.
The PFS censoring rules in this SAP and definition of progression date follow the Food and 
Drug Administration (FDA), Guidance for Industry Clinical Trial Endpoints for the 
Approval of Cancer Drugs and Biologics (2007) (See SAP Table 3). The PFS censoring rules 
are referenced in SAP Table 3 and TTP censoring rules are referenced in SAP Table 4.
Table 3 Censoring Rules for Analysis of Progression-Free Survival
No
Situation
Date of Progression or Censoring
Outcome
1
No baseline tumor assessments
Date of first dose
Censored
2
No postbaseline tumor assessments
Date of first dose
Censored
3
Progression documented between
scheduled visits
Date of first radiologic PD assessment
Progressed
4
More than 1 NE tumor timepoint assessment Date of last adequate 
radiologic assessment before 
NE tumor assessments
Censored
5 
No progression at time of data cutoff
Date of last adequate 
radiologic assessment
Censored
6
New anticancer treatment started
Date of last adequate radiologic 
assessment prior to or on date of
new anticancer treatment
Censored
7
Death before first tumor assessment
Date of death
Progressed
8
Death between adequate assessment visits*
Date of death
Progressed
9
Death or progression after more than
one missed visit/tumor assessment**
Date of last adequate
radiologic assessment before
missed tumor assessments
Censored
10
Treatment discontinuation for reasons
other than PD
Date of last radiologic
assessment before treatment
discontinuation
Censored
CR = complete response, NE = not evaluable, PD = progressive disease, PR = partial response, q6w = every 
6 weeks, q8w = every 8 weeks, SD =stable disease.
* Adequate tumor assessment is radiologic assessment at regular interval as defined in the
protocol.
** More than 1 missed visit/adequate tumor assessment is defined as having either 1 of the following
2 durations being longer than 18 weeks – 1 day, which is 125 days ( = ((8+1) x 2 x 7) – 1) for subjects
on the q8w tumor assessment schedule in Cohorts 1, 2A and 2B; while 14 weeks – 1 day, which is 97 


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days ( = ((6+1) x 2 x 7) – 1) for subjects on the q6w tumor assessment schedule in Cohorts 3A and 3B:
   a. Duration between 2 consecutive tumor assessments
   b. Duration between the last adequate tumor assessment and death or PD
The priority of the censoring rules is as follows:
1. If the subject had PD or death, the following sequence will be applied:
•
If a subject did not have a baseline or postbaseline tumor assessment (Nos. 1 and 2), the subject
will be censored on the date of first dose. However, if the subject died within 125 days in Cohorts 
1, 2A and 2B or 97 days in Cohorts 3A and 3B following the first dose and did not receive a
new anticancer treatment, it will be counted as PFS event at the date of death. If a subject had new
anticancer treatment before PD or death (No. 6), the subject will be censored on the date of the 
last adequate tumor assessment prior to or on the date of new anticancer treatment. If PD is
reported after the drug discontinuation visit, the subject will be censored at the date of last
radiologic assessment before drug discontinuation except when PD happened at the same visit as
drug discontinuation (No. 10). If PD happened within 4 weeks of drug discontinuation (Week 16 
for Cohort 2 and Week 18 for Cohorts 3A and 3B), it will be considered PD at drug
discontinuation visit and counted as PFS event.
•
If a subject missed 2 or more tumor assessments before PD or death (No. 9), the subject
will be censored on the date of the last adequate tumor assessment before PD or death. Note that
if a subject is censored by both this criterion and the anticancer treatment criterion, the earliest
censoring date will be used.
•
Otherwise, if a subject had an event (No. 3, No. 7, or No. 8), the earliest event date will be used.
2. 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 (No. 1, No. 2, No. 4, No. 5, No. 6, No. 9).


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Table 4 Censoring Rules for Analysis of Time to Progression
No
Situation
Date of Progression or Censoring
Outcome
1
No baseline tumor assessments
Date of first dose 
Censored
2
No postbaseline tumor assessments
Date of first dose
Censored
3
Progression documented between
scheduled visits
Date of first radiologic PD assessment
Progressed
4
More than 1 NE tumor timepoint assessment
Date of last adequate 
radiologic assessment before 
NE tumor assessments
Censored
5
No progression at time of data cutoff
Date of last adequate 
radiologic assessment
Censored
6
New anticancer treatment started
Date of last adequate radiologic 
assessment prior to or on date of
new anticancer treatment
Censored
7
Death before first tumor assessment
Date of death
Censored
8
Death between adequate assessment visits*
Date of death
Censored
9
Death or progression after more than
one missed visit/tumor assessment**
Date of last adequate
radiologic assessment before
missed tumor assessments
Censored
10
Treatment discontinuation for reasons
other than PD
Date of last radiologic
assessment before treatment
discontinuation
Censored


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CR = complete response, NE = not evaluable, PD = progressive disease, PR = partial response, q6w = every 
6 weeks, q8w = every 8 weeks, SD =stable disease.
* Adequate tumor assessment is radiologic assessment at regular interval as defined in the protocol.
** More than 1 missed visit/adequate tumor assessment is defined as having either 1 of the following
2 durations being longer than 18 weeks – 1 day, which is 125 days ( = ((8+1) × 2 × 7) – 1) for subjects
on the q8w schedule for tumor assessment in Cohorts 1, 2A, and 2B; while 14 weeks – 1 day, which is
97 days ( = ((6+1) × 2 × 7) – 1) for subjects on the q6w schedule for tumor assessment in Cohorts 3A 
and 3B:
  a. Duration between two consecutive tumor assessments
  b. Duration between the last adequate tumor assessment and PD
The priority of the censoring rules is as follows:
1. If the subject had PD, the following sequence will be applied:
•
If a subject did not have a baseline or postbaseline tumor assessment (Nos. 1 and 2), the subject
will be censored on the date of first dose. If a subject had new anticancer treatment before PD (No.
6), the subject will be censored on the date of the last adequate tumor assessment prior to or on the
date of new anticancer treatment. If PD is reported after the drug discontinuation visit, the subject
will be censored at the date of last radiologic assessment before drug discontinuation except when
PD happened at the same visit as drug discontinuation (No. 8). If PD happened within 4 weeks of
drug discontinuation (Week 16 for Cohort 2 and Week 18for Cohorts 3A and 3B), it will be censored 
at drug discontinuation visit.
•
If a subject died before first tumor assessment (No. 7) or died between adequate assessment visits 
(No. 8), the subject will be censored on the date of death.
•
If a subject missed 2 or more tumor assessments before PD or death (No. 9), the subject will be 
censored on the date of the last adequate tumor assessment before PD or death. Note that if a subject
is censored by both this criterion and the anticancer treatment criterion, the earliest censoring date
will be used.
•
Otherwise, if a subject had an event (No. 3), the earliest event date will be used.
2. If a subject did not have PD, the censoring date will be the earliest censoring date if the subject met 
multiple censoring criteria (No. 1, No. 2, No. 4, No. 5, No. 6, No 9).
The distribution of PFS and TTP will be estimated using the KM method. Median, Q1 and 
Q2 times to PFS, TTP, and the 95% CIs will be provided for each treatment cohort
(estimated with the Brookmeyer and Crowley method). Four-month and 12-month PFS and 
TTP rates will be estimated using the KM method and corresponding 80 and 95% CIs will be 
provided (estimated with the Greenwood formula using the log-log transformation
[Greenwood, 1926; Kalbfleisch and Prentice, 2002]) when an adequate number of at-risk 
subjects at those time points warrant the estimate. Follow-up time for PFS and follow-up 
time for progression-free duration will be presented for PFS and TTP, respectively (estimated 
using the KM method with median, Q1, and Q2 times). The 95% CIs will be estimated with 
the Brookmeyer and Crowley method. Estimates for both PFS and TTP follow-up times are 
calculated in the same way as the KM estimates of PFS and TTP, but with the meaning of 
‘censor’ and ‘event’ status indicator reversed.
The secondary efficacy analyses for Cohort 3B will be based on the lenvatinib-naïve subjects 
in the Full Analysis Set, while subjects enrolled from Cohorts 1 and 2B will be summarized 
as appropriate.


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5.4.3
Other Efficacy Analyses
5.4.3.1
Exploratory Efficacy Analyses
OS
OS is measured from the start date of the treatment period until date of death from any cause.
All events of death will be included, regardless of whether the event occurred while the 
subject was still taking study drug, or after the subject discontinued study drug. If a subject 
has no record of death, then the data will be censored at the date the subject was last known 
to be alive, or the data cutoff date, whichever is earlier (censoring rules see SAP Table 5).
The distribution of OS will be estimated using the KM method. Median, Q1 and Q2 survival 
times will be estimated by KM method, and the 95% confidence interval estimated with the
Brookmeyer and Crowley method. Survival rates at 4 and 12 months will be estimated using 
the KM method (and corresponding 95% CIs estimated with the Greenwood formula using 
the log-log transformation) for each treatment cohort when an adequate number of at-risk 
subjects at those time points warrant the estimate. Follow-up time for OS will be presented 
KM method. Median, Q1, and Q2 follow-up times, and the 95% CIs (using the Brookmeyer 
and Crowley method) will be estimated. Estimates for OS follow-up time are calculated in 
the same way as the KM estimate of OS, but with the meaning of ‘censor’ and ‘event’ status 
indicator reversed.
Table 5 Censoring Rules for Overall Survival Endpoint
Situation
End Date
Outcome
Death during study
Date of death
Death
Death after data cut-off
Date of data cut-off
Censored event
Subject still alive at data cut-off
Date of data cut-off
Censored event
Subject lost to follow-up before data cut-off
Date last known to be alive 
Censored event
PFS-4 RATE FOR COHORT 3A
This analysis will be performed for Cohort 3A. See Section 5.4.2.1 cohort 3B: osteosarcoma 
combination expansion for details.
5.5
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Analyses
5.5.1
Pharmacokinetic Analyses
Plasma concentration of lenvatinib versus time data will be listed. Pharmacokinetic data will 
be summarized using n, mean, SD, median, Q1, Q2, minimum, and maximum.
Plasma concentration of lenvatinib versus time data from all cohorts will be pooled and 
analyzed using a population PK approach to estimate population PK parameters. The analysis 
will be detailed in a separate analysis plan.


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5.5.2
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Analyses
Correlation between clinical response to lenvatinib treatment or AEs associated with 
lenvatinib treatment and blood or tumor biomarkers may be examined using descriptive 
statistics and graphic displays as appropriate. A separate analysis plan will be developed for 
the analyses of PK/pharmacodynamics, pharmacogenomic and other biomarker analyses.
Results from these analyses will not be included in the clinical study report but reported 
separately.
5.6
Safety Analyses
All safety analyses will be performed on the Safety Analysis Set. Safety data, including 
treatment-emergent adverse events (TEAEs), clinical laboratory parameters, vital signs, 
12-lead ECG results, and left ventricular ejection fraction (LVEF) will be presented by study 
cohort 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). Study Day 1 for all safety analyses is defined as the date of the first 
dose of study drug.
In addition, results of urine dipstick (proteinuria), occult blood in stool, KPS or Lansky play 
scores, and proximal tibial growth plates at scheduled time points, as well as their changes 
from Baseline, will be summarized by study cohort using descriptive statistics, as 
appropriate.
5.6.1
Extent of Exposure
5.6.1.1
Extent of Exposure of Study Drug
All parameters that represent the extent of exposure will be presented for Cohorts 1 and 3A 
of Phase 1, and Cohorts 2A, 2B and 3B of Phase 2. Number of cycles received will be 
summarized by descriptive statistics and by categories. Duration of treatment (days) for oral 
drug lenvatinib will be summarized by descriptive statistics. It is calculated as: Date of last 
dose – Date of first dose + 1. While the duration of treatment for the IV drugs, ifosfamide 
and etoposide (Cohorts 3A and 3B), will be counted in days as it is actually administrated.
5.6.1.2
Study Drug Administration
Total cumulative dose per subject (mg) will be summarized separately for lenvatinib, 
ifosfamide and etoposide by descriptive statistics. It is calculated as the sum of daily doses.
Dose intensity (mg/m2/day) will be summarized separately for lenvatinib, ifosfamide, and 
etoposide 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, ifosfamide and etoposide by descriptive statistics. It is calculated as: dose 


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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, ifosfamide, and 
etoposide, respectively.
Number of subjects with dose reductions, treatment interruptions, and treatment 
discontinuation due to AEs will be summarized by counts and percentage according to 
dosing data. Cycle of first dose interruption/reduction, and treatment discontinuation will be 
summarized by descriptive statistics. Frequency of dose interruptions will also be 
summarized by appropriate categories (e.g., 1, 2, 3, 4). Frequency of dose reductions will be 
summarized by categories (1, 2, 3).
The first dose reduction is defined as the first time the subject’s daily dose level was reduced 
to a non-zero value from its maximum designated 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 dosing error. For example, 17 mg/m2 followed by 0 mg/m2 followed by 
14 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 will only be determined for lenvatinib. Definition of dose interruption:
1. Only includes the scenario that before and after dose 0 mg/m2 (interruption period), 
the dose levels are the same. For example: 17 mg/m2 followed by 0 mg/m2 and 
followed by 17 mg/m2; 14 mg/m2 followed by 0 mg/m2 followed by 14 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: 
17 mg/m2 followed by 0 mg/m2 followed by 14 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 were recorded during Cycle 1 (Day 1 to Day 28) for Cohort 1 and during Cycle 1 (Day 
1 to Day 21) for Cohort 3A. The DLT (Yes/No) and reason(s) (see Section 13.1) for each 
subject will be listed, as well as the date, and dosage of drug when the DLT occurred.


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5.6.2
Adverse Events
The AE verbatim descriptions (investigator terms from the eCRF) will be classified into 
standardized medical terminology using MedDRA version 21.1. Adverse events will be 
coded to primary System Organ Class (SOC), preferred term (PT) and lower level term 
(LLT) using MedDRA.
A TEAE is defined as an AE that had an onset date on or after the first dose of study drug up 
to 30 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 cohort and 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 
within an SOC and PT. Subjects 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 
to be possibly or probably related to study drug or missing causality.
In summary, the following TEAE tables will be provided:
•
Overview of TEAEs
•
TEAEs by SOC and PT
•
TEAEs in decreasing frequency of PT
•
TEAEs by SOC, PT, and CTCAE grade
•
TEAEs with CTCAE Grades ≥3 by decreasing frequency of PT
•
Treatment-related TEAEs by SOC and PT
•
Treatment-related TEAEs by SOC, PT, and CTCAE grade
•
Treatment-related TEAEs by decreasing frequency of PT
•
Treatment-related TEAEs by decreasing frequency of PT with CTCAE Grades ≥3
•
Treatment-related TEAEs by decreasing frequency of PT with CTCAE Grades 3 or 4
•
Treatment-related TEAEs with CTCAE Grades 3 or 4 by SOC and PT
•
Grade 5 (fatal) treatment-related TEAEs by decreasing frequency of PT


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•
Grade 5 (fatal) treatment-related TEAEs by SOC and PT
The following TEAE tables will be provided by age group category (2 to <6 and 6 to <18).
•
TEAEs in decreasing frequency of PT by age group
•
Serious TEAEs in decreasing frequency of PT by age group
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 from study drug will 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.
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.
In summary, the following tables will be provided:
•
All deaths in the safety analysis set
•
Grade 5 (fatal) TEAEs by decreasing frequency of PT
•
Grade 5 (fatal) TEAEs by SOC and PT
•
Treatment-emergent SAEs by SOC and PT
•
Treatment-related treatment-emergent SAEs by SOC and PT
•
Treatment-emergent SAEs by decreasing frequency of PT
•
Non-fatal treatment-emergent SAEs by SOC and PT
•
TEAEs leading to study drug discontinuation by decreasing frequency of PT
•
TEAEs leading to study drug discontinuation by SOC and PT
•
TEAEs leading to study drug dose reduction and/or dose interruption by decreasing 
frequency of PT 
•
TEAEs leading to study drug dose reduction and/or dose interruption by SOC and PT
•
TEAEs leading to study drug dose reduction by decreasing frequency of PT
•
TEAEs leading to study drug dose reduction by SOC and PT
Clinically significant treatment-emergent AEs (CSAEs) for lenvatinib include arterial TE 
(thromboembolic) events, cardiac dysfunction, fistula formation, gastrointestinal (GI) 


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perforation, hemorrhage, hepatotoxicity, hypertension, hypocalcemia, palmar plantar 
erythrodysaesthesia syndrome (PPE), posterior reversible encephalopathy syndrome (PRES), 
proteinuria, QT prolongation, renal events, impaired wound healing, weight loss, and 
pneumothorax. The number and percentage of each category of treatment-emergent CSAEs 
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 will also be summarized.
The following tables will be provided only for CSAEs.
•
Summary of CSAEs by category and PT
•
Summary of serious CSAEs by category and PT
•
Overview of CSAEs by category
•
Incidence and Time to First Onset of CSAEs
•
Time to first onset of each CSAE for Lenvatinib
•
CSAEs by SOC, PT, and CTCAE grade
The following tables will be provided only for Cohort 1.
•
TEAEs in run-in period in decreasing frequency of PT
•
TEAEs in run-in period by SOC and PT
•
TEAEs in run-in period with CTCAE Grades ≥3 by decreasing frequency of PT
The following tables will be provided only for Cohorts 1 and 3A.
•
TEAEs in Cycle 1 in decreasing frequency of PT
•
TEAEs in Cycle 1 by SOC and PT
•
TEAEs in Cycle 1 with CTCAE Grades ≥3 by decreasing frequency of PT
The following subject AE listings (treatment-emergent or otherwise) will be provided:
•
All AEs
•
All deaths for all enrolled subjects
•
All SAEs
•
All AEs leading to study drug discontinuation
•
All AEs leading to dose reduction and / or dose interruption
•
All CSAEs


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The following subject TEAE listing will be provided only for Cohort 1.
•
TEAES in run-in period
The following subject listings will be provided only for Cohorts 1 and 3A.
•
DLTs in Cycle 1
•
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 30 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 cohort using descriptive statistics.
Qualitative parameters will be summarized using frequencies (number and percentage of 
subjects), and changes from baseline to the worst postbaseline visit 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:
•
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)
•
Shifts from Baseline to worst postbaseline visits relative to CTCAE grade (presenting
each dose level and overall shift table for all clinical chemistry parameters and the 
following hematology parameters: hemoglobin, platelets, WBC (leukocytes), 
neutrophils (ANC), and lymphocytes)


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All hematology and clinical chemistry laboratory parameters will be listed by subject and 
visit.
5.6.3.2
Thyroid-Stimulating Hormone 
Thyroid-stimulating hormone values will be summarized in 2 categories (≤ULN and >ULN) 
for non-DTC Cohorts 1, 2B, 3A and 3B, and in 3 categories (≤0.5, 0.5-5.5 and >5.5) for DTC 
Cohort 2A.
5.6.3.3
Urinalysis
The shift of worst postbaseline proteinuria from baseline will be summarized. All urinalysis 
parameters (RBCs/high-power-field [HPF], blood, and protein [dipstick], 24-hour urine 
protein) and guaiac fecal occult blood (negative, positive) will be provided by subject listing 
at each visit.
5.6.4
Vital Signs
Vital signs will be summarized by assessment time and cohort/dose level for Phase 1 or 
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, pulse rate, 
respiratory rate, body temperature) and weight and height, as well as changes from Baseline,
will be presented by cohort for each cycle and day.
Percentiles for BP values (only for subjects <18 years old [see Protocol Appendix 7]) 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.
5.6.5
Other Safety Analyses
5.6.5.1
Electrocardiograms
ECG assessments will be performed at Screening and at Day 1 of each cycle. 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 phase will be summarized. ECG results 
in QTc Bazett and QTc Fridericia will be categorized as follows:


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•
For subjects with Baseline and postbaseline data, maximum increase from Baseline 
(msec) of ≤ 30, > 30 to ≤ 60, and >60
•
Maximum postbaseline value (msec) of ≤ 450, > 450 to ≤ 480, > 480 to ≤ 500, and > 
500
5.6.5.2
Left Ventricular Ejection Fraction
The LVEF will be summarized by descriptive statistics by visit (mean, standard deviation, 
median, Q1, Q3, minimum, and maximum values), and percentage change from Baseline, 
and by percentage of reduction from Baseline (> 0 to ≤10%, >10 to ≤15%, >15%) as well as 
the occurrence of subjects having a lowest postbaseline value of <50%. A subject data listing 
will be provided.
5.6.5.3
Lansky Play Scores or Karnofsky Performance Status Scores
Lansky play scores or KPS scores will be summarized by shifts from Baseline to worst 
postbaseline visit. A subject listing of Lansky play scores or KPS scores, will be provided.
5.6.5.4
Proximal Tibial Growth Plates
Radiographic findings of proximal tibial growth plates will be listed.
5.7
Other Analyses
Each question in the Palatability and Acceptability Questionnaire will be listed using the
Palatability Analysis Set.
5.8
Exploratory Analyses
See Section 5.4.3.1 for Exploratory Efficacy Analyses.
6
INTERIM ANALYSES
After completion of treatment in Cohort 1 and Cohort 3A, data will be reviewed with the 
PSC to determine the RD. In addition, the sponsor will closely evaluate the risks and benefits 
of the study throughout its conduct, along with the PSC as needed.
7
CHANGES IN THE PLANNED ANALYSES
The following are changes in the analyses compared to Protocol Amendment 3 (01 
Ssep2016).
7.1
PFS-4 in Cohort 3A 
PFS-4 rate in Cohort 3A has been added as an exploratory efficacy endpoint to further 
explore the efficacy of lenvatinib in combination with ifosfamide and etoposide in pediatric 
osteosarcoma subjects.


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7.2
Analysis Sets
The following analysis sets have been included to help with analyses.
•
Full Analysis Set
•
Per Protocol Analysis Set
•
Palatability Analysis Set
The DLT Analysis Set will be defined for Cohort 1 and 3A.
7.3
Proximal Tibial Growth Plates and Palatability and Acceptability 
Questionnaire
Because of small numbers of subjects, results for these two variables will be presented in 
subject listings and not formally analyzed.
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).
Tumor assessments for efficacy analysis are to be performed every 8 weeks (within Week 8) 
for Cohorts 1, 2A and 2B and every 6 weeks (within Week 6) for Cohort 3A and 3B (or 
sooner if clinically indicated) until documentation of PD.
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.


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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
•
If only the day of the month is missing, the 15th of the month will be used to replace 
the missing day
•
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
•
If only the day of the month is missing, the 1st of the month will be used to replace 
the missing day
•
If both the day and the month are missing, "Jan 1" will be used to replace the missing 
information
•
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
•
If only the day of the month is missing, the 1st of the month will be used to replace 
the missing day
•
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
•
If only the day of the month is missing, the 1st of the month will be used to replace 
the missing day
•
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.


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8.2.1.5
Date of Start of Subsequent Anticancer Therapy
•
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 dosing date. Otherwise, it is 
assumed that the subsequent therapy started on the day following the last dosing date.
•
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 dosing date.
Otherwise, it is assumed that the subsequent therapy started on the day following the 
last dosing date.
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 or years:
1 month = 30.4375 days
•
Time from first diagnosis to first dose (months) is:
(Date of first dose – Date of first diagnosis) / 30.4375
•
Time from first metastatic diagnosis to first dose (months) is:
(Date of first dose – Date of first metastatic diagnosis) / 30.4375
•
Time from last medication to first dose (months) is:
(Date of first dose – End date of last medication) / 30.4375
•
Time from last procedure to first dose (months) is:
(Date of first dose – Start date of the last anti-cancer procedure) /30.4375
•
Time from last radiotherapy to first dose (months) is:
(Date of first dose – End date of the last radiotherapy) / 30.4375
•
Time from last radioiodine therapy to first dose (months) is:
(Date of first dose – End date of the last radioiodine therapy) /30.4375
8.3.3
Radioiodine Therapy Conversions
The SI unit for radioiodine therapy is GBq (1 gigabecquerel = 109 Bq). Data was also 
collected with the unit mCi (millicuries). The conversion is 1 mCi = 0.037 GBq.


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8.3.4
Creatinine Clearance
The pediatric Schwartz equation for creatinine clearance is:
•
GFR (mL/min/1.73 m2) = (0.41 x Height) / Scr, where Scr is serum/plasma creatinine 
in mg/dL
8.3.5
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.
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 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.


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2. Cheung YK. Sample size formulae for the Bayesian continual reassessment method. Clin 
Trials. 2009;6:227-38.
3. Clopper, CJ and Pearson, ES. The Use of Confidence or Fiducial Limits Illustrated in the 
Case of the Binomial. Biometrika. 1934;26:404–13.
4. Common Terminology Criteria for Adverse Events (CTCAE). Version 4.03. United 
States Department of Health and Human Services, National Institutes of Health. National 
Cancer Institute, Washington, DC, USA, June 14, 2010.
5. Doussau A, Asselain B, LeDeley MC, Geoerger B, et al. Dose-finding designs in 
pediatric phase I clinical trials: comparison by simulations in a realistic timeline 
framework. Contemp Clin Trials. 2012;33(4):657-65.
6. Eisenhauer EA, Therasse P, Bogaerts J et al. New response evaluation criteria in solid 
tumours: Revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45(2):228-47.
7. Greenwood, M. The natural duration of cancer. Reports on Public Health
and Medical Subjects. 1926:33:1-26. Her Majesty's Stationery Office, London.
8. Food and Drug Administration Guidance for Industry: Clinical Trial Endpoints for the 
Approval of Cancer Drugs and Biologics, May 2007 [internet; cited 3 March 2011] 
Available from:
https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/ucm071590.pdf.
9. Kaplan, E. and Meier, P. Nonparametric Estimation from Incomplete Observations. J Am 
Stat Assoc. 1958;53:457-81.
10. Kalbfleisch, J.D. and Prentice, R.L. The Statistical Analysis of Failure
Time Data. 2nd Edition. John Wiley & Sons, Inc. New York:2002.
11. Lee DP, Skolnik JM, Adamson OC. Pediatric phase I trials in oncology: an analysis of 
study conduct efficiency. J Clin Oncol. 2005;23(33): 8431-41.
12. 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.
13. Schwartz GJ, Work DF. Measurement and estimation of GFR in children and 
adolescents. Clin J Am Soc Nephrol. 2009b;4(11):1832-43.
14. Simon R. Optimal two-stage designs for phase II clinical trials. Controlled Clinical 
Trials. 1989;10:1-10.
15. Smith M, Bernstein M, Bleyer WA, et al. Conduct of phase I trials in children with 
cancer. J Clin Oncol. 1998;16(3):966-78.
16. Study Protocol Number: E7080-G000-207: Phase 1/2 Study of Lenvatinib in Children 
and Adolescents With Refractory or Relapsed Solid Malignancies and Young Adults with 
Osteosarcoma (V3.0 Amendment 03, 1 September 2016).


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13 APPENDICES
13.1
Dose-Limiting Toxicities
Dose-limiting toxicity (DLT): A DLT in subjects treated with lenvatinib will be assessed 
according to Common Terminology Criteria for Adverse Events (CTCAE) v4.03 and is 
defined as any of the following toxicities related to lenvatinib or chemotherapy drugs 
(ifosfamide and/or etoposide) occurring during Cycle 1 (Day 1 to Day 28) for Cohort 1 and 
during Cycle 1 (Day 1 to Day 21) for Cohort 3A.
•
Hematologic Toxicity
◦
Grade 4 neutropenia for ≥7 days (≥10 days for Cohort 3A)
◦
Grade ≥3 thrombocytopenia with bleeding, or lasting >7 days (≥10 days for 
Cohort 3A)
◦
Grade ≥3 febrile neutropenia(lasting ≥7 days for Cohort 3A)
◦
Next course of chemotherapy delayed for ≥7 days (Cohort 3A)
•
Nonhematologic toxicity
◦
Grade ≥3 nonhematological toxicity persisting more than 7 days despite optimal 
supportive care. Isolated laboratory abnormalities that resolve within a week, 
allergic reactions, and symptoms related to tumor progression will be excluded.
◦
Grade 4 hypertension, confirmed systolic or diastolic blood pressure more than 
25 mmHg above the 95th percentile for age, or an elevated diastolic blood 
pressure (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 two antihypertensive ingredient medications will count as one 
antihypertensive medication.
◦
Grade 3 proteinuria
◦
Any recurrent Grade 2 nonhematological toxicity requiring ≥2 interruption and 
dose reductions
•
Any dose interruption or reduction due to toxicity which results in administration of
less than 75% of the planned dosage of lenvatinib.
•
Any other Grade ≥3 toxicity (hematologic and nonhematologic) assessed as related to 
lenvatinib treatment, and which in the opinion of the principal investigator and Eisai 
medical monitor constitutes a dose-limiting toxicity
All DLTs must be reported to the Eisai medical monitor within 24 hours of their occurrence.
Determination of a DLT will be made by the investigator and Eisai Medical Monitor in 
consultation with the PSC, as needed. Subjects who discontinue study drug for any reason 
other than DLT during Cycle 1 (Day 1 to Day 28) for Cohort 1 and Cycle 1 (Day 1 to Day 
21) for Cohort 3A will be replaced.


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13.2
Summary of Efficacy Analyses
Efficacy Variable
Analysis Set
Statistical Method
Tumor 
Assessments
PFS-4
Full Analysis 
Set, Per 
Protocol 
Analysis Set
Number (percent) of subjects who are 
alive, free of disease progression, and did 
not receive anticancer medication 4 
months after the first dose, and its exact 
80 and 95% CIs using method of Clopper 
and Pearson.
Cohort 2B: PFS-4 rate will be tested 
using a Null hypothesis that PFS-4 is 
≤25% tested against the alternative 
hypothesis of a PFS-4 ≥45%, using the 
1-sample exact test of a single 
proportion, at the 1-sided 0.1 level.
Cohort 3B: PFS-4 rate will be tested 
using a Null hypothesis that PFS-4 is 
≤25% tested against the alternative 
hypothesis of a PFS-4 ≥50%, using the 
1-sample exact test of a single 
proportion, at the 1-sided 0.1 level.
Investigator
ORR 
Full Analysis 
Set, Per 
Protocol 
Analysis Set
Number (percent) of subjects (with PR + 
CR) and its exact 95% CI using method 
of Clopper and Pearson.
Investigator
PFS
Full Analysis 
Set, Per 
Protocol 
Analysis Set
KM method: Median, Q1, and Q2 PFS
will be presented, with 2-sided 95% CIs
(Brookmeyer and Crowley). Cumulative 
probability of PFS at 4 and 12 months 
will be presented with 2-sided 80 and 
95% CIs (Greenwood using the log-log).
KM plot will also be provided.
Investigator
OS
Full Analysis 
Set
KM method: Median, Q1, and Q2 OS, 
and cumulative probability of OS at 4 
and 12 months will be presented. 2-sided 
95% CIs (Brookmeyer and Crowley for 
quartiles and Greenwood using log-log 
for probability of 4 and 12 Months). KM
Not 
Applicable


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Efficacy Variable
Analysis Set
Statistical Method
Tumor 
Assessments
plot will also be provided.
BOR
Full Analysis 
Set, Per 
Protocol 
Analysis Set
Number (percent) and 95% exact CIs 
will be provided for each BOR category
Investigator
DOR
Full Analysis 
Set, Per 
Protocol 
Analysis Set
KM method: Median, Q1, and Q2 PFS
will be presented, with 2-sided 95% CIs
(Brookmeyer and Crowley).
Investigator
TTP
Full Analysis 
Set, Per 
Protocol 
Analysis Set
Kaplan-Meier method: Median, Q1, and 
Q2 TTP will be presented with 2-sided 
95% CIs (Brookmeyer and Crowley).
Cumulative probability of TTP at 4 and 
12 months will be presented with 2-sided 
80 and 95% CIs (Greenwood using log-
log). Kaplan-Meier plot will also be 
provided.
Investigator


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Efficacy Variable Analysis Set
Statistical Method
Tumor 
Assessments
DCR
Full Analysis 
Set
Number (percent) of subjects 
(measurable disease with CR + PR + 
stable disease [SD] ≥ 7 weeks, evaluable 
disease with CR + Non-CR/Non-PD ≥ 7 
weeks) and its exact 95% CI using 
method of Clopper and Pearson.
Investigator
CBR
Full Analysis 
Set
Number (percent) of subjects 
(measurable disease with CR+ PR + SD≥ 
23weeks, evaluable disease with CR + 
Non-CR/Non-PD ≥ 23 weeks) and its 
exact 95% CI using method of Clopper 
and Pearson.
Investigator


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13.3
Common Terminology Criteria For Adverse Events (CTCAE) For 
Hematology & Clinical Chemistry
Laboratory 
Parameter
Common Terminology Criteria for Adverse Events (CTCAE)
Grade 1
Grade 2
Grade 3
Grade 4
Hematology
Hemoglobin
< LLN – 10 g/dL
< LLN – 6.2 mmol/L
< 10 – 8 g/dL
< 6.2 – 4.9 mmol/L
< 8 – 6.5 g/dL
< 4.9 – 4 mmol/L
–
Platelet Count
< LLN – 75,000/mm3
< LLN – 75 x 109/L
< 75,000 – 50,000/mm3
< 75 – 50 x 109/L
< 50,000 – 25,000/mm3
< 50 – 25 x 109/L
< 25,000/mm3
< 25 x 109/L
Leukocytes (Total WBC)
< LLN – 3,000/mm3
< LLN – 3 x 109/L
< 3,000 – 2,000/mm3
< 3 – 2 x 109/L
< 2,000 – 1000/mm3
< 2 – 1 x 109/L
< 1,000/mm3
< 1 x 109/L
Lymphocytes (hypo)
< LLN – 800/mm3
< LLN – 0.8 x 109/L
< 800 – 500/mm3
< 0.8 – 0.5 x 109/L
< 500 – 200/mm3
< 0.5 – 0.2 x 109/L
< 200/mm3
< 0.2 x 109/L
Lymphocytes (hyper)
-
> 4,000 – 20,000/mm3
> 4 – 20 x 109/L
> 20,000/mm3
> 20 x 109/L
–
Neutrophils
< LLN – 1,500/mm3
< LLN – 1.5 x 109/L
< 1,500 – 1,000/mm3
< 1.5 – 1 x 109/L
< 1,000 – 500/mm3
< 1 – 0.5 x 109/L
< 500/mm3
< 0.5 x 109/L
Clinical Chemistry
Albumin
< LLN – 3 g/dL
< LLN – 30 g/L
< 3 – 2 g/dL
< 30 – 20 g/L
< 2 g/dL
< 20 g/L
Alkaline Phosphatase
> 1 – ≤2.5 x ULN
> 2.5 – ≤5 x ULN
> 5 – ≤20 x ULN
> 20 x ULN
ALT
> 1 – ≤3 x ULN
> 3 – ≤5 x ULN
> 5 – ≤20 x ULN
> 20 x ULN
Amylase
> 1 – ≤1.5 x ULN
> 1.5 – ≤2 x ULN
> 2 – ≤5 x ULN
> 5 x ULN


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Laboratory 
Parameter
Common Terminology Criteria for Adverse Events (CTCAE)
Grade 1
Grade 2
Grade 3
Grade 4
AST
> 1 – ≤3 x ULN
> 3 – ≤5 x ULN
> 5 – ≤20 x ULN
> 20 x ULN
Bilirubin, Total
> 1 – ≤1.5 x ULN
> 1.5 – ≤3 x ULN
> 3 – ≤10 x ULN
> 10 x ULN
Calcium (hyper)
> ULN – ≤11.5 mg/dL
> ULN – ≤2.9 mmol/L
> 11.5 – ≤12.5 mg/dL
> 2.9 – ≤3.1 mmol/L
> 12.5 – ≤13.5 mg/dL
> 3.1 – ≤3.4 mmol/L
> 13.5 mg/dL
> 3.4 mmol/L
Calcium (hypo)
< LLN – 8 mg/dL
< LLN – 2 mmol/L
< 8 – 7 mg/dL
< 2 – 1.75 mmol/L
< 7 – 6 mg/dL
< 1.75 – 1.5 mmol/L
< 6 mg/dL
< 1.5 mmol/L
Cholesterol, Total
> ULN – 300 mg/dL
> ULN – 7.75 mmol/L
> 300 – 400 mg/dL
> 7.75 – 10.34 mmol/L
> 400 – 500 mg/dL
> 10.34 – 12.92 mmol/L
> 500 mg/dL
> 12.92 mmol/L
Creatinine
> 1 – ≤1.5 x ULN
> 1.5 – ≤3 x ULN
> 3 – ≤6 x ULN
> 6 x ULN
Glucose (hyper)
> ULN – ≤160 mg/dL
> ULN – ≤8.9 mmol/L
> 160 – ≤250 mg/dL
> 8.9 – ≤13.9 mmol/L
> 250 – ≤500 mg/dL
> 13.9 – ≤27.8 mmol/L
> 500 mg/dL
> 27.8 mmol/L
Glucose (hypo)
< LLN – 55 mg/dL
< LLN – 3 mmol/L
< 55 – 40 mg/dL
< 3 – 2.2 mmol/L
< 40 – 30 mg/dL
< 2.2 – 1.7 mmol/L
< 30 mg/dL
< 1.7 mmol/L
Lipase
> 1 – 1.5 x ULN
> 1.5 – ≤2 x ULN
> 2 – 5 x ULN
> 5 x ULN
Magnesium (hyper)
> ULN – ≤3 mg/dL
> ULN – ≤1.23 mmol/L
–
> 3 – ≤8 mg/dL
> 1.23 – ≤3.3 mmol/L
> 8 mg/dL
> 3.3 mmol/L
Magnesium (hypo)
< LLN – 1.2 mg/dL
< LLN – 0.5 mmol/L
< 1.2 – 0.9 mg/dL
< 0.5 – 0.4 mmol/L
< 0.9 – 0.7 mg/dL
< 0.4 – 0.3 mmol/L
< 0.7 mg/dL
< 0.3 mmol/L
Phosphate
< LLN – 2.5 mg/dL
< LLN – 0.8 mmol/L
< 2.5 – 2 mg/dL
< 0.8 – 0.6 mmol/L
< 2 – 1 mg/dL
< 0.6 – 0.3 mmol/L
< 1 mg/dL
< 0.3 mmol/L
Potassium (hyper)
> ULN – ≤5.5 mmol/L
> 5.5 – ≤6 mmol/L
> 6 – ≤7 mmol/L
> 7 mmol/L


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Laboratory 
Parameter
Common Terminology Criteria for Adverse Events (CTCAE)
Grade 1
Grade 2
Grade 3
Grade 4
Potassium (hypo)
< LLN – 3 mmol/L
–
< 3 – 2.5 mmol/L
< 2.5 mmol/L
Sodium (hyper)
> ULN – ≤150 mmol/L
> 150 – ≤155 mmol/L
> 155 – ≤160 mmol/L
> 160 mmol/L
Sodium (hypo)
< LLN – 130 mmol/L
–
< 130 – 120 mmol/L
< 120 mmol/L


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SIGNATURE PAGE
Author:
c.
Date
Date
Approval:
.
Date
Oncology Business Group, Eisai Ltd.
Date
PPD
PPD
PPD
PPD
PPD