Clinical trial NCT04154189
Conditions: Osteosarcoma
Keywords: Osteosarcoma Lenvatinib Ifosfamide Etoposide E7080 Relapsed or Refractory Osteosarcoma Pediatrics Chemotherapy
Sponsor: Eisai Inc.
Start date: 2020-03-23; Completion date: 2023-08-17
Enrollment: 81 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This Is a Multicenter, Randomized, Open-Label, Parallel-Group, Phase 2 Study to Compare the Efficacy and Safety of Lenvatinib in Combination with Ifosfamide and Etoposide Versus Ifosfamide and Etoposide in Children, Adolescents, and Young Adults with Relapsed or Refractory Osteosarcoma.

Detailed description:

Arms: arm 1: Participants with relapsed or refractory osteosarcoma will receive lenvatinib in combination with ifosfamide and etoposide. arm 2: Participants with relapsed or refractory osteosarcoma will receive ifosfamide with etoposide. Participants with relapsed or refractory osteosarcoma may receive optional lenvatinib plus or minus chemotherapy (Ifosfamide and Etoposide) if disease progression is observed in study.
Interventions: intervention 1: Lenvatinib intervention 2: Ifosfamide intervention 3: Etoposide intervention 4: Lenvatinib
Intervention descriptions: intervention 1: Lenvatinib 14 milligrams per square meter (mg/m\^2) capsules will be administered once daily on Days 1 to 21 of each 21-day cycle until disease progression (PD), development of unacceptable toxicity, participant request, withdrawal of consent, or discontinuation of study by the sponsor.

An extemporaneous suspension of lenvatinib capsules may be used for participants unable to swallow capsules. intervention 2: Ifosfamide 3000 milligrams per square meter per day (mg/m\^2/day) intravenous infusion will be administered on Days 1 to 3 of each 21-day cycle for a total of 5 cycles. intervention 3: Etoposide 100 mg/m\^2/day intravenous infusion will be administered on Days 1 to 3 of each 21-day cycle for a total of 5 cycles. intervention 4: Lenvatinib 14 mg/m\^2 capsules will be administered once daily on Days 1 to 21 of each 21-day cycle until the next PD (per response evaluation criteria in solid tumors \[RECIST\] 1.1 as assessed by investigator), development of unacceptable toxicity, participant request, or withdrawal of consent, whichever occurs first.

Protocol documents:
Prot_004.pdf: 
Clinical Study Report 
E7080-G000-230 
 
16.1.1 
Protocol or Protocol Amendments 
The final global protocol (Protocol Amendment 2) incorporating all amendments is provided on 
the following pages. Also provided is the original protocol as well as Amendment 01. 
• Protocol Amendment 02, dated 10 Sep 2020 
• Protocol Amendment 01, dated 09 Mar 2020 
• Original Protocol, dated 08 Oct 2019 
Eisai
Confidential
Page 1 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 1 of 147
1
TITLE PAGE
Clinical Study Protocol
Study Protocol 
Number:
E7080-G000-230
Study Protocol 
Title:
A Multicenter, Open-label, Randomized Phase 2 Study to Compare 
the Efficacy and Safety of Lenvatinib in Combination with 
Ifosfamide and Etoposide versus Ifosfamide and Etoposide in 
Children, Adolescents and Young Adults with Relapsed or 
Refractory Osteosarcoma (OLIE)
Sponsor:
Eisai Inc.
155 
Tice 
Boulevard
Woodcliff Lake, 
New Jersey 07677
US
Eisai Ltd. 
European Knowledge 
Centre
Mosquito Way 
Hatfield, Hertfordshire 
AL10 9SN UK
Eisai Co., Ltd. 
4-6-10 Koishikawa
Bunkyo-Ku, 
Tokyo 112 8088
JP
Sponsor’s 
Investigational 
Product Name:
E7080/Lenvatinib
Indication:
Osteosarcoma
Phase:
2
Approval Date(s):
Original Protocol
08 Oct 2019
Amendment 01
09 Mar 2020
Amendment 02
10 Sep 2020
IND Number:
146642
EudraCT Number:
2019-003696-19
GCP Statement:
This study is to be performed in full compliance with International 
Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) and all applicable local 
Good Clinical Practice (GCP) and regulations.  All required study 
documentation will be archived as required by regulatory 
authorities.
Page 2 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 2 of 147
Confidentiality 
Statement:
This document is confidential.  It contains proprietary information 
of Eisai (the sponsor).  Any viewing or disclosure of such 
information that is not authorized in writing by the sponsor is 
strictly prohibited.  Such information may be used solely for the 
purpose of reviewing or performing this study.
Page 3 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 3 of 147
REVISION HISTORY
Amendment 02
Date: 10 Sep 2020
Change
New text is in bold and deleted text is in 
strikethrough font.
Rationale
Affected Protocol 
Sections
Age of consent: clarified that the age at which 
a subject is required to sign the informed 
consent and/or assent form will follow local 
country requirements. Additionally, biomarker 
analysis for subjects who are not/cannot be 
consented, at the appropriate age per local 
country requirements, will not be performed.
Added for clarity as different 
countries have different age 
requirements for providing 
consent.
Synopsis, Study Design 
Section 5.3
Section 9.7.1.7.2
This study will be conducted by qualified 
investigators under the sponsorship of Eisai 
(the sponsor) at approximately 8070
investigational sites worldwide.
Revised the number of sites.
Synopsis, Sites
Section 6
Revised primary objective and endpoint to 
progression-free survival (PFS), and revised 
PFS rate at 4 months (PFS-4m) to be a 
secondary objective and endpoint.
Updated based on Health 
Authority feedback.
Synopsis, Objectives
Section 7.4
Section 8.1
Section 8.2
Section 9.2
Section 9.7.1.1.1
Section 9.7.1.1.2
Section 9.7.1.6
Section 9.7.1.6.1
Section 9.7.2
Added objective response rate (ORR) as a 
secondary objective and endpoint.
ORR was added to supplement 
the secondary endpoint of 
ORR at 4 months
Synopsis, Secondary 
Objectives
Section 8.2
Section 9.2
Section 9.7.1.1.2
Section 9.7.1.6.1
Compare the proportion of subjects who 
achieve complete removal of baseline 
lesion(s) following completion of 
chemotherapy between the 2 arms.
Update made for clarification  
Synopsis, Statistical 
Methods 
Section 8.3
The SponsorEisai will closely monitor 
enrollment, to ensure that a minimum of 36 
subjects are <17 at least 32 subjects are <18
years of age at the time of informed consent.  
Updated per health authority 
feedback.
Synopsis, Study Design
Section 9.1
Section 9.3
Page 4 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 4 of 147
The Randomization Phase will begin at the 
time of randomization of the first subject and 
will end on the data cutoff date for the 
primary analysis (ie, when approximately 38 
PFS events, as determined by IIR, are 
observed) for the PFS-1y and OS-1y analysis.  
After the data cutoff date for the primary 
analysis for the PFS-1y and OS-1y analysis 
has occurred, all subjects who are still on 
study treatment will enter the Extension 
Phase. Data cutoff (for PFS-1y and OS-1y 
analysis) will occur when the last subject has 
completed 18 cycles of treatment or 
discontinues before the end  of Cycle 18, 
whichever occurs first.
Change made in-line with 
updates to the primary 
endpoint.
Synopsis, Study Design
Section 9.1.2
Section 9.1.2.2
Section 9.1.3.1
Section 9.3.3
Section 9.5.1.2.1
Section 9.7.1.6
All AEs, including SAEs will be captured up 
to 30 days after last dose of study drug.
To clarify SAE collection 
period.
Synopsis, 
Section 9.1.2.2
Section 9.1.3.1
Table 5, z 
Table 6, t
Table 7. t
The Follow-up Period will begin the day after 
the Off-Treatment Visit and will last for up 
tountil death or for 2 years after end of 
treatment for a subject, unless the study is 
terminated by the sponsor, or the subject 
discontinues due to withdrawal of consent, or 
is lost to follow-up. 
Clarified that the survival 
follow-up period may last for 
up to 2 years.
Synopsis, 
Section 9.1.2.2
Section 9.1.3.2
Section 9.3.3
Section 9.5.1.2.1
Off-Treatment: Tumor assessments at the 
Off-Treatment Visit (within 1 week of the 
Off-treatment Visit) are only necessary for 
subjects who discontinue study treatment 
without disease progression, if more than 4 
weeks have passed since the previous 
assessment and if the subject will not 
continue with follow-up scans.
Follow-up: After treatment discontinuation, 
tumor assessmentFor subjects who 
discontinue study treatment without disease 
progression, tumor assessments should 
continue to be performed according to the 
schedule:  every 6±1 weeks until Week 18±1 
week, then every 9±1 weeks until Week 54±1 
week, thereafter, to be performed every 12±2 
weeks, until documentation of progression or 
start of a new anticancer agent.
Clarified tumor assessment 
requirements at the Off-
Treatment visit and during 
Follow-up.
Table 5, q
Added Optional Lenvatinib Crossover 
Treatment for Subjects in Arm B who 
experience progressive disease.
Considering the high unmet 
medical need in this 
population, the option to 
crossover to lenvatinib was 
added.
Synopsis, Study Design
Section 9.1.4
Section 9.5.1.2.1
Section Figure 1
Table 7, footnotes a and l
Page 5 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 5 of 147
In case the study is discontinued by the 
sponsor, the sponsor will continue to provide 
study drug (outside the study) for subjects 
who have not met the criteria for study 
drug discontinuation requiring continuation 
of treatment.
Clarified study drug provision 
in the event of study 
discontinuation by Sponsor.
Synopsis, Study Design 
Section 9.1.3.1
Section 9.1.3.2
Section 9.1.4
Table 7, footnote l
Inclusion Criterion 2: Refractory or relapsed 
osteosarcoma after 1 to 2 prior lines of
systemic treatments. 
Clarified that subjects are 
eligible after 1 or 2 prior lines 
of systemic treatment.
Synopsis, Inclusion 
Criteria
Section 9.3.1
Inclusion Criterion 3: Measurable disease is 
defined as a lesion A lesion Must be 
accurately measurable with a minimum size 
(by long axis) of 10 mm using computed 
tomography/magnetic resonance imaging 
(CT/MRI) (lymph nodes must be accurately 
measurable with a minimum size [by short 
axis] of 15 mm)…
Any other non-measurable lesions will be 
considered evaluable disease.
Clarified the definitions of 
measurable and evaluable 
disease.
Synopsis, Inclusion 
Criteria
Section 9.3.1
Inclusion Criterion 8:  Adequate blood 
coagulation function defined by International 
Normalized Ratio or prothrombin time 
(INR/PT) and activated partial 
thromboplastin time or partial 
thromboplastin time (aPTT/PTT) ≤1.5 
unless participant is receiving anticoagulant 
therapy, as long as INR/PT and aPTT/PTT  
are within therapeutic range of intended use 
of anticoagulants.
Update INR assessment to 
INR/PT and aPTT/PTT.
Synopsis, Inclusion 
Criteria
Section 9.3.1
Table 4, c
Inclusion Criterion 11: Adequate cardiac 
function as evidenced by left ventricular 
ejection fraction ≥50% at baseline as 
determined by echocardiography or 
multigated acquisition (MUGA) scan.
Clarification that cardiac 
function can be evaluated by 
ECHO or MUGA scan.
Synopsis, Inclusion 
Criteria
Section 9.3.1
Section 9.5.1.4
Section 9.5.1.4.7
Table 5, k 
Table 6, g
Inclusion Criterion 13: Washout before Cycle 
1 Day 1 of 3 weeks in case of prior 
chemotherapy, 6 weeks if treatment included 
nitrosoureas; 4 weeks for definitive 
radiotherapy, 2 weeks for palliative 
radiotherapy; and 3 months from high-dose 
chemotherapy and stem cell rescue.  For all 
other anti-cancer therapies, washout before 
Cycle 1 Day 1 of at least 5 half-lives (or at 
least 28 days, whichever is shorter).
Subjects must have recovered (to Grade ≤1, 
except for alopecia, ototoxicity, and Grade ≤2 
peripheral neuropathy, per Common 
Terminology Criteria for Adverse Events
[CTCAE] v5.0) from the acute toxic effects of 
all prior anticancer therapy before Cycle 1 
Day 1.
Clarified the washout period 
for other prior anti-cancer 
therapies not otherwise 
specified in Inclusion Criterion 
13
Synopsis, Inclusion 
Criteria
Section 9.3.1
Page 6 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 6 of 147
Added Inclusion Criterion 14: Must have no 
prior history of lenvatinib treatment.
Added to clarify that prior 
treatment with lenvatinib is not 
permitted.
Synopsis, Inclusion 
Criteria
Section 9.3.1
Exclusion Criterion 9:  Has clinically 
significant cardiovascular disease within 6
months from first dose of study  
intervention, including New York Heart 
Association Class III or IV congestive heart 
failure, unstable angina, myocardial 
infarction, cerebral vascular accident, or 
cardiac arrhythmia associated with 
hemodynamic instability. Note: Medically 
controlled arrhythmia would be permitted.
Added additional exclusion 
criterion to account for risk of 
cardiotoxicity with vascular 
endothelial growth factor 
(VEGF) tyrosine kinase 
inhibitors (TKIs).
Synopsis, Exclusion 
Criteria
Section 9.3.2
Exclusion Criterion 17:  Active viral hepatitis 
(B or C) as demonstrated by positive serology
Known active Hepatitis B (eg, HBsAg 
reactive) or Hepatitis C (eg, HCV RNA 
[qualitative] is detected).  Note:  Testing for 
Hepatitis B or Hepatitis C is required at 
screening only when mandated by local health 
authority.
Clarified definition of known 
active hepatitis B and C.
Synopsis, Exclusion 
Criteria
Section 9.3.2
Exclusion Criterion 19: Females of 
childbearing potential* who:
- Do not agree to use a highly effective 
method of contraception for the entire study 
period and for 28 days after lenvatinib 
discontinuation or 12 months after etoposide 
and ifosfamide discontinuation, ie:
◦ total abstinence (if it is their preferred and 
usual lifestyle)
◦ an intrauterine device (IUD) or intrauterine 
hormone-releasing system (IUS)
◦ a contraceptive implant
◦ an oral contraceptive.  **(with additional 
barrier method) Subject must be on a stable 
dose of the same oral contraceptive product 
for at least 28 days before dosing with study 
drug and throughout the study and for 28 days 
after lenvatinib discontinuation or 12 months 
after etoposide and ifosfamide discontinuation
OR
- Do not have a vasectomized partner with 
confirmed azoospermia.
For sites outside of the EU, it is permissible 
that if a highly effective method of 
contraception is not appropriate or acceptable 
to the subject, or the subject has changed oral 
hormonal contraceptive product/dose within 4 
weeks prior to study drug administration, 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. 
* All post pubertal females will be considered 
Updated to align with  
lenvatinib standard 
contraceptive language.
Synopsis, Exclusion 
Criteria
Section 9.3.2
Page 7 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 7 of 147
to be of childbearing potential unless they 
have early menopause (amenorrheic for at 
least 12 consecutive months, in the 
appropriate age group, and without other 
known or suspected cause) or have been 
sterilized surgically (ie, bilateral tubal 
ligation, total hysterectomy, or bilateral 
oophorectomy, all with surgery at least 1 
month before dosing), or are pre-menarcheal 
(Tanner Stage 1-3).
**Must be on stable dose of the same oral 
hormonal contraceptive product for at least 
4 weeks before dosing with study drug(s) 
and for the duration of the study.
Bisphosphonates and denosumab for the 
treatment of osteosarcoma are not 
permitted.
Due to their potential 
antitumor activity, denosumab 
and bisphosphonates are 
prohibited (unless indicated for 
the management of an AE, eg, 
hypercalcemia). 
Synopsis, Concomitant 
Drug/Therapy
Section 9.4.7.2
The concomitant use of live vaccines (e.g., 
measles, mumps, rubella, chicken pox,
yellow fever, rabies, BCG, and typhoid 
[oral] vaccines) are not permitted. Seasonal 
influenza vaccines for injection are 
generally killed virus vaccines and 
therefore, are permitted. However 
intranasal influenza vaccines (e.g., 
FluMist®) are live attenuated vaccines, and 
therefore, are not permitted. Additionally, 
the concomitant use of live vaccines with 
chemotherapy is contraindicated in 
immunosuppressed patients.
Per health authority feedback, 
the prohibited concomitant 
treatments have been updated 
to exclude yellow fever or 
other live vaccines.
Synopsis, Concomitant 
Drug/Therapy
Section 9.4.7.2
Granulocyte-colony stimulating factor (G-
CSF) may be used to mitigate the toxicity of 
ifosfamide and etoposide. 
Clarificiation: G-CSF is 
already stated as permitted 
within Section 8.4.1.2 
(Management of Ifosfamide-
Etoposide Associated 
Toxicity) and Section 8.4.7 
(Prior and Concomitant 
Therapy).
Synopsis, Concomitant 
Drug/Therapy
Subjects in Arm A in the presence of clinical 
benefit, may continue study treatment with 
lenvatinib after protocol permissible surgery,
in the presence of clinical benefit, with 
Sponsor approval.
Clarification: option to 
continue treatment after 
protocol permissible surgery 
(i.e. after Week 18) applies to 
both treatment arms.
Synopsis, Concomitant 
Drug/Therapy 
Section 9.4.7.3
PK Assessments: Blood samples for plasma 
concentrations of lenvatinib will be collected 
from all subjects from Arm A only as 
described in the Schedule of Assessments. 
Pharmacokinetic sampling should not be 
performed for any subject with a body 
weight <13 kg (please see Section 8.5.1.3.1).
Updated per health authority 
feedback and standard 
guidelines for pediatric blood 
draw volumes in order to 
ensure that the maximum is 
not exceeded.
Synopsis, 
Pharmacokinetic 
Assessments
Table 5, n 
Section 9.5.1.3.1
Page 8 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 8 of 147
Pharmacodynamic Assessments: Optional
Ppharmacodynamic serum and archived fixed 
tumor tissue samples for biomarker analysis 
maywill be collected from subjects 
randomized to Arm A only, as described in 
the Schedule of Assessments. 
Pharmacodynamic sampling should not be 
performed for any subject with a body 
weight <16 kg (please see Section 8.5.1.3.2).
Pharmacodynamic serum and tumor 
biomarkers assessed in this study will be 
based on those identified in other lenvatinib 
clinical studies.  Pharmacodynamic biomarker 
analysis will be performed as described in a 
separate analysis plan.
Note: Providing blood samples for 
pharmacodynamic biomarker assessment is 
optional and will not impact subject 
eligibility. 
Updated per health authority 
feedback and standard 
guidelines for pediatric blood 
draw volumes in order to 
ensure that the maximum is 
not exceeded, 
Text was also revised to clarify 
that blood samples for 
pharmacodynamic assessments 
are optional and do not impact 
study eligibility.
Synopsis, 
Pharmacodynamic and 
Other Biomarker 
Assessments
Table 5, v 
Section 9.5.1.3.2
Section 9.7.1.7.2
Appendix Table 11-1
Other Assessments: Every effort should be 
made to administer the PedsQL 
questionnaires as soon as possible after the 
decision to discontinue study treatment is 
made.
Clarification added per health 
authority feedback.
Section 9.5.1.5
Table 5, u
Table 6, o
Objectives and Endpoints updated to specify 
review based on independent and investigator 
assessment.
Clarified the evaluation of 
efficacy endpoints based on 
independent and investigator 
review.
Synopsis, Objectives
Section 8.2
Section 8.3
Section 9.7.1.1
Section 9.7.1.1.2
Section 9.7.1.1.3
Tumor assessments will then be performed 
every 6 weeks ±1 week following the date of 
randomizationstart of treatment on Cycle 1 
Day 1 during the chemotherapy treatment 
period until Week 18.
Clarified that tumor 
assessments will occur 
following the date of 
randomization.
Synopsis, Efficacy 
Assessments
Section 9.5.1.2.1
Table 5 
Appendix Table 11-1
Efficacy analyses: All primary statistical 
analyses will be conducted at the data 
cutoff date for the primary analysis (ie, 
when approximately 38 PFS events, as 
determined by IIR, are observed). 
Additional follow-up analysis will be
based on the date of data cutoff for the 
additional follow up analysis for OS or at the 
time of last subject last visit, whichever occurs 
later.All the statistical analysis will be 
conducted at the PFS-1y/OS-1y analysis data 
cutoff date (ie, when the last subject has 
completed 18 cycles of treatment or 
discontinues before the end of Cycle 18, 
whichever occurs first), including the analysis 
of PFS 4m rate.  Additional follow-up analysis 
will be based on the date of data cutoff for the 
additional follow up analysis for OS or at the 
Revised based on the change 
in primary objective and 
endpoint.
Synopsis, Randomization 
Phase, Efficacy Analysis
Section 9.1.2
Section 9.7.1.6
Page 9 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 9 of 147
time of last subject last visit, whichever occurs 
later. 
Primary analysis: Progression-free survival 
(PFS) will be analyzed and compared 
between the treatment arm and control 
arm using the stratified log-rank test with 
time to first relapse/refractory disease 
(early [<18 months] or late [≥18 months]) 
and age (<18 or ≥18 years) as strata.  PFS 
censoring rules will follow FDA guidance of 
2007 and will be detailed in the statistical 
analysis plan. Median PFS will be 
calculated using the K-M [Kaplan-Meier 
(1958)] product-limit estimates for each 
treatment arm along with 2-sided 95% CIs 
(estimated with a generalized Brookmeyer 
and Crowley method [Brookmeyer and 
Crowley (1982)].  The K-M estimates of 
PFS will be plotted over time. The Cox 
regression model will be used to estimate 
the hazard ratio and its 95% CIs stratified 
by the stratification factors.  The primary 
analysis of PFS-4m rate will be based upon 
data provided by IIR of tumor assessments.  
PFS-4m rate and their Greenwood standard 
errors will be evaluated using the K-M 
estimates from both treatment groups.  The 
statistical significance of the difference in the 
2 K M PFS-4m rates comparing lenvatinib + 
chemotherapy agent (Test Arm) vs. 
chemotherapy agent alone (Control Arm) will 
be tested using a 2-sided 80% CI.  This 2-
sided 80% CI and a p value will be 
constructed using the difference of these 2 K-
M PFS-4m rates and the 2 corresponding 
Greenwood standard errors.  Statistical 
significance of the difference is declared if the 
CI is entirely above 0.  This is equivalent to a 
test using a 1-sided test at alpha=0.1.  The 2-
sided 95% CIs will also be provided for 
descriptive purposes.  PFS-4m rate will also 
be analyzed using a binomial approach as a 
sensitivity analysis by excluding subjects 
whose PFS are censored prior to 18 weeks.
Revised based on the change 
in primary objective and
endpoint.
Synopsis, Primary 
Analysis
Section 9.7.1.6.1
Page 10 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 10 of 147
Secondary analyses: PFS-4m and PFS-1y rate 
will be analyzed using the same methods as 
the primary efficacy analysis.  PFS censoring 
rules will follow FDA guidance of 2007, 
however, removal of baseline lesions after 
completion of Week 18 without progression is 
not a trigger for PFS censoring after 18 weeks 
(refer to Concomitant Drug/Therapy –
allowed concomitant treatment/procedures).
The PFS-4m rate and PFS-1y rate will be 
estimated on the Full Analysis Set using the 
K-M method for the primary efficacy PFS 
analysis. PFS-4m/PFS-1y rate and their 
Greenwood standard errors will be 
evaluated using the K-M estimates from 
both treatment groups.  The statistical 
significance of the difference in the 2 K-M 
PFS-4m rates will base on its 2-sided 95% 
CI.  This 2-sided 95% CI and a p-value will 
be constructed using the difference of these 
2 K-M PFS-4m/PFS-1y rates and the 2 
corresponding Greenwood standard errors.
  
Overall survival (OS) will be compared 
between treatment arm and control arm
following the same statistical method for 
the primary efficacy PFS endpoint.using the 
stratified logrank test with time to first 
relapse/refractory disease (early [<18 months] 
or late [≥18 months]) and age (<18 or ≥18 
years) as strata.  Median OS with 2-sided 80% 
and 95% CIs will be calculated using K-M 
product-limit estimates for each treatment 
arm, and the K-M estimates of OS will be 
plotted over time.  The Cox regression model 
will be used to estimate the hazard ratio and 
its 80% and 95% CIs stratified by time to first 
relapse/refractory disease (early [<18 months] 
or late [≥18 months]) and age (<18 or ≥18 
years).  Kaplan-Meier (K-M) estimates will 
also be presented for 4, 6, 9, and 12 months 
with 2-sided 80% and 95% CIs.
Revised based on the change 
in secondary objectives and 
endpoints.
Synopsis, Secondary 
Analysis
Section 9.7.1.6.1
Page 11 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 11 of 147
Sample size rationale: A binomial-based 
comparison of 2 proportions using correction 
for continuity was used for sample size 
estimation.  A total sample size of 72 subjects 
is estimated to achieve 80% statistical power 
at 1 sided alpha of 0.1 to detect a difference of 
30% based on the assumption that PFS-4m for 
Arm A (lenvatinib arm) is 55% and for Arm B 
is 25%.  Alpha is the type 1 error probability 
of declaring lenvatinib arm being effective 
when the true lenvatinib arm PFS-4m rate is 
only 25%. A total sample size of 72 subjects 
is estimated for the primary efficacy 
endpoint of PFS. Assuming a hazard ratio 
of 0.4 (median PFS of 3.5 and 8.75 months 
for the control and investigational arms, 
respectively), a one-sided type 1 error rate 
of 0.025, and power of 80%, 38 PFS events 
are required for the primary analysis. 
Statistical assumptions 
updated based on revised 
primary endpoint.
Synopsis, Sample Size 
Rationale
Section 9.7.2
Discussion of Study Design: The endpoint 
was determined as appropriate for the study, 
given the unique biology of the osteosarcoma.
(bone lesions do not shrink) and the vital role 
of surgical resection of metastatic lesions, 
where possible, in the management of patients 
with this tumor.  Pulmonary metastases are 
most common in osteosarcoma, and the ability 
to achieve a second surgical remission has 
consistently been shown essential for long-
term survival following relapse (Kempf 
Bielack, et al., 2005; Leary, et al., 2013; 
Bacci, et al., 2005; Chou, et al., 2005; 
Hawkins and Arndt, 2003).  The protocol 
allows for surgical resection of baseline 
lesions after completion of the Week 18 tumor 
assessment.  This timepoint allows for 
surgical resection after completion of 
chemotherapy without confounding data due 
to subjects undergoing surgery. 
Justification has been revised 
to align with the updated 
primary endpoint.
Section 9.2
Blood Pressure: BP that is consistently above 
the 95th percentile based on sex, age, and 
height/length for subjects <18 years old; or 
BP ≥140/90 mmHg for subjects ≥18 to 25 
years old requires further evaluation... BP 
values for the management of hypertension 
for participants 18 to 25 years old are 
included in parentheses in Section 8.4.1.1.2.
Clarified that guidelines also 
specify BP values for subjects 
>18 years old.
Section 9.4.1.1.1
Table 5, h
Table 6, e
Table 7, e 
Figure 2
New section added: Management of Fistula 
Formation and Gastrointestinal 
Perforation
Added to align with current 
lenvatinib toxicity 
management guidelines
Section 9.4.1.1.10
Page 12 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 12 of 147
New section added:  Management 
Guidelines for QT Prolongation
Added to align with current 
lenvatinib QT prolongation 
management guidelines.
Section 9.4.1.1.11
The chemotherapy regimen schedule will 
consist of ifosfamide 3000 mg/m2/day IV 
infusion over at least 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).  
Clarified the minimum 
infusion time for 
chemotherapy administration.
Section 9.4.2.2
It is recommended that mesna 
uroprotection be administered at a dose 
equivalent to that administered for 
ifosfamide. 
Clarified the administration of 
mesna along with ifosfamide.
Section 9.4.2.2
The safety, tolerability and activity of 
single-agent lenvatinib, and lenvatinib in 
combination with chemotherapy 
(ifosfamide and etoposide), have been 
assessed in E7080-G000-207 (Study 207), a 
phase 1/2, multicenter, open-label study in 
children, adolescents and young adults with 
solid tumors, including relapsed or 
refractory osteosarcoma, and 
radioiodine- refractory differentiated 
thyroid carcinoma.  The recommended 
phase 2 dose (RP2D) of lenvatinib was 
determined in the phase 1b portion as 14 
mg/m2 orally once daily when given as 
single-agent as well as in combination with 
etoposide (100 mg/m2 IV once daily for 
3 days) + ifosfamide (3000 mg/m2 IV once 
daily for 3 days), administered on days 1 to 
3 of each 21-day cycle, for 5 cycles. The dose 
of lenvatinib is the same as the RP2D for 
lenvatinib monotherapy, also established in 
Study 207. BSA will be used to determine 
the dose of lenvatinib for each subject. 
After adjustment for BSA, the daily dose of 
lenvatinib cannot exceed 24 mg. Please see 
section 6.3.1 for further details on the 
results of Study 207. 
Additional details of Study 
207 have been provided to 
justify the dose selection in 
study 230.
Section 9.4.4
Added dental examinations to the study 
assessments
Added per health authority 
feedback in order to monitor 
tooth formation.
Section 9.5.1.1.2
Section 9.5.1.4
Section 9.5.1.4.7
Table 5, s 
Table 6, q 
Section 9.7.1.8
Section 9.7.1.8.6
Page 13 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 13 of 147
Clarification of tumor assessment 
requirements.
Revised to specify frequency 
and methodology for tumor 
assessments.
Synopsis, Efficacy 
Assessments
Section 9.5.1.2.1
CT scans: Screening CT scans should be 
performed with oral and iodinated intravenous 
contrast and MRI scans should be performed 
with intravenous gadolinium chelate.
Clarified that only iodinated 
IV contrast is required for CT 
scans, and not both oral and 
iodinated IV contrast.
Section 9.5.1.2.1
Table 5, q
Changed description of palatability 
questionnaire to 'facial hedonic scale' from a 
'visual analog scale.'
Revised to correct the 
description of the scale used in 
the palatability questionnaire.
Section 9.5.1.2.2
Section 9.7.1.9.2
Changed criteria for completing the 
palatability questionnaire: All subjects who 
receive suspension formulation with the 
exception of subjects using a nasogastric or 
gastrostomy tube, must complete the 
questionnaire according to the Schedule of 
Assessments on C1D1 (or the subsequent 
visit).
Clarified that the palatability 
questionnaire must be 
completed on C1D1 or the 
subsequent visit.
Section 9.5.1.2.2
Table 5, p
Table 7, m
For this study, the study drug is are 
lenvatinib, ifosfamide, and etoposide.
Clarified that there are 3 study 
drugs in study 230.
Section 9.5.1.4.1
An echocardiogram or MUGA scan to assess 
LVEF will be performed during the screening 
phase, every 16±2 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.  
Clarified the time window 
permitted for ECHO during 
study.
Section 9.5.1.4.7
Vital Signs Assessment
On Cycle 1 Day 8, subjects will have a 
telephone or clinic visit be contacted by 
telephone to assess for the development of 
early toxicity. Subjects will be provided with a 
BP cuff to monitor BP at home or can have 
the measurement done by a local healthcare 
provider, and will report the C1D8 
measurement at telephone contact.  An 
unscheduled visit can occur prior to C1D15 if 
deemed necessary by the investigator.
Clarified that C1D8 contact 
can be via telephone call or 
clinic visit.
Table 5, i 
Section 9.5.1.4.4
Archival Tumor Samples
An archival tumor sample from the most 
recent surgery or biopsy for identification of 
predictive biomarkers and pathology review 
may be collected from subjects in Arm A at 
any time during the study, unless no such 
material is available. Providing archival 
tumor samples is optional and does not 
impact subject eligibility.
Clarified that providing 
archival tumor samples is 
optional and does not impact 
eligibility.
Table 5, w
Page 14 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 14 of 147
Height will be assessed at the Baseline Visit, 
Day 1 of every 4 cycles during the Treatment 
Phase, at the Off-treatment Visit and every 3 
months during the Post-treatment Follow-up.
Assessment of height in Post-treatment 
Follow-up is not required once pubertal 
development is complete. Proximal tibial 
growth plate x-rays should be conducted 
for subjects aged <18 years at baseline and 
at the Off-treatment visit. 
Clarified the required age for 
proximal tibial growth plate x-
rays, and the requirement for 
height assessment in post-
treatment follow-up.
Table 5, s 
Table 6, m
Tanner Staging is only required for female 
subjects ≥8 years old, and male subjects ≥9 
years old. Tanner Stage will be assessed at 
the Baseline Visit, at the Off-treatment Visit, 
and annually thereafter during the Post-
treatment Follow-up. Tanner Staging is not 
required once pubertal development is 
complete (i.e. Tanner Stage 5).  
Clarified the required ages for 
Tanner Staging, and the 
requirement for Tanner 
Staging in post-treatment 
follow-up.
Table 5, t 
Table 6, n
Extension Phase: HRQoL will be collected at 
week 18 and the Off-Treatment visit.
Revised to include PROs 
during the Extension Phase.
Table 6, o
Exploratory analyses: The difference in the 
proportion of subjects who achieve 
complete removal of baseline lesion(s) and 
the proportion of subjects with 
unresectable baseline lesions(s) that are 
converted to resectable between the 2 
treatment arms and corresponding 2-sided 
95% CIs will be calculated.
Added text to detail 
exploratory analysis of the 
difference in lesions removal 
between the 2 study arms.
Synopsis, Exploratory 
Objectives
Section 8.3
Section 9.7.1.6.2
Extent of exposure: The number of 
cycles/days on treatment, quantity of study 
drug administered, dose intensity, and the 
number of subjects requiring dose reductions, 
treatment interruption, and treatment 
discontinuation due to adverse events will be 
summarized.
Revised to specify that dose 
intensity will be summarized.
Section 9.7.1.8.1
Other safety analyses: Tooth formation 
abnormalities will be listed and analyzed if 
appropriate.
Added in line with the 
inclusion of dental 
examination.
Section 9.7.1.8.6
Added a new sub-section describing the 
benefit-risk assessment for this study.
Added based on HA feedback.
Section 7.4.1
Removed Appendix 4: Preparation of 
Lenvatinib Suspension
The preparation instructions 
have been removed from the 
protocol appendix and are now 
included in the Pharmacy 
Manual.
Appendix 4
Section 9.4.1
Section 9.4.2
Appendix 54: Palatability Questionnaire
The free text field has been 
removed from the taste and 
appearance sections of the 
questionnaire, as 
subject/guardian response will 
Appendix 4
Page 15 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 15 of 147
be based on the selection of 
the faces.
Appendix 11 (new)
Included to reflect country-
specific changes incorporated 
into the study protocol for 
Sweden and Germany.
Appendix 11
France amendment (current FRA-2)
The changes noted in the 
country specific amendments 
for France, are included in this 
global amendment; therefore 
this global amendment will 
now be used as the protocol 
for France.
Appendix 11
Administrative changes
Minor editorial and formatting 
changes.
Throughout the protocol
Amendment 01
Date: 09 March 2020
Change
New text is in bold and deleted text is in 
strikethrough font.
Rationale
Affected Protocol 
Sections
Inclusion Criterion 7 is updated as follows:
7. Adequate bone marrow function as 
evidenced by:
a.
absolute neutrophil count (ANC) ≥1.0
1.5×109/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 of 
<8.0 g/dL is acceptable if it is corrected 
by growth factor or transfusion before
Cycle 1 Day 1).
c.
platelet count ≥75 100×109/L.
The minimum neutrophil and 
platelet counts required to 
establish eligibility have been 
revised for consistency with 
the etoposide Summary of 
Product Characteristics per 
health authority request.
Synopsis, Section 8.3.1
Exclusion Criterion 20 is added:
A contraindication to any of the study drugs 
(lenvatinib, ifosfamide, and etoposide) per 
local prescribing information.
An exclusion criterion due to 
contraindications to any of the 
study drugs has been added 
per health authority request.
Synopsis, Section 8.3.2
Prior and Concomitant Therapy
Per health authority request,
subjects who receive other
anticancer therapy, except as 
Synopsis, Section 8.4.7.2
Page 16 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 16 of 147
Subjects should not receive other antitumor 
therapies while on study.  If a subject receives 
additional antitumor therapies other than the 
study drug(s), such as chemotherapy, targeted 
therapies, immunotherapy, or antitumor 
interventions - such as surgery or palliative 
radiotherapy (other than as described below), 
this will be judged to represent evidence of 
disease progression, and continuation of 
thestudy medication should be discontinued
and further participation in the study must be 
discussed and agreed upon with the sponsor .
specified in the protocol,
should be discontinued from 
study treatment.
For major procedures: stop lenvatinib at least 
1 week (5 half-lives) prior to surgery and then 
restart it at least 1 week2 weeks after, once 
there is evidence of adequate healing and no 
risk of bleeding.
Revised to align with the 
updated lenvatinib label
Synopsis, 8.4.7.3
Vital Signs Assessment
On Cycle 1 Day 8, subjects will be 
contacted by telephone to assess for the 
development of early toxicity. Subjects will 
be provided with a BP cuff to monitor BP 
at home or can have the measurement done 
by a local healthcare provider, and will 
report the C1D8 measurement at telephone 
contact. An unscheduled visit can occur 
prior to C1D15 if deemed necessary by the 
investigator.
Per health authority request, a 
Cycle 1 Day 8 telephone 
contact has been added to 
monitor for early toxicity 
(including increase in blood 
pressure).
Section 8.5.2 (Schedule of 
Procedures/Assessments, 
Table 5 footnote j – new 
footnote, subsequent 
footnotes renumbered)
Pharmacodynamic Biomarkers
The Schedule of Procedures/Assessments 
(Table 5) has been updated as follows:
Blood samples will be collected only from 
subjects in Arm A at the Baseline Visit, 
C1D15 C1D8, Day 1 of Cycles 2, 4, and 6, 
for assessment of blood serum sample to 
measure factors implicated in angiogenesis.
To lessen patient burden, the 
protocol has been updated to 
move the optional 
pharmacodynamic blood 
sample collection from C1D8 
to C1D15. This eliminates the 
potential need for a study site 
visit for the sole purpose of 
collecting this optional 
pharmacodynamic blood 
sample on C1D8.
Section 8.5.2 (Schedule of 
Procedures/Assessments, 
Table 5, footnote v)
Administrative changes.
Minor editorial and formatting 
changes.
Throughout the protocol.
2
CLINICAL PROTOCOL SYNOPSIS
Compound No.  E7080
Name of Active Ingredient:  Lenvatinib
Study Protocol Title
Page 17 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 17 of 147
A Multicenter, Open-label, Randomized Phase 2 Study to Compare the Efficacy and Safety of 
Lenvatinib in Combination with Ifosfamide and Etoposide versus Ifosfamide and Etoposide in 
Children, Adolescents and Young Adults with Relapsed or Refractory Osteosarcoma (OLIE)
Investigator
Principal Investigator:  Dr Nathalie Gaspar
Sites
Approximately 80 sites worldwide 
Study Period and Phase of Development
Approximately 36 months
Phase 2
Objectives
Primary Objective
To evaluate whether lenvatinib in combination with ifosfamide and etoposide (Arm A) is superior 
to ifosfamide and etoposide (Arm B) in improving progression-free survival (PFS) by independent 
imaging review (IIR) using Response Evaluation Criteria In Solid Tumors (RECIST 1.1), in 
children, adolescents, and young adults with relapsed or refractory osteosarcoma.
Secondary Objectives
The secondary objectives of the study are to:
1.
Compare difference in PFS rate at 4 months (PFS-4m) between the 2 treatment arms per IIR
2.
Compare difference in PFS rate at 1 year (PFS-1y) between the 2 treatment arms per IIR
3.
Compare difference in overall survival (OS) and OS rate at 1 year (OS-1y) between the 
2 treatment arms
4.
Compare difference in objective response rate  at 4 months (ORR-4m) between the 2 treatment 
arms per IIR
5.
Compare difference in objective response rate (ORR) between the 2 treatment arms per IIR
6.
Compare difference in safety and tolerability between the 2 treatment arms
7.
Characterize the pharmacokinetics (PK) of lenvatinib, when administered in combination with 
ifosfamide and etoposide 
8.
Compare difference in health-related quality of life (HRQoL) as assessed by using the Pediatric 
Quality of Life Inventory (PedsQL) Generic Core Scales and Cancer Module between the 2 
treatment arms
9.
Assess the palatability and acceptability of the suspension formulation of lenvatinib in subjects
receiving the suspension formulation in the study
Exploratory Objectives
The exploratory objectives of the study are to: 
1.
Explore difference in duration of response (DOR), disease control rate (DCR), and clinical 
benefit rate (CBR) between the 2 treatment arms per IIR and investigator assessment
2.
Explore difference in PFS, PFS-4m, PFS-1y, ORR-4m, and ORR between the 2 treatment arms 
per investigator assessment
3.
Compare between the 2 treatment arms:
-
the proportion of subjects who achieve complete removal of baseline lesion(s)
-
the proportion of subjects with unresectable baseline lesion(s) that are converted to 
resectable
Page 18 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 18 of 147
4.
Investigate the relationship between tumor biomarkers and clinical response and toxicity of 
lenvatinib in combination with ifosfamide and etoposide
Study Design
E7080-G000-230 is a multicenter, randomized, open-label, parallel-group, Phase 2 study to 
compare the efficacy and safety of lenvatinib in combination with ifosfamide and etoposide versus 
ifosfamide and etoposide in children, adolescents, and young adults with relapsed or refractory 
osteosarcoma.  
Approximately 72 eligible subjects will be randomized to 1 of the following 2 treatment arms in a 
1:1 ratio within the strata:

Arm A:  lenvatinib 14 mg/m2 (orally, once daily) plus ifosfamide 3000 mg/m2/day 
(intravenously [IV], Day 1 to Day 3 of each cycle for a total of up to 5 cycles) and etoposide 
100 mg/m2/day (IV, Day 1 to Day 3 of each cycle for a total of up to 5 cycles)

Arm B:  ifosfamide 3000 mg/m2/day (IV, Day 1 to Day 3 of each cycle for a total of up to 
5 cycles) and etoposide 100 mg/m2/day (IV, Day 1 to Day 3 of each cycle for a total of up to 5 
cycles)
Randomization will follow a predefined randomization scheme based on the following 
stratification factors: time to first relapse/refractory disease (early [<18 months] or late [≥18 
months]) and age (<18 and ≥18 years).  
The Sponsor will closely monitor enrollment, to ensure that a minimum of 36 subjects are <17
years of age at the time of informed consent.  
The study will be conducted in 3 Phases: a Prerandomization Phase, a Randomization Phase, and 
an Extension Phase.  
The Prerandomization Phase will consist of 2 periods: Screening and Baseline. The 
Prerandomization Phase will last no longer than 28 days.  The Screening Period will establish 
protocol eligibility and the Baseline Period will confirm eligibility. 
The Randomization Phase will consist of 2 periods: Treatment Period and Follow-up Period.  The 
Randomization Phase will begin at the time of randomization of the first subject and will end on 
the data cutoff date for the primary analysis (ie, when approximately 38 PFS events, as determined 
by  IIR, are observed).  After the data cutoff date for the primary analysis has occurred, all subjects 
who are still on study treatment will enter the Extension Phase.
The Treatment Period for each subject will begin at the time of randomization and will end at the 
completion of the Off-Treatment Visit, which will occur within 30 days after the final dose of 
study treatment.  
Subjects will receive study treatment as continuous 21-day cycles in both treatment arms.
Treatment cycles will be counted continuously regardless of dose interruptions. If chemotherapy 
administration is precluded on Day 1 of a treatment cycle, the subject may resume treatment once 
recovered at the discretion of investigator. Subsequent chemotherapy will be administered every 21 
(±1) days starting from the timepoint it was resumed.
Subjects will undergo safety and efficacy assessments as defined in the Schedule of 
Procedures/Assessments.  Subjects randomized to Arm A will continue to receive lenvatinib until 
disease progression (PD) confirmed by IIR, development of unacceptable toxicity, subject request, 
withdrawal of consent, or study termination by the sponsor, whichever occurs first. 
Disease progression (PD) must be confirmed by IIR prior to the investigator discontinuing study 
treatment for a subject.  In situations where the investigator judges that alternative treatments must 
be instituted immediately for a subject’s safety, study drugs may be discontinued without waiting 
Page 19 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 19 of 147
for IIR confirmation of radiographic evidence of PD.  If possible, before discontinuation of the 
subject from the study, the investigator should consult with the sponsor.
The Follow-up Period begins the day after the Off-Treatment Visit and will continue for up to 2 
years after end of treatment for a subject, unless the subject withdraws consent, or is lost to follow 
up, or the sponsor terminates the study.  
Subjects may at any time withdraw consent for further study participation.  No further data will be 
collected on subjects once consent has been withdrawn, however, an investigator may consult 
public records to establish survival status if permitted by local regulations.
All adverse events (AEs), including serious adverse events (SAEs), will be captured for 30 days 
after the last dose of study drug.  
All subjects who end study treatment  without IIR confirmed PD, will continue to undergo tumor 
assessments every 6 weeks until Week 18, then every 9 weeks until Week 54, thereafter, every 12 
weeks until confirmation of disease progression by IIR as described in the tumor assessments in the 
assessment schedule, or until another anticancer therapy is initiated.
Subjects in both Arm A and Arm B will be followed for survival every 12 weeks (±1 week) and all 
subsequent anticancer treatments received will be recorded.  Subjects who are being followed for 
survival at the time of data cutoff for the primary analysis (ie, at the end of the Randomization 
Phase) will continue to be followed for survival during the Follow-up Period of the Extension 
Phase.
Extension Phase:  The Extension Phase will consist of 2 periods: Treatment Period and Follow-
up Period.  
In the Treatment Period, subjects still on study treatment following the completion of the 
Randomization Phase will continue study treatment as outlined in Section 9.4.1 until disease 
progression, development of unacceptable toxicity, subject request, withdrawal of consent, or 
discontinuation of study by the sponsor.  Tumor assessments will be performed according to the 
local standard of care.  Independent imaging review (IIR) review and confirmation of radiographic 
evidence of PD will not be required, and scans will no longer be required to be sent to the imaging 
core laboratory (ICL).  The Off-Treatment Visit will occur within 30 days after the final dose of 
study treatment. All AEs, including SAEs will be captured up to 30 days after last dose of study 
drug.  In case the study is discontinued by the sponsor, the sponsor will provide study drug (outside 
the study) for subjects who have not met the criteria for study drug discontinuation. 
The Follow-up Period will begin the day after the Off-Treatment Visit and will last for up to 2 
years after end of treatment for a subject, unless the study is terminated by the sponsor, or the 
subject discontinues due to withdrawal of consent, or is lost to follow-up.  Subjects will be treated 
by the investigator according to the prevailing local standard of care.  Subjects will be followed 
every 12 weeks (±1week) for survival and all subsequent anticancer treatments received will be 
recorded.   
The definition of end of the study, as required by certain regulatory agencies, will be the date of 
data cutoff for the final analysis or the time of last subject last visit, whichever occurs later.
Optional Lenvatinib Crossover (for Subjects in Arm B Only):
Subjects in Arm B with disease progression per RECIST 1.1 may be eligible for optional 
treatment with lenvatinib±chemotherapy. Note: subjects may only receive a maximum of 5 
cycles of chemotherapy for the duration of the study. Optional crossover treatment must be 
initiated within 30 days of documented disease progression.
Optional lenvatinib crossover is only available if the following conditions are met:
Page 20 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 20 of 147
-
Subject experiences disease progression per RECIST 1.1 (as confirmed by IIR for 
all subjects who crossover prior to the start of the Extension Phase); and
-
No new systemic anti-cancer medication was administered after the last dose of study 
drugs; and
-
The subject meets all of the safety parameters listed in the inclusion criteria and none 
of the safety parameters listed in the exclusion criteria; and
-
The study is ongoing.
Treatment with lenvatinib±chemotherapy will continue until the next disease progression 
(per RECIST 1.1 as assessed by investigator), development of unacceptable toxicity, subject 
request, or withdrawal of consent, whichever occurs first. If the sponsor terminates the study, 
the sponsor will continue to provide study drug(s) (outside of the study) for subjects 
requiring continuation of treatment. 
Prior to optional lenvatinib crossover, baseline tumor assessment must be re-established
(i.e., new tumor assessment scans performed), unless the last tumor assessment scans were 
performed within 4 weeks prior to Cycle 1 Day 1 of the crossover treatment.
Subjects who qualify to receive Optional Lenvatinib Crossover Treatment will be followed 
according to the schedule of procedures/assessments in Table 7.
Number of Subjects
Approximately 72 subjects will be randomized (36 subjects in each arm).
For the primary endpoint (intent–to-treat analysis), a minimum of 36 patients <17 years old (at the 
time of informed consent) will be randomized.
Inclusion Criteria
1.
Histologically or cytologically confirmed diagnosis of high grade osteosarcoma.
2.
Refractory or relapsed osteosarcoma after 1 to 2 prior lines of systemic treatments.
3.
Measurable or evaluable disease per RECIST 1.1 that meets the following criteria:
-
Measurable disease is defined as a lesion with a minimum size (by long axis) of 10 mm
using computed tomography/magnetic resonance imaging (CT/MRI) (lymph nodes must 
be accurately measurable with a minimum size [by short axis] of 15 mm).
-
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. 
-
Any other non-measurable lesions will be considered evaluable disease.
4.
Aged 2 years to ≤25 years at the time of informed consent.
5.
Life expectancy of 12 weeks or more.
6.
Lansky play score ≥50% or Karnofsky Performance Status score ≥50%.  Use Karnofsky for 
subjects ≥16 years of age and Lansky for subjects <16 years of age.  Subjects who are unable 
to walk because of paralysis, but who are able to perform ADL while wheelchair bound, will 
be considered ambulatory for the purpose of assessing the performance score.
7.
Adequate bone marrow function as evidenced by:
a.
absolute neutrophil count (ANC) ≥1.5×109/L.
(subjects with bone marrow involvement should have ANC ≥0.8×109/L and leucocyte 
count ≥1×109/L).
Page 21 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 21 of 147
b.
hemoglobin ≥8.0 g/dL (a hemoglobin of <8.0 g/dL is acceptable if it is corrected by growth 
factor or transfusion before Cycle 1 Day 1).
c.
platelet count ≥100×109/L. 
8.
Adequate blood coagulation function defined by International Normalized ratio or prothrombin 
time (INR/PT) and activated partial thromboplastin time or partial thromboplastin time
(aPTT/PTT) ≤1.5 unless participant is receiving anticoagulant therapy, as long as INR/PT and 
aPTT/PTT are within therapeutic range of intended use of anticoagulants.
9.
Adequate liver function as evidenced by:
a.
Bilirubin ≤1.5 times the upper limit of normal (ULN).
b.
Alanine aminotransferase (ALT), and aspartate aminotransferase (AST) ≤3×ULN (in the 
case of liver metastases ≤5×ULN).
10. 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.
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 Common Terminology Criteria for Adverse Events (CTCAE) v5.0 and if possible 
perform a 24-hour urine collection (children and adolescents ≤12 years of age must have 
≤500 mg of protein/24 hours and subjects >12 years of age must have ≤1 g of protein/24 
hours).
c.
No clinical evidence of nephrotic syndrome. 
11. Adequate cardiac function as evidenced by left ventricular ejection fraction ≥50% at baseline 
as determined by echocardiography or multigated acquisition (MUGA) scan.
12. 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 guidelines) and no change in antihypertensive medications within 
1 week prior to Cycle 1 Day 1. Subjects >18 years of age should have BP ≤150/90 mm Hg 
at screening and no change in antihypertensive therapy within 1 week prior to Cycle 1 Day 
1.
13. Washout before Cycle 1 Day 1 of 3 weeks in case of prior chemotherapy, 6 weeks if treatment 
included nitrosoureas; 4 weeks for definitive radiotherapy, 2 weeks for palliative radiotherapy; 
Page 22 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 22 of 147
and 3 months from high-dose chemotherapy and stem cell rescue.  For all other anti-cancer 
therapies, washout before Cycle 1 Day 1 of at least 5 half-lives (or at least 28 days, whichever 
is shorter). Subjects must have recovered (to Grade ≤1, except for alopecia, ototoxicity, and 
Grade ≤2 peripheral neuropathy, per CTCAE v5.0) from the acute toxic effects of all prior 
anticancer therapy before Cycle 1 Day 1.
14. Must have no prior history of lenvatinib treatment.
15. 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.
16. Willing and able to comply with the protocol, scheduled follow-up, and management of 
toxicity as judged by the investigator.
Exclusion Criteria
1.
Any active infection or infectious illness unless fully recovered  prior to Cycle 1 Day 1 (ie, no 
longer requiring systemic treatment).
2.
Subjects with central nervous system metastases are not eligible, unless they have completed 
local therapy (eg, whole brain radiation therapy, surgery, or radiosurgery) and have 
discontinued the use of corticosteroids for this indication for at least 2 weeks before Cycle 1
Day 1.  
3.
Active second malignancy within 2 years prior to enrollment ([in addition to osteosarcoma], 
but not including definitively treated superficial melanoma, carcinoma-in-situ, basal or 
squamous cell carcinoma of the skin).
4.
Any medical or other condition that in the opinion of the investigator(s) would preclude the 
subject’s participation in a clinical study.  
5.
Has had major surgery within 3 weeks prior to Cycle 1 Day 1.
Note: Adequate wound healing after major surgery must be assessed clinically, independent of 
time elapsed for eligibility.
6.
Known hypersensitivity to any component(s) of the study drugs (lenvatinib, ifosfamide, and 
etoposide, or their ingredients).
7.
Currently receiving any investigational drug or device in another clinical study or within 
28 days prior to Cycle 1 Day 1.
8.
A clinically significant ECG abnormality, including a marked baseline prolonged QT or QTc 
interval (eg, a repeated demonstration of a QTc interval >480 msec).
9.
Has clinically significant cardiovascular disease within 6 months from first dose of study  
intervention, including New York Heart Association Class III or IV congestive heart failure, 
unstable angina, myocardial infarction, cerebral vascular accident, or cardiac arrhythmia 
associated with hemodynamic instability. Note: Medically controlled arrhythmia would be 
permitted.
10. Gastrointestinal malabsorption, gastrointestinal anastomosis, or any other condition that in the 
opinion of the investigator might affect the absorption of lenvatinib.
11. Pre-existing Grade ≥3 gastrointestinal or non-gastrointestinal fistula.
12. Gastrointestinal bleeding or active hemoptysis (bright red blood of at least ½ teaspoon) within 
3 weeks prior to Cycle 1 Day 1.
13. Radiographic evidence of intratumoral cavitation, encasement, or invasion of a major blood 
vessel. Additionally, the degree of proximity to major blood vessels should be considered for 
exclusion because of the potential risk of severe hemorrhage associated with tumor 
shrinkage/necrosis after lenvatinib therapy.
Page 23 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 23 of 147
14. History of ifosfamide-related Grade ≥3 nephrotoxicity or encephalopathy.
15. Evidence of clinically significant disease (eg, cardiac, respiratory, gastrointestinal, renal 
disease) that in the opinion of the investigator(s) could affect the subject’s safety or interfere 
with the study assessments.
16. Known to be human immunodeficiency virus (HIV) positive.  Note:  HIV testing is required at 
screening only when mandated by local health authority.
17. Known active Hepatitis B (eg, HBsAg reactive) or Hepatitis C (eg, HCV RNA [qualitative] is 
detected).  Note:  Testing for Hepatitis B or Hepatitis C is required at screening only when 
mandated by local health authority.
18. 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.
19. Females of childbearing potential* who:
-
Do not agree to use a highly effective method of contraception for the entire study period 
and for 28 days after lenvatinib discontinuation or 12 months after etoposide and 
ifosfamide discontinuation, ie:
◦
total abstinence (if it is their preferred and usual lifestyle)
◦
an intrauterine device (IUD) or intrauterine hormone-releasing system (IUS)
◦
a contraceptive implant
◦
an oral contraceptive  **(with additional barrier method)
OR
-
Do not have a vasectomized partner with confirmed azoospermia.
For sites outside of the EU, it is permissible that if a highly effective method of contraception 
is not appropriate or acceptable to the subject, then the subject must agree to use a medically 
acceptable method of contraception, ie, double-barrier methods of contraception such as 
condom plus diaphragm or cervical/vault cap with spermicide. 
* All post pubertal females will be considered to be of childbearing potential unless they have 
early menopause (amenorrheic for at least 12 consecutive months, in the appropriate age group, 
and without other known or suspected cause) or have been sterilized surgically (ie, bilateral 
tubal ligation, total hysterectomy, or bilateral oophorectomy, all with surgery at least 1 month 
before dosing), or are pre-menarcheal (Tanner Stage 1-3).
**Must be on stable dose of the same oral hormonal contraceptive product for at least 4 weeks 
before dosing with study drug(s) and for the duration of the study.
20. Males who have not had a successful vasectomy (confirmed azoospermia) or if they and their 
female partners do not meet the criteria above (ie, not of childbearing potential or practicing 
highly effective contraception throughout the study period and for 28 days after lenvatinib 
discontinuation or 6 months after discontinuation of etoposide and ifosfamide).  No sperm 
donation is allowed during the study period and for 28 days after lenvatinib discontinuation or 
6 months after discontinuation of etoposide and ifosfamide.
21. A contraindication to any of the study drugs (lenvatinib, ifosfamide, and etoposide) per local 
prescribing information.
Study Treatments
Page 24 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 24 of 147
Body surface area (BSA) will be used to determine the amount of study drugs administered, and 
must be calculated on Day 1 of each cycle based on the subject’s current height and body weight.  
The dose should be rounded to the nearest whole number.  
Test Arm (Arm A):  Lenvatinib + Ifosfamide + Etoposide
Lenvatinib 14 mg/m2, orally administered once daily in each 21-day cycle.
Lenvatinib is provided as hard capsules containing 1 mg, 4 mg, or 10 mg lenvatinib.  An 
extemporaneous suspension of lenvatinib capsules should be used for subjects unable to swallow 
capsules. After adjustment for BSA, the daily dose cannot exceed 24 mg QD.
Ifosfamide 3000 mg/m2/day, IV, for 3 consecutive days (Day 1 to 3), every 21 days, for a 
maximum of 5 cycles.
Etoposide 100 mg/m2/day, IV, for 3 consecutive days (Day 1 to 3) , every 21 days, for a maximum 
of 5 cycles. 
Treatment with lenvatinib will continue in 21-day cycles after chemotherapy is discontinued, until 
disease progression, development of unacceptable toxicity, subject request, withdrawal of consent, 
or discontinuation of study by the sponsor.
In case the study is discontinued by the sponsor, the sponsor will provide study drug (outside the 
study) for subjects who have not met the criteria for study drug discontinuation.
Control Arm (Arm B):  Ifosfamide + Etoposide
Ifosfamide 3000 mg/m2/day, IV, daily for 3 consecutive days (Day 1 to 3), every 21 days, for a 
maximum of 5 cycles.
Etoposide 100 mg/m2/day, IV, daily for 3 consecutive days (Day 1 to 3), every 21 days, for a 
maximum of 5 cycles.
Optional Lenvatinib Crossover (for Subjects in Arm B Only):
Subjects in Arm B with disease progression per RECIST 1.1 may be eligible for optional treatment 
with lenvatinib±chemotherapy. Please see Section 9.1.4 for further details.
Duration of Treatment
A subject will remain on study treatment until 1 or more of the following events occur(s):

Progressive disease (as confirmed by IIR*)

Unacceptable toxicity

Subject request

Withdrawal of consent 

Termination of the study by the Sponsor
*Confirmation of disease progression by IIR is only required during the Randomization Phase.
Concomitant Drug/Therapy
Prohibited Concomitant Therapies and Drugs
Subjects should not receive other antitumor therapies while on study. If a subject receives 
additional antitumor therapies other than the study drug(s), such as chemotherapy, targeted 
therapies, immunotherapy, or antitumor interventions - such as surgery or palliative radiotherapy 
(other than as described below), this will be judged to represent evidence of disease progression, 
and the study medication should be discontinued.
Bisphosphonates and denosumab for the treatment of osteosarcoma are not permitted.
The concomitant use of live vaccines (e.g., measles, mumps, rubella, chicken pox, yellow fever, 
rabies, BCG, and typhoid [oral] vaccines) are not permitted. Seasonal influenza vaccines for 
Page 25 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 25 of 147
injection are generally killed virus vaccines and therefore, are permitted. However intranasal 
influenza vaccines (e.g., FluMist®) are live attenuated vaccines, and therefore, are not permitted. 
Additionally, the concomitant use of live vaccines with chemotherapy is contraindicated in 
immunosuppressed patients.
For further information on the prohibited concomitant therapies for ifosfamide and etoposide, 
please refer to the respective prescribing information.
The following concomitant treatments/procedures are allowed:
a.
Removal of existing (not new) osteosarcoma lesion (eg, surgical, radiofrequency ablation, 
cryotherapy, thermoablation, stereotactic radiotherapy, etc.) after completion of the Week 18 
tumor assessment.  Subjects may continue study treatment after protocol permissible surgery, 
in the presence of clinical benefit, with Sponsor approval.
b.
Palliative radiotherapy is allowed for ≤2 significantly symptomatic nontarget lesions. 
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 2 weeks after, once there is evidence of adequate healing and no risk of 
bleeding.
Any additional procedural or subject specific particularities should be discussed with the sponsor.  
Assessments
Efficacy Assessments
Tumor assessment will be performed based on RECIST 1.1.  Investigator–determined response 
assessments will be performed at each assessment time point and entered onto the case report form 
(CRF).  Copies of all tumor assessment scans will be sent to an imaging core laboratory (ICL)
designated by the sponsor for efficacy assessment and for confirmation of PD.  Tumor assessments 
will be carried out following the guidelines provided by the ICL.  
During the Screening Period, 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 Cycle 1
Day 1.  A brain scan (CT scan with contrast or MRI pre- and post-gadolinium) will be performed at 
screening as clinically indicated, and thereafter during the study as clinically indicated.  Historical 
CT or MRI scans performed within 28 days prior to Cycle 1 Day 1 may be used as screening scans 
(baseline scans) to demonstrate eligibility, as long as they meet minimum standards as separately 
defined by the ICL.  
If available, bone imaging obtained within 8 weeks prior to Cycle 1 Day 1 should be sent to the 
ICL.  Bone lesions noted on the screening/baseline images should be followed as non-target lesions 
with modalities other than nuclear medicine scans.
Tumor assessments will then be performed every 6 weeks ±1 week following the date of 
randomization until Week 18.  Following completion of the chemotherapy treatment period (ie,
after Week 18), the frequency of tumor assessments will be every 9 weeks ±1 week until Week 54
±1 week.  Thereafter, they will be performed every 12 weeks ±2 weeks until documentation of PD
(please see schedule of assessments for details).  At any point, the CT/MRI scan should be 
performed earlier than the scheduled time point, if clinically indicated.  After data cutoff for the 
primary analysis, tumor assessments should be performed following the prevailing local standard 
of care.
Page 26 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 26 of 147
Disease progression per RECIST 1.1 during the randomization phase must be confirmed by IIR 
prior to the investigator discontinuing study treatment.
In the event that the investigator considers alternative treatments must be instituted immediately for 
management of urgent medical complications of PD, study drugs may be discontinued without 
waiting for independent confirmation of radiographic evidence of PD.  Subjects who discontinue 
study treatment without PD will continue to undergo tumor assessments according to the schedule 
until PD is documented or another anticancer therapy is initiated.
Prior to optional lenvatinib crossover, baseline tumor assessment must be re-established (i.e., new 
tumor assessment scans performed), unless the last tumor assessment scans were performed within 
4 weeks prior to Cycle 1 Day 1 of the crossover treatment.
During the Optional Lenvatinib Crossover Treatment Phase, tumor assessments will be performed 
as clinically indicated per the institutional guidelines (but no less frequently than every 12 weeks), 
following the prevailing local standard of care. Scans are not required to be submitted to the 
independent imaging core laboratory during the Optional Lenvatinib Crossover Treatment Phase. 
Pharmacokinetic Assessments
Blood samples for plasma concentrations of lenvatinib will be collected from all subjects from 
Arm A only as described in the Schedule of Assessments. Pharmacokinetic sampling should not be 
performed for any subject with a body weight <13 kg (please see Section 9.5.1.3.1).
Pharmacodynamic and Other Biomarker Assessments
Optional pharmacodynamic serum and archived fixed tumor tissue samples for biomarker analysis 
may be collected from subjects randomized to Arm A only, as described in the Schedule of 
Assessments. Pharmacodynamic sampling should not be performed for any subject with a body 
weight <16 kg (please see Section9.5.1.3.2 ). Pharmacodynamic serum and tumor biomarkers 
assessed in this study will be based on those identified in other lenvatinib clinical studies.  
Pharmacodynamic biomarker analysis will be performed as described in a separate analysis plan.
Note: Providing blood samples for pharmacodynamic biomarker assessment is optional and will 
not impact subject eligibility.
Safety Assessments
Safety assessments will consist of monitoring and recording all adverse events (AEs), including all 
grades per National Cancer Institute (NCI) CTCAE v5.0 (for both increasing and decreasing 
severity), and serious adverse events (SAEs); regular laboratory evaluation for hematology, blood 
chemistry, and urine values; periodic measurement of vital signs and ECGs; and physical 
examinations.
Progression of osteosarcoma and signs and symptoms clearly related to the progression of the 
osteosarcoma should not be captured as an AE.  Disease progression is a study endpoint and should 
be captured in the CRF as per the guidelines for reporting disease progression.
Other Assessments
HRQoL assessment will be performed per the Schedule of Assessments.  Impact of treatment on 
HRQoL will be assessed using the PedsQL (including the Generic Core Scales and Cancer 
Module). 
Bioanalytical Methods
Lenvatinib in plasma will be quantified using a validated liquid chromatography tandem mass 
spectrometry (LC-MS/MS) method.  Pharmacodynamic biomarker analysis will be performed as 
described in a separate analysis plan.  Clinical laboratory tests will be performed at qualified local 
laboratories.
Page 27 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 27 of 147
Statistical Methods
Study Endpoints
Efficacy endpoints related to tumor assessments will be evaluated by independent imaging review 
(IIR) and investigator assessment.
Primary Endpoint
PFS (progression-free survival) by IIR is defined as the time from the date of randomization to 
the date of the first documentation of PD or death (whichever occurs first) as determined by 
IIR using RECIST 1.1.
Secondary Endpoints

PFS-4m rate (progression-free survival rate at 4 months) by IIR is defined as the 
percentage of subjects who are alive and without PD at 4 months from the randomization date 
as determined by IIR of radiological imaging using RECIST 1.1.  The PFS-4m rate is estimated 
using the Kaplan-Meier (K-M) method.

PFS-1y rate (progression-free survival rate at 1 year) by IIR is defined as the percentage of 
subjects who are alive and without PD at 1 year from the randomization date as determined by 
IIR of radiological imaging using RECIST 1.1.  The PFS-1y rate is estimated using the K-M 
method. 

Overall survival (OS) is defined as the time from the date of randomization to 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 for the primary analysis, will be censored at the date the subject was last known to 
be alive, or date of data cutoff for the primary analysis, whichever occurs first. Overall survival 
rate at 1 year (OS-1y) will be estimated using the K-M method.

Objective response rate by IIR at 4 months (ORR-4m) is defined as the proportion of 
subjects who have best overall response of complete response (CR) or partial response (PR) as 
determined by IIR using RECIST 1.1 within the first 4 months.

Objective response rate (ORR) by IIR is defined as the proportion of subjects who have best 
overall response of complete response (CR) or partial response (PR) as determined by IIR 
using RECIST 1.1.

Safety will be assessed summarizing the incidence of treatment-emergent adverse events 
(TEAEs) and SAEs together with all other safety parameters.  

Assessment of population-based PK parameters of lenvatinib.

Score changes from baseline for all PedsQL scales including Generic Core Scales and Cancer 
Module.  Scores will be calculated for total generic score, total cancer score, each physical 
function subscale including physical health, psychosocial health, emotional function, social 
function, school/work function in the Generic Core Scales, and each subscales in the cancer 
module.  

Palatability and acceptability of the suspension formulation of lenvatinib in subjects receiving 
the suspension formulation in the study will be assessed using the Palatability Questionnaire 
(see Appendix 4).
Exploratory Endpoints

Duration of response (DOR) by IIR and investigator assessment is defined as the time from 
the date a response was first documented until the date of the first documentation of PD or date 
of death from any case.

Disease control rate (DCR) by IIR and investigator assessment is the proportion of subjects 
who have a best overall response of CR or PR or stable disease (SD).  In this context, stable 
Page 28 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 28 of 147
disease is defined as stable disease at ≥7 weeks after randomization to be considered best 
overall response.

Clinical benefit rate (CBR) by IIR and investigator assessment is the proportion of subjects 
who have best overall response of CR or PR or durable SD (duration of SD ≥23 weeks after 
randomization).

Efficacy endpoints (PFS, PFS-4m, PFS-1y, ORR-4m, and ORR) evaluated based on 
investigator assessment

Proportion of subjects who achieve complete removal of baseline lesions.

Blood and tumor biomarkers will be assessed for identifying potential correlation with 
clinical outcomes-related endpoints.
Analysis Sets
The Full Analysis Set (Intent-to-Treat Analysis [ITT]) includes all randomized subjects 
regardless of the treatment actually received.  This is the primary analysis population used for the 
efficacy analyses which will be based on the ITT principle.
The Per Protocol Analysis Set includes those subjects from the ITT set who received at least 1 
dose of any study drug, had no major protocol deviations and had both baseline and at least one 
postbaseline tumor assessment.  Subjects for whom death occurred prior to the first postbaseline 
tumor assessment will also be included.  The per protocol analysis set will be the secondary 
analysis set for efficacy endpoints.
The Safety Analysis Set includes subjects who received at least 1 dose of any study drug.  This is 
the analysis population used for all safety analyses which will be based on as-treated principle.
Population Pharmacokinetic (PK) Analysis Set includes the subjects who have received at least 
1 dose of lenvatinib with documented dosing history and have measurable plasma levels of
lenvatinib.
The Pharmacodynamic Analysis Set includes subjects who received at least 1 dose of study drug 
and had sufficient pharmacodynamic data (eg, at least 1 evaluable/measurable pharmacodynamic
parameter).
The HRQoL Analysis Set will consist of all randomized subjects who have received at least 1 
dose of study medication, and have at least 1 patient-reported outcome (PRO) assessment 
completed beyond baseline.  For PRO analysis, subjects will be analyzed as randomized and not 
according to treatment actually received.
Efficacy Analyses
Efficacy analyses will be based primarily on the Full Analysis Set.
All primary statistical analyses will be conducted at the data cutoff date for the primary analysis 
(ie, when approximately 38 PFS events, as determined by IIR, are observed).
Primary Analysis
Progression-free survival (PFS) will be analyzed and compared between the 2 treatment arms using 
the stratified log-rank test with time to first relapse/refractory disease (early [<18 months] or late 
[≥18 months]) and age (<18 or ≥18 years) as strata.  PFS censoring rules will follow FDA guidance 
of 2007 and will be detailed in the statistical analysis plan. Median PFS will be calculated using the 
Kaplan-Meier (K-M) product-limit estimates for each treatment arm along with 2-sided 95% 
confidence  intervals (CIs) .  The K-M estimates of PFS will be plotted over time. The Cox 
regression model will be used to estimate the hazard ratio and its 95% CIs stratified by the 
stratification factors.  
Page 29 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 29 of 147
Secondary Analyses
The PFS-4m rate and PFS-1y rate will be estimated on the Full Analysis Set using the K-M method 
for the primary efficacy PFS analysis. PFS-4m/PFS-1y rate and their Greenwood standard errors 
will be evaluated using the K-M estimates from both treatment groups.  The statistical significance 
of the difference in the 2 K-M PFS-4m rates will be based on its 2-sided 95% CI.  This 2-sided 
95% CI and a p-value will be constructed using the difference of these 2 K-M PFS-4m/PFS-1y 
rates and the 2 corresponding Greenwood standard errors.    
Overall survival (OS) will be compared between treatment arm and control arm following the same 
statistical method for the primary efficacy PFS endpoint. Kaplan-Meier (K-M) estimates of OS rate 
will also be presented for 4, 6, 9, and 12 months with 2-sided 95% CIs.
The ORR will be summarized and compared between the two treatment arms using stratified 
Miettinen and Nurminen’s method. The difference in ORR and its 2-sided 95% confidence interval 
from the stratified Miettinen and Nurminen’s method with strata weighting by sample size will be 
reported. The stratification factors used for randomization will be applied to the analysis. The 
ORR-4m will be summarized and compared between arms using the same approach as for ORR.
Exploratory Analyses
Median DOR among responders for each arm will be presented along with its corresponding 2-
sided 95% CIs.  Disease Control Rate (DCR) and CBR will be summarized and compared between 
arms using the same approach as for ORR. 
Pharmacodynamic and Other Biomarker Analyses
Pharmacodynamic, and other biomarker analyses may be performed and reported separately.  
Details of these analyses may be described in a separate analysis plan.
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. 
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.
Data obtained from the pharmacodynamic samples will be used for research.  The 
pharmacodynamic 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 the age of 18 years (or at the 
appropriate age per local country requirements) while on the study, and becomes competent to give 
informed consent, his/her consent will be obtained using separate informed consent forms (ICFs) to 
continue on the study. Further analyses will not be performed on samples collected from subjects 
who do not reconsent at the age of 18 years (or at the appropriate age per local country 
requirements).
Pharmacokinetic Analyses
Lenvatinib concentration versus time data will be tabulated and summarized and graphically 
presented.
Lenvatinib data from Arm A of the study will be pooled with available data from other studies and 
subjected to population PK analysis.  The PK model will be parameterized in terms of clearance 
Page 30 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 30 of 147
and volume of distribution. Details of the population PK analysis will be provided in a separate 
analysis plan. 
Other Analyses
Health-Related Quality of Life (HRQoL):
The PedsQL for all subjects(self- and proxy-rating) will be collected at baseline, at C2D1, C3D1, 
Week 18, C8D1, C18 D1, and at the Off-Treatment visit.
Interim Analyses
No interim analysis is planned for this study.
The safety monitoring will be conducted by the independent data monitoring committee (IDMC).
The frequency of safety reviews will be defined in the IDMC charter. Minutes from the open 
meetings of the IDMC will be provided if requested by regulatory agencies. The recommendation 
whether to stop the study for safety will be reached by the IDMC based on their review of safety 
data with treatment information. The function and membership of the IDMC will be described in 
the IDMC charter.
Sample Size Rationale
A total sample size of 72 subjects is estimated for the primary efficacy endpoint of PFS. Assuming 
a hazard ratio of 0.4 (median PFS of 3.5 and 8.75 months for the control arm and the test arm, 
respectively), a one-sided type 1 error rate of 0.025, and power of 80%, 38 PFS events are required 
for the primary analysis. The total sample size of 72 subjects is estimated to achieve 38 PFS events 
assuming the analysis occurs  approximately 32 months after the first subject is randomized 
(assuming a 20-month enrollment period), and accounts for a dropout rate of up to 40%.
Page 31 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 31 of 147
3
TABLE OF CONTENTS
1
TITLE PAGE ................................................................................................................1
2
CLINICAL PROTOCOL SYNOPSIS..........................................................................16
3
TABLE OF CONTENTS.............................................................................................31
4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................37
5
ETHICS.......................................................................................................................41
5.1
Institutional Review Boards/Independent Ethics Committees.............................41
5.2
Ethical Conduct of the Study..............................................................................41
5.3
Subject Information and Informed Consent ........................................................42
6
INVESTIGATORS AND STUDY PERSONNEL .......................................................43
7
INTRODUCTION.......................................................................................................43
7.1
Osteosarcoma.....................................................................................................43
7.2
Current Therapeutic Options ..............................................................................44
7.3
Lenvatinib..........................................................................................................45
7.3.1
Clinical Data on Lenvatinib in Combination with Ifosfamide and 
Etoposide for Treatment of Relapsed or Refractory Osteosarcoma............46
7.4
Study Rationale..................................................................................................47
7.4.1
Benefit-Risk Assessment..........................................................................47
8
STUDY OBJECTIVES................................................................................................48
8.1
Primary Objective ..............................................................................................48
8.2
Secondary Objectives.........................................................................................48
8.3
Exploratory Objective(s) ....................................................................................48
9
INVESTIGATIONAL PLAN ......................................................................................49
9.1
Overall Study Design and Plan...........................................................................49
9.1.1
Prerandomization Phase ...........................................................................51
Screening Period...............................................................................51
Baseline Period.................................................................................51
9.1.2
Randomization Phase ...............................................................................51
Treatment Period ..............................................................................52
Follow-Up Period .............................................................................52
9.1.3
Extension Phase .......................................................................................53
Treatment Period ..............................................................................53
Follow-Up Period .............................................................................53
9.1.4
Optional Lenvatinib Crossover (for Subjects in Arm B Only):..................53
9.2
Discussion of Study Design, Including Choice of Control Groups......................54
9.3
Selection of Study Population ............................................................................54
9.3.1
Inclusion Criteria......................................................................................55
Page 32 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 32 of 147
9.3.2
Exclusion Criteria.....................................................................................57
9.3.3
Removal of Subjects From Therapy or Assessment ..................................59
9.4
Treatment(s).......................................................................................................59
9.4.1
Treatment(s) Administered.......................................................................59
Lenvatinib Dose Reduction and Interruption Instructions..................61
9.4.1.1.1
Blood Pressure............................................................................62
9.4.1.1.2
Management of Hypertension .....................................................63
9.4.1.1.3
Management of Posterior Reversible encephalopathy 
Syndrome/Reversible Posterior Leukoencephalopathy 
Syndrome ...................................................................................66
9.4.1.1.4
Management of Proteinuria.........................................................66
9.4.1.1.5
Management of Hepatotoxicity ...................................................67
9.4.1.1.6
Management of Thromboembolic Events....................................67
9.4.1.1.7
Management of Hypocalcemia....................................................67
9.4.1.1.8
Management of Gastrointestinal Symptoms and Acute 
Abdominal Pain ..........................................................................68
9.4.1.1.9
Management of Hemorrhage.......................................................68
9.4.1.1.10 MANAGEMENT OF FISTULA FORMATION AND 
GASTROINTESTINAL PERFORATION..................................68
9.4.1.1.11 management guidelines for QT prolongation...............................68
Management of Ifosfamide-Etoposide Associated Toxicity...............68
9.4.2
Identity of Investigational Product(s)........................................................69
Chemical Name of E7080.................................................................69
Comparator Drug..............................................................................70
Labeling for Study Drug ...................................................................70
Storage Conditions ...........................................................................71
9.4.3
Method of Assigning Subjects to Treatment Groups .................................71
9.4.4
Selection of Doses in the Study ................................................................72
9.4.5
Selection and Timing of Dose for Each Subject ........................................72
9.4.6
Blinding ...................................................................................................72
9.4.7
Prior and Concomitant Therapy................................................................72
Drug-Drug Interactions.....................................................................73
Prohibited Concomitant Therapies and Drugs ...................................73
Permitted Concomitant Treatment/Procedures ..................................74
9.4.8
Treatment Compliance .............................................................................74
9.4.9
Drug Supplies and Accountability ............................................................74
9.5
Study Assessments.............................................................................................76
9.5.1
Assessments .............................................................................................76
Page 33 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 33 of 147
Screening/Baseline Assessments.......................................................76
9.5.1.1.1
Demography ...............................................................................76
9.5.1.1.2
Baseline Assessments .................................................................76
9.5.1.1.3
Medical History ..........................................................................76
Efficacy Assessments .......................................................................77
9.5.1.2.1
Tumor Response Assessments.....................................................77
9.5.1.2.2
Palatability and Acceptability of Lenvatinib Suspension 
Formulation ................................................................................79
Pharmacokinetic, Pharmacodynamic, and Other Biomarker 
Assessments .....................................................................................79
9.5.1.3.1
Pharmacokinetic Assessments.....................................................79
9.5.1.3.2
Pharmacodynamic and Other Biomarker Assessments ................80
Safety Assessments...........................................................................81
9.5.1.4.1
Adverse Events...........................................................................81
9.5.1.4.2
Serious Adverse Events and Events Associated with Special 
Situations....................................................................................83
9.5.1.4.3
Laboratory Measurements...........................................................83
9.5.1.4.4
Vital Signs and Weight Measurements........................................85
9.5.1.4.5
Physical Examinations ................................................................85
9.5.1.4.6
Electrocardiograms .....................................................................86
9.5.1.4.7
Other Safety Assessments ...........................................................86
Other Assessments............................................................................87
9.5.2
Schedule of Procedures/Assessments........................................................87
Schedule of Procedures/Assessments................................................87
Description of Procedures/Assessments Schedule ...........................102
9.5.3
Appropriateness of Measurements..........................................................102
9.5.4
Reporting of Serious Adverse Events, Pregnancy, and Events 
Associated with Special Situations .........................................................102
Reporting of Serious Adverse Events..............................................102
Reporting of Pregnancy and Exposure to Study Drug Through 
Breastfeeding..................................................................................103
Reporting of Events Associated with Special Situations..................103
9.5.4.3.1
Reporting of Adverse Events Associated With Study Drug 
Overdose, Misuse, Abuse, or Medication Error .........................103
9.5.4.3.2
Reporting of Abnormal Hepatic Tests of Clinical Interest .........104
Expedited Reporting .......................................................................104
Breaking the Blind..........................................................................105
Regulatory Reporting of Adverse Events ........................................105
9.5.5
Completion/Discontinuation of Subjects.................................................105
Page 34 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 34 of 147
9.5.6
Abuse or Diversion of Study Drug..........................................................105
9.5.7
Confirmation of Medical Care by Another Physician..............................106
9.6
Data Quality Assurance....................................................................................106
9.6.1
Data Collection.......................................................................................106
9.6.2
Clinical Data Management .....................................................................106
9.7
Statistical Methods...........................................................................................106
9.7.1
Statistical and Analytical Plans...............................................................107
Study Endpoints..............................................................................107
9.7.1.1.1
Primary Endpoint......................................................................107
9.7.1.1.2
Secondary Endpoints.................................................................107
9.7.1.1.3
Exploratory Endpoints ..............................................................108
Definitions of Analysis Sets............................................................108
Subject Disposition.........................................................................109
Demographic and Other Baseline Characteristics............................109
Prior and Concomitant Therapy ......................................................109
Efficacy Analyses...........................................................................109
9.7.1.6.1
Primary Efficacy Analysis.........................................................110
9.7.1.6.2
Exploratory Efficacy Analyses..................................................110
Pharmacokinetic, Pharmacodynamic, and Other Biomarker 
Analyses.........................................................................................111
9.7.1.7.1
Pharmacokinetic Analyses ........................................................111
9.7.1.7.2
Pharmacodynamic and Other Biomarker Analyses ....................111
Safety Analyses ..............................................................................112
9.7.1.8.1
Extent of Exposure....................................................................112
9.7.1.8.2
Adverse Events.........................................................................112
9.7.1.8.3
Laboratory Values.....................................................................113
9.7.1.8.4
Vital Signs ................................................................................114
9.7.1.8.5
Electrocardiograms ...................................................................114
9.7.1.8.6
Other Safety Analyses...............................................................114
Other Analyses ...............................................................................114
9.7.1.9.1
Health-Related Quality of Life..................................................114
9.7.1.9.2
Palatability and Acceptability Questionnaire .............................115
9.7.2
Determination of Sample Size ................................................................115
9.7.3
Interim Analysis.....................................................................................115
9.7.4
Other Statistical/Analytical Issues ..........................................................115
9.7.5
Procedure for Revising the Statistical Analysis Plan ...............................115
10
REFERENCE LIST...................................................................................................116
11
PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE PROCEDURES).....120
Page 35 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 35 of 147
11.1
Changes to the Protocol....................................................................................120
11.2
Adherence to the Protocol................................................................................120
11.3
Monitoring Procedures.....................................................................................120
11.4
Recording of Data............................................................................................121
11.5
Identification of Source Data............................................................................121
11.6
Retention of Records........................................................................................121
11.7
Auditing Procedures and Inspection .................................................................122
11.8
Handling of Study Drug ...................................................................................122
11.9
Publication of Results ......................................................................................122
11.10 Disclosure and Confidentiality .........................................................................123
11.11 Discontinuation of Study..................................................................................123
11.12 Subject Insurance and Indemnity......................................................................123
12
APPENDICES...........................................................................................................124
LIST OF IN-TEXT TABLES
Table 1
Criteria for Temporary Discontinuation of Study Drug, Dose 
Reduction, and Resumption of Treatment ...............................................62
Table 2
Criteria for Dose Modification of Chemotherapy Dose...........................69
Table 3
Lenvatinib Pharmacokinetic Sampling Time Points................................80
Table 4
Clinical Laboratory Tests........................................................................84
Table 5
Schedule of Assessments in Study E7080-G000-230 – Randomization 
Phase......................................................................................................89
Table 6
Schedule of Assessments in Study E7080-G000-230 – Extension 
Phase......................................................................................................96
Table 7
Schedule of Assessments in Study E7080-G000-230 – Optional 
Lenvatinib Crossover Treatment Phase...................................................99
Appendix Table 11-1  Measures to Reduce Participant Risk and Burden: ....................141
LIST OF IN-TEXT FIGURES
Figure 1
Overall Study Design..............................................................................50
Figure 2
Management of Hypertension.................................................................65
LIST OF APPENDICES
Appendix 1
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 ...............124
Appendix 2
Lansky Score........................................................................................125
Appendix 3
Karnofsky Performance Status Scale Definitions Rating (%) Criteria ...126
Page 36 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 36 of 147
Appendix 4
Palatability Questionnaire.....................................................................127
Appendix 5
Blood Pressure Levels for Boys by Age and Height Percentile .............129
Appendix 6
Blood Pressure Levels for Girls by Age and Height Percentile..............131
Appendix 7
Body Mass Index-For-Age Percentiles..................................................133
Appendix 8
Body Mass Index-For-Age Percentiles..................................................134
Appendix 9
Tanner’s Staging ..................................................................................135
Appendix 10
Pharmacodynamic, and Other Biomarker Research...............................137
Appendix 11  Country-Specific Requirements .............................................................140
Page 37 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 37 of 147
4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
ADL
Activities of daily living
AE
adverse event
ALT
alanine aminotransferase
aPTT
activated partial thromboplastin time 
AST
aspartate aminotransferase
ANC
absolute neutrophil count
β-hCG
beta-human chorionic gonadotropin
BP
blood pressure
BSA
body surface area
C1, C5, CX
Cycle 1, Cycle 5, Cycle X
CA
Competent Authorities
CBR
clinical benefit rate
CFR
Code of Federal Regulations
Cmax
maximum drug or metabolite concentration
CR
complete response
CRA
clinical research associate
CRF
case report form
CRO
contract research organization
CT
computerized tomography
CTCAE
Common Terminology Criteria for Adverse Events
CYP/CYP3A4
Cytochrome P450/cytochrome P4503A4
DCR
disease control rate
DOR
duration of response
DTC
differentiated thyroid cancer
ESMO
European Society for Medical Oncology
ETO
Etoposide
FGFR
fibroblast growth factor receptor
FGF
fibroblast growth factor
Page 38 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 38 of 147
GFR
glomerular filtration rate 
G-CSF
granulocyte-colony stimulating factor
HRQoL
health-related quality of life 
HR
heart rate
ICF
informed consent form
ICH
International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use
ICL
imaging core laboratory 
ID
identification
IDMC
independent data monitoring committee 
IEC
Independent Ethics Committee
IFO
Ifosfamide
INR
International Normalized Ratio
IIR
independent imaging review 
IRB
Institutional Review Board
ITT
intent-to-treat
IV
intravenously
IVRS
interactive voice response system
KDR
kinase insert domain receptor
K-M
Kaplan-Meier
LEN
Lenvatinib
LVEF
left ventricular ejection fraction
MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
MUGA
multigated acquisition
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
ORR
objective response rate
OS
overall survival
OS-1y
overall survival rate at 1 year
PD
progressive disease/disease progression
PDGFR
platelet-derived growth factor receptor
Page 39 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 39 of 147
PedsQL
Pediatric Quality of Life Inventory 
PFS
progression-free survival
PFS-4m
progression-free survival rate at 4 months
PFS-1y
progression-free survival rate at 1 year
PK
pharmacokinetic(s)
PR
partial  response
PRES 
posterior reversible encephalopathy syndrome 
PT
preferred term
PT
prothrombin time
PTT
partial thromboplastin time
QD
once daily
QTc
QT interval corrected for heart rate
RECIST
Response Evaluation Criteria in Solid Tumors
RET
rearranged during transfection
RP2D
recommended Phase 2 dose 
RPLS
reversible posterior leukoencephalopathy syndrome
RTK
receptor tyrosine kinase
RTKI
receptor tyrosine kinase inhibitor
SAE
serious adverse event
SAP
statistical analysis plan 
SD
stable disease
SmPC
summary of product characteristics
SOC
system organ class
SOP
standard operating procedure
SUSARs
suspected unexpected serious adverse reactions
TEAEs
treatment-emergent adverse events
TKI
tyrosine kinase inhibitors
TNM
tumor-node metastasis
TSH
thyroid stimulating hormone
ULN
upper limit of normal
UPCR
urine protein-to-creatinine ratio 
VEGF
vascular endothelial growth factor 
Page 40 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 40 of 147
VEGFR
vascular endothelial growth factor receptor
WHO DD
World Health Organization Drug Dictionary
Page 41 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 41 of 147
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 the International Council 
for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (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(s) [CRAs], 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.
Documented study approval from the IRB/IEC chairman must be sent to the principal 
investigator (or if regionally required, the head of the medical institution) 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 (or if regionally required, the head of the medical institution) 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 of the end of the study is the date of the data cutoff for 
the final analysis or last subject/last visit, including discontinuation from the study for any 
reason, whichever occurs later.
In the case of early termination/temporary halt of the study, the investigator should notify the 
IRB/IEC and CA within 15 calendar 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:
Page 42 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 42 of 147

Principles of the World Medical Association Declaration of Helsinki 2013

ICH E6 Guideline for GCP (CPMP/ICH/135/95) of the European Agency for the 
Evaluation of Medicinal Products, Committee for Proprietary Medicinal Products, 
International Council for Harmonisation of Technical Requirements for Pharmaceuticals 
for Human Use

Title 21 of the United States Code of Federal Regulations (US 21 CFR) regarding clinical 
studies, including Part 50 and Part 56 concerning informed subject consent and IRB 
regulations and applicable sections of US 21 CFR Part 312

An IRB waiver request will be submitted before study initiation for non-US sites 
conducted under an Investigational New Drug (IND) application.

European Good Clinical Practice Directive 2005/28/EC and Clinical Trial Directive 
2001/20/EC for studies conducted within any EU country.  All suspected unexpected 
serious adverse reactions (SUSARs) will be reported, as required, to the Competent 
Authorities of all involved EU member states.

Other applicable regulatory authorities’ requirements or directives
5.3
Subject Information and Informed Consent
As part of administering the informed consent document, the investigator must explain to 
each subject or guardian, in accordance with applicable professional standards and local 
laws/regulations or legally acceptable 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 should be given by means of a standard written statement, written in 
nontechnical language.  The subject or the subject’s legally acceptable representative should 
understand the statement before signing and dating it and will be given a copy of the signed 
document.  If a subject is unable to read or if a legally acceptable representative is unable to 
read, an impartial witness should be present during the entire informed consent discussion.  
In countries where specific laws for children are established for informed consent, those local 
laws will be applied.  After the ICF and/or assent form and any other written information to 
be provided to subjects is read and explained to the subject or the subject’s 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 and/or assent form, 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 ICF and/or assent form before any study-
Page 43 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 43 of 147
specific procedures are performed. The subject is required to sign an ICF and/or assent at 18 
years of age (or at the appropriate age per local country requirements). No subject can enter 
the study before his/her informed consent has been obtained.
An unsigned copy of an IRB/IEC-approved ICF 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).  Each subject and the 
subject’s parent(s) or legally acceptable representative must sign an approved ICF before 
study participation.  The form must be signed and dated by the appropriate parties.  The 
original, signed ICF for each subject will be verified by the sponsor and kept on file 
according to local procedures at the site.
The subject and/or the subject’s parent(s) or the subject’s legally acceptable representative 
should be informed in a timely manner if new information becomes available that may be 
relevant to the subject’s willingness to continue participation in the study.  The 
communication of this information should be documented.
When the subject reaches the age of 18 years (or at the appropriate age per local country 
requirements) while on study, and becomes competent to give informed consent, his/her 
consent will be obtained using separate ICF 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 80 investigational sites worldwide.
The name, telephone and fax numbers of the medical monitor and other contact personnel at 
the sponsor and of the contract research organization(s) (CRO[s]) are listed in the Regulatory 
Binder provided to each site.
7
INTRODUCTION
7.1
Osteosarcoma
Cancer is a relatively uncommon diagnosis in the pediatric population, and the overall 
incidence is low (18.6 cases per 100,000 children [Howlader, et al., 2019]).  Solid tumors 
constitute approximately 60% of childhood malignancies (Howlader, et al., 2019).  
Malignant bone tumors are the fifth most common solid tumor type accounting for about 5% 
of childhood tumors (Howlader, et al., 2019; Kaatsch, 2010). 
Osteosarcoma is the most commonly diagnosed primary malignancy of the bone in children 
and young adults, and accounts for approximately 5% of childhood tumors, with an estimated
annual incidence of 4.4 cases per 1 million in people younger than 24 years (Mirabello, et al., 
2009).  Osteosarcoma occurs predominantly in adolescents and young adults.  The median 
age at diagnosis is 20 years, with the incidence peaking at 15 to 19 years of age (ESMO, 
guidelines, 2014).  According to the American Cancer Society, osteosarcoma in this age 
group is 8 per 1 million (Ward, et al., 2014).  
Page 44 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 44 of 147
There are both intrinsic and extrinsic factors that have been shown to contribute to the 
development of osteosarcoma. Studies have demonstrated that several genetic abnormalities, 
including the overexpression of vascular endothelial growth factor (VEGF) receptor 
(VEGFR), platelet-derived growth factor (PDGF) receptor (PDGFR), and c-fos, are
associated with the development of osteosarcoma in laboratory models as well as humans 
(Gorlick and Khanna, 2010).  However, osteosarcoma is not characterized by a single 
oncogenic driver.  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).  Extrinsic factors such as ionizing radiation, which is used for the treatment 
of childhood solid tumors, have 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).
The management of osteosarcoma is multimodal; patients not amenable to surgery or patients 
at second or third relapse have a poor prognosis.  Metastatic osteosarcoma is common (10% 
to 20%) (NCCN, Bone cancer guidelines, 2020; Casali, et al., 2018), with the most frequent 
site being the lung (>85%).  In the case of isolated lung metastases, more than a third of 
patients with a second surgical remission survive for >5 years (Casali, et al., 2018).  
Approximately 25% of all patients with primary metastatic osteosarcoma and >40% of those 
who achieve a complete surgical remission may become long-term survivors (Casali, et al., 
2018) as compared with 65% to 70% of patients with localized disease (Meazza and 
Scanagatta, 2016).
About 30% to 40% of patients with localized disease and 80% of those with metastatic 
disease experience relapse (NCCN Bone Cancer Guidelines, 2020; Casali, et al., 2018; 
Ferrari, 2003).  The presence of solitary metastasis, time to first relapse, and complete 
resectability of disease at first recurrence are the most significant prognostic indicators for 
improved survival.  Patients whose tumor is not amenable to surgery, or with second or third 
recurrence, or who have metastases to the bone, have a poor prognosis.  In general, despite 
second-line treatment, the prognosis of recurrent disease in osteosarcoma has remained poor, 
with long-term postrelapse survival of <20% (NCCN Bone Cancer Guidelines, 2020; Casali, 
et al., 2018).  
7.2
Current Therapeutic Options
There has been no substantial progress in the treatment of osteosarcoma since the 1980s. 
Current treatment utilizes multi-agent chemotherapy and surgical resection of all clinically 
detectable disease.  
Treatment of Newly Diagnosed Disease
Newly diagnosed osteosarcoma is typically managed with neoadjuvant chemotherapy 
followed by surgical removal of the primary tumor and all clinically evident metastatic 
disease, followed by adjuvant chemotherapy.  Surgical resection of all clinically detectable 
sites of disease is vital, regardless of number and site, as complete resection is predictive of 
Page 45 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 45 of 147
survival (Meazza and Scanagatta, 2016).  For patients with unresectable disease at multiple 
sites, experimental therapy is also considered, due to the poor prognosis for these patients. 
The most effective chemotherapy regimens include the combination of high-dose 
methotrexate, doxorubicin, and cisplatin and has become the standard treatment for 
high-grade osteosarcoma (NCCN Bone Cancer Guidelines, 2020; Ferrari and Serra, 2015; 
Isakoff, et al., 2015).
Treatment of Relapsed, Refractory, and Progressive Disease
Second-line treatment for relapsed disease consists of chemotherapy and/or surgical resection
(NCCN Bone Cancer Guidelines, 2020; Casali, et al., 2018). The role of second-line 
chemotherapy for recurrent osteosarcoma is much less well defined than that of surgery, and 
there is no accepted standard regimen (Casali, et al., 2018). For patients with resectable 
solitary metastasis to the lung, surgical resection only may be adequate. For those with 
recurrent pulmonary metastases that are resectable, surgery is advised in addition to 
neoadjuvant or adjuvant chemotherapy, regardless of the number of previous lung relapses 
and the number of secondary pulmonary lesions (Briccoli, et al., 2005). Aggressive surgical 
resection of metastases and the ability to achieve a second surgical remission have 
consistently been shown essential for long-term survival following relapse (Leary, et al., 
2013; Kempf-Bielack, et al., 2005; Bacci, et al., 2005; Chou, et al., 2005; Hawkins and 
Arndt, 2003).  
As per the European Society for Medical Oncology (ESMO) guidelines for bone sarcoma, 
treatment options for recurrent osteosarcoma include ifosfamide ± etoposide ± carboplatin, 
and other active drugs (Casali, et al., 2018). Preferred regimens for second-line therapy per 
the National Comprehensive Cancer Network (NCCN) bone sarcoma guidelines include
ifosfamide (high dose) with or without etoposide, regorafenib, sorafenib, and sorafenib plus 
everolimus (NCCN Bone Cancer Guidelines, 2020).
In the event of subsequent relapse, the NCCN guidelines (NCCN Bone Cancer Guidelines, 
2020) and ESMO guidelines (Casali, et al., 2018) strongly encourage participation in clinical 
studies.  Otherwise, patients with disease progression or relapse after second-line therapy are 
managed with surgical resection, palliative radiotherapy, or best supportive care.
7.3
Lenvatinib
E7080 (lenvatinib) is a potent multiple receptor tyrosine kinase (RTK) inhibitor (RTKI) that 
selectively inhibits VEGF receptors, VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 
(FLT4), in addition to other pro-angiogenic and oncogenic pathway-related RTKs, including 
fibroblast growth factor (FGF) receptor (FGFR) 1-4, PDGF receptor alpha (PDGFRα), KIT, 
and RET.  Therefore, lenvatinib exerts its in vivo antitumoural activity based on multiple 
mechanisms involved in and through effects related to angiogenesis (including reversion of 
resistance) and the tumor microenvironment, as well as direct inhibitory action on the tumour 
cells.  Recent studies have also demonstrated lenvatinib’s immunomodulatory activity in the 
tumor microenvironment.  This includes decreases in immunosuppressive tumor-associated 
Page 46 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 46 of 147
macrophages, activated cytotoxic T cell increases, and activation of interferon-gamma  
signaling.  These all contribute to lenvatinib’s antitumor activity in immunocompetent mice 
(Kato, et al., 2019; Kimura, et al., 2018).
7.3.1
Clinical Data on Lenvatinib in Combination with Ifosfamide and Etoposide 
for Treatment of Relapsed or Refractory Osteosarcoma
The safety, tolerability and activity of single-agent lenvatinib, and lenvatinib in combination 
with chemotherapy (ifosfamide and etoposide), have been assessed in E7080-G000-207 
(hereafter referred to as Study 207), an ongoing Phase 1/2, multicenter, open-label study in 
children, adolescents and young adults with solid tumors, including relapsed or refractory 
osteosarcoma, and radioiodine- refractory differentiated thyroid carcinoma. The 
recommended Phase 2 dose (RP2D) of lenvatinib was determined in the Phase 1b portion as
14 mg/m2 orally once daily when given as single-agent as well as in combination with 
etoposide (100 mg/m2 IV once daily for 3 days) + ifosfamide (3000 mg/m2 IV once daily for 
3 days), administered on days 1 to 3 of each 21-day cycle, for 5 cycles. Safety and efficacy
is being assessed in the Phase 2 portion of the study.
Data from Study 207 have shown that patients with osteosarcoma may benefit from treatment 
with lenvatinib. In the single agent expansion cohort in relapsed/refractory osteosarcoma, 
(n=31; Cohort 2B), 9 of 28 evaluable patients (32.1%) achieved progression-free survival 
(PFS) at 4 months (PFS-4m), median PFS was 3.0 months (95% CI: 1.8, 5.5). Two out of 
29 subjects (6.9%) with measurable disease had a partial response (PR) (Gaspar, et al., 2018).  
Among the 31 subjects included in the safety analysis set for the single-agent lenvatinib 
expansion cohort, the most common adverse events were: headache (48%), vomiting (45%), 
decreased appetite, diarrhea, and hypothyroidism (42% each), proteinuria (39%), increased 
blood TSH, hypertension, nausea, pyrexia, and weight decreased (36% each).  Five subjects 
(16.1%) discontinued treatment due to TEAEs, and 8 subjects (25.8%) reported TEAEs 
leading to study drug dose reduction.  There were no treatment-related fatal TEAEs (Gaspar, 
et al., 2018).  
In a pooled analysis of subjects from Phase 1b and 2 receiving lenvatinib 14 mg/m2 in 
combination with ifosfamide plus etoposide (N=35; full analysis set), the primary efficacy 
endpoint, PFS-4 rate based on RECIST 1.1 by investigator assessment, was 67.9% (95% CI: 
47.6, 84.1). As of the data cutoff date of 23 Jul 2019, the objective response rate (ORR) was 
12.5%, including 4 subjects with PR. Median PFS was 11.1 months (95% CI: 4.5, 12.6), and 
median overall survival (OS) was 16.3 months (95% CI: 12.6, NE) (Gaspar, et al., 2019).
Overall treatment with lenvatinib in combination with ifosfamide and etoposide in this 
patient population was associated with a manageable safety profile, and no unexpected 
toxicities were observed. Among the 31 subjects included in the safety analysis set, the most 
frequent treatment-emergent adverse events (TEAEs) were anemia (71%), nausea and 
vomiting (61% each), diarrhea (52%), neutropenia, platelet count decreased, and white blood 
cell count decreased (48% each).  The most common treatment-related grade ≥3 TEAEs were 
anemia (52%), neutropenia (48%), platelet count decreased and white blood cell count 
Page 47 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 47 of 147
decreased (42% each), neutrophil count decreased (32%), and thrombocytopenia (29%).  
Eight subjects (25.8%) discontinued treatment due to TEAEs, and 15 subjects (48.4%) 
reported TEAEs leading to study drug dose reduction. There were no treatment-related fatal
TEAEs (Gaspar, et al., 2019).
7.4
Study Rationale
Study 230, a randomized, controlled Phase 2 study, will evaluate the efficacy and safety of 
lenvatinib in combination with ifosfamide and etoposide in children, adolescents, and young 
adults with relapsed or refractory osteosarcoma. Eligible patients aged 2 to 25 years old will 
receive ifosfamide and etoposide with or without lenvatinib (14 mg/m2; RP2D from 
Study 207). Subjects randomized to Arm A can continue to receive lenvatinib until disease 
progression, intolerable toxicity, or withdrawal of consent. Approximately 72 subjects will 
be treated in the study.  The primary objective of the study is to demonstrate that lenvatinib 
in combination with ifosfamide and etoposide has superior efficacy compared to ifosfamide 
and etoposide based on PFS in children, adolescents and young adults with relapsed or 
refractory osteosarcoma.
Pediatric solid tumors are highly vascularized.  Angiogenesis and vasculogenesis are the 
fundamental processes by which new blood vessels are formed.  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. Thus, inhibition of angiogenesis is a viable target for 
anticancer therapy.  Moreover, vascular normalization allows reoxygenation, hence the 
addition of an anti-VEGF to chemotherapy may result in increased uptake of drugs into 
tumor tissue (Tuettenberg, et al., 2006).
7.4.1
Benefit-Risk Assessment
As discussed in Section 7.3.1, the safety, tolerability and activity of single-agent lenvatinib, 
and lenvatinib in combination with chemotherapy (ifosfamide and etoposide), have been 
assessed in Study 207.  A pooled analysis of patients enrolled in Phase 1b and Phase 2, who 
received lenvatinib at the RP2D in combination with chemotherapy was conducted (N=35; 
data cutoff date 23 Jul 2019). In this heavily pretreated population, PFS-4m was 67.9% 
(95% CI:  47.6, 84.1), median PFS was 11.1 months (95% CI:  4.5, 12.6), and median overall 
survival was 16.3 months (95% CI:  12.6, NE).  The activity of lenvatinib in combination 
with ifosfamide plus etoposide, as assessed by PFS-4m is clinically meaningful, displaying 
encouraging results when compared to other agents recommended in the ESMO guidelines 
for relapsed or refractory osteosarcoma (PFS-4m from 42% to 46%) (Casali, et al., 2018;
Grignani et al., 2012; Berger et al., 2009).
In Study 207, no treatment-related fatal TEAEs were observed and safety data indicate that 
the toxicity of the combination is manageable and consistent with the known toxicities of 
each study drug and the disease under study.
Page 48 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 48 of 147
Based on these data, the benefit-risk profile is considered favorable and further study of the 
combination within a randomized controlled trial is warranted.
8
STUDY OBJECTIVES
8.1
Primary Objective
To evaluate whether lenvatinib in combination with ifosfamide and etoposide (Arm A) is 
superior to ifosfamide and etoposide (Arm B) in improving PFS by independent imaging 
review (IIR) using Response Evaluation Criteria In Solid Tumors (RECIST 1.1), in children, 
adolescents, and young adults with relapsed or refractory osteosarcoma.
8.2
Secondary Objectives
The secondary objectives of the study are to:
1. Compare difference in PFS rate at 4 months (PFS-4m) between the 2 treatment arms per 
IIR
2. Compare difference in PFS rate at 1 year (PFS-1y) between the 2 treatment arms per IIR
3. Compare difference in OS and OS rate at 1 year (OS-1y) between the 2 treatment arms
4. Compare difference in objective response rate at 4 months (ORR-4m) between the 
2 treatment arms per IIR
5. Compare difference in objective response rate (ORR) between the 2 treatment arms per 
IIR
6. Compare difference in safety and tolerability between the 2 treatment arms
7. Characterize the pharmacokinetics (PK) of lenvatinib, when administered in combination 
with ifosfamide and etoposide 
8. Compare difference in health-related quality of life (HRQoL) as assessed by using the 
Pediatric Quality of Life Inventory (PedsQL) Generic Core Scales and Cancer Module
between the 2 treatment arms
9. Assess the palatability and acceptability of the suspension formulation of lenvatinib in 
subjects receiving the suspension formulation in the study
8.3
Exploratory Objective(s)
The exploratory objectives of the study are to:
1.
Explore difference in duration of response (DOR), disease control rate (DCR), and 
clinical benefit rate (CBR) between the 2 treatment arms per IIR and investigator 
assessment
2.
Explore difference in PFS, PFS-4m, PFS-1y, ORR-4m, and ORR between the 2 treatment 
arms based on investigator assessment
3.
Compare between the 2 treatment arms:
-
the proportion of subjects who achieve complete removal of baseline lesion(s)
-
the proportion of subjects with unresectable baseline lesion(s) that are converted to 
resectable
Page 49 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 49 of 147
4. Investigate the relationship between subject tumor biomarkers and clinical response and 
toxicity of lenvatinib in combination with ifosfamide and etoposide
9
INVESTIGATIONAL PLAN
9.1
Overall Study Design and Plan
This is a multicenter, randomized, open-label, parallel-group, Phase 2 study to compare the 
efficacy and safety of lenvatinib in combination with ifosfamide and etoposide versus 
ifosfamide and etoposide in children, adolescents, and young adults with relapsed or
refractory osteosarcoma.
Approximately 72 eligible subjects will be randomized to 1 of the following 2 treatment arms 
in a 1:1 ratio within the strata:

Arm A:  lenvatinib 14 mg/m2 (orally, once daily) plus ifosfamide 3000 mg/m2/day 
(intravenously [IV], Day 1 to Day 3 of each cycle for a total of up to 5 cycles) and 
etoposide 100 mg/m2/day (IV, Day 1 to Day 3 of each cycle for a total of up to 5 cycles)

Arm B:  ifosfamide 3000 mg/m2/day (IV, Day 1 to Day 3 of each cycle for a total of up to 
5 cycles) and etoposide 100 mg/m2/day (IV, Day 1 to Day 3 of each cycle for a total of up 
to 5 cycles)
Randomization will follow a predefined randomization scheme based on the following 
stratification factors: time to first relapse/refractory disease (early [<18 months] or late 
[≥18 months]) and age (<18 and ≥18 years).
The Sponsor will closely monitor enrollment, to ensure that a minimum of 36 subjects are 
<17 years of age at the time of informed consent.  
The study will be conducted in 3 Phases: a Pre-randomization Phase, a Randomization 
Phase, and an Extension Phase.  
The end of the study will be the date of data cutoff for the final analysis or the time of last 
subject last visit, whichever occurs later.
An overview of the overall study design is presented in Figure 1.
Page 50 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 50 of 147
Prerandomization Phase
Screening Day-28 to 2/Baseline Day -1
Key Eligibility

Relapsed/refractory osteosarcoma

1 or 2 prior systemic regimens

Measurable or evaluable disease (RECIST 1.1)

Lansky/Karnofsky ≥50%

No history of Grade ≥3 IFO-related nephrotoxicity or encephalopathy
Randomization Phase
N= 72  1:1
Stratification

Age (<18 and ≥18 years)

Time to 1st relapse (<18 and  ≥18 months)
  
          Treatment Period
Arm Aa
Len QD + IFO + ETO
D1-3 per cycle for ≤5 cycles
(1 cycle = 21 days)
Len monotherapy until IIR confirmed PDc, 
unacceptable toxicity, subject request, 
withdrawal of consent, or termination of 
study by Sponsor, whichever occurs first
Arm Bb
IFO + ETO
D1-3 per cycle for ≤5 cycles
(1 cycle = 21 days)
C1
C5
CX
Followed until IIR confirmed PD*, 
withdrawal of consent, or start of a new 
anticancer therapy
Arm B only
Optional crossover at PD per 
IIR*  ≤4 cycles
Arm B only
Optional crossover at PD per IIR* 
after 5 cycles
Len + IFO + ETO
(up to a total of 5 cycles)
Len monotherapy
Follow-up Periodd
After Off-Treatment visit (within 30 days 
after final dose of study treatment), during 
the Randomization Phase or during the 
Extension Phase
– Subjects who end treatment without IIR 
confirmed PD will continue to undergo tumor 
assessments per Schedule of Assessments
- Survival follow-up every 12 weeks
  
Extension Phase
After completion of Randomization Phase (data cutoff for primary analysis)

Treatment until PD (IIR confirmation not required), unacceptable toxicity, 
subject request, withdrawal of consent, or termination of study by Sponsor, 
whichever occurs first

Follow-up
Figure 1 Overall Study Design
a
Arm A = lenvatinib+ifosfamide+ etoposide (ifosfamide+etoposide for maximum of 5 cycles); lenvatinib to 
be continued until disease progression, intolerable toxicity, subject request, withdrawal of consent , or 
study termination by the sponsor, whichever occurs first.
b
Arm B = ifosfamide+ etoposide (maximum of 5 cycles). *Subjects in Arm B with disease progression per 
RECIST 1.1 may be eligible for optional treatment with lenvatinib±chemotherapy. Please see Section 9.1.4
for further details.
c
IIR confirmation of disease progression is only required prior to the start of the Extension Phase.
d
Follow-up can occur during the Randomization Phase (if the subject discontinued treatment during the 
Randomization Phase), or during the Extension Phase, after the termination of study treatment.
C1 = Cycle 1; C2 = Cycle 2; CX = Cycle X; ETO = etoposide; IFO = ifosfamide; IIR = independent imaging 
review; Len = lenvatinib; PD = progressive disease/disease progression; QD = once daily; RECIST = Response 
Evaluation for Solid Tumors
Page 51 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 51 of 147
9.1.1
Prerandomization Phase
The Prerandomization Phase will consist of 2 periods: Screening and Baseline. The 
Prerandomization Phase will last no longer than 28 days.  The Screening Period will establish 
protocol eligibility and the Baseline Period will confirm eligibility.
Screening Period
Screening will occur between Day –28 and Day –2.  The purpose of the Screening Period is 
to obtain informed consent and to establish protocol eligibility.  Informed consent will be 
obtained after the study has been fully explained to each subject and before the conduct of 
any screening procedures or assessments.  Procedures to be followed when obtaining 
informed consent are detailed in Section 5.3.
Subjects must have a histologically or cytologically confirmed diagnosis of high grade 
refractory or relapsed osteosarcoma 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.
Baseline Period
The purpose of the Baseline Period is to confirm protocol eligibility as specified in the 
inclusion/exclusion criteria (as detailed in Section 9.3.1 and Section 9.3.2).  Results of 
baseline assessments must be obtained prior to the first dose of study 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 4), 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 
Randomization Phase of this study.
9.1.2
Randomization Phase
The Randomization Phase will consist of 2 periods: Treatment Period and Follow-up Period.  
The Randomization Phase will begin at the time of randomization of the first subject and will 
end on the data cutoff date for the primary analysis (ie, when approximately 38 PFS events, 
as determined by IIR, are observed).
After the data cutoff date for the primary analysis has occurred, all subjects who are still on 
study treatment will enter the Extension Phase.  
Page 52 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 52 of 147
Treatment Period
The Treatment Period for each subject will begin at the time of randomization and will end at 
the completion of the Off-Treatment Visit which will occur within 30 days after the final 
dose of study treatment.
Subjects will receive study treatment as continuous 21-day cycles in both treatment arms.
Treatment cycles will be counted continuously regardless of dose interruptions.  If 
chemotherapy administration is precluded on Day 1 of a treatment cycle, the subject may 
resume treatment once recovered at the discretion of investigator.  Subsequent chemotherapy 
will be administered every 21 (±1) days starting from the timepoint it was resumed.  Subjects 
will undergo safety and efficacy assessments as defined in the Schedule of 
Procedures/Assessments (Table 5).  Subjects randomized to Arm A will continue to receive 
lenvatinib until disease progression (PD) confirmed by IIR, development of unacceptable 
toxicity, subject request, withdrawal of consent, or study termination by the sponsor, 
whichever occurs first. 
Disease progression (PD) must be confirmed by IIR prior to the investigator discontinuing 
study treatment for a subject.  In situations where the investigator judges that alternative 
treatments must be instituted immediately for a subject’s safety, study drugs may be 
discontinued without waiting for IIR confirmation of radiographic evidence of PD.  If 
possible, before discontinuation of the subject from the study, the investigator should consult 
with the sponsor.
Follow-Up Period
The Follow-up Period begins the day after the Off-Treatment Visit and will continue for up 
to 2 years after end of treatment for a subject, unless the subject withdraws consent or the 
sponsor terminates the study.  
Subjects may at any time withdraw consent for further study participation.  No further data 
will be collected on subjects once consent has been withdrawn, however, an investigator may 
consult public records to establish survival status if permitted by local regulations.
All adverse events (AEs), including serious adverse events (SAEs), will be captured for 30 
days after the last dose of study drug.  
All subjects who end study treatment without IIR confirmed PD, will continue to undergo 
tumor assessments every 6 weeks until Week 18, then every 9 weeks until Week 54, 
thereafter, every 12 weeks until IIR confirmation of radiographic evidence of PD as 
described in the tumor assessments in the assessment schedule, or until another anticancer 
therapy is initiated.
Subjects in both Arm A and Arm B will be followed for survival every 12 weeks (±1 week) 
and all subsequent anticancer treatments received will be recorded.  Subjects who are being 
followed for survival at the time of data cutoff for the primary analysis (ie, at the end of the 
Page 53 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 53 of 147
Randomization Phase) will continue to be followed for survival during the Follow-up Period 
of the Extension Phase. 
9.1.3
Extension Phase
The Extension Phase will consist of 2 periods: Treatment Period and Follow-up Period.  
Treatment Period
In the Treatment Period, subjects still on study treatment following the completion of the 
Randomization Phase will continue to receive study treatment as outlined in Section 9.1.2.1
until disease progression, development of unacceptable toxicity, subject request, withdrawal 
of consent, or discontinuation of study by the sponsor.  Tumor assessments will be performed 
according to the local standard of care.  Independent imaging review (IIR) review and 
confirmation of radiographic evidence of PD will not be required, and scans will no longer be 
required to be sent to the imaging core laboratory (ICL).  The Off-Treatment Visit will occur 
within 30 days after the final dose of study treatment. All AEs, including SAEs will be 
captured up to 30 days after last dose of study drug.  In case the study is discontinued by the 
sponsor, the sponsor will provide study drug (outside the study) for subjects who have not 
met the criteria for study drug discontinuation.
Follow-Up Period
The Follow-up Period will begin the day after the Off-Treatment Visit and will last for up to
2 years after end of treatment for a subject, unless the study is terminated by the sponsor, or 
the subject discontinues due to withdrawal of consent, or is lost to follow-up.  Subjects will 
be treated by the investigator according to the prevailing local standard of care.  Subjects will 
be followed every 12 weeks (±1week) for survival and all subsequent anticancer treatments 
received will be recorded.
9.1.4
Optional Lenvatinib Crossover (for Subjects in Arm B Only):
Subjects in Arm B with disease progression per RECIST 1.1 may be eligible for optional 
treatment with lenvatinib±chemotherapy. Note: subjects may only receive a maximum of 5 
cycles of chemotherapy for the duration of the study. Optional crossover treatment must be
initiated within 30 days of documented disease progression.
Optional lenvatinib crossover is only available if the following conditions are met:
-
Subject experiences disease progression per RECIST 1.1 (as confirmed by IIR for all 
subjects who crossover prior to the start of the Extension Phase); and
-
No new systemic anti-cancer medication was administered after the last dose of study 
drugs; and
-
The subject meets all of the safety parameters listed in the inclusion criteria and none 
of the safety parameters listed in the exclusion criteria; and
-
The study is ongoing.
Page 54 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 54 of 147
Treatment with lenvatinib±chemotherapy will continue until the next disease progression 
(per RECIST 1.1 as assessed by investigator), development of unacceptable toxicity, subject 
request, or withdrawal of consent, whichever occurs first. If the sponsor terminates the study, 
the sponsor will continue to provide study drug(s) (outside of the study) for subjects 
requiring continuation of treatment. 
Prior to optional lenvatinib crossover, baseline tumor assessment must be re-established (i.e., 
new tumor assessment scans performed), unless the last tumor assessment scans were 
performed within 4 weeks prior to Cycle 1 Day 1 of the crossover treatment.
Subjects who qualify to receive Optional Lenvatinib Crossover Treatment will be followed 
according to the schedule of procedures/assessments in Table 7.
9.2
Discussion of Study Design, Including Choice of Control Groups
The study has been designed as an open-label, randomized study to compare the safety and 
efficacy of lenvatinib in combination with the ifosfamide and etoposide with ifosfamide and 
etoposide alone in children, adolescents, and young adults with relapsed or refractory 
osteosarcoma. Ifosfamide and etoposide will be used as the control group since it is a 
recognized treatment option for patients with relapsed osteosarcoma.
Progression-free survival (PFS) as compared to control, with blinded IIR of radiological 
imaging using RECIST 1.1 criteria will be evaluated as the primary endpoint.  The endpoint 
was determined as appropriate for the study, given the unique biology of the osteosarcoma.
To avoid bias in efficacy assessment, the analysis for primary endpoint is based on tumor 
assessment by IIR, a central independent blinded assessment. Progression-free survival at 4 
months (PFS-4m), at 1 year (PFS-1y), ORR at 4 months, ORR, OS at 1 year (OS-1y), and OS 
will also be evaluated in the study as secondary endpoints. 
Pharmacodynamic serum and tumor biomarkers identified in other lenvatinib clinical studies 
may be assessed in samples collected from subjects enrolled in this study in the test arm only 
(Arm A: lenvatinib + ifosfamide + etoposide) and may be used for exploratory analysis for 
evaluation of response-related and/or safety-related outcomes.
The study will also assess health related quality of life (HRQoL) using validated 
questionnaires.
Randomization will be used in this study to avoid bias in the assignment of subjects to 
treatment, to increase the likelihood that known and unknown subject attributes (eg, 
demographics and baseline characteristics) are balanced across treatment groups, and to 
ensure the validity of statistical comparisons across treatment groups.
9.3
Selection of Study Population
Approximately 72 subjects between 2 and ≤25 years of age will be randomized (36 subjects 
in each arm). 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.
Page 55 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 55 of 147
For evaluation of the primary endpoint (intent–to-treat analysis), a minimum of 36 subjects 
<17 years old (at the time of informed consent) will be randomized.
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 high grade osteosarcoma.
2.
Refractory or relapsed osteosarcoma after 1 to 2 prior lines of systemic treatments.  
3.
Measurable or evaluable disease per RECIST 1.1 that meets the following criteria:
-
Measurable disease is defined as a lesion with a minimum size (by long axis) of 10 
mm using computed tomography/magnetic resonance imaging (CT/MRI) (lymph 
nodes must be accurately measurable with a minimum size [by short axis] of 15 mm). 
-
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. 
-
Any other non-measurable lesions will be considered evaluable disease.
4.
Aged 2 years to ≤25 years at the time of informed consent.
5.
Life expectancy of 12 weeks or more.
6.
Lansky play score ≥50% or Karnofsky Performance Status score ≥50%.  Use Karnofsky 
for subjects ≥16 years of age and Lansky for subjects <16 years of age.  Subjects who are 
unable to walk because of paralysis, but who are able to perform ADL while wheelchair 
bound, will be considered ambulatory for the purpose of assessing the performance score.
7.
Adequate bone marrow function as evidenced by:
a.
absolute neutrophil count (ANC) ≥1.5×109/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 of <8.0 g/dL is acceptable if it is corrected by 
growth factor or transfusion before Cycle 1 Day 1).
c.
platelet count ≥100×109/L. 
8.
Adequate blood coagulation function defined by International Normalized ratio or 
prothrombin time (INR/PT) and activated partial thromboplastin time or partial 
thromboplastin time (aPTT/PTT) ≤1.5 unless participant is receiving anticoagulant 
therapy, as long as INR/PT and aPTT/PTT  are within therapeutic range of intended use 
of anticoagulants.
9.
Adequate liver function as evidenced by:
a.
Bilirubin ≤1.5 times the upper limit of normal (ULN).
b. Alanine aminotransferase (ALT), and aspartate aminotransferase (AST) ≤3×ULN (in 
the case of liver metastases ≤5×ULN).
10. 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 
Page 56 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 56 of 147
creatinine clearance (or radioisotope glomerular filtration rate [GFR]) must be 
>70 mL/min/1.73 m2.
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 Common Terminology Criteria for Adverse Events (CTCAE) v5.0 and 
if possible perform a 24-hour urine collection (children and adolescents ≤12 years of 
age must have ≤500 mg of protein/24 hours and subjects >12 years of age must have 
≤1 g of protein/24 hours).
c.
No clinical evidence of nephrotic syndrome. 
11. Adequate cardiac function as evidenced by left ventricular ejection fraction (LVEF)
≥50% at baseline as determined by echocardiography or multigated acquisition (MUGA) 
scan.
12. 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 guidelines) and no change in antihypertensive 
medications within 1 week prior to Cycle 1 Day 1.  Subjects >18 years of age should 
have BP ≤150/90 mm Hg at screening and no change in antihypertensive therapy 
within 1 week prior to Cycle 1 Day 1.
13. Washout before Cycle 1 Day 1 of 3 weeks in case of prior chemotherapy, 6 weeks if 
treatment included nitrosoureas; 4 weeks for definitive radiotherapy, 2 weeks for 
palliative radiotherapy; and 3 months from high-dose chemotherapy and stem cell rescue.
For all other anti-cancer therapies, washout before Cycle 1 Day 1 of at least 5 half-lives
(or at least 28 days, whichever is shorter).  Subjects must have recovered (to Grade ≤1, 
except for alopecia, ototoxicity, and Grade ≤2 peripheral neuropathy, per CTCAE v5.0) 
from the acute toxic effects of all prior anticancer therapy before Cycle 1 Day 1.
14. Must have no prior history of lenvatinib treatment.
15. 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.
16. Willing and able to comply with the protocol, scheduled follow-up, and management of 
toxicity as judged by the investigator.
Page 57 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 57 of 147
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 Cycle 1 Day 1 
(ie, no longer requiring systemic treatment).
2.
Subjects with central nervous system metastases are not eligible, unless they have 
completed local therapy (eg, whole brain radiation therapy, surgery or radiosurgery) and 
have discontinued the use of corticosteroids for this indication for at least 2 weeks before 
Cycle 1 Day 1.  
3.
Active second malignancy within 2 years prior to enrollment ([in addition to 
osteosarcoma], but not including definitively treated superficial melanoma, 
carcinoma-in-situ, basal or squamous cell carcinoma of the skin).
4.
Any medical or other condition that in the opinion of the investigator(s) would preclude 
the subject’s participation in a clinical study.  
5.
Has had major surgery within 3 weeks prior to Cycle 1 Day 1.

  Note: Adequate wound healing after major surgery must be assessed clinically, 
independent of time elapsed for eligibility.
6.
Known hypersensitivity to any component(s) of the study drugs (lenvatinib, ifosfamide,
and etoposide, or their ingredients).
7.
Currently receiving any investigational drug or device in another clinical study or within 
28 days prior to Cycle 1 Day 1.
8.
A clinically significant ECG abnormality, including a marked baseline prolonged QT or 
QTc interval (eg, a repeated demonstration of a QTc interval >480 msec).
9.
Has clinically significant cardiovascular disease within 6 months from first dose of study  
intervention, including New York Heart Association Class III or IV congestive heart 
failure, unstable angina, myocardial infarction, cerebral vascular accident, or cardiac 
arrhythmia associated with hemodynamic instability. Note: Medically controlled 
arrhythmia would be permitted.
10. Gastrointestinal malabsorption, gastrointestinal anastomosis, or any other condition that 
in the opinion of the investigator might affect the absorption of lenvatinib.
11. Pre-existing Grade ≥3 gastrointestinal or non-gastrointestinal fistula.
12. Gastrointestinal bleeding or active hemoptysis (bright red blood of at least ½ teaspoon) 
within 3 weeks prior to Cycle 1 Day 1.
13. Radiographic evidence of intratumoral cavitation, encasement, or invasion of a major 
blood vessel. Additionally, the degree of proximity to major blood vessels should be 
considered for exclusion because of the potential risk of severe hemorrhage associated 
with tumor shrinkage/necrosis after lenvatinib therapy.
14. History of ifosfamide-related Grade ≥3 nephrotoxicity or encephalopathy.
15. Evidence of clinically significant disease (eg, cardiac, respiratory, gastrointestinal, renal 
disease) that in the opinion of the investigator(s) could affect the subject’s safety or 
interfere with the study assessments.
Page 58 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 58 of 147
16. Known to be human immunodeficiency virus (HIV) positive.  Note: HIV testing is 
required at screening only when mandated by local health authority. 
17. Known active Hepatitis B (eg, HBsAg reactive) or Hepatitis C (eg, HCV RNA 
[qualitative] is detected).  Note: Testing for Hepatitis B or Hepatitis C is required at 
screening only when mandated by local health authority.
18. 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 any study drug.
19. Females of childbearing potential* who:
-
Do not agree to use a highly effective method of contraception for the entire study 
period and for 28 days after lenvatinib discontinuation or 12 months after etoposide 
and ifosfamide discontinuation, ie:
◦
total abstinence (if it is their preferred and usual lifestyle)
◦
an intrauterine device (IUD) or intrauterine hormone-releasing system (IUS)
◦
A contraceptive implant
◦
an oral contraceptive** (with additional barrier method)
OR
-
Do not have a vasectomized partner with confirmed azoospermia.
For sites outside of the EU, it is permissible that if a highly effective method of 
contraception is not appropriate or acceptable to the subject, then the subject must agree 
to use a medically acceptable method of contraception, ie, double-barrier methods of 
contraception such as condom plus diaphragm or cervical/vault cap with spermicide. 
* All post pubertal females will be considered to be of childbearing potential unless they 
have early menopause (amenorrheic for at least 12 consecutive months, in the appropriate 
age group, and without other known or suspected cause) or have been sterilized surgically 
(ie, bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, all with surgery 
at least 1 month before dosing), or are pre-menarcheal (Tanner Stage 1-3).
**Must be on stable dose of the same oral hormonal contraceptive product for at least 4 
weeks before dosing with study drug(s) and for the duration of the study.
20. Males who have not had a successful vasectomy (confirmed azoospermia) or if they and 
their female partners do not meet the criteria above (ie, not of childbearing potential or 
practicing highly effective contraception throughout the study period and for 28 days 
after lenvatinib discontinuation or 6 months after discontinuation of etoposide and 
ifosfamide).  No sperm donation is allowed during the study period and for 28 days after 
lenvatinib discontinuation or 6 months after discontinuation of etoposide and ifosfamide.
21. A contraindication to any of the study drugs (lenvatinib, ifosfamide, and etoposide) per 
local prescribing information.
Page 59 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 59 of 147
9.3.3
Removal of Subjects From Therapy or Assessment
Subjects will continue to receive study treatment until any of the following occur:  

Progressive disease (as confirmed by IIR*)

Unacceptable toxicity

Subject request

Withdrawal of consent 

Termination of the study by the Sponsor
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 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.
During the Follow-Up Period, subjects who have discontinued study treatment without 
progression should have disease assessments as per the appropriate tumor assessment 
schedule in Table 5 and Table 6 from the date of the last assessment until PD is documented 
or another anticancer therapy is initiated.  After data cutoff for the primary analysis, tumor 
assessments may be performed as clinically indicated per institutional guidelines (but no less 
frequently than every 12 weeks), following the prevailing local standard of care, and IIR 
confirmation of radiographic evidence of PD will not be required.
All subjects will be followed for survival for up to 2 years after end of treatment for a 
subject, except where a subject withdraws consent or the sponsor chooses to halt survival 
follow-up after completion of the primary study analysis.
*Confirmation of disease progression by IIR is only required during the Randomization 
Phase.
9.4
Treatment(s)
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 subjects unable to 
swallow capsules, as detailed in the Pharmacy Manual.
Test Arm (Arm A):  Lenvatinib + Ifosfamide + Etoposide
Lenvatinib 14 mg/m2, orally administered once daily in each 21-day cycle.
Page 60 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 60 of 147
Lenvatinib is provided as hard capsules containing 1 mg, 4 mg, or 10 mg lenvatinib.  An 
extemporaneous suspension of lenvatinib capsules should be used for subjects unable to 
swallow capsules. After adjustment for body surface area (BSA), the daily dose cannot
exceed 24 mg QD.
Ifosfamide 3000 mg/m2/day, IV, for 3 consecutive days (Day 1 to 3), every 21 days, for a 
maximum of 5 cycles.
Etoposide 100 mg/m2/day, IV, for 3 consecutive days (Day 1 to 3) , every 21 days, for a 
maximum of 5 cycles. 
Treatment with lenvatinib will continue in 21-day cycles after chemotherapy is discontinued, 
until disease progression, development of unacceptable toxicity, subject request, withdrawal 
of consent, or discontinuation of study by the sponsor.  In case the study is discontinued by 
the sponsor, the sponsor will provide study drug (outside the study) for subjects who have not 
met the criteria for study drug discontinuation.
Control Arm (Arm B):  Ifosfamide + Etoposide
Ifosfamide 3000 mg/m2/day, IV, daily for 3 consecutive days (Day 1 to 3), every 21 days, for 
a maximum of 5 cycles.
Etoposide 100 mg/m2/day, IV, daily for 3 consecutive days (Day 1 to 3), every 21 days, for a 
maximum of 5 cycles.
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) × body surface area (BSA) (m2) = lenvatinib dose (mg)
Body surface area (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. 
Subjects will receive study treatment as continuous 21-day cycles in both treatment arms.  
Treatment cycles will be counted continuously regardless of dose interruptions.  If 
chemotherapy administration is precluded on Day 1 of a treatment cycle, the subject may 
resume treatment once recovered at the discretion of investigator.  Subsequent chemotherapy 
will be administered every 21 (±1) days starting from the timepoint it was resumed.
Optional Lenvatinib Crossover (for Subjects in Arm B Only):
Subjects in Arm B with disease progression per RECIST 1.1 may be eligible for optional 
treatment with lenvatinib±chemotherapy. Please see Section 9.1.4 for further details. 
Page 61 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 61 of 147
Lenvatinib Dose Reduction and Interruption Instructions
Adverse events will be graded using CTCAE version 5.0.
Dose reduction and interruptions for subjects who experience lenvatinib related toxicity will 
be managed as described in Table 1.  
The starting dose of lenvatinib is 14 mg/m2. 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 study drug dose level has been reduced, it may not be increased at a later date, 
unless the dose was mistakenly decreased; in this situation, the sponsor’s approval is required 
to increase the dose.
Refer to the subsections below for management of hypertension, posterior reversible 
encephalopathy syndrome/reversible posterior leukoencephalopathy syndrome 
(PRES/RPLS), proteinuria, hepatotoxicity, thromboembolic events, hypocalcemia, 
gastrointestinal symptoms and acute abdominal pain, and hemorrhage, as appropriate, before 
consulting the dose modification table below.
Page 62 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 62 of 147
Table 1
Criteria for Temporary Discontinuation of Study Drug, Dose 
Reduction, and Resumption of Treatment
Dose Modification Guidelines for Lenvatinib Related Toxicity
Treatment-Related Toxicitya,b
Management
Dose Adjustment
Grade 1 or Tolerable Grade 2
Continue treatment
No change
Intolerable Grade 2c, d or Grade 3e
First occurrence
Interrupt lenvatinib until 
resolved to Grade 0-1, or 
tolerable Grade 2
11.2 mg/m2 (or 20% 
reduction of the starting 
dose) orally QD (one-level 
reduction)
Second occurrence
(same toxicity or new toxicity)
Interrupt lenvatinib until 
resolved to Grade 0-1, or 
tolerable Grade 2
9.0 mg/m2 (or 20% 
reduction of the previous 
dose) orally QD (one-level 
reduction)
Third occurrence
(same toxicity or new toxicity)
Interrupt lenvatinib until 
resolved to Grade 0-1, or 
tolerable Grade 2
7.2 mg/m2 (or 20% 
reduction of the previous 
dose) orally QD (one-level 
reduction)  
Fourth occurrence
(same toxicity or new toxicity)
Interrupt lenvatinib
Discuss with sponsor
Grade 4f: Discontinue Study Treatment
Note: For grading see CTCAE version 5.0. Collect all CTC grades of adverse events, decreasing and 
increasing grade. 
BMI =  body mass index, CTCAE = Common Terminology Criteria for Adverse Events
a: An interruption of study treatment for more than 28 days will require sponsor`s approval before treatment 
can be resumed.
b: Initiate optimal medical management for nausea, vomiting, hypertension, hypothyroidism, and/or diarrhea 
prior to any study treatment interruption or dose reduction. 
c: Applicable only to Grade 2 toxicities judged by the subject and/or physician to be intolerable.
d: Obese subjects with weight loss do not need to return to the baseline weight or 10% of baseline weight (ie, 
Grade 1 weight loss).  These subjects will restart the study drug(s) at a lower dose once their weight 
remains stable for at least 1 week and they reached the normal BMI (if the weight loss occurred but it is 
still above normal BMI, they can restart the study treatment at a lower dose once the weight has been 
stable for at least 1 week).  Normal BMI should be used as the new baseline for further dose reductions.   
Obesity is defined as body mass index (BMI) percentiles corresponding to 30 kg/m², related to the age of 
the children (Cole, et al., 2000) or BMI ≥ the 95th percentile for children and teens of the same age and sex 
(Ogden, et al., 2002) (Appendix 7 and Appendix 8).   
e: For asymptomatic laboratory abnormalities, such as Grade ≥3 elevations of amylase and lipase that are not 
considered clinically relevant by the investigator, continuation of treatment should be discussed with the 
Sponsor. 
f: Excluding laboratory abnormalities judged to be non-life-threatening, in which case manage as Grade 3.
9.4.1.1.1
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 are
provided in Appendix 5 and Appendix 6.  BP that is consistently above the 95th percentile 
based on sex, age, and height/length for subjects <18 years old; or BP ≥140/90 mmHg for 
Page 63 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 63 of 147
subjects ≥18 to 25 years old 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 the management of hypertension for participants 18 to 25 years 
old are included in parentheses in Section 9.4.1.1.1 .
9.4.1.1.2
MANAGEMENT OF HYPERTENSION
Hypertension is a recognized side-effect of treatment with drugs inhibiting VEGF signaling.
Investigators should therefore ensure that subjects enrolled to receive treatment with 
lenvatinib have BP <95th percentile [BP ≤150/90 mm Hg] for sex, age, and height/length at 
the time of study entry and, if known to be hypertensive, have been on a stable dose of 
antihypertensive therapy for at least 1 week before Cycle 1 Day 1. Early detection and 
effective management of hypertension are important to minimize the need for lenvatinib dose 
interruptions and reductions.  
Regular assessment of BP should be conducted as detailed in the Schedule of Procedures/
Assessments (Table 5 and Table 6).  Hypertension will be graded using CTCAE v5.0, based 
on BP measurements only (and not on the number of antihypertensive medications).
If the subject’s initial BP measurement is elevated (systolic BP ≥95th percentile [BP 
≥140 mm Hg] or diastolic BP ≥95th percentile [BP ≥90 mm Hg]), the BP measurement 
should be repeated at least 5 minutes later. The mean value of 2 measurements at least 
5 minutes apart is defined as 1 BP assessment. If the BP assessment (ie, the mean of the 
2 BP measurements obtained at least 5 minutes apart) is elevated (systolic BP ≥140 mm Hg 
or diastolic BP ≥90 mm Hg), a confirmatory assessment should be obtained at least 
30 minutes later by performing 2 measurements (at least 5 minutes apart) to yield a mean 
value.
Antihypertensive agents should be started as soon as elevated BP (systolic BP ≥95th 
percentile [BP ≥140 mm Hg] or diastolic BP ≥95th percentile [BP ≥90 mm Hg]) is confirmed 
on 2 assessments obtained 30 minutes apart.  The choice of antihypertensive treatment should 
be individualized to the 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 
30 minutes apart.  For those subjects already on antihypertensive medication, treatment 
modification may be necessary if hypertension persists.
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 
Page 64 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 64 of 147
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 on Day 15 
(or more frequently as clinically indicated) until systolic BP has been <95th percentile 
(≤150 mm Hg) and diastolic BP has been <95th percentile (≤95 mm Hg) for 2 consecutive 
treatment cycles.  If a repeat event of systolic BP ≥99th percentile (BP ≥160 mm Hg) or 
diastolic BP ≥99th percentile (BP ≥100 mm Hg) occurs, the 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 2 consecutive treatment cycles. 
The following guidelines should be followed for the management of systolic BP ≥99th 
percentile (BP ≥160 mm Hg) or diastolic BP ≥99th percentile (BP ≥100 mm Hg) confirmed 
on repeat measurements after at least 30 minutes: 

Continue lenvatinib and institute antihypertensive therapy for subjects not already 
receiving this. 

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%]) 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. 
-
If systolic BP ≥99th percentile (BP ≥160 mm Hg) or diastolic BP ≥99th percentile 
(BP ≥100 mm Hg) recurs on the first dose reduction despite optimal management 
of hypertension with antihypertensive medications (either by dose increase or the 
addition of a different class of antihypertensive), then lenvatinib administration 
should be interrupted and restarted at an additional dose reduction only when 
systolic BP <95th percentile (BP ≤150 mm Hg) and diastolic BP <95th percentile 
(BP ≤95 mm Hg) and the subject has been on a stable dose of antihypertensive 
medication for at least 48 hours. 
-
If systolic BP ≥99th percentile (BP ≥160 mm Hg) or diastolic BP ≥99th percentile 
(BP ≥100 mm Hg) recurs on the second dose reduction despite optimal 
management of hypertension with antihypertensive medications (either by dose 
increase or the addition of a different class of antihypertensive), then lenvatinib 
administration should be interrupted and restarted at a third dose reduction only 
when systolic BP <95th percentile (BP ≤150 mm Hg and diastolic BP <95th 
Page 65 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 65 of 147
percentile (BP ≤95 mm Hg) and the participant has been on a stable dose of 
antihypertensive medication for at least 48 hours.
-
Additional dose reduction should be discussed with the Sponsor. 
The following guidelines should be followed for the management of Grade 4 hypertension 
(life-threatening consequences): 

Institute appropriate medical management 

Discontinue lenvatinib
Figure 2 shows the procedures associated with the management of hypertension.
SCREENING
BP mmHg <95th Percentile [<150/90 mmHg]
If known with HTN, no change in anti-HTN meds within 1 week
On the Study (Starting Dose)
BP mmHg ≥ 95th percentile [≥140/90 mmHg] on 2 assessments 
30 mins apart
No Tx with HTN Meds
On anti-HTN Meds
Start anti-HTN Monotherapy
Start anti-HTN Monotherapy
Increase Dose of 
Current anti-HTN AgentOR
Add 1 or more agents of 
different Class of anti-HTN Med
BP mmHg ≥ 99th percentile [≥160/100 
mmHg] on 2 assessments 30 mins apart
If not on anti-HTN meds, institute 
monotherapy anti-HTN meds
If on anti-HTN meds, increase dose or 
add 1 more agent of different class of 
anti-HTN meds 
BP mmHg ≥99th percentile [≥160/100 mmHg] persists despite 
optimal anti-HTN meds
Interrupt study drug and restart at a lower dose (20% reduction of 
starting dose) once BP (mmHg) is <95th percentile  [<150/90 mmHg]
BP mmHg ≥99th percentile [≥160/100 mmHg] recurs despite 
optimal anti-HTN meds
BP mmHg ≥99th percentile [≥160/100 mmHg] recurs despite 
optimal anti-HTN meds
Additional dose reduction should be discussed with the Sponsor
Management of Hypertension
Interrupt study drug and restart at a lower dose (20% reduction of 
starting dose) once BP (mmHg) is <95th percentile  [<150/90 mmHg]
Interrupt study drug and restart at a lower dose (20% reduction of 
starting dose) once BP (mmHg) is <95th percentile  [<150/90 mmHg]
1 BP assessment is defined as the mean value 
of 2 measurements at least 5 min apart
Figure 2
Management of Hypertension
BP = blood pressure, HTN = hypertension, Tx = treatment.
Page 66 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 66 of 147
9.4.1.1.3
MANAGEMENT OF POSTERIOR REVERSIBLE ENCEPHALOPATHY 
SYNDROME/REVERSIBLE POSTERIOR LEUKOENCEPHALOPATHY SYNDROME
Posterior Reversible encephalopathy Syndrome (PRES)/Reversible Posterior 
Leukoencephalopathy Syndrome (RPLS) is a neurological disorder that can present with 
headache, seizure, lethargy, confusion, altered mental function, blindness, and other visual or 
neurological disturbances.  Mild to severe hypertension may be present.  An MRI is 
necessary to confirm the diagnosis of PRES/RPLS.  Appropriate measures should be taken to 
control BP (see Section 9.4.1.1.1 and 9.4.1.1.2), and neurologic consultation is advised.  In 
subjects with signs or symptoms of PRES/RPLS, dose modification guidelines as per Table 1
should be followed.
9.4.1.1.4
MANAGEMENT OF PROTEINURIA
Regular assessment for proteinuria should be conducted as detailed in the Schedule of 
Assessments (Table 5 and Table 6).  Guidelines for assessment and management of 
proteinuria are summarized as follows: 
Grading of Proteinuria

Grading according to CTCAE 5.0 (Cancer Therapy Evaluation Program, 2017) will be 
based on the protein-creatinine ratio or 24-hour urinary protein result, if available. For 
subjects ≥18 years of age, if the subject has 4+ proteinuria by dipstick, a 24-hour urinary 
protein result is required to confirm Grade 3 proteinuria.
Management of Proteinuria

Management of lenvatinib administration will be based on the grade of proteinuria 
according to Table 1.

In the event of nephrotic syndrome, lenvatinib must be discontinued.
Detection and Confirmation

Perform urine dipstick testing per the Schedule of Assessments (Table 5 and Table 6)

For subjects ≥18 years of age, a 24-hour urine collection initiated as soon as possible and 
at least within 72 hours (or an immediate spot urine protein-to-creatinine ratio [UPCR]
test) AND for subjects <18 years of age, an immediate spot UPCR test, and if possible, a 
24-hour urine collection (initiated as soon as possible and at least within 72 hours) is 
required in the following situations:
-
The first (initial) occurrence of ≥2+ proteinuria on urine dipstick while on lenvatinib
-
A subsequent increase in severity of urine dipstick proteinuria occurring on the same 
lenvatinib dose level
-
When there has been a lenvatinib dose reduction and at the new dose level the urine 
protein dipstick result is ≥2+

For subjects ≥18 years of age, a 24-hour urine collection (initiated as soon as possible and 
at least within 72 hours) to verify the grade of proteinuria is required when UPCR is ≥2.4.
Page 67 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 67 of 147
Monitoring

Urine dipstick testing for subjects with proteinuria ≥2+ should be performed on Day 15 
(or more frequently as clinically indicated) until the results have been 1+ or negative for 
2 consecutive treatment cycles.

Proteinuria monitoring can be performed at the local laboratory or investigator site, but 
must be managed by the site physician.
9.4.1.1.5
MANAGEMENT OF HEPATOTOXICITY
Regular monitoring of liver function tests (ALT, AST, bilirubin levels) should be conducted 
as detailed in the Schedule of Assessments (Table 5 and Table 6) 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 1).  Appropriate 
supportive care should be provided together with close monitoring.  If hepatic (any grade per 
CTCAE v5) failure occurs the study drug must be discontinued.
9.4.1.1.6
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 
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 1).  
Appropriate supportive care should be provided together with close monitoring.  If a subject 
experiences a Grade 3 or a life-threatening (Grade 4) thromboembolic reaction, including 
pulmonary embolism, study drug must be discontinued.
Arterial thromboembolic events (eg, new onset, worsening, or unstable angina, myocardial 
infarction, transient ischemic attack, and cerebrovascular accident) of any grade require study 
drug discontinuation.
9.4.1.1.7
MANAGEMENT OF HYPOCALCEMIA
Serum calcium should be monitored monthly per the Schedule of Assessments (Table 5 and 
Table 6). Corrected serum calcium should be used to assess the grade of hypocalcemia per 
CTCAE v5.0, using the following formula: 
Corrected calcium = ([4 – serum albumin in g/dL] ×0.8 + serum calcium)
The formula is not applicable when serum albumin concentration is normal (˃4 g/dL); in 
such situations, the total (uncorrected) serum calcium should be used instead.
Hypocalcemia should be treated per institutional guidelines (eg, using appropriate calcium, 
magnesium, and Vitamin D supplementation) until resolution.
Page 68 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 68 of 147
9.4.1.1.8
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, follow 
instructions contained in Table 1 regarding study treatment dose reduction and interruption.  
For Grade 4 adverse events that result in abdominal pain, study drug must be discontinued.
Gastrointestinal symptoms including diarrhea should be managed by providing symptomatic 
treatment. If the symptoms persist (eg, diarrhea for more than 10 days), dose modification 
guidelines should be followed as per Table 1. 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. 
9.4.1.1.9
MANAGEMENT OF HEMORRHAGE
Dose modification guidelines as per Table 1 for lenvatinib related adverse events should be 
followed for the management of hemorrhage.  Either resume lenvatinib at a reduced dose or 
discontinue lenvatinib, depending on the severity and persistence of hemorrhage.
9.4.1.1.10 MANAGEMENT OF FISTULA FORMATION AND GASTROINTESTINAL
PERFORATION
Lenvatinib should be discontinued in any participants who develop grade ≥4 fistula 
(gastrointestinal or non-gastrointestinal), or gastrointestinal perforation of any grade.
9.4.1.1.11 MANAGEMENT GUIDELINES FOR QT PROLONGATION
Lenvatinib should be withheld in the event of development of QT interval prolongation 
greater than 500 msec. Lenvatinib should be resumed at a reduced dose when QTc 
prolongation is resolved to <480 msec or baseline. Monitor potassium, calcium and 
magnesium, and replenish as appropriate.
Management of Ifosfamide-Etoposide Associated Toxicity
Blood counts should be closely monitored during and prior to the next cycle of 
chemotherapy. Chemotherapy-associated myelosuppression should be managed by 
granulocyte-colony stimulating factor (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 white blood cell (WBC) counts are 
≥1×109/L. Guidelines for dose modification for ifosfamide and etoposide associated 
toxicities are provided in the Table 2 below. 
Page 69 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 69 of 147
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 2
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
ANC = absolute neutrophil count, RBC = red blood cell, ULN = upper limit normal.
9.4.2
Identity of Investigational Product(s)
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. Instructions for 
the preparation of the lenvatinib suspension are provided in the Pharmacy Manual.
Chemical Name of E7080

Test drug code:  E7080

Generic name:  lenvatinib
Page 70 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 70 of 147

Chemical name:  4-[3-Chloro-4-(N’-cyclopropylureido)phenoxy]-7-methoxyquinoline-6-
carboxamide methanesulfonate

Molecular formula:  C21H19CLN4O4•CH4O3S

Molecular weight: 522.96
Comparator Drug
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 or 
sourced by the clinical sites.  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 at least 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. It is recommended that 
mesna uroprotection be administered at a dose equivalent to that administered for ifosfamide.
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. 
Anti-emetic or any other prophylaxis should be administered in accordance with institutional 
guidelines.
Labeling for Study Drug
Lenvatinib and the combination chemotherapy drugs, ifosfamide and etoposide, where 
supplied by the sponsor will be labeled in accordance with text that is in full regulatory 
compliance with each participating country and is translated into the required language(s) for 
each of those countries.  
The following information will be provided (but not limited to):

For clinical trial use only

Name and address of the sponsor

Chemical name / drug identifier

Lot number/Batch number

Storage conditions, expiration date if necessary
Page 71 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 71 of 147
Storage Conditions
Lenvatinib will be stored in accordance with the labeled storage conditions.  The expiry date 
for lenvatinib will be established based on manufacturing date and is based on formulation 
testing.  The expiry date of the lenvatinib will either be on the label and in the interactive 
voice response system (IVRS) system.
Ifosfamide and etoposide will be stored in accordance with the labeled storage conditions.  The 
expiry date of the ifosfamide and etoposide will be the same as the commercial products 
provided. 
Temperature monitoring is required at the storage location to ensure that the study drugs are
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.
9.4.3
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 treatments based on a computer-generated randomization scheme that will be 
reviewed and approved by an independent statistician.  The randomization scheme and 
identification for each subject will be included in the final clinical study report for this study.
After the Baseline Period, subjects will be randomized to 1 of the following 2 treatment arms 
in a 1:1 ratio:

Arm A:  lenvatinib 14 mg/m2 (orally, once daily) plus ifosfamide 3000 mg/m2/day (IV, 
Day 1 to Day 3 of each cycle for a total of up to 5 cycles) and etoposide 100 mg/m2/day 
(IV, Day 1 to Day 3 of each cycle for a total of up to 5 cycles)

Arm B:  ifosfamide 3000 mg/m2/day (IV, Day 1 to Day 3 of each cycle for a total of up to 
5 cycles) and etoposide 100 mg/m2/day (IV, Day 1 to Day 3 of each cycle for a total of up 
to 5 cycles)
Randomization will be performed centrally by an IVRS.  Randomization will follow a 
predefined randomization scheme based on the following stratification factors: time to first 
relapse/refractory disease (early [<18 months] or late [≥18 months]) and age (<18 and 
≥18 years).  Time to first relapse/refractory disease will be calculated starting from date of 
initial diagnosis.
Page 72 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 72 of 147
9.4.4
Selection of Doses in the Study
The dose of lenvatinib, ifosfamide and etoposide in this study is the RP2D (14 mg/m2 + 
ifosfamide 3000 mg/m2 + etoposide 100 mg/m2) established in Study 207. The safety, 
tolerability and activity of single-agent lenvatinib, and lenvatinib in combination with 
chemotherapy (ifosfamide and etoposide), have been assessed in Study 207, a phase 1/2, 
multicenter, open-label study in children, adolescents and young adults with solid tumors, 
including relapsed or refractory osteosarcoma, and radioiodine- refractory differentiated 
thyroid carcinoma.  The recommended phase 2 dose (RP2D) of lenvatinib was determined in 
the phase 1b portion as 14 mg/m2 orally once daily when given as single-agent as well as in 
combination with etoposide (100 mg/m2 IV once daily for 3 days) + ifosfamide (3000 mg/m2
IV once daily for 3 days), administered on days 1 to 3 of each 21-day cycle, for 5 cycles.. 
BSA will be used to determine the daily dose of lenvatinib for each subject. After adjustment 
for BSA, the daily dose of lenvatinib cannot exceed 24 mg. Please see Section 7.3.1 for 
further details on the results of Study 207.
9.4.5
Selection and Timing of 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 21 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 drugs should be administered at the clinic on PK sampling days. All scheduled visits 
must be conducted as per protocol, irrespective of treatment interruption. 
9.4.6
Blinding
The study will not be blinded.
9.4.7
Prior and Concomitant Therapy
All prior medications (including over-the-counter medications) administered 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.
Treatment of complications or AEs, or therapy 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.
Page 73 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 73 of 147
Aspirin, nonsteroidal antiinflammatory drugs (NSAIDs), and low-molecular-weight heparin 
(LMWH) are permissible but should be used with caution.  Granulocyte colony-stimulating 
factor (g-CSF) or equivalent may be used in accordance with American Society of Clinical 
Oncology (ASCO), institutional, or national guidelines.  Erythropoietin may be used 
according to ASCO, institutional, or national guidelines, but the subject should be carefully 
monitored for increases in red blood cell (RBC) counts.
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.  There is no clinically meaningful drug-drug interaction (DDI) risk when lenvatinib 
is co-administered with CYP3A substrates such as midazolam.  Simultaneous CYP3A4/P-gp 
inhibitions by ketoconazole slightly (15% to 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.
Prohibited Concomitant Therapies and Drugs
Subjects should not receive other antitumor therapies while on study. If a subject receives 
additional antitumor therapies other than the study drug(s), such as chemotherapy, targeted 
therapies, immunotherapy, or antitumor interventions - such as surgery or palliative 
radiotherapy (other than as described below), this will be judged to represent evidence of 
disease progression, and the study medication should be discontinued.  
Bisphosphonates and denosumab for the treatment of osteosarcoma are not permitted.
The concomitant use of live vaccines (e.g., measles, mumps, rubella, chicken pox, yellow 
fever, rabies, BCG, and typhoid [oral] vaccines) are not permitted. Seasonal influenza 
vaccines for injection are generally killed virus vaccines and therefore are permitted. 
However intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines, and 
therefore are not permitted. Additionally, the concomitant use of live vaccines with 
chemotherapy is contraindicated in immunosuppressed patients.
Page 74 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 74 of 147
For further information on the prohibited concomitant therapies for ifosfamide and etoposide, 
please refer to the respective prescribing information.
Permitted Concomitant Treatment/Procedures
The following concomitant treatments/procedures are allowed:
a.
Removal of existing (not new) osteosarcoma lesion (eg, surgical, radiofrequency 
ablation, cryotherapy, thermoablation, stereotactic radiotherapy, etc.) after completion of 
the Week 18 tumor assessment.  Subjects may continue study treatment after protocol 
permissible surgery in the presence of clinical benefit, with Sponsor approval.
b. Palliative radiotherapy is allowed for ≤2 significantly symptomatic nontarget lesions. 
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 2 weeks after, once there is evidence of adequate healing and no 
risk of bleeding. 
Any additional procedural or subject specific particularities should be discussed with the 
investigator and the sponsor.
9.4.8
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.
9.4.9
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

The IRB/IEC membership list and statutes or Health and Human Services Assurance 
number
Page 75 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 75 of 147

A copy of the certification and a table of the normal laboratory ranges for the reference 
laboratory conducting the clinical laboratory tests required by this protocol

An investigator-signed and dated FDA Form FDA 1572, or a completed Investigator and 
Site Information Form

Financial Disclosure form(s) for the principal investigator (PI) and all subinvestigators 
listed on Form FDA 1572 or Investigator and Site Information Form

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 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, Medicines and Healthcare Products Regulatory Agency [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 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 
Page 76 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 76 of 147
personnel and documentation procedures by the sponsor’s personnel, study drugs that are to 
be returned to the sponsor’s designated central or local depot(s) must be boxed, sealed, and 
shipped back to the central or local depot(s) following all local regulatory requirements.  In 
some regions, study drugs may be removed from the site and hand delivered to the central or 
local depot by sponsor representatives.  Where study drugs are approved for destruction at 
the site, destruction will occur following the site’s standard procedures and certificates of 
destruction will be provided to the sponsor.
Drug accountability will be reviewed during site visits and at the completion of the study.
9.5
Study Assessments
9.5.1
Assessments
Screening/Baseline Assessments
9.5.1.1.1
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).
9.5.1.1.2
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 2) or Karnofsky performance status score (see Appendix 3), tumor-node 
metastasis (TNM) Staging (at initial diagnosis of the disease), vital signs, clinical chemistry 
and hematology, urine dipstick testing, height, Tanner’s staging (see Appendix 9), dental 
examinations, proximal tibial growth plates, and pharmacodynamic biomarkers (for Arm A 
only).
9.5.1.1.3
MEDICAL HISTORY
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 5, and Table 6).  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 
Page 77 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 77 of 147
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.
Efficacy Assessments
9.5.1.2.1
TUMOR RESPONSE ASSESSMENTS
Tumor assessment will be performed based on RECIST 1.1 (Appendix 1).  
Investigator-determined response assessments will be performed at each assessment time point 
and entered onto the appropriate CRF.  Copies of all tumor assessment scans will be sent to 
an ICL designated by the sponsor for efficacy assessment and for confirmation of PD.  
Tumor assessments will be carried out following the guidelines provided by the ICL.  
Subjects must have evaluable disease or measurable disease based on RECIST 1.1.
At Screening
During the Screening Period, 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 Cycle 1 Day 1.  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.  
Brain scans by MRI with and without contrast enhancement or CT with contrast 
enhancement will be performed at screening as clinically indicated.
Historical scans (within 28 days prior to the Cycle 1 Day 1) may be used to demonstrate 
eligibility as long as they meet minimum standards as separately defined by the ICL. For 
subjects with rapidly progressive disease, it is advised that imaging be repeated prior to 
Cycle 1 Day 1.
If available, bone imaging obtained within 8 weeks prior to Cycle 1 Day 1 should be sent to 
the ICL. Bone lesions noted on the screening/baseline images should be followed as non-
target lesions with modalities other than nuclear medicine scans.
During Treatment Phase
CT scans of the chest and CT/MRI of other known sites of disease, plus any areas of newly 
suspected disease will be performed using the same methodology as at screening every 6 
weeks ±1 week, following the date of randomization until Week 18.  Following completion 
of the chemotherapy treatment period (ie, after Week 18), the frequency of tumor 
assessments will be every 9 weeks ±1 week until Week 54 ±1 week.  Thereafter, they will be 
performed every 12 weeks ±2 weeks until documentation of PD.  At any point, scans should 
be performed earlier than the scheduled time point, if clinically indicated. Any bone imaging 
obtained during the treatment phase should be sent to the ICL. Any non-target bone lesions 
should be followed with modalities other than nuclear medicine scans; if a non-target bone 
lesion is not evaluable (NE) for a timepoint, the lesion should be considered as NE, but 
timepoint response does not need to be evaluated as NE.
Page 78 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 78 of 147
An initial assessment of CR or PR according to RECIST 1.1 must be confirmed by IIR 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 PD, tumor assessments 
should continue to be performed as per the tumor assessment schedule until documentation 
of progression or start of a new anticancer agent.  Screening CT scans should be performed 
with iodinated intravenous contrast and MRI scans should be performed with intravenous
gadolinium chelate.  Post-screening scans may be performed without contrast if a medical 
contraindication develops while on study treatment.  If iodinated intravenous contrast is 
contraindicated, chest CT should be done without intravenous 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 iodinated intravenous
contrast, and the MRI scans should be performed with intravenous 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 5-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.
Brain scans by MRI with and without contrast enhancement or CT with contrast 
enhancement will be performed 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, 9, or 12 weeks).  
Disease progression per RECIST 1.1 during the randomization phase must be confirmed by 
IIR prior to the investigator discontinuing study treatment for a subject.  In the event that the 
investigator considers alternative treatments must be instituted immediately for management 
of urgent medical complications of PD, study drugs may be discontinued without waiting for 
independent confirmation of radiographic evidence of PD.  Subjects who discontinue study 
Page 79 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 79 of 147
treatment without PD will continue to undergo tumor assessments according to the schedule 
until PD is documented or another anticancer therapy is initiated.  If possible, before 
discontinuation of the subject from the study, the investigator should consult with the 
sponsor.
During Post-treatment Follow-up 
Subjects who discontinue treatment without PD will have tumor assessments performed as 
per the appropriate tumor assessment schedule) or sooner if clinically indicated, for
documented PD or until another anticancer therapy is initiated, whichever occurs first. 
After data cutoff for the primary analysis, tumor assessments may be performed as clinically 
indicated as per the institutional guidelines (but no less frequently than every 12 weeks), 
following the prevailing local standard of care.  All subjects will be followed for survival for 
up to 2 years after end of treatment, unless the study is terminated by the sponsor, or the 
subject discontinues due to withdrawal of consent, or is lost to follow-up.
During the Optional Lenvatinib Crossover Treatment Phase
Prior to optional lenvatinib crossover, baseline tumor assessment must be re-established (i.e., 
new tumor assessment scans performed), unless the last tumor assessment scans were 
performed within 4 weeks prior to Cycle 1 Day 1 of the crossover treatment.
During the Optional Lenvatinib Crossover Treatment Phase, tumor assessments will be 
performed as clinically indicated per the institutional guidelines (but no less frequently than 
every 12 weeks), following the prevailing local standard of care. Scans are not required to be 
submitted to the independent imaging core laboratory during the Optional Lenvatinib 
Crossover Treatment Phase. 
9.5.1.2.2
PALATABILITY AND ACCEPTABILITY OF LENVATINIB SUSPENSION FORMULATION
The palatability and acceptability of lenvatinib suspension formulation will be assessed using 
the Palatability Questionnaire (see Appendix 4). All subjects who receive suspension 
formulation with the exception of subjects using a nasogastric or gastrostomy tube, must 
complete the questionnaire on C1D1 (or the subsequent visit).  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 a facial Hedonic scale (Guinard, 2001).
Pharmacokinetic, Pharmacodynamic, and Other Biomarker Assessments
9.5.1.3.1
PHARMACOKINETIC ASSESSMENTS
In order to ensure patient safety and not exceed the maximum allowable volume for blood 
collections, pharmacokinetic sampling should not be performed for any subject with a body 
weight <13 kg. Blood samples (2 mL each) will be collected from all subjects from Arm A 
only at the time points shown in Table 3.  Pharmacokinetic blood samples will also be drawn 
pretreatment on the day of tumor assessment as described in the Table 3.  Actual time and 
Page 80 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 80 of 147
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 3, 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 doses of lenvatinib will be administered at the study site at approximately the same 
time of day in order to accommodate PK sample collection timing.  Instructions for the 
collection, handling, and shipping procedures of PK samples will be provided in a separate 
Laboratory Manual.
Table 3
Lenvatinib Pharmacokinetic Sampling Time Points
Time Pointa
Time (h)
Cycle 1 Day 1
Postdose:  0.5-4 and 6-10
Cycle 1 Day 15
Predose
Postdose: 0.5-4 and 6-10
Cycle 2 Day 1
Predose
Note: All predose samples are to be drawn approximately 24 hours following the dose administered on the 
previous day.
h = hour(s).
a. If dose interruption is necessary in these time points, please contact the sponsor.
Only samples from all subjects randomized to Arm A will be collected.  Lenvatinib will be 
quantified using a validated liquid chromatography/mass spectrometry/mass spectrometry 
(LC/MS/MS) method.
9.5.1.3.2
PHARMACODYNAMIC AND OTHER BIOMARKER ASSESSMENTS
In order to ensure patient safety and not exceed the maximum allowable volume for blood 
collections, pharmacodynamic sampling should not be performed for any subject with a body 
weight <16 kg. Optional pharmacodynamic serum and archived fixed tumor tissue samples 
for biomarker analysis may be collected from study subjects randomized to Arm A (ie, 
lenvatinib + ifosfamide + etoposide), as specified in the Schedule of 
Procedures/Assessments.
Note: Providing blood samples for pharmacodynamic biomarker assessment is optional and 
will not impact subject eligibility.
Pharmacodynamic serum and tumor biomarkers identified in other lenvatinib clinical studies
may be assessed in samples collected from subjects enrolled in this study.  Pharmacodynamic 
biomarker analysis will be performed as described in an analysis plan provided separately.
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 10).
Page 81 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 81 of 147
Safety Assessments
Safety assessments will consist of monitoring and recording all AEs, including all grades per 
National Cancer Institute (NCI) CTCAE v5.0 (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 or MUGA scans, Lansky play score or Karnofsky performance status score, 
physical examinations, dental examinations, and height assessments as detailed in the 
Schedule of Assessments (Table 5 and Table 6).
Clinical and laboratory toxicities/symptomatology will be graded according to CTCAE v5.0 
(Cancer Therapy Evaluation Program, 2017). 
9.5.1.4.1
ADVERSE EVENTS
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered an investigational product.  An AE does not necessarily have a causal 
relationship with the medicinal product.  For this study, the study drugs are lenvatinib, 
ifosfamide, and etoposide. 
The criteria for identifying AEs in this study are:

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of an investigational product, 
whether or not considered related to the investigational product (Note:  Every sign or 
symptom should not be listed as a separate AE if the applicable disease [diagnosis] is 
being reported as an AE)

Any new disease or exacerbation of an existing disease. However, worsening of the 
primary disease should be captured under efficacy assessments as PD.

Any deterioration in nonprotocol-required measurements of a laboratory value or other 
clinical test (eg, ECG or x-ray) that results in symptoms, a change in treatment, or 
discontinuation of study drug

Recurrence of an intermittent medical condition (eg, headache) not present pretreatment 
(Baseline)

An abnormal laboratory test result should be considered an AE if the identified laboratory 
abnormality leads to any type of intervention, withdrawal of study drug, or withholding 
of study drug, whether prescribed in the protocol or not
All AEs, regardless of relationship to study drug or procedure, should be recorded beginning 
from the time the subject signs the study ICF through the last visit and for 30 days after the 
subject’s last dose.  Refer to Section 9.5.4.1 for the time period after the end of treatment for 
SAE collection.  
Abnormal laboratory values should not be listed as separate AEs if they are considered to be 
part of the clinical syndrome that is being reported as an AE.  It is the responsibility of the 
investigator to review all laboratory findings in all subjects and determine if they constitute 
an AE.  Medical and scientific judgment should be exercised in deciding whether an isolated 
Page 82 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 82 of 147
laboratory abnormality should be classified as an AE.  Any laboratory abnormality 
considered to constitute an AE should be reported on the Adverse Event CRF. 
Abnormal ECG (QTcF) results, if not otherwise considered part of a clinical symptom that is 
being reported as an AE, should be considered an AE if the QTcF interval is more than 
450 ms and there is an increase of more than 60 ms from baseline.  Any ECG abnormality 
that the investigator considers as an AE should be reported as such.
All AEs must be followed for 30 days after the subject’s last study drug dose, or until 
resolution, whichever comes first.  Subjects with onset of an AE or deterioration of a 
preexisting AE during the AE collection period will be followed until resolution to baseline, 
start of a new anticancer treatment, or death.  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 on a 5-point scale according to CTCAE v5.0 (Cancer Therapy 
Evaluation Program, 2017).  Investigators will report CTCAE grades for all AEs (for both 
increasing and decreasing severity).
Assessing Relationship to Study Treatment
Items to be considered when assessing the relationship of an AE to the study treatment are:

Temporal relationship of the onset of the event to the initiation of the study treatment

The course of the event, especially the effect of discontinuation of study treatment or 
reintroduction of study treatment, as applicable

Whether the event is known to be associated with the study treatment or with other 
similar treatments

The presence of risk factors in the study subject known to increase the occurrence of the 
event

The presence of nonstudy, treatment-related factors that are known to be associated with 
the occurrence of the event
Classification of Causality
The relationship of each AE to the study drug will be recorded on the CRF in response to the 
following question:
Is there a reasonable possibility that the study drug caused the AE?
Yes (related)
A causal relationship between the study drug and the AE is a reasonable 
possibility.
Page 83 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 83 of 147
No (not related) A causal relationship between the study drug and the AE is not a 
reasonable possibility.
9.5.1.4.2
SERIOUS ADVERSE EVENTS AND EVENTS ASSOCIATED WITH SPECIAL SITUATIONS
An 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 that may not be immediately life-threatening or result in 
death or hospitalization but, when based on appropriate medical judgment, may jeopardize 
the subject or may require intervention to prevent one of the outcomes in the definition of 
SAE listed above should also be considered SAEs.  Medical and scientific judgment should 
be exercised in deciding whether expedited reporting is appropriate in such situations. 
In addition to the above, events associated with special situations include pregnancy or 
exposure to study drug through breastfeeding; AEs associated with study drug overdose, 
misuse, abuse, or medication error.  These events associated with special situations are to be 
captured using the SAE procedures but are to be considered as SAEs only if they meet one of 
the above criteria.  All AEs associated with special situations are to be reported on the CRF 
whether or not they meet the criteria for SAEs.  
All SAEs must be followed to resolution or, if resolution is unlikely, to stabilization.
The following hospitalizations are not considered to be SAEs because there is no “adverse 
event” (ie, there is no untoward medical occurrence) associated with the hospitalization:

Hospitalizations for respite care 

Planned hospitalizations required by the protocol

Hospitalization planned before informed consent (where the condition requiring the 
hospitalization has not changed after study drug administration)

Hospitalization for administration of study drug or insertion of access for administration 
of study drug

Hospitalization for routine maintenance of a device (eg, battery replacement) that was in 
place before study entry
9.5.1.4.3
LABORATORY MEASUREMENTS
Clinical laboratory tests to be performed, including hematology, chemistry, and urinalysis, 
are summarized in Table 4.  Subjects should be in a seated or supine position during blood 
Page 84 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 84 of 147
collection.  The Schedule of Procedures/Assessments (Table 5 and Table 6) shows the visits 
and time points at which blood for clinical laboratory tests and urine for urinalysis will be 
collected in the study.
Table 4
Clinical Laboratory Tests
Category
Parameters
Hematology
Hematocrit, hemoglobin, platelets, RBC count, and WBC count 
with differential (bands, basophils, eosinophils, lymphocytes, 
monocytes, neutrophils)
Chemistry
Electrolytesa
Bicarbonate, chloride, potassium, sodium, calcium, magnesium, 
phosphorus
Liver function tests
ALT, alkaline phosphatase, AST, conjugated (direct) bilirubinb, 
total bilirubin, INR/PT, aPTT/PTTc
Renal function tests
BUN or urea, creatinine
Other chemistries
Albumin, amylase, glucose, LDH, lipase, total protein 
Thyroid function testsd
Thyroid stimulating hormone, free T4 level
Urinalysis for microscopye
RBCs
Urine dipstick testinge,f
Blood, protein, glucose
Otherg
Pregnancy test (serum or urine β–hCG)
ALT = alanine aminotransferase, aPTT = activated partial thromboplastin time, AST = aspartate 
aminotransferase, BUN = blood urea nitrogen, β hCG = beta-human chorionic gonadotropin, INR = 
International Normalized ratio, LDH = lactate dehydrogenase, aPTT = activated partial thromboplastin time, 
RBC = red blood cells, T4 = thyroxine, TSH = thyroid stimulating hormone, WBC = white blood cells.
a.
Electrolytes such as potassium, calcium, and magnesium should be monitored and abnormalities, when 
considered clinically significant, should be corrected in all participants before starting treatment.
b.
Direct bilirubin should be assessed if total bilirubin is elevated.
c.
INR/PT and aPTT/PTT should only be performed as part of the screening assessment.  During the
study, INR/PT and aPTT/PTT should be performed if clinically indicated.
d.
Thyroid function will be assessed every 2 cycles for all subjects.
e.
If urine dipstick testing suggests a urinary tract infection, or if clinically indicated, a urine microscopy, 
culture, and sensitivity should be performed at the institution’s laboratory
f.
If urine protein is ≥ 2+, then a spot test for protein-creatinine ratio and if possible, a 24-hour urine 
collection should be done to quantify the 24 hour urine protein excretion.
g.
For sites in Germany: HIV and Hepatitis B/C tests are required during Screening.
All clinical laboratory tests during the study will be performed at qualified local laboratories.  
All hematology, blood chemistry (including pregnancy test, as applicable), and urinalysis 
samples are to be obtained prior to study drug administration and sent to the local laboratory 
on the day of collection unless otherwise instructed. 
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.  Electrolytes such as potassium, calcium, and magnesium should be monitored and 
Page 85 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 85 of 147
abnormalities, when considered clinically significant, should be corrected in all participants 
before starting treatment. 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 Table 1
(study drug dose reduction and interruption instructions) 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 9.5.1.4.1 and the CRF Completion Guidelines.  In these instances, the 
AE corresponding to the laboratory abnormality will be recorded on the Adverse Event CRF
(see Section 9.5.4.3.2).
9.5.1.4.4
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 5
and Table 6) 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.  On Cycle 1 Day 8, subjects will have a telephone 
or clinic visit to assess for the development of early toxicity. Subjects will be provided with 
a BP cuff to monitor BP at home or can have the measurement done by a local healthcare 
provider, and will report the C1D8 measurement at telephone contact. An unscheduled visit 
can occur prior to C1D15 if deemed necessary by the investigator.
Only 1 BP measurement is needed for subjects with systolic BP <95th percentile (BP 
<140 mm Hg) and diastolic BP <95th percentile (BP <90 mmHg). If the subject’s initial BP 
measurement is elevated (systolic BP ≥95th percentile [≥140 mmHg] or diastolic BP ≥95th 
percentile [≥90 mmHg]), the BP measurement should be repeated at least 5 minutes later. 
The mean value of 2 measurements at least 5 minutes apart is defined as 1 BP assessment. If 
the BP assessment (ie, the mean of the 2 BP measurements obtained at least 5 minutes apart) 
is elevated (systolic BP ≥95th percentile [≥140 mm Hg] or diastolic BP ≥95th percentile 
[≥90 mm Hg]), a confirmatory assessment should be obtained at least 30 minutes later by 
performing 2 measurements (at least 5 minutes apart) to yield a mean value.
9.5.1.4.5
PHYSICAL EXAMINATIONS
Physical examinations will be performed as designated in the Schedule of 
Procedures/Assessments (Table 5 and Table 6).  Documentation of the physical examination 
will be included in the source documentation at the site.  Only changes from screening 
physical examination findings that meet the definition of an AE will be recorded on the 
Adverse Events CRF.
Page 86 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 86 of 147
9.5.1.4.6
ELECTROCARDIOGRAMS
Electrocardiograms will be obtained as designated in the Schedule of Assessments (Table 5
and Table 6).  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.  If possible, subjects must be in the 
recumbent position for a period of 5 minutes prior to the ECG.
QTc prolongation has been seen in some lenvatinib studies. Monitor ECGs every cycle (as 
specified in the Schedule of Assessments) in participants with congenital long QT syndrome, 
congestive heart failure, bradyarrhythmias, or those who are taking drugs known to prolong 
the QT interval, including Class Ia and III antiarrhythmics. Drugs known to prolong the QTc 
interval (including Class Ia and III antiarrhythmics) must be used cautiously. Please refer to 
the lenvatinib IB or lenvatinib prescribing information.
An ECG abnormality may meet the criteria of an AE as described in this protocol (see
Section 9.5.1.4.1) 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).
9.5.1.4.7
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 9.3.1 and 9.3.2).  A serum or urine 
pregnancy test will be performed at Screening, Baseline (or within 72 hours prior to the first 
dose of study medication), on Day 1 of each cycle from Cycle 2 onwards, 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 5 and
Table 6).
Echocardiogram or Multigated Acquisition (MUGA) Scan
An echocardiogram or MUGA scan to assess LVEF will be performed during the screening 
phase, every 16±2 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.
Page 87 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 87 of 147
Dental Examination
Information from studies in animals suggest that there is a risk of delayed tooth formation 
and/or physical growth and development. Therefore, dental examinations will be performed 
to evaluate subjects for potential anomalies in tooth formation and eruption schedule.
Dental examination by a qualified healthcare professional should be conducted per local 
institutional guidelines at baseline (C1D1 ± 4 weeks), and thereafter per local standard of 
care (but no less than annually), and as part of the Off-treatment assessment. If the most 
recent dental examination is within 6 months prior to the Off-Treatment visit, the dental 
examination is not required. Post-baseline dental examinations are not required for subjects 
for whom permanent teeth (excluding third molars) are evaluated to be fully erupted at 
baseline.
Other Assessments
Health-related quality of life (HRQoL) assessment will be performed per the Schedule of 
Assessments (Table 5 and Table 6). Impact of treatment on HRQoL will be assessed using 
the PedsQL (including the Generic Core Scales and Cancer Module).  Data will be collected 
as parent-report for toddlers (ages 2 to  years) and children (ages 5 to 7), and as self-report 
for subjects aged ≥8 years .  Self-report is the preferred data collection method for all 
subjects aged ≥8, however to improve adherence and reduce missing data, parents or 
caregivers  will be required to report on QoL when self-report is not available; patient’s 
proxy report is still very relevant especially when child self -report is not possible
The PedsQL is a modular instrument designed to measure HRQoL in pediatric and adults 
population. The PedsQL 4.0 Generic Core Scales are multidimensional child self-report and 
parent proxy-report scales developed as the generic core measure to be integrated with the 
PedsQL disease specific modules. The PedsQL 3.0 Cancer Module was designed to measure 
pediatric cancer specific HRQOL.
It is best practice and strongly recommended that the PedsQL measurement modules are 
administered to randomized subjects prior to drug administration or any other interaction 
with site staff. Every effort should be made to administer the PedsQL questionnaires as soon 
as possible after the decision to discontinue study treatment is made.
9.5.2
Schedule of Procedures/Assessments
Schedule of Procedures/Assessments
Table 5 presents the schedule of procedures/assessments for the Randomization Phase of the
study.
Table 6 presents the schedule of procedures/assessments for the Extension Phase of the 
study.
Page 88 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 88 of 147
Table 7 presents the schedule of procedures/assessments for the Optional Lenvatinib 
Crossover Treatment Phase of the study.
Page 89 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 89 of 147
Table 5
Schedule of Assessments in Study E7080-G000-230 – Randomization Phase
Phase
Prerandomization
Randomization a
(All cycles are 21 days in duration)
Period
Screeningb Baselinec
Treatmentd
Off-
Tx
Follow-
up
Visit 
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18+
Cycle
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5
Cycle 
6-X
Day
-28 to -2
-1
1
8
15
1
8
15
1
8
15
1
8
15
1
8
15
1
Procedures/Assessments
Informed consent
X
Inclusion/exclusion
X
X
Randomization (IVRS)
X
Demographic data
X
Medical/surgical history
X
X
Prior medication/ procedures
X
X
Pregnancy teste
X
X
X
X
X
X
X
X
Lansky play score/ 
Karnofsky PSf
X
X
X
X
X
X
X
X
TNM Staging
X
Physical examinationg
X
X
X
X
X
X
X
X
X
X
X
Vital signsh
X
X
X
Xi
X
X
X
X
X
X
X
X
12-lead ECGj
X
X
X
X
X
Echocardiogram or MUGA 
scank
X
Performed every 16±2 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
Urine dipstick testingm
X
X
X
X
X
X
X
X
X
X
PK blood samplesn
X
X
X
Page 90 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 90 of 147
Table 5
Schedule of Assessments in Study E7080-G000-230 – Randomization Phase
Phase
Prerandomization
Randomization a
(All cycles are 21 days in duration)
Period
Screeningb Baselinec
Treatmentd
Off-
Tx
Follow-
up
Visit 
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18+
Cycle
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5
Cycle 
6-X
Day
-28 to -2
-1
1
8
15
1
8
15
1
8
15
1
8
15
1
8
15
1
Procedures/Assessments
Study treatmento
Arm A:  Combination of lenvatinib (QD) + ifosfamide + etoposide (Days 1-3 of Cycles 1-5 only)
[based on BSA calculations at Day 1 of each Cycle]; after Cycle 5 subjects will receive lenvatinib alone.
Arm B:  Ifosfamide + etoposide (Days 1-3 of Cycles 1-5 only)
[based on BSA calculations at Day 1 of each Cycle] 
Palatability Questionnairep
X
Tumor assessments: 
CT/MRIq
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±1 week after the date of randomization or sooner if clinically 
indicated until Week 18±1 week, then every 9±1 weeks until Week 54±1 week.  Thereafter, to be 
performed every 12±2 weeks until documentation of PD.
Xq
Brain CT/MRIr
X
Brain scans will be performed at screening as clinically indicated, and thereafter during treatment if 
clinically indicated.  For subjects with protocol-eligible, treated brain metastases at Screening, brain 
scans should be performed at all tumor assessment time points.
Heights
X
X
X
X
X
X
Tanner Staget
X
X
X
Proximal tibial growth plate 
x-ray s
X
X
Dental examinations
X
X  as per standard of care or at least annually
X
HRQoLu
X
HRQoL will be collected on C2D1, C3D1,  Week 18, C8D1, and C18D1.  
Xu
Pharmacodynamic 
biomarkersv
X
X
X
X
X
Archival tumor block or 
slidesw
X
Survivalx
X
X
Page 91 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 91 of 147
Table 5
Schedule of Assessments in Study E7080-G000-230 – Randomization Phase
Phase
Prerandomization
Randomization a
(All cycles are 21 days in duration)
Period
Screeningb Baselinec
Treatmentd
Off-
Tx
Follow-
up
Visit 
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18+
Cycle
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5
Cycle 
6-X
Day
-28 to -2
-1
1
8
15
1
8
15
1
8
15
1
8
15
1
8
15
1
Procedures/Assessments
Concomitant medicationsy
Throughout
X
AEs/SAEsz
Throughout
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, h = hour, HR = heart rate, HRQoL = Health-Related Quality of Life, IV = intravenous, IVRS = Interactive Voice 
Response System, MRI = magnetic resonance imaging, MUGA = multiple-gated acquisition, PD = progressive disease/disease progression, 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.  
a.
During Cycle 1, efforts should be made to conduct study visits on the day scheduled (1 day); from Cycle 2 onwards, efforts should be made to conduct 
study visits on the day scheduled (±3 days).
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.
For subjects randomized to Arm A, subjects benefiting from study treatment in the opinion of the investigator will continue lenvatinib treatment until PD, 
intolerable toxicity, noncompliance with safety or efficacy assessments, voluntary discontinuation by the subject at any time, or study termination by the 
sponsor, whichever occurs first.
e.
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), on 
Day 1 of each cycle from Cycle 2 onwards, and at the Off-treatment Visit in women of childbearing potential.
f.
A Lansky play score or Karnofsky performance status score will be obtained at the Screening, Baseline, and C1D1 Visit, and Day 1 of every subsequent 
cycle visit thereafter.
g.
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, C2D1, C2D15, 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.
Page 92 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 92 of 147
Table 5
Schedule of Assessments in Study E7080-G000-230 – Randomization Phase
Phase
Prerandomization
Randomization a
(All cycles are 21 days in duration)
Period
Screeningb Baselinec
Treatmentd
Off-
Tx
Follow-
up
Visit 
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18+
Cycle
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5
Cycle 
6-X
Day
-28 to -2
-1
1
8
15
1
8
15
1
8
15
1
8
15
1
8
15
1
Procedures/Assessments
h.
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 for subjects <18 years old; or BP ≥140/90 mmHg for subjects ≥18 to 25 years old requires further evaluation.  Refer to 
hypertension management guidelines in Section 9.4.1.1.2.
i.
On Cycle 1 Day 8, subjects will have a telephone or clinic visit to assess for the development of early toxicity. Subjects will be provided with a BP cuff to 
monitor BP at home or can have the measurement done by a local healthcare provider, and will report the C1D8 measurement at telephone contact. An 
unscheduled visit can occur prior to C1D15 if deemed necessary by the investigator.
j.
Single 12-lead ECG.  If possible, subjects must be in the recumbent position for a period of 5 minutes prior to the ECG.  ECG should be conducted at 
Screening, C1D1, C2D1,  D1 of every 4th cycle (ie, C6, C10, C14, etc.). ECG at C1D1 and C2D1 should be conducted approximately 2 hours after 
lenvatinib dose.  For high risk subjects  (as defined in lenvatinib product label), conduct ECG in every cycle. 
k.
An echocardiogram or MUGA scan is to be performed during screening, every 16±2 weeks, and at the Off-Treatment visit, or sooner if clinically indicated.
l.
Clinical chemistry and hematology results must be reviewed by the investigator prior to administration of study drug on C1D1 and within 48 hours after 
administering any study drug for all subsequent cycles.  Electrolytes such as potassium, calcium, and magnesium should be monitored and abnormalities, 
when considered clinically significant, should be corrected in all participants before starting treatment. 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).  TSH should be assessed for all subjects. For sites in Germany: HIV and Hepatitis B/C tests are required during Screening.
m. Urine dipstick testing should be performed at Screening, Baseline, C1D15, C2D1, C2D15, and Day 1 of every subsequent cycle, or more frequently as 
clinically indicated, 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 2 treatment cycles.  If a new event of proteinuria ≥2+ occurs, refer to Section 9.4.1.1.4 for further management 
guidelines.  Urine glucose should be performed as part of the urine dipstick. 
n.
Sampling (one 2 mL sample per time point) for PK analysis of lenvatinib will be performed (in subjects in Arm A only) on Cycle 1 Day 1 at 0.5 to 4 hours 
and 6 to 10 hours postdose, on Cycle 1 Day 15 at predose, 0.5 to 4 hours and 6 to 10 hours postdose, and on Cycle 2 Day 1 at predose.  All predose samples 
are to be drawn approximately 24 hours following the dose administered on the previous day.  If dose interruption is necessary at  these time points, please 
contact the sponsor. Pharmacokinetic sampling should not be performed for any subject with a body weight <13 kg (please see Section 9.5.1.3.1).
Page 93 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 93 of 147
Table 5
Schedule of Assessments in Study E7080-G000-230 – Randomization Phase
Phase
Prerandomization
Randomization a
(All cycles are 21 days in duration)
Period
Screeningb Baselinec
Treatmentd
Off-
Tx
Follow-
up
Visit 
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18+
Cycle
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5
Cycle 
6-X
Day
-28 to -2
-1
1
8
15
1
8
15
1
8
15
1
8
15
1
8
15
1
Procedures/Assessments
o.
Subjects randomized to Arm A will continue to receive lenvatinib only after completion of 5 cycles with lenvatinib+ifosfamide+etoposide until progressive 
disease, unacceptable toxicity, subject request, study termination by the sponsor, subject noncompliance with safety or efficacy assessments, or withdrawal 
of consent.  Subjects randomized to Arm B will be off-treatment after 5 cycles of ifosfamide+etoposide.
p.
All subjects who receive suspension formulation, with the exception of subjects using a nasogastric or gastrostomy tube, must complete the Palatability 
Questionnaire on C1D1 (or the subsequent visit).  If the subject is unable to complete the questionnaire this must be done by their parents or their legal 
guardian.  
q.
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 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±1 weeks from the date of randomization until Week 18±1 week, then every 9±1 weeks until Week 54±1 week, and thereafter, every 12±2 weeks until 
documentation of PD 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.  Any CR or PR must be confirmed not less than 4 weeks following the initial achievement of the response.  Off-Treatment: 
Tumor assessments at the Off-Treatment Visit (within 1 week of the Off-treatment Visit) are only necessary for subjects who discontinue study treatment 
without disease progression, if more than 4 weeks have passed since the previous assessment and if the subject will not continue with follow-up scans. 
Follow-up: For subjects who discontinue study treatment without disease progression, tumor assessments should continue to be performed according to the 
schedule: every 6±1 weeks until Week 18±1 week, then every 9±1 weeks until Week 54±1 week, thereafter, to be performed every 12±2 weeks, until 
documentation of progression or start of a new anticancer agent. 
r.
Brain CT with contrast or MRI pre- and post- gadolinium contrast will be performed at the Screening Visit as clinically indicated, and thereafter during 
treatment as clinically indicated.  For subjects with protocol-eligible treated brain metastases, brain CT/MRI will be performed at all tumor assessment time 
points.
s.
Height will be assessed at the Baseline Visit, Day 1 of every 4 cycles during the Treatment Phase, at the Off-treatment Visit and every 3 months during the 
Post-treatment Follow-up. Assessment of height in Post-treatment Follow-up is not required once pubertal development is complete. Proximal tibial 
growth plate x-rays should be conducted for subjects aged <18 years at baseline and at the Off-treatment Visit.  If the growth plates are closed at baseline 
Page 94 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 94 of 147
Table 5
Schedule of Assessments in Study E7080-G000-230 – Randomization Phase
Phase
Prerandomization
Randomization a
(All cycles are 21 days in duration)
Period
Screeningb Baselinec
Treatmentd
Off-
Tx
Follow-
up
Visit 
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18+
Cycle
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5
Cycle 
6-X
Day
-28 to -2
-1
1
8
15
1
8
15
1
8
15
1
8
15
1
8
15
1
Procedures/Assessments
then the subject does not need a reassessment at the Off-treatment Visit. X-ray of only 1 leg is required, and if reassessment is needed at the Off-treatment 
Visit, the x-ray must be performed on the same leg as at Screening. Tibial growth plate x-rays will be optional for Germany. A dental examination by a 
qualified healthcare professional should be conducted per local institutional guidelines at baseline (C1D1±4 weeks), and thereafter per local standard of 
care (but no less than annually), and as part of the Off-treatment assessment.  If the most recent dental examination is within 6 months prior to the Off-
treatment Visit, the dental exam is not required. Post-baseline dental exams are not required for subjects for whom permanent teeth (excluding third 
molars) are evaluated to be fully erupted at baseline.
t.
Tanner Staging is only required for female subjects ≥8 years old, and male subjects ≥9 years old. Tanner Stage will be assessed at the Baseline Visit, at the 
Off-treatment Visit, and annually thereafter during the Post-treatment Follow-up. Tanner Staging is not required once pubertal development is complete (ie, 
Tanner Stage 5).
u.
Every effort should be made to administer the PedsQL questionnaires as soon as possible after the decision to discontinue study treatment is made.
v.
Optional blood samples may be collected only from subjects in Arm A at the Baseline Visit, C1D15, Day 1 of Cycles 2, 4, and 6, for assessment for blood 
serum sample to measure factors implicated in angiogenesis. Pharmacodynamic sampling should not be performed for any subject with a body weight <16 
kg (please see Section 9.5.1.3.1).
w.
An archival tumor sample from the most recent surgery or biopsy for identification of predictive biomarkers and pathology review may be collected from 
subjects in Arm A at any time during the study, unless no such material is available. Providing archival tumor samples is optional and does not impact 
subject eligibility.
x.
Survival data will be collected every 3 months for up to 2 years as per the protocol.  All anticancer therapies will be collected.
y.
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.  
z.
All AEs, including SAEs 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.
Page 95 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 95 of 147
Table 6 presents the Schedule of Procedures/Assessments for the Extension Phase of the 
study.  
Page 96 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 96 of 147
Table 6
Schedule of Assessments in Study E7080-G000-230 – Extension 
Phase
Phase
Extensiona
Period
Treatment Period a
Follow-up Period
Visit 
98
99
Cycle
Cycle X +1 and beyond
Off-Tx Visit
Day
1
Procedures/Assessments
Pregnancy testb
X
X
Lansky play score/ 
Karnofsky PSc
X
X
Physical examinationd
X
X
Vital signse
X
X
12-lead ECGf
As clinically indicated
Echocardiogram or 
MUGA scang
As clinically indicated
Clinical chemistry and 
hematologyh
X
X
Urine dipstick testingi
X
X
Study treatmentj
Arm A:  Lenvatinib+ifosfamide+etoposidea
Arm B: Ifosfamide + etoposidea
Tumor assessments: 
CT/MRIk
After data cutoff for the primary analysis, tumor 
assessments may be performed as clinically indicated 
as per the institutional guidelines (but no less 
frequently than every 12 weeks), following the 
prevailing local standard of care.
Brain CT/MRIl
After data cutoff for the primary analysis, tumor 
assessments may be performed as clinically indicated 
as per the institutional guidelines, following the 
prevailing local standard of care.
Heightm
To be checked every 4 cycles
X
X
Tanner Stagen
X
X
HRQoLo
X
X
Proximal Tibial growth 
plate x-rayp
X
Dental examinationsq
X
X
Survivalr
X
X
Concomitant medicationss
Throughout
X
AEs/SAEst
Throughout
X
AE = adverse event, CT = computerized tomography, ECG = electrocardiogram, HRQoL = Health-Related 
Quality of Life, ICL = imaging core laboratory, MRI = magnetic resonance imaging, MUGA = multiple-gated 
acquisition, PD = disease progression, PS = performance status, SAE = serious adverse event.
a. In the Treatment Period, subjects still on study treatment following the completion of the Randomization 
Phase will continue to receive study treatment as outlined in Section 9.1.2.1 until disease progression, 
development of unacceptable toxicity, subject request, withdrawal of consent, or discontinuation of study 
by the sponsor, whichever occurs first.
b. A serum or urine pregnancy test will be performed on Day 1 of each cycle and at the Off-treatment Visit in 
women of childbearing potential.
c. A Lansky play score or Karnofsky performance status score will be obtained at Day 1 of every cycle visit.
d. A physical examination will be performed at Day 1 visit of each cycle, and at the Off-treatment Visit.  A 
Page 97 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 97 of 147
Table 6
Schedule of Assessments in Study E7080-G000-230 – Extension 
Phase
Phase
Extensiona
Period
Treatment Period a
Follow-up Period
Visit 
98
99
Cycle
Cycle X +1 and beyond
Off-Tx Visit
Day
1
symptom-directed physical examination will be performed at any time  as clinically indicated.
e. 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 for subjects <18 years 
old; or BP ≥140/90 mmHg for subjects ≥18 to 25 years old requires further evaluation. Refer to 
hypertension management guidelines in Section 9.4.1.1.2.  
f.
Single 12-lead ECG.  Subjects must be in the recumbent position for a period of 5 minutes prior to the 
ECG.
g. An echocardiogram or MUGA scan is to be performed as clinically indicated.
h. Clinical chemistry and hematology results must be reviewed within 48 hours after administering any study 
drug for all subsequent cycles. Electrolytes such as potassium, calcium, and magnesium should be 
monitored and abnormalities, when considered clinically significant, should be corrected in all participants 
before starting treatment. 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).  TSH should be assessed for all subjects.
i.
Urine dipstick testing should be performed on Day 1 of every cycle, or more frequently as clinically 
indicated, 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 2 consecutive cycles.  If a new 
event of proteinuria ≥2+ occurs, refer to Section 9.4.1.1.4 for further management guidelines.  Urine 
glucose should be performed as part of the urine dipstick.  
j.
Subjects randomized to Arm A will continue to receive lenvatinib only until progressive disease, 
unacceptable toxicity, or withdrawal of consent.  
k. After data cutoff for the primary analysis, tumor assessments may be performed as clinically indicated as 
per the institutional guidelines (but no less frequently than every 12 weeks), following the prevailing local 
standard of care.  The scans will no longer be required to be sent to the ICL.
l.
Brain CT with contrast or MRI pre- and post- gadolinium contrast will be performed as per the institutional 
guidelines, following the prevailing local standard of care.
m. Height will be assessed at the Baseline Visit, Day 1 of every 4 cycles during the Treatment Phase, at the 
Off-treatment Visit and every 3 months during the Post-treatment Follow-up. Assessment of height in Post-
treatment Follow-up is not required once pubertal development is complete.
n. Tanner Staging is only required for female subjects ≥8 years old and male subjects ≥9 years old. Tanner 
Stage will be assessed at the Baseline Visit, at the Off-treatment Visit, and annually thereafter during the 
Post-treatment Follow-up. Tanner Staging is not required once pubertal development is complete (i.e., 
Tanner Stage 5).   
o. HRQoL will be collected at week 18 and the Off-Treatment visit. Every effort should be made to administer 
the PedsQL questionnaires as soon as possible after the decision to discontinue study treatment is made.
p. Proximal tibial growth plate x-rays should be conducted for subjects aged <18 years at baseline and at the 
Off-treatment Visit. If the growth plates are closed at baseline then the subject does not need a 
reassessment at the Off-treatment Visit. X-ray of only 1 leg is required, and if reassessment is needed at the 
Off-treatment Visit, the x-ray must be performed on the same leg as at Screening. Tibial growth plate x-
rays will be optional for Germany.
q. A dental examination by a qualified healthcare professional should be conducted per local institutional 
guidelines at baseline (C1D1±4 weeks), and thereafter per local standard of care (but no less than annually), 
and as part of the Off-treatment assessment.  If the most recent dental examination is within 6 months prior 
to the Off-treatment Visit, the dental exam is not required. Post-baseline dental exams are not required for 
subjects for whom permanent teeth (excluding third molars) are evaluated to be fully erupted at baseline.
Page 98 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 98 of 147
Table 6
Schedule of Assessments in Study E7080-G000-230 – Extension 
Phase
Phase
Extensiona
Period
Treatment Period a
Follow-up Period
Visit 
98
99
Cycle
Cycle X +1 and beyond
Off-Tx Visit
Day
1
r.
Survival data will be collected every 3 months for up to 2 years as per the protocol. All anticancer 
therapies will be collected.
s.
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.  
t.
All AEs, including SAEs 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.
Page 99 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 99 of 147
Table 7 presents the schedule of procedures/assessments for the Optional Lenvatinib 
Crossover Treatment Phase of the study.
Table 7
Schedule of Assessments in Study E7080-G000-230 – Optional 
Lenvatinib Crossover Treatment Phase
Phase
Baselinea
Optional Lenvatinib Crossovera
Period
Treatment Period
Follow-up 
Period
Visit
1
2+
Cycle
1
2
3 and beyond
Off-Tx Visit
Day
-1
1
8
15
1
15
1
Procedures/Assessments
Review eligibilityb
X
Lansky Play/Karnofsky 
PS Scorec
X
X
X
X
X
Physical Examinationd
X
X
X
X
X
X
X
Vital Signse
X
X
Xf
X
X
X
X
X
12-lead ECGg
X
X
X
X
ECHO or MUGA scanh
X
Performed every 16±2 weeks following first 
dose of study drug, or sooner if clinically 
indicated
X
Clinical chemistry and 
hematologyi
X
X
X
X
X
X
Urine dipstick testj
X
X
X
X
X
X
Pregnancy testk
X
X
X
X
Study treatmentl
Lenvatinib±chemotherapy
Palatability 
Questionnairem
X
HRQoL
X
HRQoL will be collected at Baseline, C2D1, 
C3D1, and Week 18
Tumor assessment: 
CT/MRIn
X
Tumor assessments may be performed as 
clinically indicated per the institutional 
guidelines (but no less frequently than every 12 
weeks), following the prevailing local standard 
of care.
Brain CT/MRIo
Brain CT/MRI scans may be performed as clinically indicated 
as per the institutional guidelines, following the prevailing local 
standard of care.
Heightp
X
X
X
X
X
Tanner Stageq
X
X
X
Survivalr
X
X
Concomitant 
medicationss
X
Throughout
X
AEs/SAEst
X
Throughout
X
AE = adverse event, CT = computerized tomography, ECG = electrocardiogram, HRQoL = Health-Related Quality of Life, 
ICL = imaging core laboratory, MRI = magnetic resonance imaging, MUGA = multiple-gated acquisition, PD = disease 
progression, PS = performance status, SAE = serious adverse event.
a.
Baseline assessments (except ECG, MUGA, and Tumor scans) may occur within 72 hours prior to C1D1. For subjects 
in Arm B only: subjects may be eligible for additional treatment with lenvatinib ± chemotherapy following disease 
progression. Note: subjects may only receive a maximum of 5 cycles of chemotherapy for the duration of the study. 
Page 100 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 100 of 147
Optional crossover treatment must be initiated within 30 days of documented disease progression. Please see Section 
9.1.4 of the protocol for further details.
b.
Subjects should meet all of the safety parameters listed in the inclusion criteria and none of the safety parameters listed 
in the exclusion criteria. If required locally, written informed consent will be obtained prior to assessment for Optional 
Lenvatinib Crossover treatment.
c.
A Lansky play score or Karnofsky performance status score will be obtained at Baseline, Day 1 of every cycle, and at 
the Off-treatment visit.
d.
A comprehensive physical examination (including a neurological examination) will be performed at Baseline, C1D15, 
C2D1, C2D15, Day 1 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.
e.
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 for subjects <18 years old; or BP ≥140/90 mmHg 
for subjects ≥18 to 25 years old requires further evaluation.  Refer to hypertension management guidelines in Section
9.4.1.1.2.
f.
On Cycle 1 Day 8, subjects will have a telephone or clinic visit to assess for the development of early toxicity. Subjects 
will be provided with a BP cuff to monitor BP at home or can have the measurement done by a local healthcare 
provider, and will report the C1D8 measurement at telephone contact. An unscheduled visit can occur prior to C1D15 if 
deemed necessary by the investigator.
g.
Single 12-lead ECG. Baseline ECG may be performed within 28 days prior to C1D1. If possible, subjects must be in 
the recumbent position for a period of 5 minutes prior to the ECG. ECG should be conducted at C1D1, C2D1, D1 of 
every 4th cycle (i.e., C6, C10, C14, etc.), and at the Off-treatment visit. For high risk subjects  (as defined in lenvatinib 
product label), conduct ECG in every cycle.
h.
An echocardiogram or MUGA scan is to be performed at Baseline, every 16±2 weeks following first dose of study 
drug, and at the Off-Treatment visit, or sooner if clinically indicated. The Baseline ECHO/MUGA may be performed 
within 28 days prior to C1D1.
i.
Clinical chemistry and hematology results must be reviewed by the investigator prior to administration of study drug on 
C1D1 and within 48 hours after administering any study drug for all subsequent cycles. Electrolytes such as 
potassium, calcium, and magnesium should be monitored and abnormalities, when considered clinically 
significant, should be corrected in all participants before starting treatment. 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).  TSH should be assessed for all 
subjects.
j.
Urine dipstick testing should be performed at Baseline, C1D15, C2D1, C2D15, and Day 1 of every subsequent cycle, 
or more frequently as clinically indicated, 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 2 treatment cycles.  If a new 
event of proteinuria ≥2+ occurs, refer to Section 9.4.1.1.4 for further management guidelines. Urine glucose should be 
performed as part of the urine dipstick.  
k.
A serum or urine pregnancy test will be performed at the Baseline Visit (or within 72 hours prior to the first dose of 
study medication), on Day 1 of each cycle from Cycle 2 onwards, and at the Off-treatment Visit in women of 
childbearing potential.
l.
Subjects on optional lenvatinib crossover treatment will continue to receive lenvatinib until disease progression, 
development of unacceptable toxicity, subject request, or withdrawal of consent, whichever occurs first. If the sponsor 
terminates the study, the sponsor will provide study drug(s) (outside of the study) for subjects who have not met the 
criteria for study drug discontinuation. 
m.
All subjects who receive suspension formulation, with the exception of subjects using a nasogastric or gastrostomy 
tube, must complete the Palatability Questionnaire on C1D1 (or the subsequent visit).  If the subject is unable to 
complete the questionnaire this must be done by their parents or their legal guardian.  
n.
Prior to optional lenvatinib crossover, baseline tumor assessment must be re-established (i.e.,  new tumor assessment
scans performed), unless the last assessment was performed within 4 weeks prior to Cycle 1 Day 1 of the crossover 
treatment. Tumor assessments may be performed as clinically indicated as per the institutional guidelines (but no less 
frequently than every 12 weeks), following the prevailing local standard of care. The scans will no longer be required 
to be sent to the ICL.
o.
Brain CT with contrast or MRI pre- and post- gadolinium contrast will be performed as clinically indicated as per the 
institutional guidelines, following the prevailing local standard of care.
Page 101 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 101 of 147
p.
Height will be assessed at the Baseline Visit, Day 1 of every 4 cycles during treatment, at the Off-treatment Visit and 
every 3 months during the Post-treatment Follow-up. Assessment of height in Post-treatment Follow-up is not required 
once pubertal development is complete.
q.
Tanner Staging is only required for female subjects ≥8 years old, and male subjects ≥9 years old. Tanner Stage will be 
assessed at the Baseline Visit, at the Off-treatment Visit, and annually thereafter during the Post-treatment Follow-up. 
Tanner Staging is not required once pubertal development is complete (i.e. Tanner Stage 5).  
r.
Survival data will be collected every 3 months for up to 2 years as per the protocol. All anticancer therapies will be 
collected.
s.
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.  
t.
All AEs, including SAEs 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.
Page 102 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 102 of 147
Description of Procedures/Assessments Schedule
Refer to Table 5 for schedule and description of procedures in the Randomization Phase and 
Table 6 for the Extension Phase.
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
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 date the investigator becomes aware of the event.
Serious adverse events, regardless of causality assessment, must be collected for 30 days 
after the subject’s last dose.  All SAEs must be followed to resolution or, if resolution is 
unlikely, to stabilization.  Any SAE judged by the investigator to be related to the study 
treatment or any protocol-required procedure should be reported to the sponsor regardless of 
the length of time that has passed since study completion.
The detailed contact information for reporting of SAEs is provided in the Investigator Study 
File.
For urgent safety issues, please ensure all appropriate medical care is administered to the 
subject and contact the appropriate study team member listed in the Investigator Study
File.
It is very important that the SAE report form be filled out as completely as possible at the 
time of the initial report.  This includes the investigator’s assessment of causality.
Any relevant follow-up information received on SAEs should be forwarded within 24 hours
of its receipt.  If the relevant 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.
Page 103 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 103 of 147
The investigator must notify his/her IRB/IEC of the occurrence of the SAE in writing, if 
required by their institution.  A copy of this communication must be forwarded to the sponsor 
and/or the designated CRO monitor to be filed in the sponsor’s Trial Master File.
Reporting of Pregnancy and Exposure to Study Drug Through Breastfeeding
Any pregnancy in a female subject 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 exposure, this 
should be reported regardless of the length of time that has passed since the exposure to study 
treatment.
A congenital anomaly, death during perinatal period, a spontaneous abortion or an induced 
abortion done due to safety concerns for either mother or fetus 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 date the investigator becomes 
aware of the pregnancy.  The contact information for the reporting of pregnancies and 
exposure to study drug through breastfeeding is provided in the Investigator Study File.  The 
Pregnancy Report Form must be used for reporting.  All pregnancies must be followed to 
outcome.  The outcome of the pregnancy must be reported as soon as possible but no later 
than 24 hours from the date the investigator becomes aware of the outcome.
A subject who becomes pregnant must be withdrawn from the study.
Reporting of Events Associated with Special Situations
9.5.4.3.1
REPORTING OF ADVERSE EVENTS ASSOCIATED WITH STUDY DRUG OVERDOSE,
MISUSE, ABUSE, OR MEDICATION ERROR
Adverse events associated with study drug overdose, misuse, abuse, and medication error 
refer to AEs associated with uses of the study drug outside of that specified by the protocol.  
Overdose, misuse, abuse, and medication error are defined as follows:
Overdose
Accidental or intentional use of the study drug in an amount higher 
than the protocol-defined dose
Misuse
Intentional and inappropriate use of study drug not in accordance with 
the protocol
Abuse
Sporadic or persistent intentional excessive use of study drug 
accompanied by harmful physical or psychological effects
Page 104 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 104 of 147
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 
and Intentional Overdose, even if asymptomatic, are always to be captured as an AE.  If the 
AE associated with an overdose, misuse, abuse, or medication error does not meet serious 
criteria, it must still be reported using the SAE form and in an expedited manner but should 
be noted as nonserious on the SAE form and the Adverse Event CRF.
9.5.4.3.2
REPORTING OF ABNORMAL HEPATIC TESTS OF CLINICAL INTEREST
The following combination of abnormal laboratory tests*, as determined by way of 
protocol-specified laboratory testing or unscheduled laboratory testing and whether 
nonserious or serious, 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). If the event 
does not meet serious criteria, the seriousness criteria on the SAE form should be indicated as 
“nonserious.”  

Elevated AST or ALT lab value that is greater than or equal to 3× the upper limit of 
normal 
AND

Elevated total bilirubin lab value that is greater than or equal to 2× the upper limit of 
normal 
AND AT THE SAME TIME

Alkaline phosphatase lab value that is less than 2× the upper limit of normal
*Note: These criteria are based upon available regulatory guidance documents. The purpose 
of the criteria is to specify a threshold of abnormal hepatic tests that may require additional 
evaluation for an underlying etiology. In addition to reporting the abnormal hepatic 
laboratory tests on a SAE form, the site should also consult the medical monitor for guidance 
on assessment and follow-up.  At a minimum, laboratory testing should be repeated at least 
once weekly until improvement or identification of a cause unrelated to study drug use that is 
unlikely to improve.
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.
Page 105 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 105 of 147
Breaking the Blind
Not applicable
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 
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 PD will be followed in the post-study treatment follow-up period and continue to undergo 
regularly scheduled disease assessment until documentation of PD or start of an alternative 
anticancer treatment.  All subjects who discontinue study drug will be followed for OS 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 5 and Table 6). 
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 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.
Page 106 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 106 of 147
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, 
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 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 end of the 
Randomization Phase after database lock and randomization codes have been 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).
Page 107 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 107 of 147
9.7.1
Statistical and Analytical Plans
The statistical analyses of 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.
Study Endpoints
Efficacy endpoints related to tumor assessments will be evaluated by independent imaging 
review (IIR) and investigator assessment.
9.7.1.1.1
PRIMARY ENDPOINT
Progression-free survival (PFS) by IIR is defined as the time from the date of randomization 
to the date of the first documentation of PD or death (whichever occurs first) as determined 
by IIR using RECIST 1.1.
9.7.1.1.2
SECONDARY ENDPOINTS

Progression-free survival rate at 4 months (PFS-4m) by IIR is defined as the percentage 
of subjects who are alive and without PD at 4 months from the randomization date as 
determined by IIR of radiological imaging using RECIST 1.1. The PFS-4m rate is 
estimated using the Kaplan-Meier (K-M) method.

Progression-free survival rate at 1 year (PFS-1y rate) by IIR is defined as the percentage 
of subjects who are alive and without PD at 1 year from the randomization date as 
determined by IIR of radiological imaging using RECIST 1.1.  The PFS-1y rate is 
estimated using the K-M method.

Overall survival (OS) is defined as the time from the date of randomization to 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 for the primary analysis, will be censored at the date the subject was 
last known to be alive, or date of data cutoff for the primary analysis, whichever occurs 
first.  Overall survival rate at 1 year will be estimated using the K-M method.

Objective response rate  by IIR at 4 months (ORR-4m) is defined as the proportion of 
subjects who have best overall response of complete response (CR) or partial response 
(PR) as determined by IIR using RECIST 1.1 within the first 4 months.

Objective response rate (ORR) by IIR is defined as the proportion of subjects who have 
best overall response of complete response (CR) or partial response (PR) as determined 
by IIR using RECIST 1.1.

Safety will be assessed summarising the incidence of TEAEs and SAEs together with all 
other safety parameters.

Assessment of population-based PK parameters of lenvatinib.

Score changes from baseline for all PedsQL scales including Generic Core Scales and 
Cancer Module.  Scores will be calculated for total generic score, total cancer score, each 
physical function subscale including physical health, psychosocial health, emotional 
function, social function, school/work function in the Generic Core Scales, and each 
subscales in the cancer module.
Page 108 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 108 of 147

Palatability and acceptability of the suspension formulation of lenvatinib in subjects 
receiving the suspension formulation in the study will be assessed using the Palatability 
Questionnaire (see Appendix 4).
9.7.1.1.3
EXPLORATORY ENDPOINTS 

Duration of response (DOR) by IIR and investigator assessment is defined as the time 
from the date a response was first documented until the date of the first documentation of 
PD or date of death from any case.

Disease control rate (DCR) by IIR and investigator assessment is the proportion of 
subjects who have a best overall response of CR or PR or stable disease (SD).  In this 
context, stable disease is defined as stable disease at ≥7 weeks after randomization to be 
considered best overall response.

Clinical benefit rate (CBR) by IIR and investigator assessment is the proportion of 
subjects who have best overall response of CR or PR or durable SD (duration of SD ≥23 
weeks after randomization).

Efficacy endpoints (PFS, PFS-4m, PFS-1y, ORR-4m, and ORR) evaluated based on 
investigator assessment

Proportion of subjects who achieve complete removal of baseline lesions and the 
proportion of subjects with unresectable baseline lesions(s) that are converted to 
resectable between the 2 treatment arms.

Blood and tumor biomarkers will be assessed for identifying potential correlation with 
clinical outcomes-related endpoints.
Definitions of Analysis Sets
The Full Analysis Set (Intent-to-Treat Analysis [ITT]) includes all randomized subjects 
regardless of the treatment actually received.  This is the primary analysis population used 
for the efficacy analyses which will be based on the ITT principle.
The Per Protocol Analysis Set includes those subjects from the ITT set who received at least 
1 dose of any study drug, had no major protocol deviations, and had both baseline and at 
least one postbaseline tumor assessment.  Subjects for whom death occurred prior to the first 
postbaseline tumor assessment will also be included.  The per protocol analysis set will be 
the secondary analysis set for efficacy endpoints.
The Safety Analysis Set includes subjects who received at least 1 dose of any study drug.  
This is the analysis population used for all safety analyses which will be based on as-treated 
principle.
Population Pharmacokinetic (PK) Analysis Set includes the subjects who have received at 
least 1 dose of lenvatinib with documented dosing history and have measurable plasma levels 
of lenvatinib.
Page 109 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 109 of 147
The Pharmacodynamic Analysis Set includes subjects who received at least 1 dose of study 
drug and had sufficient pharmacodynamic data (eg, at least 1 evaluable/measurable
pharmacodynamic parameter).
The HRQoL Analysis Set will consist of all randomized subjects who have received at least 1 
dose of study medication, and have at least 1 patient-reported outcome (PRO) assessment 
completed beyond baseline.  For PRO analysis, subjects will be analyzed as randomized and 
not according to treatment actually received.
Subject Disposition
Reasons for screening failure will be summarized.
The number and percentage of subjects who completed the study will be summarized by 
treatment group, and for overall, and the number and percentage of subjects who 
discontinued prematurely will also be summarized by reason for discontinuation.
Demographic and Other Baseline Characteristics
Demographic and other baseline characteristics for the Full Analysis Set will be summarized 
using descriptive statistics.  Continuous demographic and baseline variables (including age, 
sex, race, height, and weight) will be summarized using n (number of subjects with available 
data), mean, standard deviation, median, quartiles 1 and 3, and range (minimum and 
maximum) unless otherwise specified.  Categorical variables will be summarized by number 
and percentage.
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 started prior to the first dose of study drug and were either continued during 
the study or stopped prior to the first dose of study drug.  Concomitant medications will be 
defined as medications that (1) started before the first dose of study drug and were continuing 
at the time of the first dose of study drug, or (2) started on or after the date of the first dose of 
study drug 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 treatment arm.
Efficacy Analyses
Efficacy analyses will be based primarily on the Full Analysis Set.
All primary statistical analyses will be conducted at the data cutoff date for the primary 
analysis (ie, when approximately 38 PFS events, as determined by IIR, are observed).  
Page 110 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 110 of 147
9.7.1.6.1
PRIMARY EFFICACY ANALYSIS
The primary efficacy endpoint of progression-free survival (PFS) per IIR will be analyzed 
and compared between the 2 treatment armsusing the stratified log-rank test with time to first 
relapse/refractory disease (early [<18 months] or late [≥18 months]) and age (<18 or ≥18 
years) as strata.  PFS censoring rules will follow FDA guidance of 2007 and will be detailed
in the statistical analysis plan. Median PFS will be calculated using the K-M product-limit 
estimates for each treatment arm along with 2-sided 95% CIs (estimated with a generalized 
Brookmeyer and Crowley method [Brookmeyer and Crowley (1982)].  The K-M estimates of 
PFS will be plotted over time. The Cox regression model will be used to estimate the hazard 
ratio and its 95% CIs stratified by the stratification factors.  
Secondary Efficacy Analyses
The PFS-4m rate and PFS-1y rate per IIR will be estimated using the K-M method for the 
primary efficacy endpoint PFS per IIR. PFS-4m/PFS-1y rate and their Greenwood standard 
errors will be evaluated using the K-M estimates from both treatment groups.  The statistical 
significance of the difference in the 2 K-M PFS-4m rates will base on its 2-sided 95% CI.  
This 2-sided 95% CI and a p-value will be constructed using the difference of these 2 K-M 
PFS-4m/PFS-1y rates and the 2 corresponding Greenwood standard errors. 
Overall survival (OS) will be compared between treatment arm and control arm following the 
same statistical method for the primary efficacy PFS endpoint. The K-M estimates will also 
be presented for 4, 6, 9, and 12 months (ie OS-1y) with 2-sided 95% CIs.  OS-1y will be 
analyzed using the same approach as for the PFS-4m. 
The ORR by IIR will be summarized and compared between the two treatment arms using 
stratified Miettinen and Nurminen’s method. The difference in ORR and its 2-sided 95% 
confidence interval from the stratified Miettinen and Nurminen’s method with strata 
weighting by sample size will be reported. The stratification factors used for randomization 
will be applied to the analysis. The ORR-4m by IIR will be summarized and compared 
between arms using the same approach as for ORR.
9.7.1.6.2
EXPLORATORY EFFICACY ANALYSES
Median DOR by IIR among responders for each arm will be presented along with its 
corresponding 2-sided 95% CIs.  Disease Control Rate (DCR) and CBR by IIR will be 
summarized and compared between arms using the same approach as for ORR. Efficacy 
endpoints PFS, PFS-4m, PFS-1y, ORR-4m, ORR, DOR, DCR, and CBR evaluated based on 
investigator assessment will be analyzed using the same approach as for the endpoints 
assessed by IIR.
The difference in the proportion of subjects who achieve complete removal of baseline 
lesion(s) and the proportion of subjects with unresectable baseline lesions(s) that are 
Page 111 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 111 of 147
converted to resectable between the 2 treatment arms and corresponding two-sided 95% CIs 
will be calculated.
Pharmacokinetic, Pharmacodynamic, and Other Biomarker Analyses
9.7.1.7.1
PHARMACOKINETIC ANALYSES
Lenvatinib concentration versus time data will be tabulated and summarized and graphically 
presented.
Lenvatinib data from Arm A of the study will be pooled with available data from other 
studies and subjected to population PK analysis.  The PK model will be parameterized in 
terms of clearance and volume of distribution. Details of the population PK analysis will be 
provided in a separate analysis plan.
9.7.1.7.2
PHARMACODYNAMIC AND OTHER BIOMARKER ANALYSES
Pharmacodynamic, and other biomarker analyses may be performed and reported separately.  
Details of these analyses may be described in a separate analysis plan.
Optional pharmacodynamic serum and archived, fixed tumor tissue biomarkers may be 
collected from subjects in Arm A only as described in the Schedule of Assessments.  
Pharmacodynamic serum and tumor biomarkers in this study will be identified as in other 
lenvatinib clinical studies. 
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. 
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.
Data obtained from the pharmacodynamic samples will be used for research.  The 
pharmacodynamic 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 the age of 18 
years (or at the appropriate age per local country requirements) 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. Further analyses will not be performed on samples collected 
from subjects who do not reconsent at the age of 18 years (or at the appropriate age per local 
country requirements).
Page 112 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 112 of 147
Safety Analyses
All safety analyses will be performed on the Safety Analysis Set.  Safety data, presented by 
treatment group, will be summarized on an “as treated” basis using descriptive statistics (eg, 
n, mean, standard deviation, median, minimum, maximum for continuous variables; n [%] 
for categorical variables), as appropriate.  Safety variables include TEAEs, clinical laboratory 
parameters, vital signs, 12-lead ECG results, Lansky play scores or Karnofsky performance 
scores, physical examination, height, tooth formation abnormalities, closure of proximal 
tibial plates, and LVEF.  Study Day 1 for all safety analyses will be defined as the date of the 
first dose of study drug.
9.7.1.8.1
EXTENT OF EXPOSURE
The number of cycles/days on treatment, quantity of study drug administered, dose intensity, 
and the number of subjects requiring dose reductions, treatment interruption, and treatment 
discontinuation due to adverse events will be summarized.
9.7.1.8.2
ADVERSE EVENTS
The AE verbatim descriptions (investigator terms from the CRF) will be classified into 
standardized medical terminology using the Medical Dictionary for Regulatory Activities 
(MedDRA).  Adverse events will be coded to the MedDRA (Version 20.1 or higher) lower 
level term (LLT) closest to the verbatim term.  The linked MedDRA preferred term (PT) and 
primary system organ class (SOC) are also captured in the database.
A TEAE is defined as an AE that emerges during treatment (and within 30 days of the last 
study treatment), having been absent at pretreatment (Baseline) or 

Re-emerges during treatment, having been present at pretreatment (Baseline) but 
stopped before treatment, 
or 

Worsens in severity during treatment relative to the pretreatment state, when the AE 
is continuous.
Only those AEs that are treatment-emergent will be included in summary tables.  All AEs, 
treatment-emergent or otherwise, will be presented in subject data listings.
The TEAEs will be summarized by treatment group.  The incidence of TEAEs will be 
reported as the number (percentage) of subjects with TEAEs by SOC and PT.  A subject will 
be counted only once within an SOC and PT, even if the subject experienced more than 1
TEAE within a specific SOC and PT.  The number (percentage) of subjects with TEAEs will 
also be summarized by highest CTCAE grade.
The number (percentage) of subjects with TEAEs will also be summarized by relationship to 
study drug (Yes [related] and No [not related]).
Page 113 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 113 of 147
The number (percentage) of subjects with treatment-related TEAEs will be summarized by 
SOC and PT.  Treatment-related TEAEs include those events considered by the investigator 
to be related to study treatment.  The number (percentage) of subjects with treatment-related 
TEAEs will also be summarized by highest CTCAE grade.
Adverse events will be summarized using the Safety Analysis Set.  The number of AEs and 
number and incidence (%) of subjects with AEs will be summarized by treatment group and 
overall.  To obtain the incidence (%), the number of subjects with at least 1 event and the 
percentage of subjects with AEs by SOC and by PT will be calculated.  Incidence (%) by 
causal relationship with study drug and by severity (CTCAE v5.0) will also be calculated.  
For clinically significant events, time of onset, and recovery will be reported.
Adverse events will be summarized for descriptive purposes by age (2 to <6, 6 to <18, and 
≥18), and sex.
The number (percentage) of subjects with TEAEs leading to death will be summarized by 
MedDRA SOC and PT for each treatment group.  A subject data listing of all AEs leading to 
death will be provided.  All deaths will also be summarized.
The number (percentage) of subjects with treatment-emergent SAEs will be summarized by 
MedDRA SOC and PT for each treatment group.  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 for each treatment group. A subject data 
listing of all AEs leading to discontinuation from study drug will be provided.
9.7.1.8.3
LABORATORY VALUES
Laboratory results will be summarized using Système International (SI) units, as appropriate.  
For all quantitative parameters listed in Section 9.5.1.4.3, 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 treatment group using descriptive 
statistics.  Qualitative parameters listed in Section 9.5.1.4.3 will be summarized using 
frequencies (number and percentage of subjects), and changes from baseline to each 
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.  Within-treatment comparisons for each laboratory parameter will be based 
on shift tables that compare the baseline LNH classification to the LNH classification at each 
postbaseline visit and at the end of treatment.  Similar shift tables will also compare the 
baseline LNH classification to the LNH classification for the highest and lowest value during 
the treatment period.
Page 114 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 114 of 147
9.7.1.8.4
VITAL SIGNS
Descriptive statistics for vital signs parameters (ie, systolic and diastolic BP, pulse, 
respiratory rate, temperature, weight, and height) and changes from baseline will be 
presented by visit and treatment group.
Percentiles for BP values (only for subjects <18 years old) 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, systolic BP or diastolic BP >99th 
percentile).  See Appendix 5 and Appendix 6 for detail on percentiles.
9.7.1.8.5
ELECTROCARDIOGRAMS
Descriptive statistics for electrocardiogram parameters (HR, PR, QRS, QT, QTcB, QTcF and 
RR) and changes from Baseline will be presented by visit. Electrocardiogram (ECG)
findings will be summarized. A shift table of worst postbaseline values from Baseline for 
ECG findings will be provided.
QTc Bazett and QTc Fridericia will be summarized.  QTc Bazett and QTc Fridericia will be 
categorized as both maximum increases from Baseline and maximum postbaseline values.
9.7.1.8.6
OTHER SAFETY ANALYSES
Descriptive summary statistics for LVEF changes from baseline will be calculated and 
summarized.
The shift of worst postbaseline proteinuria from Baseline will be summarized.
Thyroid-stimulating hormone values will be summarized in 2 categories (≤ULN and >ULN).
Lansky play scores or Karnofsky Performance Status score scores will be summarized by 
shifts from Baseline to worst postbaseline visit.
Radiographic findings of proximal tibial growth plates will be listed and analyzed if 
appropriate.
Tooth formation abnormalities will be listed and analyzed if appropriate.
Other Analyses
9.7.1.9.1
HEALTH-RELATED QUALITY OF LIFE 
Descriptive statistics will be presented for all PedsQL endpoints at each analysis time period 
by treatment arm.  Baseline is defined as the later value of Day -1 or at Cycle 1 Day 1 prior 
to treatment. 
This will be collected at baseline, at C2D1, C3D1, Week 18, C8D1, C18 D1 and at the 
Off-Treatment Visit.  Score change from baseline in PedsQL at each analysis timepoint will 
be analyzed. Primary timepoint for assessment is at week 18 for all PedsQL endpoints.  
Page 115 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 115 of 147
Detailed HRQoL analysis plan will be provided in a separate analysis plan and the results 
will be provided in a stand-alone report.
9.7.1.9.2
PALATABILITY AND ACCEPTABILITY QUESTIONNAIRE
Measurement of palatability will be assessed using a facial Hedonic scale (Guinard, 2001), in 
subjects receiving the suspension formulation in the study.
9.7.2
Determination of Sample Size
A total sample size of 72 subjects is estimated for the primary efficacy endpoint of PFS. A 
median PFS of 3.5 months for Arm B (control arm) has been estimated by comparing 
available PFS data from clinically active agents in this patient population (Davis, et al., 2019; 
Palmerini, et al, 2016; Grignani, et al., 2012).  With respect to Arm A (lenvatinib plus 
chemotherapy arm), a median PFS of 8.75 months is estimated based on the results from 
Study 207. 
Therefore, assuming a hazard ratio of 0.4, a 1-sided type 1 error rate of 0.025, and power of 
80%, the required number of PFS events for the study is 38.  The primary PFS analysis is 
estimated to occur at approximately 32 months after the first subject is randomized 
(assuming a 20-month enrollment period), and accounts for a dropout rate of up to 40%. 
9.7.3
Interim Analysis
No interim analysis is planned for this study.
The safety monitoring will be conducted by the independent data monitoring committee 
(IDMC).  The frequency of the safety reviews will be defined in the IDMC charter.  Minutes 
from the open meetings of the IDMC will be provided if requested by regulatory agencies.  
The recommendation of whether to stop the study for safety will be reached by the IDMC 
based on their review of safety data with treatment information.  The function and 
membership of the IDMC will be described in the IDMC charter.
9.7.4
Other Statistical/Analytical Issues
Not applicable.
9.7.5
Procedure for Revising the Statistical Analysis Plan
If the SAP needs to be revised after the study starts, the sponsor will determine how the 
revision impacts the study and how the revision should be implemented.  The details of the 
revision will be documented and described in the clinical study report.
Page 116 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 116 of 147
10 REFERENCE LIST
Bacci G, Briccoli A, Longhi A, Ferrari S, Mercuri M, Faggioli F, et al. Treatment and 
outcome of recurrent osteosarcoma: experience at Rizzoli in 235 patients initially treated 
with neoadjuvant chemotherapy. Acta Oncol. 2005;44(7):748-55.
Berger M, Grignani G, Ferrari S, Biasin E, Brach del Prever A, Aliberti S, et al. Phase 2 trial 
of two courses of cyclophoamide and etoposide for relapsed high-risk osteosarcoma patients. 
Cancer. 2009;115:2980-7.
Briccoli A, Rocca M, Salone M, Bacci G, Ferrari S, Balladelli A, et al. Resection of recurrent 
pulmonary metastases in patients with osteosarcoma. Cancer. 2005;104(8):1721-5.
Casali PG, Bielack S, Abecassis N, Aro HT, Bauer S, Biagini R, ESMO Guidelines 
Committee, PaedCan and ERN EURACAN, et al. Bone sarcomas: ESMO-PaedCan-
EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 
2018;29(Suppl 4):iv79-iv95.
Cancer Therapy Evaluation Program, Common Terminology Criteria for Adverse Events 
(CTCAE) version 5.0 [published 27 November 2017. Available from:  
https://ctep.cancer.gov/protocoldevelopment/.../ctcae_v5_quick_reference_5x7.pdf.
Chou AJ, Merola PR, Wexler LH, Gorlick RG, Vyas YM, Healey JH, et al. Treatment of 
osteosarcoma at first recurrence after contemporary therapy: the Memorial Sloan-Kettering 
Cancer Center experience. Cancer. 2005;104(10):2214-21.
Cole TJ., Bellizzi MC., Flegal KM, Dietz WH: Establishing a standard definition for child 
overweight and obesity worldwide: international survey. BMJ. 2000;320:1240.
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.
Davis LE, Bolejack V, Ryan CW, Ganjoo KN, Loggers ET, Chawla S, et al. Randomized
double-blind Phase II study of regorafenib in patients with metastatic osteosarcoma. J Clin
Oncol. 2019;37(16):1424-31.
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New 
response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J 
Cancer. 2009;45(2):228-47.
ESMO/European Sarcoma Network Working Group. Bone sarcomas: ESMO Clinical 
Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2014;25(3):113–23.
Ferrari S, Briccoli A, Mercuri M, Bertoni F, Picci P, Tienghi A, et al. Postrelapse survival in 
osteosarcoma of the extremities: Prognostic factors for long-term survival. J Clin Oncol. 
2003;21(4):710-5.
Page 117 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 117 of 147
Ferrari S, Serra M. An update on chemotherapy for osteosarcoma. Expert Opin 
Pharmacother. 2015;16(18):2727-36.
Gaspar N, Casanova M, Bautista Sirvent FJ, Venkatramani R, Morland B, Gambart M, et al. 
Single agent expansion cohort of lenvatinib (LEN) and combination dose-finding cohort of 
LEN + etoposide (ETP) + ifosfamide (IFM) in patients (pts) aged 2 to ≤ 25 years with 
relapsed/refractory osteosarcoma (OS). Poster presented at the International Society for 
Paediatric Oncology (SIOP); 2018, Nov 16–19; Kyoto, Japan.
Gaspar N, Bautista Sirvent FJ, Venkatramani R, Longhi L, Lervat C, Casanova M, et al.  
Phase 1 combination dose-finding/phase 2 expansion cohorts of lenvatinib + etoposide + 
ifosfamide in patients (pts) aged 2 to ≤25 years with relapsed/refractory (r/r) osteosarcoma. 
Poster presented at the: European Society for Medical Oncology (ESMO) meeting; 
September 27 to October 1, 2019; Barcelona, Spain 2019.
Gorlick R, Khanna C. Osteosarcoma. J Bone and Mineral Research. 2010;25(4): 683–691.
Grignani G, Palmerini E, Dileo P, Asaftei SD, D'Ambrosio L, Pignochino Y, et al. A phase II
study of sorafenib in relapsed and unresectable high-grade osteosarcoma after failure of
standard multimodal therapy: an Italian Sarcoma Group study. Ann Oncol. 2012;23(2):508-
16.
Guinard FX. Sensory and consumer testing with children. Trends Food Sci Technol
2001;11:273–83.
Hawkins DS, Arndt CA. Pattern of disease recurrence and prognostic factors in patients with 
osteosarcoma treated with contemporary chemotherapy. Cancer. 2003;98(11):2447-56.
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.
Howie, SRC. Blood sample volumes in child health research: review of safe limits. Bulletin
of the World Health Organization; ID: BLT.10.080010. September 2010:1-17.
Howlader N, Noone AM, Krapcho M, Miller D, Brest A, Yu M, Ruhl J, Tatalovich Z, 
Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA (eds). SEER Cancer Statistics 
Review, 1975-2016, National Cancer Institute. Bethesda, MD. Available from: 
https://seer.cancer.gov/csr/1975_2016/, based on November 2018 SEER data submission, 
posted to the SEER web site, April 2019.
Isakoff MS, Bielack SS, Meltzer P, Gorlick R. Osteosarcoma: Current treatment and a 
collaborative pathway to success. J Clin Oncol. 2015;33(27):3029-35.
Kaatsch P. Epidemiology of childhood cancer. Cancer Treat Rev. 2010;36(4):277-85.
Page 118 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 118 of 147
Kato Y, Tabata K, Kimura T, Yachie-Kinoshita A, Ozawa Y, Yamada K, et al. Lenvatinib 
plus anti-PD-1 antibody combination treatment activates CD8+ T cells through reduction of 
tumor-associated macrophage and activation of the interferon pathway. PLoS ONE. 
2019;14(2):e0212513.
Kempf-Bielack B, Bielack SS, Jürgens H, Branscheid D, Berdel WE, Exner GU, et al. 
Osteosarcoma relapse after combined modality therapy: an analysis of unselected patients in 
the Cooperative Osteosarcoma Study Group (COSS). J Clin Oncol. 2005;23(3):559-68.
Kimura T, Kato Y, Ozawa Y, et al. Immunomodulatory activity of lenvatinib contributes to
antitumor activity in the Hepa1-6 hepatocellular carcinoma model. Cancer Sci. 
2018;109:3993–4002.
Lansky SB, List MA, Lansky LL, Ritter-Sterr C, Miller DR. The measurement of 
performance in childhood cancer patients. Cancer. 1987;60(7):1651-6.
Leary SE, Wozniak AW, Billups CA, Wu J, McPherson V, Neel MD, et al. Survival of 
pediatric patients after relapsed osteosarcoma: the St. Jude Children's Research Hospital 
experience. Cancer. 2013;119(14):2645-53.
Le Vu B, de Vathaire F, Shamsaldin A, Hawkins MM, Grimaud E, Hardiman C, Diallo I, 
Vassal G, Bessa E, Campbell S, Panis X, Daly-Schveitzer N, Lagrange JL, Zucker JM, 
Eschwège F, Chavaudra J, Lemerle J. Radiation dose, chemotherapy and risk of 
osteosarcoma after solid tumours during childhood. Int. J. Cancer. 1998;77:370–377.
Meazza C, Scanagatta P. Metastatic osteosarcoma: a challenging multidisciplinary treatment. 
Expert Rev Anticancer Ther. 2016 May;16(5):543-56. 
Mirabello L, Troisi RJ, Savage SA: Osteosarcoma incidence and survival rates from 1973 to 
2004: data from the Surveillance, Epidemiology, and End Results Program. Cancer. 
2009;115(7):1531-43.
Morris NM, Udry JR. Validation of a self-administered instrument to assess stage of 
adolescent development. J Youth Adolesc. 1980;9(3):271-80.
NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) Bone Cancer. 
Version 1.2020 – August 12, 2019.  
Ogden CL, Flegal KM, Carroll MD, Johnson CL. Prevalence and trends in overweight 
among US children and adolescents, 1999-2000. JAMA. 2002;288:1728–32.
O'Toole DM, Golden AM. Evaluating cancer patients for rehabilitation potential. West J Med. 
1991;155:384-7.
Palmerini E, Jones RL, Marchesi E, Paioli A, Cesari M, Longhi A, et al. Gemcitabine and 
docetaxel in relapsed and unresectable high-grade osteosarcoma and spindle cell sarcoma of 
bone. BMC Cancer. 2016 Apr 20;16:280. doi: 10.1186/s12885-016-2312-3.
Page 119 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 119 of 147
Schwartz GJ, Gauthier B. A simple estimate of glomerular filtration rate in adolescent boys. J 
Pediatr. 1985;106(3):522-6.
Tuettenberg J, Friedel C, Vajkoczy P. Angiogenesis in malignant glioma--a target for 
antitumor therapy? Crit Rev Oncol Hematol. 2006;59(3):181-93.
University of British Columbia – Children’s & Women’s Health Centre of BC Research
Ethics Board 2006.[Children’s Memorial Research Center (CMRC) IRB allowable blood
limits] Available from: http://www.phsa.ca/research/Documents/pediatric-blood-
drawguidance. pdf
Ward E, DeSantis C, Robbins A, Kohler B, Jemal A. Childhood and adolescent cancer 
statistics. 2014. Cancer J Clin. 2014;64(2):83-103.
Page 120 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 120 of 147
11 PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE 
PROCEDURES)
11.1
Changes to the Protocol
Any change to the protocol requires a written protocol amendment or administrative change 
that must be approved by the sponsor before implementation.  Amendments specifically 
affecting the safety of subjects, the scope of the investigation, or the scientific quality of the 
study require submission to health or regulatory authorities as well as additional approval by 
the applicable IRBs/IECs.  These requirements should in no way prevent any immediate 
action from being taken by the investigator, or by the sponsor, in the interest of preserving 
the safety of all subjects included in the study.  If the investigator determines that an 
immediate change to or deviation from the protocol is necessary for safety reasons to 
eliminate an immediate hazard to the subjects, the sponsor’s medical monitor and the 
IRB/IEC for the site must be notified immediately.  The sponsor must notify the health or 
regulatory authority as required per local regulations.
Protocol amendments that affect only administrative aspects of the study may not require 
submission to health or regulatory authority or the IRB/IEC, but the health or regulatory 
authority and IRB/IEC (or if regionally required, the head of the medical institution) should 
be kept informed of such changes as required by local regulations.  In these cases, the 
sponsor may be required to send a letter to the IRB/IEC and the Competent Authorities (or, if 
regionally required, the head of the medical institution) detailing such changes.
11.2
Adherence to the Protocol
The investigator will conduct the study in strict accordance with the protocol (refer to 
ICH E6, Section 4.5).
11.3
Monitoring Procedures
The sponsor’s/CRO’s CRA will maintain contact with the investigator and designated staff 
by telephone, letter, or email between study visits.  Monitoring visits to each site will be 
conducted by the assigned CRA as described in the monitoring plan.  The investigator (or if 
regionally required, the head of the medical institution) will allow the CRA to inspect the 
clinical, laboratory, and pharmacy facilities to assure compliance with GCP and local 
regulatory requirements.  The CRFs and subject’s corresponding original medical records 
(source documents) are to be fully available for review by the sponsor’s representatives at 
regular intervals.  These reviews verify adherence to study protocol and data accuracy in 
accordance with local regulations.  All records at the site are subject to inspection by the 
local auditing agency and to IRB/IEC review.
In accordance with ICH E6, Section 1.52, source documents include, but are not limited to,
the following:

Clinic, office, or hospital charts
Page 121 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 121 of 147

Copies or transcribed health care provider notes that have been certified for accuracy 
after production

Recorded data from automated instruments such as IVRS, 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

Electronic Patient-Reported Outcome by self-reported measures
11.4
Recording of Data
A CRF is required and must be completed for each subject by qualified and authorized 
personnel.  All data on the CRF must reflect the corresponding source document, except 
when a section of the CRF itself is used as the source document.  Any correction to entries 
made on the CRF must be documented in a valid audit trail where the correction is dated, the 
individual making the correct is identified, the reason for the change is stated, and the 
original data are not obscured.  Only data required by the protocol for the purposes of the 
study should be collected.
The investigator must sign each CRF.  The investigator will report the CRFs to the sponsor 
and retain a copy of the CRFs.
11.5
Identification of Source Data
All data to be recorded on the CRF must reflect the corresponding source documents.  
11.6
Retention of Records
The circumstances of completion or termination of the study notwithstanding, the 
investigator (or if regionally required, the head of the medical institution or the designated 
representative) is responsible for retaining all study documents, including but not limited to 
the protocol, copies of CRFs, the Investigator’s Brochure, and regulatory agency registration 
documents (eg, Form FDA 1572 for US sites), Investigator and Site Information Form (for 
non-US sites), ICFs, and IRB/IEC correspondence). The site should plan to retain study 
Page 122 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 122 of 147
documents, as directed by the sponsor, for at least 15 years following the completion of the 
study.
It is requested that at the completion of the required retention period, or should the 
investigator retire or relocate, the investigator contact the sponsor, allowing the sponsor the 
option of permanently retaining the study records.
11.7
Auditing Procedures and Inspection
In addition to routine monitoring procedures, the sponsor’s Clinical Quality Assurance 
department conducts audits of clinical research activities in accordance with the sponsor’s 
SOPs to evaluate compliance with the principles of ICH GCP and all applicable local 
regulations.  If a government regulatory authority requests an inspection during the study or 
after its completion, the investigator must inform the sponsor immediately.
11.8
Handling of Study Drug
All study drug will be supplied to the principal investigator (or a designated pharmacist) by 
the sponsor.  Drug supplies must be kept in an appropriate secure area (eg, locked cabinet) 
and stored according to the conditions specified on the drug labels.  The investigator (or a 
designated pharmacist) must maintain an accurate record of the shipment and dispensing of 
the study drug in a drug accountability ledger, a copy of which must be given to the sponsor 
at the end of the study.  An accurate record of the date and amount of study drug dispensed to 
each subject must be available for inspection at any time.  The CRA will visit the site and 
review these documents along with all other study conduct documents at appropriate 
intervals once study drug has been received by the site.
All drug supplies are to be used only for this study and not for any other purpose.  The 
investigator (or site personnel) must not destroy any drug labels or any partly used or unused 
drug supply before approval to do so by the sponsor.  At the conclusion of the study and as 
appropriate during the study, the investigator (or a designated pharmacist) will return all used 
and unused drug containers, drug labels, and a copy of the completed drug disposition form 
to the sponsor’s CRA (or designated contractor) or, when approval is given by the sponsor, 
will destroy supplies and containers at the site.
11.9
Publication of Results
All manuscripts, abstracts, or other modes of presentation arising from the results of the 
study must be reviewed and approved in writing by the sponsor in advance of submission 
pursuant to the terms and conditions set forth in the executed Clinical Trial Agreement 
between the sponsor/CRO and the institution/investigator.  The review is aimed at protecting 
the sponsor's proprietary information existing either at the date of the commencement of the 
study or generated during the study.
Page 123 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 123 of 147
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.
Page 124 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 124 of 147
12 APPENDICES
Appendix 1
Response Evaluation Criteria in Solid Tumors 
(RECIST) 1.1
Tumor response assessments in this clinical study 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 study 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.
Page 125 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 125 of 147
Appendix 2
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.
Page 126 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 126 of 147
Appendix 3
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.
Page 127 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 127 of 147
Appendix 4
Palatability Questionnaire
Treatment Dose:
Visit Cycle:
Date:
Subject ID:
(Please circle according to your experience) 
Taste
(Please circle according to your experience)
Appearance
(Please circle according to your experience)
Smell
(Please circle according to your experience)
Mouth Feel (how does it 
feel in your mouth?)
Study E7080-G000-230- Palatability Questionnaire
Page 128 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 128 of 147
(Please circle according to your experience)
Overall Acceptability
Page 129 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 129 of 147
Appendix 5
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
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
Page 130 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 130 of 147
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
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/ 
Page 131 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 131 of 147
Appendix 6
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
11
50th
100
101
102
103
105
106
107
60
60
60
61
62
63
63
Page 132 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 132 of 147
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
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/ 
Page 133 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 133 of 147
Appendix 7
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
Page 134 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 134 of 147
Appendix 8
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.ht
Page 135 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 135 of 147
Appendix 9
Tanner’s Staging
Boys Tanner Stage progression scale*
Genitalia:
1= The testes, scrotum and penis are about the same size and shape as they were when you were 
a child
2= The testes and scrotum are bigger.  The skin of the scrotum has changed.  The scrotum, the 
sack holding the testes, has gotten lower.  The penis has gotten only a little bigger.
3= The penis has grown in length.  The testes and scrotum have grown and dropped lower.
4= The penis has gotten even bigger.  It is wider.  The glans (the head of the penis) is bigger.  
The scrotum is darker than before. It is bigger because the testes are bigger.
5= The penis, scrotum, and testes are the size and shape of an adult man.
Pubic Hair:
1= There is no pubic hair at all.
2= There is a little soft, long, lightly-colored hair. Most of the hair is at the base of the penis.
This hair may be straight or a little curly.
3= The hair is darker in this stage. It is more curled. It has spread out and thinly covers a bigger 
area.
4= the hair is now as dark, curly, and course as that of an adult man.  The area that the hair 
covers is not as big as that of an adult man.  The hair has NOT spread out to the legs.
5= The hair has spread out to the legs.  The hair is now like that of an adult man. It covers the 
same area as that of an adult man.
Girls Tanner Stage progression scale
Breast:
1= The nipple is raised a little. The rest of the breast is still flat.
2= This is the breast bud stage.  In this stage, the nipple is raised more than in stage 1.  The 
breast is a small mound.  The areola is larger than stage 1.
3= The breast and areola are both larger than in stage 2.  The areola does not stick out away from 
the breast.
Page 136 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 136 of 147
4= The areola and the nipple make up a mound that sticks up above the shape of the breast.  
NOTE:  This stage may not happen at all for some girls.  Some girls develop from stage 3 to 
stage 5 with no stage 4
5= This is the mature adult stage.  The breasts are fully developed. Only the nipple sticks out in 
this stage.  The areola has moved back in the general shape of the breast.
Pubic Hair:
1= There is no pubic hair at all.
2= There is a little soft, long lightly-colored hair.  This hair may be straight or a little curly.
3= The hair is darker in this stage. It is coarser more curled. It has spread out and thinly covers 
a bigger area.
4= the hair is now as dark, curly, and course as that of an adult female. The area that the hair 
covers is not as big as that of an adult female. The hair has NOT spread out to the legs.
5= The hair is now like that of an adult female. It covers the same area as that of an adult 
female. The hair usually forms a triangular (V) pattern as it spreads out to the legs.
*Adapted from: Morris, N.M., and Udry, J.R., (1980).  Validation of a Self-Administered Instrument to Assess 
Stage of Adolescent Development. Journal of Youth and Adolescence, Vol. 9, No. 3: 271-80.
Page 137 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 137 of 147
Appendix 10
Pharmacodynamic, and Other Biomarker Research
Subjects enrolled in this clinical study may have biologic samples collected for 
pharmacodynamic, 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.
Collection of the pharmacodynamic, and other biomarker samples will be bound by the sample 
principles and processes outlined in the main study protocol.  Sample collection for 
pharmacodynamic, 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
Sample collection for pharmacodynamic analysis is optional. 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.
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 
Page 138 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 138 of 147
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 pharmacodynamic 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 study 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.
Given the research nature of the pharmacodynamic, 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, pharmacodynamic, 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 
Page 139 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 139 of 147
with individual patients should only occur when data have been validated by multiple studies and 
testing has been done in CLIA-approved laboratories.
Page 140 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 140 of 147
Appendix 11  Country-Specific Requirements
Sweden
As requested by the Swedish health authority, the calculation of serum creatinine is revised to 
include the 2009 Schwartz equation for subjects < 18 years of age and the maxumun serum 
creatinine values are provided in µmol/L because Standard International Units are used for 
reporting plasma creatinine in Sweden.
8.3.1 Inclusion Criteria
10. 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.  If applicable, the 2009 Schwartz equation must be used to estimate GFR for subjects 
aged <18 years (ie, eGFR = 36.5 x height [cm]/plasma creatinine [µmol/L]) (Schwartz, et 
al., 2009).
Age
Maximum Serum Creatinine 
(mg/dL)
Maximum Serum Creatinine 
(µmol/L)
Male
Female
Male
Female
2 to <6 years
0.8
0.8
70.72
70.72
6 to <10 years
1
1
88.4
88.4
10 to <13 years
1.2
1.2
106.08
106.08
13 to <16 years
1.5
1.4
132.6
123.76
≥16 years
1.7
1.4
150.28
123.76
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 Common Terminology Criteria for Adverse Events (CTCAE) v5.0 and if possible 
perform a 24-hour urine collection (children and adolescents ≤12 years of age must have 
≤500 mg of protein/24 hours and subjects >12 years of age must have ≤1 g of protein/24 
hours).
c.  No clinical evidence of nephrotic syndrome. 
References
Schwartz GJ, Munoz A, Schneider MF, Mak RH, Kaskel F, Warady BA. New equations to 
estimate GFR in children with CKD. J Am Soc Nephrol. 2009;20(3):629-37.
Germany
Page 141 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 141 of 147
New section added to outline the measures taken within the protocol to reduce risk and burden as 
per the German health authority request.
8.2.1 Participant Risk and Burden 
The clinical study protocol will be conducted in accordance with ‘Ethical Considerations for 
Clinical Trials on Medicinal Products Conducted with the Pediatric Population' in order to 
reduce the risk and burden to the participants.  The degree of burden and risk is continuously 
monitored and assessed by the Investigator through the various study assessments outlined in the 
Section 9.5.2 – Schedule of Procedures/Assessments, and the threshold for discontinuation is 
clearly defined in Section 9.3.3 – Removal of Subjects From Therapy or Assessment. Thus, 
should the benefit/risk assessment adversely change during the study for a subject, he/she will be 
discontinued.
Safety assessments will be conducted per Section 9.5.1.4 of the protocol to ensure participant 
safety and reduce risks. Both safety and efficacy assessments have been outlined to allow for 
adequate assessment of clinical benefit, and when possible, have been gradually reduced in 
frequency with consideration of minimizing patient burden. The summary of measures taken to 
mitigate risk and burden within the protocol are outlined in Appendix Table 11-1. 
Appendix Table 11-1  Measures to Reduce Participant Risk and Burden:
Protocol Section
Considerations and Measures Taken
Section 9.1.2, Tumor 
Assessments:
During the randomization phase the frequency in which 
tumor assessments are performed reduces gradually; 
initially performed, every 6 weeks ±1 week, following the 
date of randomization.
Following Week 18, tumor assessments occur every 9 
weeks ±1 week until week 54 ±1 week. Thereafter, they 
will be performed every 12 weeks ±2 weeks until 
documentation of PD.
The initial schedule of scans allows for the detection of 
early progression in order to ensure the subjects is deriving 
treatment benefit, and then reduces gradually to reduce risk 
and burden.
Section 9.3, Selection of 
Study Population
To ensure appropriate monitoring of subject risk, inclusion 
and exclusion criteria have taken consideration of age and 
gender where clinically relevant, eg, serum creatinine and 
blood pressure thresholds, performance status scoring, and 
proteinuria determination.
Page 142 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 142 of 147
Section 9.5.1.4, Safety 
assessment
The protocol requires continuous monitoring of patient 
safety and recording of all adverse events (AE)s and serious 
adverse events (SAEs), including laboratory data, graded 
per National Cancer Institute (NCI), CTCAE v5.0 
beginning from the time the subject signs the study ICF 
through the last visit and for 30 days after the subject’s last 
dose.
Section 8.5.2, Table 6, 
Schedule of Assessments 
(Randomization Phase)
Urinalysis by urine dipstick, and cardiac monitoring by 
ECG reduce in frequency. This allows for detection of early 
toxicity, and then reduces gradually to reduce patient 
burden.
Furthermore, safety monitoring measures have been taken 
with consideration of age and gender to ensure appropriate 
monitoring of subject risk.  This includes age-specific 
performance status scoring systems, and the inclusion of 
age-specific thresholds in the toxicity management 
guidelines for proteinuria (Section 9.4.1.1.4) and
hypertension (Section 9.4.1.1.2).
Section 9.5.2, Table 7, 
Schedule of Assessments 
(Extension Phase)
Extension phase: Study assessments are reduced in number 
and frequency following the completion of the PFS-1y and 
OS-1y analysis (ie, at the end of the Randomization phase) 
to reduce patient burden and risk; tumor assessments are 
performed in accordance with local standard of care, while 
ECG, echocardiograms, sampling for PK and PD analysis, 
and HRQoL assessments will not be required.
Section 9.5.1.4.3 Laboratory 
Measurements: Maximum 
Puncture Attempts. 
Maximum Blood Volume 
Sampling.
For children requiring venipuncture, if the practitioner is 
unsuccessful after two attempts, it is recommended that 
another suitably trained professional perform venipuncture 
while assessing the child's coping skills.  A maximum of 3 
attempts may be considered; however, clinical need and 
risk/benefit of further attempts should be assessed at the 
discretion of the investigator
The maximum volume of blood to be collected is 5% of the 
total blood volume over a 30-day period (Howie, et al 2010, 
Children’s Memorial Research Center (CMRC), 2006).
Section 9.5.1.3.1: 
Pharmacokinetic 
In order to ensure subject safety and not exceed the 
maximum allowable volume for blood collections, 
Page 143 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 143 of 147
Assessments; Table 6, 
Schedule of Assessments   
pharmacokinetic (PK) sampling should not be performed 
for any subject with a body weight less than 13 kg 
Section 9.5.1.3.2: 
Pharmacodynamic and other 
Biomarker Assessments; 
Table 5, Schedule of 
Assessments
In order to ensure subject safety and not exceed the 
maximum allowable volume for blood collections, 
pharmacodynamic sampling should not be performed for 
any subject with a body weight less than 16 kg
Furthermore, to reduce subject burden, blood sampling for 
pharmacodynamic biomarker assessment is optional for all 
subjects and will not impact eligibility.
Section 9.5.2, Table 5, 
Schedule of Assessments 
(Randomization Phase): 
Footnote w
Providing archival tumor samples is optional to minimize 
subject burden and does not impact eligibility. 
Section 9.7.3 Interim 
Analysis
Periodic safety monitoring will be conducted by the 
independent data monitoring committee (IDMC) to further 
mitigate subject risk.
Additional changes for sites in Germany:

Section 9.5.1.4.3, Section 9.5.2.1, Table 6 (footnote h), Table 7 (footnote i):  Clinical 
chemistry and hematology results must be reviewed by the investigator prior to 
administration of study drug on C1D1 and within 48 hours after dispensing study drug for all 
subsequent cycles.

Section 9.5.1.4.3: Laboratory Measurements
Maximum Number of Puncture Attempts
Central venous access is recommended for subjects in this study and thus, if possible, blood 
draws should be obtained using the central line or port.  For children requiring venipuncture, 
if the practitioner is unsuccessful after two attempts, it is recommended that another suitably 
trained professional perform venipuncture while assessing the child's coping skills.  A 
maximum of 3 attempts may be considered; however, clinical need and risk/benefit of further 
attempts should be assessed at the discretion of the investigator. Utilization of procedures to 
minimize any pain, reduce distress associated with blood sampling, and increase successful 
venous access should be considered including topical anaesthesia, application of 
warmth/cooling, alternative puncture site sampling and ultrasound guidance where applicable 
and in accordance with local institutional guidelines.
Maximum Blood Volume Sampling
The maximum volume of blood to be collected is 5% of the total blood volume over a 30-day 
period (Howie, et al 2010, Children’s Memorial Research Center (CMRC), 2006). In order to 
Page 144 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 144 of 147
ensure the maximum allowable blood volume is not exceeded, please refer to 
Section 9.5.1.3.1 and Section 9.5.1.3.2 of the protocol which details weight limits for 
pharmacokinetic and pharmacodynamic blood sampling. The estimated total volume of blood 
is not expected to exceed:
The scheduled blood volume collections are outlined in the table below.
Blood Sample Collection Schedule
Period
Screening Baseline
Treatment
Off-
Tx
Visit 
1
2
3
4
5
6
7
8
9
10
11 12
13
14
15
16
17
18+
Cycle
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5
Cycle 
6-X
Day
-28 to -2
-1
1
8
15
1
8 15
1
8 15
1
8
15
1
8
15
1
Procedures/
Assessments
Clinical chemistry 
and hematologya
10
10
10
10
10
10
10
10
10
10
PK blood samples 
(Arm A)b
4
6
2
Pharmacodynamic 
biomarker (Arm 
A)c
4
4
4
4
4
Total volume
(mL)d
10
14
4
20
16
10
10
14
10
14
10
a. Clinical chemistry and hematology blood samples (approximately 10mL per time point) will be taken at 
Screening, Baseline, Cycle 1 Day 15, Cycle 2 Day 1, Cycle 2 Day 15, Day 1 of each subsequent cycle, and at the 
Off-treatment visit. 
b. For Arm A subjects only: Six (6) pharmacokinetic analysis blood samples (one 2 mL sample per time point) will 
be taken at Cycle 1 Day 1 at 0.5 to 4 hours and 6 to 10 hours postdose, on Cycle 1 Day 15 at predose, 0.5 to 4 hours 
and 6 to 10 hours postdose, and Cycle 2 Day 1 at predose. (Total 12 mL). Please see Section 9.5.1.3.1 for further 
details on PK blood sampling weight limits.
c. For Group A subjects only: Five (5) Pharmacodynamic biomarker blood samples (one 4 mL sample per time 
point) will be taken at the Baseline Visit, C1D15, Day 1 of Cycles 2, 4, and 6. (Total 20 mL). Please see Section 
9.5.1.3.2 for further details on pharmacodynamic blood sampling weight limits.
d. Total maximum volume of blood taken at each visit (mL)
Section 9.3.2 Exclusion Criteria

Exclusion Criterion 15: Known to be human immunodeficiency virus (HIV) positive. Note:  
HIV testing is a required evaluation for study entry and needs to be performed in order 
to evaluate eligibility. This testing can be performed at any time during the Screening 
period
Exclusion Criterion 16: Active viral hepatitis (B or C) as demonstrated by positive serology. 
Note: Hepatitis B/C tests are required evaluations for study entry and need to be 
Page 145 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 145 of 147
performed in order to evaluate eligibility. This testing can be performed at any time 
during the Screening period
Page 146 of 388


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 146 of 147
PROTOCOL SIGNATURE PAGE
Study Protocol Number:
E7080-G000-230
Study Protocol Title:
A Multicenter, Open-label, Randomized Phase 2 Study to 
Compare the Efficacy and Safety of Lenvatinib in Combination 
with Ifosfamide and Etoposide versus Ifosfamide and Etoposide 
in Children, Adolescents and Young Adults with Relapsed or 
Refractory Osteosarcoma (OLIE)
Investigational Product 
Name:
E7080/Lenvatinib 
IND Number:
146642
EudraCT Number:
2019-003696-19
SIGNATURES
Authors:
Oncology Business Group, Eisai Ltd.  
Date
Oncology Business Group, Eisai Ltd.
Date
Director, Biostatistics
Oncology Business Group, Eisai Inc.
Date
Page 147 of 388
PPD
PPD
PPD
PPD


Clinical Study Protocol
incorporating Amendment 02
E7080-G000-230
Eisai
FINAL: 10 Sep 2020
Confidential
Page 147 of 147
INVESTIGATOR SIGNATURE PAGE
Study Protocol Number:
E7080-G000-230
Study Protocol Title:
A Multicenter, Open-label, Randomized Phase 2 Study to 
Compare the Efficacy and Safety of Lenvatinib in Combination 
with Ifosfamide and Etoposide versus Ifosfamide and Etoposide 
in Children, Adolescents and Young Adults with Relapsed or 
Refractory Osteosarcoma (OLIE)
Investigational Product
Name:
E7080/Lenvatinib 
IND Number:
146642
EudraCT Number:
2019-003696-19
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
Page 148 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 1 of 121
TITLE PAGE
Clinical Study Protocol
Study Protocol 
Number:
E7080-G000-230
Study Protocol 
Title:
A Multicenter, Open-label, Randomized Phase 2 Study to Compare 
the Efficacy and Safety of Lenvatinib in Combination with Ifosfamide 
and Etoposide versus Ifosfamide and Etoposide in Children,
Adolescents and Young Adults with Relapsed or Refractory 
Osteosarcoma (OLIE)
Sponsor:
Eisai Inc.
155 Tice Boulevard
Woodcliff Lake, 
New Jersey 07677
US
Eisai Ltd. 
European Knowledge 
Centre
Mosquito Way 
Hatfield, Hertfordshire 
AL10 9SN UK
Eisai Co., Ltd. 
4-6-10 Koishikawa
Bunkyo-Ku, 
Tokyo 112 8088
JP
Sponsor’s 
Investigational 
Product Name:
E7080/Lenvatinib
Indication:
Osteosarcoma
Phase:
2
Approval Date(s):
Original Protocol
08 Oct 2019
Amendment 01
09 Mar 2020
IND Number:
146642
EudraCT Number:
2019-003696-19
GCP Statement:
This study is to be performed in full compliance with International 
Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) and all applicable local Good 
Clinical Practice (GCP) and regulations.  All required study 
documentation will be archived as required by regulatory authorities.
Confidentiality 
Statement:
This document is confidential.  It contains proprietary information of 
Eisai (the sponsor).  Any viewing or disclosure of such information 
that is not authorized in writing by the sponsor is strictly prohibited.  
Page 149 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 2 of 121
Such information may be used solely for the purpose of reviewing or 
performing this study.
Page 150 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 3 of 121
REVISION HISTORY
Amendment 01
Date: 09 March 2020
Change
New text is in bold and deleted text is in 
strikethrough font.
Rationale
Affected Protocol 
Sections
Inclusion Criterion 7 is updated as follows:
7. Adequate bone marrow function as 
evidenced by:
a.
absolute neutrophil count (ANC) ≥1.0
1.5×109/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 of 
<8.0 g/dL is acceptable if it is corrected by 
growth factor or transfusion before Cycle 1 
Day 1).
c.
platelet count ≥75 100×109/L.
The minimum neutrophil and 
platelet counts required to 
establish eligibility have been 
revised for consistency with the 
etoposide Summary of Product 
Characteristics per health 
authority request.
Synopsis, Section 8.3.1
Exclusion Criterion 20 is added:
A contraindication to any of the study drugs
(lenvatinib, ifosfamide, and etoposide) per local 
prescribing information.
An exclusion criterion due to 
contraindications to any of the 
study drugs has been added per 
health authority request.
Synopsis, Section 8.3.2
Prior and Concomitant Therapy
Subjects should not receive other antitumor 
therapies while on study.  If a subject receives 
additional antitumor therapies other than the 
study drug(s), such as chemotherapy, targeted 
therapies, immunotherapy, or antitumor 
interventions - such as surgery or palliative 
radiotherapy (other than as described below), 
this will be judged to represent evidence of 
disease progression, and continuation of 
thestudy medication should be discontinued
and further participation in the study must be 
discussed and agreed upon with the sponsor .
Per health authority request,
subjects who receive other
anticancer therapy, except as 
specified in the protocol, should 
be discontinued from study 
treatment.
Synopsis, Section 8.4.7.2
Vital Signs Assessment
On Cycle 1 Day 8, subjects will be contacted 
by telephone to assess for the development of 
early toxicity. Subjects will be provided with 
a BP cuff to monitor BP at home or can have 
the measurement done by a local healthcare 
Per health authority request, a 
Cycle 1 Day 8 telephone 
contact has been added to 
monitor for early toxicity 
(including increase in blood 
pressure).
Section 8.5.2 (Schedule of 
Procedures/Assessments, 
Table 5 footnote j – new 
footnote, subsequent 
footnotes renumbered)
Page 151 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 4 of 121
provider, and will report the C1D8 
measurement at telephone contact. An 
unscheduled visit can occur prior to C1D15 
if deemed necessary by the investigator.
Pharmacodynamic Biomarkers
The Schedule of Procedures/Assessments 
(Table 5) has been updated as follows:
Blood samples will be collected only from 
subjects in Arm A at the Baseline Visit, C1D15 
C1D8, Day 1 of Cycles 2, 4, and 6, for 
assessment of blood serum sample to measure 
factors implicated in angiogenesis.
To lessen patient burden, the 
protocol has been updated to 
move the optional 
pharmacodynamic blood 
sample collection from C1D8 
to C1D15. This eliminates the 
potential need for a study site 
visit for the sole purpose of 
collecting this optional PD 
blood sample on C1D8.
Section 8.5.2 (Schedule of 
Procedures/Assessments, 
Table 5, footnote v)
Administrative changes.
Minor editorial and formatting 
changes.
Throughout the protocol.
Page 152 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 5 of 121
1
CLINICAL PROTOCOL SYNOPSIS
Compound No.  E7080
Name of Active Ingredient:  Lenvatinib
Study Protocol Title
A Multicenter, Open-label, Randomized Phase 2 Study to Compare the Efficacy and Safety of 
Lenvatinib in Combination with Ifosfamide and Etoposide versus Ifosfamide and Etoposide in 
Children, Adolescents and Young Adults with Relapsed or Refractory Osteosarcoma (OLIE)
Investigator
Principal Investigator:  Dr Nathalie Gaspar
Sites
Approximately 70 sites worldwide 
Study Period and Phase of Development
Approximately 36 months
Phase 2
Objectives
Primary Objective
To evaluate whether lenvatinib in combination with ifosfamide and etoposide (Arm A) is superior to 
ifosfamide and etoposide (Arm B) in improving progression-free survival (PFS) rate at 4 months
(PFS-4m) (by independent imaging review [IIR] using Response Evaluation Criteria In Solid Tumors
[RECIST 1.1]), in children, adolescents, and young adults with relapsed or refractory osteosarcoma.
Secondary Objectives
The secondary objectives of the study are to:
1.
Compare differences in PFS rate at 1 year (PFS-1y) between the 2 treatment arms 
2.
Compare differences in PFS Kaplan-Meier (K-M) survival curves and median PFS between the 
2 treatment arms
3.
Compare differences in overall survival (OS) and OS rate at 1 year (OS-1y) between the 
2 treatment arms
4.
Compare differences in objective response rate (ORR) at 4 months between the 2 treatment arms
5.
Compare differences in safety and tolerability between the 2 treatment arms
6.
Characterize the pharmacokinetics (PK) of lenvatinib, when administered in combination with 
ifosfamide and etoposide 
7.
Compare differences in health-related quality of life (HRQoL) as assessed by using the the 
Pediatric Quality of Life Inventory (PedsQL) Generic Core Scales and Cancer Module between
the 2 treatment arms
8.
Assess the palatability and acceptability of the suspension formulation of lenvatinib in pediatric 
subjects receiving the suspension formulation in the study
Exploratory Objectives
The exploratory objectives of the study are to: 
1.
Explore differences in duration of response (DOR), disease control rate (DCR), and clinical 
benefit rate (CBR) between the 2 treatment arms
Page 153 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 6 of 121
2.
Compare the proportion of subjects who achieve complete removal of baseline lesion(s) 
following completion of chemotherapy between the 2 treatment arms
3.
Investigate the relationship between subject tumor biomarkers and clinical response and toxicity 
of lenvatinib in combination with ifosfamide and etoposide
Study Design
E7080-G000-230 is a multicenter, randomized, open-label, parallel-group, Phase 2 study to compare 
the efficacy and safety of lenvatinib in combination with ifosfamide and etoposide versus ifosfamide 
and etoposide in children, adolescents, and young adults with relapsed or refractory osteosarcoma.  
Approximately 72 eligible subjects will be randomized to 1 of the following 2 treatment arms in a 1:1 
ratio within the strata:

Arm A:  lenvatinib 14 mg/m2 (orally, once daily) plus ifosfamide 3000 mg/m2/day (intravenously 
[IV], Day 1 to Day 3 of each cycle for a total of up to 5 cycles) and etoposide 100 mg/m2/day 
(IV, Day 1 to Day 3 of each cycle for a total of up to 5 cycles)

Arm B:  ifosfamide 3000 mg/m2/day (IV, Day 1 to Day 3 of each cycle for a total of up to 
5 cycles) and etoposide 100 mg/m2/day (IV, Day 1 to Day 3 of each cycle for a total of up to 5 
cycles)
Randomization will follow a predefined randomization scheme based on the following stratification 
factors: time to first relapse/refractory disease (early [<18 months] or late [≥18 months]) and age 
(<18 and ≥18 years).  
Eisai will closely monitor enrolment, to ensure that at least 32 subjects <18 years of age at the time of 
informed consent are randomized.  
The study will be conducted in 3 Phases: a Prerandomization Phase, a Randomization Phase, and an 
Extension Phase.  
The Prerandomization Phase will consist of 2 periods: Screening and Baseline. The 
Prerandomization Phase will last no longer than 28 days. The Screening Period will establish 
protocol eligibility and the Baseline Period will confirm eligibility. 
The Randomization Phase will consist of 2 periods: Treatment Period and Follow-up Period. The 
Randomization Phase will begin at the time of randomization of the first subject and will end on the 
data cutoff date for the PFS-1y and OS-1y analysis.  After the data cutoff date for the PFS-1y and 
OS-1y has occurred, all subjects who are still on study treatment will enter the Extension Phase. 
Data cutoff (for PFS-1y and OS-1y analysis) will occur when the last subject has completed 
18 cycles of treatment or discontinues before the end of Cycle 18, whichever occurs first. 
The Treatment Period for each subject will begin at the time of randomization and will end at the 
completion of the Off-Treatment Visit which will occur within 30 days after the final dose of study 
treatment  
Subjects will receive study treatment as continuous 21-day cycles in both treatment arms. Treatment 
cycles will be counted continuously regardless of dose interruptions. If chemotherapy administration 
is precluded on Day 1 of a treatment cycle, the subject may resume treatment once recovered at the 
discretion of investigator. Subsequent chemotherapy will be administered every 21 (±1) days starting 
from the timepoint it was resumed.
Subjects will undergo safety and efficacy assessments as defined in the Schedule of 
Procedures/Assessments.  Subjects randomized to Arm A will continue to receive lenvatinib until 
disease progression (PD) confirmed by IIR, development of unacceptable toxicity, subject request, 
withdrawal of consent, or study termination by the sponsor, whichever occurs first.
Disease progression (PD) must be confirmed by IIR prior to the investigator discontinuing study 
treatment for a subject.  In situations where the investigator judges that alternative treatments must be 
Page 154 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 7 of 121
instituted immediately for a subject’s safety, study drugs may be discontinued without waiting for IIR
confirmation of radiographic evidence of PD.  If possible, before discontinuation of the subject from 
the study, the investigator should consult with the sponsor.
The Follow-up Period begins the day after the Off-Treatment Visit and will continue as long as the 
subject is alive, unless the subject withdraws consent, or the sponsor terminates the study.  
Subjects may at any time withdraw consent for further study participation.  No further data will be 
collected on subjects once consent has been withdrawn, however, an investigator may consult public 
records to establish survival status if permitted by local regulations.
All adverse events (AEs) will be captured for 30 days after the last dose of study drug.  
All subjects who discontinue study treatment early for reasons other than PD, will continue to 
undergo tumor assessments every 6 weeks until Week 18, then every 9 weeks until Week 54, 
thereafter, every 12 weeks until confirmation of disease progression by IIR as described in the tumor 
assessments in the assessment schedule, or until another anticancer therapy is initiated.
Subjects in both Arm A and Arm B will be followed for survival every 12 weeks (±1 week) and all 
subsequent anticancer treatments received will be recorded.  Subjects who are being followed for 
survival at the time of data cutoff for the for PFS-1y and OS-1y analysis (ie, at the end of the 
Randomization Phase) will continue to be followed for survival during the Follow-up Period of the 
Extension Phase.
Extension Phase:  The Extension Phase will consist of 2 periods: Treatment Period and Follow-up 
Period.  
In the Treatment Period, subjects still on lenvatinib in Arm A following the completion of the 
PFS-1y and OS-1y analysis (ie, at the end of the Randomization Phase) will continue to receive 
lenvatinib in 21-day cycles until disease progression, development of unacceptable toxicity, subject 
request, withdrawal of consent, or discontinuation of study by the sponsor.  Tumor assessments will 
be performed according to the local standard of care.  Independent imaging review (IIR) review and 
confirmation of radiographic evidence of PD will not be required, and scans will no longer be 
required to be sent to the imaging core laboratory (ICL).  The Off-Treatment Visit will occur within 
30 days after the final dose of study treatment. All AEs will be captured up to 30 days after last dose 
of study drug.  In case the study is discontinued by the sponsor, the sponsor will continue to provide 
study drug (outside the study) for subjects requiring continuation of treatment. 
The Follow-up Period will begin the day after the Off-Treatment Visit and will last until death or for 
2 years after end of treatment for a subject, unless the study is terminated by the sponsor, or the 
subject discontinues due to withdrawal of consent, or is lost to follow-up.  Subjects will be treated by 
the investigator according to the prevailing local standard of care. Subjects will be followed every 
12 weeks (±1week) for survival and all subsequent anticancer treatments received will be recorded.   
The definition of end of the study, as required by certain regulatory agencies, will be the date of data 
cutoff for the final analysis or the time of last subject last visit, whichever occurs later.
Number of Subjects
Approximately 72 subjects will be randomised (36 subjects in each arm).
For the primary endpoint (intent–to-treat analysis), at least 32 subjects 18 years old (at the time of 
informed consent) will be randomized.
Inclusion Criteria
1.
Histologically or cytologically confirmed diagnosis of high grade osteosarcoma.
2.
Refractory or relapsed osteosarcoma after 1 to 2 prior systemic treatments. 
3.
Measurable or evaluable disease per RECIST 1.1 that meets the following criteria:
Page 155 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 8 of 121
-
Must be accurately measurable with a minimum size (by long axis) of 10 mm using 
computed tomography/magnetic resonance imaging (CT/MRI) (lymph nodes must be 
accurately measurable with a minimum size [by short axis] of 15 mm). 
-
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.
Aged 2 years to ≤25 years at the time of informed consent.
5.
Life expectancy of 12 weeks or more.
6.
Lansky play score ≥50% or Karnofsky Performance Status score ≥50%.  Use Karnofsky for 
subjects ≥16 years of age and Lansky for subjects <16 years of age.  Subjects who are unable to 
walk because of paralysis, but who are up in wheelchair, will be considered ambulatory for the 
purpose of assessing the performance score.
7.
Adequate bone marrow function as evidenced by:
a.
absolute neutrophil count (ANC) ≥1.5×109/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 of <8.0 g/dL is acceptable if it is corrected by growth 
factor or transfusion before Cycle 1 Day 1).
c.
platelet count ≥100×109/L.
8.
Adequate blood coagulation function defined by International Normalized ratio (INR) ≤1.5 
unless participant is receiving anticoagulant therapy, as long as INR is within therapeutic range 
of intended use of anticoagulants.
9.
Adequate liver function as evidenced by:
a.
Bilirubin ≤1.5 times the upper limit of normal (ULN).
b.
Alanine aminotransferase (ALT), and aspartate aminotransferase (AST) ≤3×ULN (in the case 
of liver metastases ≤5×ULN).
10. 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.
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 
Common Terminology Criteria for Adverse Events (CTCAE) v5.0 and if possible perform a 
Page 156 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 9 of 121
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. 
11. Adequate cardiac function as evidenced by left ventricular ejection fraction ≥50% at baseline as 
determined by echocardiography.
12. 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 guidelines) and no change in antihypertensive medications within 1 week 
prior to Cycle 1 Day 1. Subjects >18 years of age should have BP ≤150/90 mm Hg at 
screening and no change in antihypertensive therapy within 1 week prior to Cycle 1 Day 1.
13. Washout before Cycle 1 Day 1 of 3 weeks in case of prior chemotherapy, 6 weeks if treatment 
included nitrosoureas; 4 weeks for definitive radiotherapy, 2 weeks for palliative radiotherapy; 
and 3 months from high-dose chemotherapy and stem cell rescue.  Subjects must have recovered 
(to Grade ≤1, except for alopecia, ototoxicity, and Grade ≤2 peripheral neuropathy, per CTCAE 
v5.0) from the acute toxic effects of all prior anticancer therapy before Cycle 1 Day 1.
14. 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.
15. Willing and able to comply with the protocol, scheduled follow-up, and management of toxicity 
as judged by the investigator.
Exclusion Criteria
1.
Any active infection or infectious illness unless fully recovered  prior to Cycle 1 Day 1 (ie, no 
longer requiring systemic treatment).
2.
Subjects with central nervous system metastases are not eligible, unless they have completed 
local therapy (eg, whole brain radiation therapy, surgery, or radiosurgery) and have discontinued 
the use of corticosteroids for this indication for at least 2 weeks before Cycle 1 Day 1.  
3.
Active second malignancy within 2 years prior to enrollment ([in addition to osteosarcoma], but 
not including definitively treated superficial melanoma, carcinoma-in-situ, basal or squamous 
cell carcinoma of the skin).
4.
Any medical or other condition that in the opinion of the investigator(s) would preclude the 
subject’s participation in a clinical study.  
5.
Has had major surgery within 3 weeks prior to Cycle 1 Day 1. Note: Adequate wound healing 
after major surgery must be assessed clinically, independent of time elapsed for eligibility.
6.
Known hypersensitivity to any component(s) of the study drugs (lenvatinib, ifosfamide, and 
etoposide, or their ingredients).
7.
Currently receiving any investigational drug or device in another clinical study or within 28 days 
prior to Cycle 1 Day 1.
8.
A clinically significant ECG abnormality, including a marked baseline prolonged QT or QTc 
interval (eg, a repeated demonstration of a QTc interval >480 msec).
9.
Gastrointestinal malabsorption, gastrointestinal anastomosis, or any other condition that in the 
opinion of the investigator might affect the absorption of lenvatinib.
10. Pre-existing Grade ≥3 gastrointestinal or non-gastrointestinal fistula.
11. Gastrointestinal bleeding or active hemoptysis (bright red blood of at least ½ teaspoon) within 
3 weeks prior to Cycle 1 Day 1.
12. Radiographic evidence of intratumoral cavitation, encasement, or invasion of a major blood 
Page 157 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 10 of 121
vessel. Additionally, the degree of proximity to major blood vessels should be considered for 
exclusion because of the potential risk of severe hemorrhage associated with tumor 
shrinkage/necrosis after lenvatinib therapy.
13. History of ifosfamide-related Grade ≥3 nephrotoxicity or encephalopathy.
14. Evidence of clinically significant disease (eg, cardiac, respiratory, gastrointestinal, renal disease) 
that in the opinion of the investigator(s) could affect the subject’s safety or interfere with the 
study assessments.
15. Known to be human immunodeficiency virus (HIV) positive.  Note:  HIV testing is required at 
screening only when mandated by local health authority.
16. Active viral hepatitis (B or C) as demonstrated by positive serology.  Note:  Testing for Hepatitis 
B or Hepatitis C is required at screening only when mandated by local health authority.
17. 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.
18. Females of childbearing potential* who:
-
Do not agree to use a highly effective method of contraception for the entire study period and 
for 28 days after lenvatinib discontinuation or 12 months after etoposide and ifosfamide 
discontinuation, ie:
◦
total abstinence (if it is their preferred and usual lifestyle)
◦
an intrauterine device (IUD) or intrauterine hormone-releasing system (IUS)
◦
a contraceptive implant
◦
an oral contraceptive.  Subject must be on a stable dose of the same oral contraceptive 
product for at least 28 days before dosing with study drug and throughout the study and 
for 28 days after lenvatinib discontinuation or 12 months after etoposide and ifosfamide 
discontinuation
OR
-
Do not have a vasectomized partner with confirmed azoospermia.
For sites outside of the EU, it is permissible that if a highly effective method of contraception is 
not appropriate or acceptable to the subject, or the subject has changed oral hormonal 
contraceptive product/dose within 4 weeks prior to study drug administration, 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. 
* All post pubertal females will be considered to be of childbearing potential unless they have 
early menopause (amenorrheic for at least 12 consecutive months, in the appropriate age group, 
and without other known or suspected cause) or have been sterilized surgically (ie, bilateral tubal 
ligation, total hysterectomy, or bilateral oophorectomy, all with surgery at least 1 month before 
dosing), or are pre-menarcheal (Tanner Stage 1-3).
19. Males who have not had a successful vasectomy (confirmed azoospermia) or if they and their 
female partners do not meet the criteria above (ie, not of childbearing potential or practicing 
highly effective contraception throughout the study period and for 28 days after lenvatinib 
discontinuation or 6 months after discontinuation of etoposide and ifosfamide).  No sperm 
donation is allowed during the study period and for 28 days after lenvatinib discontinuation or 
6 months after discontinuation of etoposide and ifsofamide.
Page 158 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 11 of 121
20. A contraindication to any of the study drugs (lenvatinib, ifosfamide, and etoposide) per local 
prescribing information.
Study Treatments
Body surface area (BSA) will be used to determine the amount of study drugs administered, and must 
be calculated on Day 1 of each cycle based on the subject’s current height and body weight. The 
dose should be rounded to the nearest whole number. 
Test Arm (Arm A): Lenvatinib + Ifosfamide + Etoposide
Lenvatinib 14 mg/m2, orally administered once daily in each 21-day cycle.
Lenvatinib is provided as hard capsules containing 1 mg, 4 mg, or 10 mg lenvatinib. An 
extemporaneous suspension of lenvatinib capsules should be used for subjects unable to swallow 
capsules. After adjustment for BSA, the daily dose cannot exceed 24 mg QD.
Ifosfamide 3000 mg/m2/day, IV, for 3 consecutive days (Day 1 to 3), every 21 days, for a maximum 
of 5 cycles.
Etoposide 100 mg/m2/day, IV, for 3 consecutive days (Day 1 to 3) , every 21 days, for a maximum of 
5 cycles. 
Treatment with lenvatinib will continue in 21-day cycles after chemotherapy is discontinued, until 
disease progression, development of unacceptable toxicity, subject request, withdrawal of consent, or 
discontinuation of study by the sponsor.
In case the study is discontinued by the sponsor, the sponsor will continue to provide study drug 
(outside the study) for subjects requiring continuation of treatment.
Control Arm (Arm B):  Ifosfamide + Etoposide
Ifosfamide 3000 mg/m2/day, IV, daily for 3 consecutive days (Day 1 to 3), every 21 days, for a 
maximum of 5 cycles.
Etoposide 100 mg/m2/day, IV, daily for 3 consecutive days (Day 1 to 3), every 21 days, for a 
maximum of 5 cycles.
Duration of Treatment
A subject will remain on study treatment until 1 or more of the following events occur(s):

Progressive disease (as confirmed by IIR)

Unacceptable toxicity

Subject request

Withdrawal of consent 

Termination of the study by the Sponsor
Concomitant Drug/Therapy
Prohibited Concomitant Therapies and Drugs
Subjects should not receive other antitumor therapies while on study. If a subject receives additional 
antitumor therapies other than the study drug(s), such as chemotherapy, targeted therapies, 
immunotherapy, or antitumor interventions - such as surgery or palliative radiotherapy (other than as 
described below), this will be judged to represent evidence of disease progression, and the study 
medication should be discontinued.
For further information on the prohibited concomitant therapies for ifosfamide and etoposide, please 
refer to the respective prescribing information.
Granulocyte-colony stimulating factor (G-CSF) may be used to mitigate the toxicity of ifosfamide 
and etoposide.
Page 159 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 12 of 121
The following concomitant treatments/procedures are allowed:
a.
Removal of existing (not new) osteosarcoma lesion (eg, surgical, radiofrequency ablation,
cryotherapy, thermoablation, stereotaxic ratiotherapy, etc.) after completion of the Week 18 
tumor assessment.  Subjects in Arm A in the presence of clinical benefit, may continue treatment 
with lenvatinib after protocol permissible surgery.
b.
Palliative radiotherapy is allowed for ≤2 significantly symptomatic nontarget lesions. 
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.
Any additional procedural or subject specific particularities should be discussed with the sponsor.  
Assessments
Efficacy Assessments
Tumor assessment will be performed based on RECIST 1.1. Investigator–determined response 
assessments will be performed at each assessment time point and entered onto the case report form 
(CRF). Copies of all tumor assessment scans will be sent to an imaging core laboratory (ICL)
designated by the sponsor for efficacy assessment and for confirmation of PD.  Tumor assessments 
will be carried out following the guidelines provided by the ICL.  
During the Screening Period, 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 Cycle 1
Day 1.  A brain scan (CT scan with contrast or MRI pre- and post-gadolinium) will be performed at 
screening as clinically indicated, and thereafter during the study as clinically indicated.  Historical 
CT or MRI scans performed within 28 days prior to Cycle 1 Day 1 may be used as screening scans 
(baseline scans) to demonstrate eligibility, as long as they meet minimum standards as separately 
defined by the ICL.  
Tumor assessments will then be performed every 6 weeks ±1 week following the start of treatment 
on Cycle 1 Day 1 during the chemotherapy treatment period until Week 18.  Following completion of 
the chemotherapy treatment period (ie, after Week 18), the frequency of tumor assessments will be 
every 9 weeks ±1 week until Week 54 ±1 week.  Thereafter, they will be performed every 12 weeks 
±2 weeks until documentation of PD (please see schedule of assessments for details).  At any point, 
the CT/MRI scan should be performed earlier than the scheduled time point, if clinically indicated.  
After data cutoff for PFS-1y and OS-1y analysis, tumor assessments should be performed following 
the prevailing local standard of care.
Disease progression per RECIST 1.1 during the randomization phase must be confirmed by IIR prior 
to the investigator discontinuing study treatment.
In the event that the investigator considers alternative treatments must be instituted immediately for 
management of urgent medical complications of PD, study drugs may be discontinued without 
waiting for independent confirmation of radiographic evidence of PD.  Subjects who discontinue 
study treatment without PD will continue to undergo tumor assessments according to the schedule 
until PD is documented or another anticancer therapy is initiated. 
Pharmacokinetic Assessments
Blood samples for plasma concentrations of lenvatinib will be collected from all subjects from 
Arm A only as described in the Schedule of Assessments.
Page 160 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 13 of 121
Pharmacodynamic and Other Biomarker Assessments
Pharmacodynamic serum and archived fixed tumor tissue samples for biomarker analysis will be 
collected from subjects randomized to Arm A only, as described in the Schedule of Assessments.  
Pharmacodynamic serum and tumor biomarkers assessed in this study will be based on those
identified in other lenvatinib clinical studies.  Pharmacodynamic biomarker analysis will be 
performed as described in a separate analysis plan. 
Safety Assessments
Safety assessments will consist of monitoring and recording all adverse events (AEs), including all 
grades per National Cancer Institute (NCI) CTCAE v5.0 (for both increasing and decreasing 
severity), and serious adverse events (SAEs); regular laboratory evaluation for hematology, blood 
chemistry, and urine values; periodic measurement of vital signs and ECGs; and physical 
examinations.
Progression of osteosarcoma and signs and symptoms clearly related to the progression of the 
osteosarcoma should not be captured as an AE.  Disease progression is a study endpoint and should 
be captured in the CRF as per the guidelines for reporting disease progression.
Other Assessments
HRQoL assessment will be performed per the Schedule of Assessments.  Impact of treatment on 
HRQoL will be assessed using the PedsQL (including the Generic Core Scales and Cancer Module).  
Bioanalytical Methods
Lenvatinib in plasma will be quantified using a validated liquid chromatography tandem mass
spectrometry (LC-MS/MS) method.  Pharmacodynamic biomarker analysis will be performed as 
described in a separate analysis plan.  Clinical laboratory tests will be performed at qualified local 
laboratories.
Statistical Methods
Primary Endpoint

PFS-4m rate (progression-free survival rate at 4 months) by IIR is defined as the percentage 
of subjects who are alive and without PD at 4 months from the randomization date as determined 
by IIR of radiological imaging using RECIST 1.1.  The PFS-4m rate is estimated on the full 
analysis set for this study using the K-M method.  
Secondary Endpoints

PFS-1y rate (progression-free survival rate at 1 year) by IIR is defined as the percentage of 
subjects who are alive and without PD at 1 year from the randomization date as determined by 
IIR of radiological imaging using RECIST 1.1.  The PFS-1y rate is estimated on the full analysis 
set for this study using the K-M method.  

Progression-free survival (PFS) by IIR is defined as the time from the date of randomization to 
the date of the first documentation of PD or death (whichever occurs first) as determined by IIR 
using RECIST 1.1.  

Overall survival (OS) is defined as the time from the date of randomization to 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 alive, or date of data cutoff, 
whichever occurs first.  Overall survival rate at 1 year will be estimated.

Objective response rate (ORR) by IIR at 4 months is defined as the proportion of subjects who 
have best overall response of complete response (CR) or partial response (PR) as determined by 
IIR using RECIST 1.1 within the first 4 months.

Safety will be assessed summarizing the incidence of treatment-emergent adverse events 
Page 161 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 14 of 121
(TEAEs) and SAEs together with all other safety parameters.  

Assessment of population-based PK parameters of lenvatinib.

Score changes from baseline for all PedsQL scales including Generic Core Scales and Cancer 
Module.  Scores will be calculated for total generic score, total cancer score, each physical 
function subscale including physical health, psychosocial health, emotional function, social 
function, school/work function in the Generic Core Scales, and each subscales in the cancer 
module.  

Palatibility and acceptability of the suspension formulation of lenvatinib in subjects receiving the 
suspension formulation in the study will be assessed using the Palatability Questionnaire (see 
Appendix 5).
Exploratory Endpoints

Duration of response (DOR) by IIR is defined as the time from the date a response was first 
documented until the date of the first documentation of PD or date of death from any case.

Disease control rate (DCR) by IIR is the proportion of subjects who have a best overall 
response of CR or PR or stable disease (SD).  In this context, stable disease is defined as stable 
disease at ≥7 weeks after randomization to be considered best overall response.

Clinical benefit rate (CBR) by IIR is the proportion of subjects who have best overall response 
of CR or PR or durable SD (duration of SD ≥23 weeks after randomization).

Proportion of subjects who achieve complete removal of baseline lesions following completion 
of chemotherapy.

Blood and tumor biomarkers will be assessed for identifying potential correlation with clinical 
outcomes-related endpoints.

All efficacy endpoints listed above (except OS) evaluated based on investigator 
assessment using RECIST 1.1.
Analysis Sets
The Full Analysis Set (Intent-to-Treat Analysis [ITT]) includes all randomized subjects regardless
of the treatment actually received. This is the primary analysis population used for the efficacy 
analyses which will be based on the ITT principle.
The Per Protocol Analysis Set includes those subjects from the ITT set who received at least 1 dose 
of any study drug, had no major protocol deviations and had both baseline and at least one 
postbaseline tumor assessment. Subjects for whom death occurred prior to the first postbaseline 
tumor assessment will also be included. The per protocol analysis set will be the secondary analysis 
set for efficacy endpoints.
The Safety Analysis Set includes subjects who received at least 1 dose of any study drug. This is 
the analysis population used for all safety analyses which will be based on as-treated principle.
Population Pharmacokinetic (PK) Analysis Set includes the subjects who have received at least 1
dose of lenvatinib with documented dosing history and have measurable plasma levels of lenvatinib.
The Pharmacodynamic Analysis Set includes subjects who received at least 1 dose of study drug 
and had sufficient pharmacodynamic data (eg, at least 1 evaluable/measurable pharmacodynamic
parameter).
The HRQoL Analysis Set will consist of all randomized subjects who have received at least 1 dose 
of study medication, and have completed at least 1 patient-reported outcome (PRO) assessment 
beyond baseline.  For PRO analysis, subjects will be analyzed as randomized and not according to 
treatment actually received.
Page 162 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 15 of 121
Efficacy Analyses
Efficacy analyses will be based primarily on the Full Analysis Set.
All the statistical analysis will be conducted at the PFS-1y/OS-1y analysis data cutoff date (ie, 
when the last subject has completed 18 cycles of treatment or discontinues before the end of 
Cycle 18, whichever occurs first), including the analysis of PFS-4m rate.  Additional follow-up 
analysis will be based on the date of data cutoff for the additional follow-up analysis for OS or at the 
time of last subject last visit, whichever occurs later.  
Primary Analysis
The primary analysis of PFS-4m rate will be based upon data provided by IIR of tumor assessments.  
PFS-4m rate and their Greenwood standard errors will be evaluated using the K-M estimates from 
both treatment groups.  The statistical significance of the difference in the 2 K-M PFS-4m rates 
comparing lenvatinib + chemotherapy agent (Test Arm) vs. chemotherapy agent alone (Control Arm) 
will be tested using a 2-sided 80% CI. This 2-sided 80% CI and a p-value will be constructed using 
the difference of these 2 K-M PFS-4m rates and the 2 corresponding Greenwood standard errors. 
Statistical significance of the difference is declared if the CI is entirely above 0. This is equivalent to 
a test using a 1-sided test at alpha=0.1. The 2-sided 95% CIs will also be provided for descriptive 
purposes. PFS-4m rate will also be analyzed using a binomial approach as a sensitivity analysis by 
excluding subjects whose PFS are censored prior to 18 weeks.
Secondary Analyses
PFS-1y rate will be analyzed using the same methods as the primary efficacy analysis. PFS 
censoring rules will follow FDA guidance of 2007, however, removal of baseline lesions after 
completion of Week 18 without progression is not a trigger for PFS censoring after 18 weeks (refer to 
Concomitant Drug/Therapy – allowed concomitant treatment/procedures).
Overall survival (OS) will be compared between treatment arm and control arm using the stratified 
logrank test with time to first relapse/refractory disease (early [<18 months] or late [≥18 months]) 
and age (<18 or ≥18 years) as strata.  Median OS with 2-sided 80% and 95% CIs will be calculated 
using K-M product-limit estimates for each treatment arm, and the K-M estimates of OS will be 
plotted over time. The Cox regression model will be used to estimate the hazard ratio and its 80% 
and 95% CIs stratified by time to first relapse/refractory disease (early [<18 months] or late 
[≥18 months]) and age (<18 or ≥18 years).  Kaplan-Meier (K-M) estimates will also be presented for 
4, 6, 9, and 12 months with 2-sided 80% and 95% CIs.
Median PFS and 2-sided 80% and 95% (as exploratory) CIs will be presented, and the K-M estimates 
of PFS will be plotted over time. The Cox regression model will be used to estimate the hazard ratio 
and its 80% and 95% CIs stratified by time to first relapse/refractory disease (early [<18 months] or 
late [≥18 months]) and age (<18 or ≥18 years).  Kaplan-Meier (K-M) estimates will also be presented 
for 4, 6, 9, and 12 months with 2-sided 80% and 95% CIs.
The ORR will be compared between the test and control groups using either a chi-square test or a 
Cochran-Mantel-Haenszel test stratified by time to first relapse/refractory disease (early 
[<18 months] or late [≥18 months]) and age (<18 or ≥18 years), as appropriate.  Corresponding odds 
ratios and their 2-sided 80% and 95% CIs comparing the groups will also be presented.  The 
individual treatment group ORRs will also be calculated along with exact 95% confidence intervals 
using the Clopper and Pearson method.
Exploratory Analyses
Median DOR among responders for each arm will be presented along with its corresponding 2-sided 
95% CIs. Disease Control Rate (DCR) and CBR will be calculated with exact 95% CIs using the 
Clopper and Pearson method. The differences of the above rates between 2 groups and 
corresponding two-sided 95% CIs will be calculated respectively.
Page 163 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 16 of 121
Pharmacodynamic and Other Biomarker Analyses
Pharmacodynamic, and other biomarker analyses may be performed and reported separately.  Details 
of these analyses may be described in a separate analysis plan.
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. 
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.
Data obtained from the pharmacodynamic samples will be used for research.  The pharmacodynamic
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 informed consent forms (ICFs) to continue on the study.
Pharmacokinetic Analyses
Lenvatinib concentration versus time data will be tabulated and summarized and graphically 
presented.
Lenvatinib data from Arm A of the study will be pooled with available data from other studies and 
subjected to population PK analysis.  The PK model will be parameterized in terms of clearance and 
volume of distribution. Details of the population PK analysis will be provided in a separate analysis 
plan. 
Other Analyses
Health-Related Quality of Life (HRQoL):
The PedsQL for all subjects(self- and proxy-rating) will be collected at baseline, at C2D1, C3D1, 
Week 18, C8D1, C18 D1, and at the Off-Treatment visit.
Interim Analyses
No interim analysis is planned for this study.
The safety monitoring will be conducted by the independent data monitoring committee (IDMC).
The frequency of safety reviews will be defined in the IDMC charter. Minutes from the open 
meetings of the IDMC will be provided if requested by regulatory agencies. The recommendation 
whether to stop the study for safety will be reached by the IDMC based on their review of safety data 
with treatment information. The function and membership of the IDMC will be described in the 
IDMC charter.
Sample Size Rationale
A binomial-based comparison of 2 proportions using correction for continuity was used for sample 
size estimation.  A total sample size of 72 subjects is estimated to achieve 80% statistical power at 
1-sided alpha of 0.1 to detect a difference of 30% based on the assumption that PFS-4m for Arm A 
(lenvatinib arm) is 55% and for Arm B is 25%.  Alpha is the type 1 error probability of declaring 
lenvatinib arm being effective when the true lenvatinib arm PFS-4m rate is only 25%. 
Page 164 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 17 of 121
2
TABLE OF CONTENTS
TITLE PAGE........................................................................................................................1
1
CLINICAL PROTOCOL SYNOPSIS............................................................................5
2
TABLE OF CONTENTS.............................................................................................17
3
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................23
4
ETHICS.......................................................................................................................26
4.1
Institutional Review Boards/Independent Ethics Committees.............................26
4.2
Ethical Conduct of the Study..............................................................................26
4.3
Subject Information and Informed Consent ........................................................27
5
INVESTIGATORS AND STUDY PERSONNEL .......................................................28
6
INTRODUCTION.......................................................................................................28
6.1
Osteosarcoma.....................................................................................................28
6.2
Current Therapeutic Options ..............................................................................29
6.3
Lenvatinib..........................................................................................................30
6.3.1
Clinical Data on Lenvatinib in Combination with Ifosfamide and 
Etoposide for Treatment of Relapsed or Refractory Osteosarcoma............31
6.4
Study Rationale..................................................................................................32
7
STUDY OBJECTIVES................................................................................................32
7.1
Primary Objective ..............................................................................................32
7.2
Secondary Objectives.........................................................................................32
7.3
Exploratory Objective(s)....................................................................................33
8
INVESTIGATIONAL PLAN ......................................................................................33
8.1
Overall Study Design and Plan...........................................................................33
8.1.1
Prerandomization Phase ...........................................................................34
8.1.1.1
Screening Period...............................................................................34
8.1.1.2
Baseline Period.................................................................................35
8.1.2
Randomization Phase ...............................................................................35
8.1.2.1
Treatment Period ..............................................................................35
8.1.2.2
Follow-Up Period .............................................................................36
8.1.3
Extension Phase .......................................................................................36
8.1.3.1
Treatment Period ..............................................................................36
8.1.3.2
Follow-Up Period .............................................................................37
8.2
Discussion of Study Design, Including Choice of Control Groups......................37
8.3
Selection of Study Population ............................................................................38
8.3.1
Inclusion Criteria......................................................................................38
8.3.2
Exclusion Criteria.....................................................................................40
8.3.3
Removal of Subjects From Therapy or Assessment ..................................42
Page 165 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 18 of 121
8.4
Treatment(s).......................................................................................................42
8.4.1
Treatment(s) Administered.......................................................................42
8.4.1.1
Lenvatinib Dose Reduction and Interruption Instructions..................43
8.4.1.1.1
Blood Pressure............................................................................45
8.4.1.1.2
Management of Hypertension .....................................................46
8.4.1.1.3
Management of Posterior Reversible Leukoencephalopathy 
Syndrome/Reversible Posterior Leukoencephalopathy 
Syndrome ...................................................................................48
8.4.1.1.4
Management of Proteinuria.........................................................49
8.4.1.1.5
Management of Hepatotoxicity ...................................................50
8.4.1.1.6
Management of Thromboembolic Events....................................50
8.4.1.1.7
Management of Hypocalcemia....................................................50
8.4.1.1.8
Management of Gastrointestinal Symptoms and Acute 
Abdominal Pain ..........................................................................50
8.4.1.1.9
Management of Hemorrhage.......................................................51
8.4.1.2
Management of Ifosfamide-Etoposide Associated Toxicity...............51
8.4.2
Identity of Investigational Product(s)........................................................52
8.4.2.1
Chemical Name of E7080.................................................................52
8.4.2.2
Comparator Drug..............................................................................53
8.4.2.3
Labeling for Study Drug ...................................................................53
8.4.2.4
Storage Conditions ...........................................................................53
8.4.3
Method of Assigning Subjects to Treatment Groups.................................54
8.4.4
Selection of Doses in the Study ................................................................54
8.4.5
Selection and Timing of Dose for Each Subject........................................55
8.4.6
Blinding ...................................................................................................55
8.4.7
Prior and Concomitant Therapy................................................................55
8.4.7.1
Drug-Drug Interactions.....................................................................55
8.4.7.2
Prohibited Concomitant Therapies and Drugs ...................................56
8.4.7.3
Permitted Concomitant Treatment/Procedures ..................................56
8.4.8
Treatment Compliance .............................................................................57
8.4.9
Drug Supplies and Accountability ............................................................57
8.5
Study Assessments.............................................................................................58
8.5.1
Assessments .............................................................................................58
8.5.1.1
Screening/Baseline Assessments.......................................................58
8.5.1.1.1
Demography ...............................................................................58
8.5.1.1.2
Baseline Assessments .................................................................58
8.5.1.1.3
Medical History ..........................................................................59
8.5.1.2
Efficacy Assessments .......................................................................59
Page 166 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 19 of 121
8.5.1.2.1
Tumor Response Assessments.....................................................59
8.5.1.2.2
Palatability and Acceptability of Lenvatinib Suspension 
Formulation ................................................................................61
8.5.1.3
Pharmacokinetic, Pharmacodynamic, and Other Biomarker 
Assessments .....................................................................................61
8.5.1.3.1
Pharmacokinetic Assessments.....................................................61
8.5.1.3.2
Pharmacodynamic and Other Biomarker Assessments ................62
8.5.1.4
Safety Assessments...........................................................................62
8.5.1.4.1
Adverse Events...........................................................................63
8.5.1.4.2
Serious Adverse Events and Events Associated with Special 
Situations....................................................................................64
8.5.1.4.3
Laboratory Measurements...........................................................65
8.5.1.4.4
Vital Signs and Weight Measurements........................................67
8.5.1.4.5
Physical Examinations ................................................................67
8.5.1.4.6
Electrocardiograms .....................................................................67
8.5.1.4.7
Other Safety Assessments ...........................................................68
8.5.1.5
Other Assessments............................................................................68
8.5.2
Schedule of Procedures/Assessments........................................................69
8.5.2.1
Schedule of Procedures/Assessments................................................69
8.5.2.2
Description of Procedures/Assessments Schedule .............................78
8.5.3
Appropriateness of Measurements............................................................78
8.5.4
Reporting of Serious Adverse Events, Pregnancy, and Events 
Associated with Special Situations ...........................................................78
8.5.4.1
Reporting of Serious Adverse Events................................................78
8.5.4.2
Reporting of Pregnancy and Exposure to Study Drug Through 
Breastfeeding....................................................................................79
8.5.4.3
Reporting of Events Associated with Special Situations....................79
8.5.4.3.1
Reporting of Adverse Events Associated With Study Drug 
Overdose, Misuse, Abuse, or Medication Error...........................79
8.5.4.3.2
Reporting of Abnormal Hepatic Tests of Clinical Interest ...........80
8.5.4.4
Expedited Reporting .........................................................................80
8.5.4.5
Breaking the Blind............................................................................81
8.5.4.6
Regulatory Reporting of Adverse Events ..........................................81
8.5.5
Completion/Discontinuation of Subjects...................................................81
8.5.6
Abuse or Diversion of Study Drug............................................................81
8.5.7
Confirmation of Medical Care by Another Physician................................82
8.6
Data Quality Assurance......................................................................................82
8.6.1
Data Collection.........................................................................................82
8.6.2
Clinical Data Management .......................................................................82
Page 167 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 20 of 121
8.7
Statistical Methods.............................................................................................82
8.7.1
Statistical and Analytical Plans.................................................................83
8.7.1.1
Study Endpoints................................................................................83
8.7.1.1.1
Primary Endpoint........................................................................83
8.7.1.1.2
Secondary Endpoints...................................................................83
8.7.1.1.3
Exploratory Endpoints ................................................................84
8.7.1.2
Definitions of Analysis Sets..............................................................84
8.7.1.3
Subject Disposition...........................................................................85
8.7.1.4
Demographic and Other Baseline Characteristics..............................85
8.7.1.5
Prior and Concomitant Therapy ........................................................85
8.7.1.6
Efficacy Analyses.............................................................................85
8.7.1.6.1
Primary Efficacy Analysis...........................................................85
8.7.1.6.2
Secondary Efficacy Analyses......................................................86
8.7.1.6.3
Exploratory Efficacy Analyses....................................................86
8.7.1.7
Pharmacokinetic, Pharmacodynamic, and Other Biomarker 
Analyses...........................................................................................87
8.7.1.7.1
Pharmacokinetic Analyses ..........................................................87
8.7.1.7.2
Pharmacodynamic and Other Biomarker Analyses......................87
8.7.1.8
Safety Analyses ................................................................................87
8.7.1.8.1
Extent of Exposure......................................................................88
8.7.1.8.2
Adverse Events...........................................................................88
8.7.1.8.3
Laboratory Values.......................................................................89
8.7.1.8.4
Vital Signs ..................................................................................89
8.7.1.8.5
Electrocardiograms .....................................................................90
8.7.1.8.6
Other Safety Analyses.................................................................90
8.7.1.9
Other Analyses .................................................................................90
8.7.1.9.1
Health-Related Quality of Life....................................................90
8.7.1.9.2
Palatability and Acceptability Questionnaire ...............................90
8.7.2
Determination of Sample Size ..................................................................91
8.7.3
Interim Analysis.......................................................................................91
8.7.4
Other Statistical/Analytical Issues ............................................................91
8.7.5
Procedure for Revising the Statistical Analysis Plan.................................91
9
REFERENCE LIST.....................................................................................................92
10
PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE PROCEDURES).......95
10.1
Changes to the Protocol......................................................................................95
10.2
Adherence to the Protocol..................................................................................95
10.3
Monitoring Procedures.......................................................................................95
10.4
Recording of Data..............................................................................................96
Page 168 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 21 of 121
10.5
Identification of Source Data..............................................................................96
10.6
Retention of Records..........................................................................................96
10.7
Auditing Procedures and Inspection ...................................................................97
10.8
Handling of Study Drug .....................................................................................97
10.9
Publication of Results ........................................................................................97
10.10 Disclosure and Confidentiality ...........................................................................98
10.11 Discontinuation of Study....................................................................................98
10.12 Subject Insurance and Indemnity........................................................................98
11
APPENDICES.............................................................................................................99
LIST OF IN-TEXT TABLES
Table 1
Criteria for Temporary Discontinuation of Study Drug, Dose 
Reduction, and Resumption of Treatment ...............................................45
Table 2
Criteria for Dose Modification of Chemotherapy Dose...........................52
Table 3
Lenvatinib Pharmacokinetic Sampling Time Points................................62
Table 4
Clinical Laboratory Tests........................................................................66
Table 5
Schedule of Assessments in Study E7080-G000-230 – Randomization 
Phase......................................................................................................70
Table 6
Schedule of Assessments in Study E7080-G000-230 – Extension 
Phase......................................................................................................76
LIST OF IN-TEXT FIGURES
Figure 1
Overall Study Design..............................................................................34
Figure 2
Management of Hypertension.................................................................48
LIST OF APPENDICES
Appendix 1
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 .................99
Appendix 2
Lansky Score........................................................................................100
Appendix 3
Karnofsky Performance Status Scale Definitions Rating (%) Criteria ...101
Appendix 4
Preparation of Lenvatinib suspension ...................................................102
Appendix 5
Palatability Questionnaire.....................................................................107
Appendix 6
Blood Pressure Levels for Boys by Age and Height Percentile .............109
Appendix 7
Blood Pressure Levels for Girls by Age and Height Percentile..............111
Appendix 8
Body Mass Index-For-Age Percentiles..................................................113
Appendix 9
Body Mass Index-For-Age Percentiles..................................................114
Appendix 10
Tanner’s Staging ..................................................................................115
Page 169 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 22 of 121
Appendix 11
Pharmacodynamic, and Other Biomarker Research...............................117
Page 170 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 23 of 121
3
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
ANC
absolute neutrophil count
β-hCG
beta-human chorionic gonadotropin
BP
blood pressure
BSA
body surface area
CA
Competent Authorities
CBR
clinical benefit rate
CFR
Code of Federal Regulations
Cmax
maximum drug or metabolite concentration
CR
complete response
CRA
clinical research associate
CRF
case report form
CRO
contract research organization
CT
computerized tomography
CTCAE
Common Terminology Criteria for Adverse Events
CYP/CYP3A4
Cytochrome P450/cytochrome P4503A4
DCR
disease control rate
DOR
duration of response
DTC
differentiated thyroid cancer
ESMO
European Society for Medical Oncology
FGFR
fibroblast growth factor receptor
FGF
fibroblast growth factor
GFR
glomerular filtration rate 
G-CSF
granulocyte-colony stimulating factor
HRQoL
health-related quality of life 
HR
heart rate
ICF
informed consent form
Page 171 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 24 of 121
ICH
International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use
ICL
imaging core laboratory 
ID
identification
IDMC
independent data monitoring committee 
IEC
Independent Ethics Committee
IIR
independent imaging review 
IRB
Institutional Review Board
ITT
intent-to-treat
IV
intravenously
IVRS
interactive voice response system
KDR
kinase insert domain receptor
K-M
Kaplan-Meier
LVEF
left ventricular ejection fraction
MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
ORR
objective response rate
OS
overall survival
OS-1y
overall survival rate at 1 year
PD
progressive disease/disease progression
PDGFR
platelet-derived growth factor receptor
PedsQL
Pediatric Quality of Life Inventory 
PFS
progression-free survival
PFS-4m
progression-free survival rate at 4 months
PFS-1y
progression-free survival rate at 1 year
PK
pharmacokinetic(s)
PR
partial  response
PRES 
posterior reversible leukoencephalopathy syndrome 
PT
preferred term
QD
once daily
Page 172 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 25 of 121
QTc
QT interval corrected for heart rate
RECIST
Response Evaluation Criteria in Solid Tumors
RET
rearranged during transfection
RP2D
recommended Phase 2 dose 
RPLS
reversible posterior leukoencephalopathy syndrome
RTK
receptor tyrosine kinase
RTKI
receptor tyrosine kinase inhibitor
SAE
serious adverse event
SAP
statistical analysis plan 
SD
stable disease
SmPC
summary of product characteristics
SOC
system organ class
SOP
standard operating procedure
SUSARs
suspected unexpected serious adverse reactions
TEAEs
treatment-emergent adverse events
TKI
tyrosine kinase inhibitors
TNM
tumor-node metastasis
TSH
thyroid stimulating hormone
ULN
upper limit of normal
UPCR
urine protein-to-creatinine ratio 
VEGF
vascular endothelial growth factor 
VEGFR
vascular endothelial growth factor receptor
WHO DD
World Health Organization Drug Dictionary
Page 173 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 26 of 121
4
ETHICS
4.1
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 the International Council 
for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (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(s) [CRAs], 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.
Documented study approval from the IRB/IEC chairman must be sent to the principal 
investigator (or if regionally required, the head of the medical institution) 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 (or if regionally required, the head of the medical institution) 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 of the end of the study is the date of the data cutoff for 
the final analysis or last subject/last visit, including discontinuation from the study for any 
reason, whichever occurs later.
In the case of early termination/temporary halt of the study, the investigator should notify the 
IRB/IEC and CA within 15 calendar days, and a detailed written explanation of the reasons 
for the termination/halt should be given.
4.2
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:
Page 174 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 27 of 121

Principles of the World Medical Association Declaration of Helsinki 2013

ICH E6 Guideline for GCP (CPMP/ICH/135/95) of the European Agency for the 
Evaluation of Medicinal Products, Committee for Proprietary Medicinal Products, 
International Council for Harmonisation of Technical Requirements for Pharmaceuticals 
for Human Use

Title 21 of the United States Code of Federal Regulations (US 21 CFR) regarding clinical 
studies, including Part 50 and Part 56 concerning informed subject consent and IRB 
regulations and applicable sections of US 21 CFR Part 312

An IRB waiver request will be submitted before study initiation for non-US sites 
conducted under an Investigational New Drug (IND) application.

European Good Clinical Practice Directive 2005/28/EC and Clinical Trial Directive 
2001/20/EC for studies conducted within any EU country.  All suspected unexpected 
serious adverse reactions (SUSARs) will be reported, as required, to the Competent 
Authorities of all involved EU member states.

Other applicable regulatory authorities’ requirements or directives
4.3
Subject Information and Informed Consent
As part of administering the informed consent document, the investigator must explain to 
each subject or guardian, in accordance with applicable professional standards and local 
laws/regulations or legally acceptable 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 should be given by means of a standard written statement, written in 
nontechnical language.  The subject or the subject’s legally acceptable representative should 
understand the statement before signing and dating it and will be given a copy of the signed 
document.  If a subject is unable to read or if a legally acceptable representative is unable to 
read, an impartial witness should be present during the entire informed consent discussion.  
In countries where specific laws for children are established for informed consent, those local 
laws will be applied.  After the ICF and/or assent form and any other written information to 
be provided to subjects is read and explained to the subject or the subject’s 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 and/or assent form, 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 ICF and/or assent form before any study-
Page 175 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 28 of 121
specific procedures are performed.  No subject can enter the study before his/her informed 
consent has been obtained.
An unsigned copy of an IRB/IEC-approved ICF 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).  Each subject and the 
subject’s parent(s) or legally acceptable representative must sign an approved ICF before 
study participation.  The form must be signed and dated by the appropriate parties.  The 
original, signed ICF for each subject will be verified by the sponsor and kept on file 
according to local procedures at the site.
The subject and/or the subject’s parent(s) or the subject’s legally acceptable representative 
should be informed in a timely manner if new information becomes available that may be 
relevant to the subject’s willingness to continue participation in the 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 
ICF to continue on the study.
5
INVESTIGATORS AND STUDY PERSONNEL
This study will be conducted by qualified investigators under the sponsorship of Eisai (the 
sponsor) at approximately 70 investigational sites worldwide.
The name, telephone and fax numbers of the medical monitor and other contact personnel at 
the sponsor and of the contract research organization(s) (CRO[s]) are listed in the Regulatory 
Binder provided to each site.
6
INTRODUCTION
6.1
Osteosarcoma
Cancer is a relatively uncommon diagnosis in the pediatric population, and the overall 
incidence is low (18.6 cases per 100,000 children [Howlader, et al., 2019]).  Solid tumors 
constitute approximately 60% of childhood malignancies (Howlader, et al., 2019).  
Malignant bone tumors are the fifth most common solid tumor type accounting for about 5% 
of childhood tumors (Howlader, et al., 2019; Kaatsch, 2010). 
Osteosarcoma is the most commonly diagnosed primary malignancy of the bone in children 
and young adults, and accounts for approximately 5% of childhood tumors, with an estimated
annual incidence of 4.4 cases per 1 million in people younger than 24 years (Mirabello, et al., 
2009). Osteosarcoma occurs predominantly in adolescents and young adults.  The median 
age at diagnosis is 20 years, with the incidence peaking at 15 to 19 years of age (ESMO, 
guidelines, 2014).  According to the American Cancer Society, osteosarcoma in this age 
group is 8 per 1 million (Ward, et al., 2014).  
Page 176 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 29 of 121
There are both intrinsic and extrinsic factors that have been shown to contribute to the 
development of osteosarcoma. Studies have demonstrated that several genetic abnormalities, 
including the overexpression of vascular endothelial growth factor (VEGF) receptor 
(VEGFR), platelet-derived growth factor (PDGF) receptor (PDGFR), and c-fos, are 
associated with the development of osteosarcoma in laboratory models as well as humans 
(Gorlick and Khanna, 2010).  However, osteosarcoma is not characterized by a single 
oncogenic driver.  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).  Extrinsic factors such as ionizing radiation, which is used for the treatment 
of childhood solid tumors, have 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., 1998).
The management of osteosarcoma is multimodal; patients not amenable to surgery or patients 
at second or third relapse have a poor prognosis.  Metastatic osteosarcoma is common (10% 
to 20%) (NCCN, Bone cancer guidelines, 2020, Casali, et al., 2018), with the most frequent 
site being the lung (>85%).  In the case of isolated lung metastases, more than a third of 
patients with a second surgical remission survive for >5 years (Casali, et al., 2018). 
Approximately 25% of all patients with primary metastatic osteosarcoma and >40% of those 
who achieve a complete surgical remission may become long-term survivors (Casali, et al., 
2018) as compared with 65% to 70% of patients with localized disease (Meazza and 
Scanagatta, 2016).
About 30% to 40% of patients with localized disease and 80% of those with metastatic 
disease experience relapse (Casali, et al., 2018; NCCN, Bone cancer guidelines, 2020; 
Ferrari, 2003).  The presence of solitary metastasis, time to first relapse, and complete 
resectability of disease at first recurrence are the most significant prognostic indicators for 
improved survival.  Patients whose tumor is not amenable to surgery, or with second or third 
recurrence, or who have metastases to the bone, have a poor prognosis.  In general, despite 
second-line treatment, the prognosis of recurrent disease in osteosarcoma has remained poor, 
with long-term postrelapse survival of <20% (Casali, et al., 2018; NCCN Bone Cancer 
Guidelines, 2020).  
6.2 
Current Therapeutic Options
There has been no substantial progress in the treatment of osteosarcoma since the 1980s. 
Current treatment utilizes multi-agent chemotherapy and surgical resection of all clinically 
detectable disease.  
Treatment of Newly Diagnosed Disease
Newly diagnosed osteosarcoma is typically managed with neoadjuvant chemotherapy 
followed by surgical removal of the primary tumor and all clinically evident metastatic 
disease, followed by adjuvant chemotherapy.  Surgical resection of all clinically detectable 
sites of disease is vital, regardless of number and site, as complete resection is predictive of 
Page 177 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 30 of 121
survival (Meazza and Scanagatta, 2016).  For patients with unresectable disease at multiple 
sites, experimental therapy is also considered, due to the poor prognosis for these patients. 
The most effective chemotherapy regimens include the combination of high-dose 
methotrexate, doxorubicin, and cisplatin and has become the standard treatment for 
high-grade osteosarcoma (Ferrari and Serra, 2015; Isakoff, et al., 2015; NCCN Bone Cancer 
Guidelines, 2020).
Treatment of Relapsed, Refractory, and Progressive Disease
Second-line treatment for relapsed disease consists of chemotherapy and/or surgical resection
(Casali, et al., 2018; NCCN Bone Cancer Guidelines, 2020). The role of second-line 
chemotherapy for recurrent osteosarcoma is much less well defined than that of surgery, and 
there is no accepted standard regimen (Casali, et al., 2018). For patients with resectable 
solitary metastasis to the lung, surgical resection only may be adequate. For those with 
recurrent pulmonary metastases that are resectable, surgery is advised in addition to 
neoadjuvant or adjuvant chemotherapy, regardless of the number of previous lung relapses 
and the number of secondary pulmonary lesions (Briccoli, et al., 2005). Aggressive surgical 
resection of metastases and the ability to achieve a second surgical remission have 
consistently been shown essential for long-term survival following relapse (Kempf-Bielack,
et al., 2005; Leary, et al., 2013; Bacci, et al., 2005; Chou, et al., 2005; Hawkins and Arndt, 
2003). 
As per the European Society for Medical Oncology (ESMO) guidelines for bone sarcoma, 
treatment options for recurrent osteosarcoma include ifosfamide ± etoposide ± carboplatin, 
and other active drugs (Casali, et al., 2018). Preferred regimens for second-line therapy per 
the National Comprehensive Cancer Network (NCCN) bone sarcoma guidelines include
ifosfamide (high dose) with or without etoposide, regorafenib, sorafenib, and sorafenib plus 
everolimus (NCCN Bone Cancer Guidelines, 2020).
In the event of subsequent relapse, the NCCN guidelines (NCCN Bone Cancer Guidelines,
2020) and ESMO guidelines (Casali, et al., 2018) strongly encourage participation in clinical 
studies.  Otherwise, patients with disease progression or relapse after second-line therapy are 
managed with surgical resection, palliative radiotherapy, or best supportive care.
6.3
Lenvatinib
E7080 (lenvatinib) is a potent multiple receptor tyrosine kinase (RTK) inhibitor (RTKI) that 
selectively inhibits VEGF receptors, VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 
(FLT4), in addition to other pro-angiogenic and oncogenic pathway-related RTKs, including 
fibroblast growth factor (FGF) receptor (FGFR) 1-4, PDGF receptor alpha (PDGFRα), KIT, 
and RET.  Therefore, lenvatinib exerts it’s in vivo antitumoural activity based on multiple 
mechanisms involved in and through effects related to angiogenesis (including reversion of 
resistance) and the tumor microenvironment, as well as direct inhibitory action on the tumour 
cells.  Recent studies have also demonstrated lenvatinib’s immunomodulatory activity in the 
tumor microenvironment.  This includes decreases in immunosuppressive tumor-associated 
Page 178 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 31 of 121
macrophages, activated cytotoxic T cell increases, and activation of interferon-gamma  
signaling.  These all contribute to lenvatinib’s antitumor activity in immunocompetent mice 
(Kato, et al., 2019; Kimura, et al., 2018).
6.3.1
Clinical Data on Lenvatinib in Combination with Ifosfamide and Etoposide
for Treatment of Relapsed or Refractory Osteosarcoma
The safety, tolerability and activity of single-agent lenvatinib, and lenvatinib in combination 
with chemotherapy (ifosfamide and etoposide), have been assessed in E7080-G000-207 
(Study 207), a phase 1/2, multicenter, open-label study in children, adolescents and young 
adults with solid tumors, including relapsed or refractory osteosarcoma, and
radioiodine- refractory differentiated thyroid carcinoma. The recommended phase 2 dose 
(RP2D) of lenvatinib was determined in the phase 1b portion as 14 mg/m2 orally once daily 
when given as single-agent as well as in combination with etoposide (100 mg/m2 IV once 
daily for 3 days) + ifosfamide (3000 mg/m2 IV once daily for 3 days), administered on days 1
to 3 of each 21-day cycle, for 5 cycles. Safety and efficacy is being assessed in the Phase 2 
portion of the study.
Data from Study 207 have shown that patients with osteosarcoma may benefit from treatment 
with lenvatinib. In the single agent expansion cohort in relapsed/refractory osteosarcoma,
(n=31; Cohort 2B), 9 of 28 evaluable patients (32.1%) achieved progression-free survival 
(PFS) at 4 months (PFS-4m), median PFS was 3.0 months (95% CI: 1.8, 5.5). Two out of 
29 subjects (6.9%) with measurable disease had a partial response (PR) (Gaspar, et al., 2018).  
Among the 31 subjects included in the safety analysis set for the single-agent lenvatinib 
expansion cohort, the most common adverse events were: headache (48%), vomiting (45%), 
decreased appetite, diarrhea, and hypothyroidism (42% each), proteinuria (39%), increased 
blood TSH, hypertension, nausea, pyrexia, and weight decreased (36% each).  Five subjects 
(16.1%) discontinued treatment due to TEAEs, and 8 subjects (25.8%) reported TEAEs 
leading to study drug dose reduction.  There were no treatment-related fatal TEAEs (Gaspar, 
et al., 2018).  
In a pooled analysis of subjects from Phase 1b and 2 receiving lenvatinib 14 mg/m2 in 
combination with ifosfamide plus etoposide (N=35; full analysis set), the primary efficacy 
endpoint, PFS-4 rate based on RECIST 1.1 by investigator assessment, was 67.9% (95% CI: 
47.6, 84.1). As of the data cutoff date of 23 Jul 2019, the objective response rate (ORR) was 
12.5%, including 4 subjects with PR. Median PFS was 11.1 months (95% CI: 4.5, 12.6), and 
median overall survival (OS) was 16.3 months (95% CI: 12.6, NE) (Gaspar, et al., 2019).
Overall treatment with lenvatinib in combination with ifosfamide and etoposide in this 
patient population was associated with a manageable safety profile, and no unexpected 
toxicities were observed. Among the 31 subjects included in the safety analysis set, the most 
frequent treatment-emergent adverse events (TEAEs) were anemia (71%), nausea and 
vomiting (61% each), diarrhea (52%), neutropenia, platelet count decreased, and white blood 
cell count decreased (48% each).  The most common treatment-related grade ≥3 TEAEs were 
anemia (52%), neutropenia (48%), platelet count decreased and white blood cell count 
Page 179 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 32 of 121
decreased (42% each), neutrophil count decreased (32%), and thrombocytopenia (29%).  
Eight subjects (25.8%) discontinued treatment due to TEAEs, and 15 subjects (48.4%) 
reported TEAEs leading to study drug dose reduction. There were no treatment-related fatal
TEAEs (Gaspar, et al., 2019).
6.4
Study Rationale
Study 230, a randomized, controlled Phase 2 study, will evaluate the efficacy and safety of 
lenvatinib in combination with ifosfamide and etoposide in children, adolescents, and young 
adults with relapsed or refractory osteosarcoma. Eligible patients aged 2 to 25 years old will 
receive ifosfamide and etoposide with or without lenvatinib (14 mg/m2; RP2D from 
Study 207). Subjects randomized to Arm A can continue to receive lenvatinib until disease 
progression, intolerable toxicity, or withdrawal of consent. Approximately 72 subjects will 
be treated in the study.  The primary objective of the study is to demonstrate that lenvatinib 
in combination with ifosfamide and etoposide has superior efficacy compared to ifosfamide 
and etoposide based on the PFS-4m rate in children, adolescents and young adults with 
relapsed or refractory osteosarcoma.
Pediatric solid tumors are highly vascularized.  Angiogenesis and vasculogenesis are the 
fundamental processes by which new blood vessels are formed.  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. Thus, inhibition of angiogenesis is a viable target for 
anticancer therapy.  Moreover, vascular normalisation allows reoxygenation, hence the 
addition of an anti-VEGF to chemotherapy may result in increased uptake of drugs into 
tumor tissue (Tuettenberg, et al., 2006).
7
STUDY OBJECTIVES
7.1
Primary Objective
To evaluate whether lenvatinib in combination with ifosfamide and etoposide (Arm A) is 
superior to ifosfamide and etoposide (Arm B) in improving PFS-4m rate (by independent 
imaging review [IIR] using Response Evaluation Criteria In Solid Tumors [RECIST 1.1]), in 
children, adolescents, and young adults with relapsed or refractory osteosarcoma.
7.2
Secondary Objectives
The secondary objectives of the study are to:
1. Compare differences in PFS rate at 1 year (PFS-1y) between the 2 treatment arms 
2. Compare differences in PFS Kaplan-Meier (K-M) survival curves and median PFS 
between the 2 treatment arms
3. Compare differences in OS and OS rate at 1 year (OS-1y) between the 2 treatment arms
Page 180 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 33 of 121
4. Compare differences in objective response rate (ORR) at 4 months between the 
2 treatment arms
5. Compare differences in safety and tolerability between the 2 treatment arms
6. Characterize the pharmacokinetics (PK) of lenvatinib, when administered in combination 
with ifosfamide and etoposide 
7. Compare differences in health-related quality of life (HRQoL) as assessed by using the 
the Pediatric Quality of Life Inventory (PedsQL) Generic Core Scales and Cancer 
Module between the 2 treatment arms
8. Assess the palatability and acceptability of the suspension formulation of lenvatinib in 
pediatric subjects receiving the suspension formulation in the study
7.3
Exploratory Objective(s)
The exploratory objectives of the study are to:
1.
Explore differences in duration of response (DOR), disease control rate (DCR), and 
clinical benefit rate (CBR) between the 2 treatment arms
2.
Compare the proportion of subjects who achieve complete removal of baseline lesion(s) 
following completion of chemotherapy between the 2 treatment arms 
3. Investigate the relationship between subject tumor biomarkers and clinical response and 
toxicity of lenvatinib in combination with ifosfamide and etoposide
8
INVESTIGATIONAL PLAN
8.1
Overall Study Design and Plan
This is a multicenter, randomized, open-label, parallel-group, Phase 2 study to compare the 
efficacy and safety of lenvatinib in combination with ifosfamide and etoposide versus 
ifosfamide and etoposide in children, adolescents, and young adults with relapsed or 
refractory osteosarcoma.
Approximately 72 eligible subjects will be randomized to 1 of the following 2 treatment arms 
in a 1:1 ratio within the strata:

Arm A:  lenvatinib 14 mg/m2 (orally, once daily) plus ifosfamide 3000 mg/m2/day 
(intravenously [IV], Day 1 to Day 3 of each cycle for a total of up to 5 cycles) and 
etoposide 100 mg/m2/day (IV, Day 1 to Day 3 of each cycle for a total of up to 5 cycles)

Arm B:  ifosfamide 3000 mg/m2/day (IV, Day 1 to Day 3 of each cycle for a total of up to 
5 cycles) and etoposide 100 mg/m2/day (IV, Day 1 to Day 3 of each cycle for a total of up 
to 5 cycles)
Randomization will follow a predefined randomization scheme based on the following 
stratification factors: time to first relapse/refractory disease (early [<18 months] or late 
[≥18 months]) and age (<18 and ≥18 years).
Eisai will closely monitor enrolment, to ensure that at least 32 subjects <18 years of age at 
the time of informed consent are randomized.  
Page 181 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 34 of 121
The study will be conducted in 3 Phases: a Pre-randomization Phase, a Randomization 
Phase, and an Extension Phase.  
The end of the study will be the date of data cutoff for the final analysis or the time of last 
subject last visit, whichever occurs later.
An overview of the study design is presented in Figure 1.
Figure 1 Overall Study Design
Follow-up can occur during the Randomization Phase (if the subject discontinued treatment during 
the Randomization Phase), or during the Extension Phase, after the termination of study treatment.
Arm A = lenvatinib+ifosfamide+ etoposide (ifosfamide+etoposide for maximum of 5 cycles; 
lenvatinib to be continued until disease progression, intolerable toxicity, subject request,
withdrawal of consent, or study termination by the sponsor, whichever occurs first.
Arm B = ifosfamide+ etoposide (maximum of 5 cycles)
R = randomization
8.1.1
Prerandomization Phase
The Prerandomization Phase will consist of 2 periods: Screening and Baseline. The 
Prerandomization Phase will last no longer than 28 days. The Screening Period will establish 
protocol eligibility and the Baseline Period will confirm eligibility.
8.1.1.1
Screening Period
Screening will occur between Day –28 and Day –2.  The purpose of the Screening Period is 
to obtain informed consent and to establish protocol eligibility.  Informed consent will be 
obtained after the study has been fully explained to each subject and before the conduct of 
any screening procedures or assessments.  Procedures to be followed when obtaining 
informed consent are detailed in Section 4.3.
Period:
Screening
Baseline
R
Arm A
Day -28 to -2
Day 1
Treatment
Follow-up
Arm B
Phase:
Treatment
Follow-up
Day -1
Randomization
Prerandomization
Randomization
Prerandomization
Extension
Page 182 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 35 of 121
Subjects must have a histologically or cytologically confirmed diagnosis of high grade 
refractory or relapsed osteosarcoma as detailed in the Inclusion Criteria (Section 8.3.1).
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.
8.1.1.2
Baseline Period
The purpose of the Baseline Period is to confirm protocol eligibility as specified in the 
inclusion/exclusion criteria (as detailed in Section 8.3.1 and Section 8.3.2).  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 4), 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 8.3.1 and Section 8.3.2) will begin the 
Randomization Phase of this study.
8.1.2
Randomization Phase
The Randomization Phase will consist of 2 periods: Treatment Period and Follow-up Period. 
The Randomization Phase will begin at the time of randomization of the first subject and will 
end on the data cutoff date for the PFS-1y and OS-1y analysis.  Data cutoff for PFS-1y and 
OS-1y analysis will occur when the last subject has completed 18 cycles of treatment or 
discontinues before the end of Cycle 18, whichever occurs first.
After the data cutoff date for the PFS-1y and OS-1y analysis has occurred, all subjects who 
are still on study treatment will enter the Extension Phase.  
8.1.2.1
Treatment Period
The Treatment Period for each subject will begin at the time of randomization and will end at 
the completion of the Off-Treatment Visit which will occur within 30 days after the final 
dose of study treatment.
Subjects will receive study treatment as continuous 21-day cycles in both treatment arms.
Treatment cycles will be counted continuously regardless of dose interruptions.  If 
chemotherapy administration is precluded on Day 1 of a treatment cycle, the subject may 
resume treatment once recovered at the discretion of investigator.  Subsequent chemotherapy 
will be administered every 21 (±1) days starting from the timepoint it was resumed.  Subjects 
will undergo safety and efficacy assessments as defined in the Schedule of 
Procedures/Assessments (Table 5).  Subjects randomized to Arm A will continue to receive
lenvatinib until disease progression (PD) confirmed by IIR, development of unacceptable 
toxicity, subject request, withdrawal of consent, or study termination by the sponsor, 
whichever occurs first.
Page 183 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 36 of 121
Disease progression (PD) must be confirmed by IIR prior to the investigator discontinuing 
study treatment for a subject.  In situations where the investigator judges that alternative 
treatments must be instituted immediately for a subject’s safety, study drugs may be 
discontinued without waiting for IIR confirmation of radiographic evidence of PD.  If 
possible, before discontinuation of the subject from the study, the investigator should consult 
with the sponsor.
8.1.2.2
Follow-Up Period
The Follow-up Period begins the day after the Off-Treatment Visit and will continue as long 
as the subject is alive, unless the subject withdraws consent or the sponsor terminates the 
study.  
Subjects may at any time withdraw consent for further study participation.  No further data 
will be collected on subjects once consent has been withdrawn, however, an investigator may 
consult public records to establish survival status if permitted by local regulations.
All adverse events (AEs) will be captured for 30 days after the last dose of study drug.  
All subjects who discontinue study treatment early for reasons other than PD, will continue 
to undergo tumor assessments every 6 weeks until Week 18, then every 9 weeks until 
Week 54, thereafter, every 12 weeks until IIR confirmation of radiographic evidence of PD 
as described in the tumor assessments in the assessment schedule, or until another anticancer 
therapy is initiated.
Subjects in both Arm A and Arm B will be followed for survival every 12 weeks (±1 week) 
and all subsequent anticancer treatments received will be recorded.  Subjects who are being 
followed for survival at the time of data cutoff for the for PFS-1y and OS-1y analysis (ie, at 
the end of the Randomization Phase) will continue to be followed for survival during the 
Follow-up Period of the Extension Phase.
8.1.3
Extension Phase
The Extension Phase will consist of 2 periods: Treatment Period and Follow-up Period.  
8.1.3.1
Treatment Period
In the Treatment Period, subjects still on lenvatinib in Arm A following the completion of the 
PFS-1y and OS-1y analysis (ie, at the end of the Randomization Phase) will continue to 
receive lenvatinib in 21-day cycles until disease progression, development of unacceptable 
toxicity, subject request, withdrawal of consent, or discontinuation of study by the sponsor.  
Tumor assessments will be performed according to the local standard of care.  Independent 
imaging review (IIR) review and confirmation of radiographic evidence of PD will not be 
required, and scans will no longer be required to sent to the imaging core laboratory (ICL).  
The Off-Treatment Visit will occur within 30 days after the final dose of study treatment. 
All AEs will be captured up to 30 days after last dose of study drug.  In case the study is 
Page 184 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 37 of 121
discontinued by the sponsor, the sponsor will continue to provide study drug (outside the 
study) for subjects requiring continuation of treatment.
8.1.3.2
Follow-Up Period
The Follow-up Period will begin the day after the Off-Treatment Visit and will last until 
death or for 2 years after end of treatment for a subject, unless the study is terminated by the 
sponsor, or the subject discontinues due to withdrawal of consent, or is lost to follow-up.  
Subjects will be treated by the investigator according to the prevailing local standard of care. 
Subjects will be followed every 12 weeks (±1week) for survival and all subsequent 
anticancer treatments received will be recorded.  
8.2
Discussion of Study Design, Including Choice of Control Groups
The study has been designed as an open-label, randomized study to compare the safety and 
efficacy of lenvatinib in combination with the ifosfamide and etoposide with ifosfamide and 
etoposide alone in children, adolescents, and young adults with relapsed or refractory 
osteosarcoma. Ifosfamide and etoposide will be used as the control group since it is a 
recognized treatment option for patients with relapsed osteosarcoma.
Progression-free survival (PFS) rate at 4 months (PFS-4m) as compared to control, with 
blinded IIR of radiological imaging using RECIST 1.1 criteria will be evaluated as the 
primary endpoint.  The endpoint was determined as appropriate for the study, given the 
unique biology of the osteosarcoma (bone lesions do not shrink) and the vital role of surgical 
resection of metastatic lesions, where possible, in the management of patients with this 
tumor.  Pulmonary metastases are most common in osteosarcoma, and the ability to achieve a 
second surgical remission has consistently been shown essential for long-term survival 
following relapse (Kempf Bielack, et al., 2005; Leary, et al., 2013; Bacci, et al., 2005; Chou,
et al., 2005; Hawkins and Arndt, 2003).  The protocol allows for surgical resection of 
baseline lesions after completion of the Week 18 tumor assessment.  This timepoint allows
for surgical resection after completion of chemotherapy without confounding data due to 
subjects undergoing surgery. To avoid bias in efficacy assessment, the analysis for primary 
endpoint is based on tumor assessment by IIR, a central independent blinded assessment. 
Progression-free survival at 1 year (PFS-1y), PFS, and OS will also be evaluated in the study
as secondary endpoints.
Pharmacodynamic serum and tumor biomarkers identified in other lenvatinib clinical studies
will be assessed in samples collected from subjects enrolled in this study in the test arm only 
(Arm A: lenvatinib + ifosfamide + etoposide) and may be used for exploratory analysis for 
evaluation of response-related and/or safety-related outcomes.
The study will also assess health related quality of life (HRQoL) using validated 
questionnaires.
Randomization will be used in this study to avoid bias in the assignment of subjects to 
treatment, to increase the likelihood that known and unknown subject attributes (eg, 
Page 185 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 38 of 121
demographics and baseline characteristics) are balanced across treatment groups, and to 
ensure the validity of statistical comparisons across treatment groups.
8.3
Selection of Study Population
Approximately 72 subjects between 2 and ≤25 years of age will be randomised (36 subjects 
in each arm). 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.
For evaluation of the primary endpoint (intent–to-treat analysis), at least 32 subjects 
18 years old (at the time of informed consent) will be randomized.
8.3.1
Inclusion Criteria
Subjects must meet all of the following criteria to be included in this study:
1.
Histologically or cytologically confirmed diagnosis of high grade osteosarcoma.
2.
Refractory or relapsed osteosarcoma after 1 to 2 prior systemic treatments.   
3.
Measurable or evaluable disease per RECIST 1.1 that meets the following criteria:
-
Must be accurately measurable with a minimum size (by long axis) of 10 mm using 
computed tomography/magnetic resonance imaging (CT/MRI) (lymph nodes must be 
accurately measurable with a minimum size [by short axis] of 15 mm). 
-
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.
Aged 2 years to ≤25 years at the time of informed consent.
5.
Life expectancy of 12 weeks or more.
6.
Lansky play score ≥50% or Karnofsky Performance Status score ≥50%.  Use Karnofsky 
for subjects ≥16 years of age and Lansky for subjects <16 years of age.  Subjects who are 
unable to walk because of paralysis, but who are up in a wheelchair, will be considered 
ambulatory for the purpose of assessing the performance score.
7.
Adequate bone marrow function as evidenced by:
a.
absolute neutrophil count (ANC) ≥1.5×109/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 of <8.0 g/dL is acceptable if it is corrected by 
growth factor or transfusion before Cycle 1 Day 1).
c.
platelet count ≥100×109/L. 
8.
Adequate blood coagulation function defined by International Normalized Ratio (INR) 
≤1.5 unless participant is receiving anticoagulant therapy, as long as INR is within 
therapeutic range of intended use of anticoagulants.
9.
Adequate liver function as evidenced by:
a.
Bilirubin ≤1.5 times the upper limit of normal (ULN).
Page 186 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 39 of 121
b. Alanine aminotransferase (ALT), and aspartate aminotransferase (AST) ≤3×ULN (in 
the case of liver metastases ≤5×ULN).
10. 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.
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 Common Terminology Criteria for Adverse Events (CTCAE) v5.0 and 
if possible perform a 24-hour urine collection (children and adolescents ≤12 years of 
age must have ≤500 mg of protein/24 hours and subjects >12 years of age must have 
≤1 g of protein/24 hours).
c.
No clinical evidence of nephrotic syndrome. 
11. Adequate cardiac function as evidenced by left ventricular ejection fraction (LVEF)
≥50% at baseline as determined by echocardiography.
12. 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 guidelines) and no change in antihypertensive 
medications within 1 week prior to Cycle 1 Day 1.  Subjects >18 years of age should 
have BP ≤150/90 mm Hg at screening and no change in antihypertensive therapy 
within 1 week prior to Cycle 1 Day 1.
13. Washout before Cycle 1 Day 1 of 3 weeks in case of prior chemotherapy, 6 weeks if 
treatment included nitrosoureas; 4 weeks for definitive radiotherapy, 2 weeks for 
palliative radiotherapy; and 3 months from high-dose chemotherapy and stem cell rescue.  
Subjects must have recovered (to Grade ≤1, except for alopecia, ototoxicity, and Grade 
≤2 peripheral neuropathy, per CTCAE v5.0) from the acute toxic effects of all prior 
anticancer therapy before Cycle 1 Day 1.
14. 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.
Page 187 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 40 of 121
15. Willing and able to comply with the protocol, scheduled follow-up, and management of 
toxicity as judged by the investigator.
8.3.2
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 Cycle 1 Day 1
(ie, no longer requiring systemic treatment).
2.
Subjects with central nervous system metastases are not eligible, unless they have 
completed local therapy (eg, whole brain radiation therapy, surgery or radiosurgery) and 
have discontinued the use of corticosteroids for this indication for at least 2 weeks before
Cycle 1 Day 1. 
3.
Active second malignancy within 2 years prior to enrollment ([in addition to 
osteosarcoma], but not including definitively treated superficial melanoma, 
carcinoma-in-situ, basal or squamous cell carcinoma of the skin).
4.
Any medical or other condition that in the opinion of the investigator(s) would preclude 
the subject’s participation in a clinical study. 
5.
Has had major surgery within 3 weeks prior to Cycle 1 Day 1.  Note: Adequate wound 
healing after major surgery must be assessed clinically, independent of time elapsed for 
eligibility.
6.
Known hypersensitivity to any component(s) of the study drugs (lenvatinib, ifosfamide,
and etoposide, or their ingredients).
7.
Currently receiving any investigational drug or device in another clinical study or within 
28 days prior to Cycle 1 Day 1.
8.
A clinically significant ECG abnormality, including a marked baseline prolonged QT or 
QTc interval (eg, a repeated demonstration of a QTc interval >480 msec).
9.
Gastrointestinal malabsorption, gastrointestinal anastomosis, or any other condition that 
in the opinion of the investigator might affect the absorption of lenvatinib.
10. Pre-existing Grade ≥3 gastrointestinal or non-gastrointestinal fistula.
11. Gastrointestinal bleeding or active hemoptysis (bright red blood of at least ½ teaspoon) 
within 3 weeks prior to Cycle 1 Day 1.
12. Radiographic evidence of intratumoral cavitation, encasement, or invasion of a major 
blood vessel. Additionally, the degree of proximity to major blood vessels should be 
considered for exclusion because of the potential risk of severe hemorrhage associated 
with tumor shrinkage/necrosis after lenvatinib therapy.
13. History of ifosfamide-related Grade ≥3 nephrotoxicity or encephalopathy.
14. Evidence of clinically significant disease (eg, cardiac, respiratory, gastrointestinal, renal 
disease) that in the opinion of the investigator(s) could affect the subject’s safety or 
interfere with the study assessments.
15. Known to be human immunodeficiency virus (HIV) positive.  Note: HIV testing is 
required at screening only when mandated by local health authority.
Page 188 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 41 of 121
16. Active viral hepatitis (B or C) as demonstrated by positive serology.  Note: Testing for 
Hepatitis B or Hepatitis C is required at screening only when mandated by local health 
authority.
17. 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 any study drug.
18. Females of childbearing potential* who:
-
Do not agree to use a highly effective method of contraception for the entire study 
period and for 28 days after lenvatinib discontinuation or 12 months after etoposide 
and ifosfamide discontinuation, ie:
◦
total abstinence (if it is their preferred and usual lifestyle)
◦
an intrauterine device (IUD) or intrauterine hormone-releasing system (IUS)
◦
A contraceptive implant
◦
an oral contraceptive.  Subject must be on a stable dose of the same oral 
contraceptive product for at least 28 days before dosing with study drug and 
throughout the study and for 28 days after lenvatinib discontinuation or 12 months 
after etoposide and ifosfamide discontinuation .
OR
-
Do not have a vasectomized partner with confirmed azoospermia.
For sites outside of the EU, it is permissible that if a highly effective method of 
contraception is not appropriate or acceptable to the subject, or the subject has changed 
oral hormonal contraceptive product/dose within 4 weeks prior to study drug 
administration, 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. 
* All post pubertal females will be considered to be of childbearing potential unless they 
have early menopause (amenorrheic for at least 12 consecutive months, in the appropriate 
age group, and without other known or suspected cause) or have been sterilized surgically 
(ie, bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, all with surgery 
at least 1 month before dosing), or are pre-menarcheal (Tanner Stage 1-3).
19. Males who have not had a successful vasectomy (confirmed azoospermia) or if they and 
their female partners do not meet the criteria above (ie, not of childbearing potential or 
practicing highly effective contraception throughout the study period and for 28 days 
after lenvatinib discontinuation or 6 months after discontinuation of etoposide and 
ifosfamide). No sperm donation is allowed during the study period and for 28 days after 
lenvatinib discontinuation or 6 months after discontinuation of etoposide and ifosfamide.
20. A contraindication to any of the study drugs (lenvatinib, ifosfamide, and etoposide) per 
local prescribing information.
Page 189 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 42 of 121
8.3.3
Removal of Subjects From Therapy or Assessment
Subjects will continue to receive study treatment until any of the following occur:  

Progressive disease (as confirmed by IIR)

Unacceptable toxicity

Subject request

Withdrawal of consent 

Termination of the study by the Sponsor
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 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.
During the Follow-Up Period, subjects who have discontinued study treatment without 
progression should have disease assessments as per the appropriate tumor assessment 
schedule in Table 5 and Table 6 from the date of the last assessment until PD is documented 
or another anticancer therapy is initiated.  After data cutoff of PFS-1y and OS-1y, tumor 
assessments may be performed as clinically indicated per institutional guidelines, following 
the prevailing local standard of care, and IIR confirmation of radiographic evidence of PD
will not be required.
All subjects will be followed for survival until death or for 2 years after end of treatment for 
a subject, except where a subject withdraws consent or the sponsor chooses to halt survival 
follow-up after completion of the primary study analysis.
8.4
Treatment(s)
8.4.1
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 subjects unable to 
swallow capsules, as detailed in Appendix 4.
Test Arm (Arm A): Lenvatinib + Ifosfamide + Etoposide
Lenvatinib 14 mg/m2, orally administered once daily in each 21-day cycle.
Lenvatinib is provided as hard capsules containing 1 mg, 4 mg, or 10 mg lenvatinib. An 
extemporaneous suspension of lenvatinib capsules should be used for subjects unable to 
Page 190 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 43 of 121
swallow capsules. After adjustment for body surface area (BSA), the daily dose can not 
exceed 24 mg QD.
Ifosfamide 3000 mg/m2/day, IV, for 3 consecutive days (Day 1 to 3), every 21 days, for a 
maximum of 5 cycles.
Etoposide 100 mg/m2/day, IV, for 3 consecutive days (Day 1 to 3) , every 21 days, for a 
maximum of 5 cycles. 
Treatment with lenvatinib will continue in 21-day cycles after chemotherapy is discontinued, 
until disease progression, development of unacceptable toxicity, subject request, withdrawal 
of consent, or discontinuation of study by the sponsor.  In case the study is discontinued by 
the sponsor, the sponsor will continue to provide study drug (outside the study) for subjects 
requiring continuation of treatment.
Control Arm (Arm B):  Ifosfamide + Etoposide
Ifosfamide 3000 mg/m2/day, IV, daily for 3 consecutive days (Day 1 to 3), every 21 days, for 
a maximum of 5 cycles.
Etoposide 100 mg/m2/day, IV, daily for 3 consecutive days (Day 1 to 3), every 21 days, for a 
maximum of 5 cycles.
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) × body surface area (BSA) (m2) = lenvatinib dose (mg)
Body surface area (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.
Subjects will receive study treatment as continuous 21-day cycles in both treatment arms. 
Treatment cycles will be counted continuously regardless of dose interruptions.  If 
chemotherapy administration is precluded on Day 1 of a treatment cycle, the subject may 
resume treatment once recovered at the discretion of investigator.  Subsequent chemotherapy 
will be administered every 21 (±1) days starting from the timepoint it was resumed.
8.4.1.1
Lenvatinib Dose Reduction and Interruption Instructions
Adverse events will be graded using CTCAE version 5.0.
Dose reduction and interruptions for subjects who experience lenvatinib related toxicity will 
be managed as described in Table 1.  
Page 191 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 44 of 121
The starting dose of lenvatinib is 14 mg/m2. 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 study drug dose level has been reduced, it may not be increased at a later date, 
unless the dose was mistakenly decreased; in this situation, the sponsor’s approval is required 
to increase the dose.
Refer to the subsections below for management of hypertension, posterior reversible 
encephalopathy syndrome/reversible posterior leukoencephalopathy syndrome 
(PRES/RPLS), proteinuria, hepatotoxicity, thromboembolic events, hypocalcemia,
gastrointestinal symptoms and acute abdominal pain, and hemorrhage, as appropriate, before 
consulting the dose modification table below.
Page 192 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 45 of 121
Table 1
Criteria for Temporary Discontinuation of Study Drug, Dose 
Reduction, and Resumption of Treatment
Dose Modification Guidelines for Lenvatinib Related Toxicity
Treatment-Related Toxicitya,b
Management
Dose Adjustment
Grade 1 or Tolerable Grade 2
Continue treatment
No change
Intolerable Grade 2c, dor Grade 3e
First occurrence
Interrupt lenvatinib until 
resolved to Grade 0-1, or 
tolerable Grade 2
11.2 mg/m2 (or 20% 
reduction of the starting 
dose) orally QD (one-level 
reduction)
Second occurrence
(same toxicity or new toxicity)
Interrupt lenvatinib until 
resolved to Grade 0-1, or 
tolerable Grade 2
9.0 mg/m2 (or 20% 
reduction of the previous 
dose) orally QD (one-level 
reduction)
Third occurrence
(same toxicity or new toxicity)
Interrupt lenvatinib until 
resolved to Grade 0-1, or 
tolerable Grade 2
7.2 mg/m2 (or 20% 
reduction of the previous 
dose) orally QD (one-level 
reduction)  
Fourth occurrence
(same toxicity or new toxicity)
Interrupt lenvatinib
Discuss with sponsor
Grade 4f: Discontinue Study Treatment
Note: For grading see CTCAE version 5.0. Collect all CTC grades of adverse events, decreasing and 
increasing grade. 
BMI =  body mass index, CTCAE = Common Terminology Criteria for Adverse Events
a: An interruption of study treatment for more than 28 days will require sponsor`s approval before treatment 
can be resumed.
b: Initiate optimal medical management for nausea, vomiting, hypertension, hypothyroidism, and/or diarrhea 
prior to any study treatment interruption or dose reduction. 
c: Applicable only to Grade 2 toxicities judged by the subject and/or physician to be intolerable.
d: Obese subjects with weight loss do not need to return to the baseline weight or 10% of baseline weight (ie, 
Grade 1 weight loss).  These subjects will restart the study drug(s) at a lower dose once their weight 
remains stable for at least 1 week and they reached the normal BMI (if the weight loss occurred but it is 
still above normal BMI, they can restart the study treatment at a lower dose once the weight has been 
stable for at least 1 week).  Normal BMI should be used as the new baseline for further dose reductions.   
Obesity is defined as body mass index (BMI) percentiles corresponding to 30 kg/m², related to the age of 
the children (Cole, et al., 2000) or BMI ≥ the 95th percentile for children and teens of the same age and sex 
(Ogden, et al., 2002) (Appendix 8 and Appendix 9).   
e: For asymptomatic laboratory abnormalities, such as Grade ≥3 elevations of amylase and lipase that are not 
considered clinically relevant by the investigator, continuation of treatment should be discussed with the 
Sponsor. 
f: Excluding laboratory abnormalities judged to be non-life-threatening, in which case manage as Grade 3.
8.4.1.1.1
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 are
provided in Appendix 6 and Appendix 7.  Blood pressure that is consistently above the 95th 
percentile [for subjects age 18 to 25 years BP ≤140/90 mm Hg] for age and height/length 
Page 193 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 46 of 121
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.
8.4.1.1.2
MANAGEMENT OF HYPERTENSION
Hypertension is a recognized side-effect of treatment with drugs inhibiting VEGF signaling.
Investigators should therefore ensure that subjects enrolled to receive treatment with 
lenvatinib have BP <95th percentile [BP ≤150/90 mm Hg] for sex, age, and height/length at 
the time of study entry and, if known to be hypertensive, have been on a stable dose of 
antihypertensive therapy for at least 1 week before Cycle 1 Day 1. Early detection and 
effective management of hypertension are important to minimize the need for lenvatinib dose 
interruptions and reductions.  
Regular assessment of BP should be conducted as detailed in the Schedule of Procedures/
Assessments (Table 5 and Table 6).  Hypertension will be graded using CTCAE v5.0, based 
on BP measurements only (and not on the number of antihypertensive medications).
If the subject’s initial BP measurement is elevated (systolic BP ≥95th percentile [BP 
≥140 mm Hg] or diastolic BP ≥95th percentile [BP ≥90 mm Hg]), the BP measurement 
should be repeated at least 5 minutes later. The mean value of 2 measurements at least 
5 minutes apart is defined as 1 BP assessment. If the BP assessment (ie, the mean of the 
2 BP measurements obtained at least 5 minutes apart) is elevated (systolic BP ≥140 mm Hg 
or diastolic BP ≥90 mm Hg), a confirmatory assessment should be obtained at least 
30 minutes later by performing 2 measurements (at least 5 minutes apart) to yield a mean 
value.
Antihypertensive agents should be started as soon as elevated BP (systolic BP ≥95th 
percentile [BP ≥140 mm Hg] or diastolic BP ≥95th percentile [BP ≥90 mm Hg]) is confirmed 
on 2 assessments obtained 30 minutes apart.  The choice of antihypertensive treatment should 
be individualized to the 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 
30 minutes apart.  For those subjects already on antihypertensive medication, treatment 
modification may be necessary if hypertension persists.
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 
Page 194 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 47 of 121
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 on Day 15 
(or more frequently as clinically indicated) until systolic BP has been <95th percentile 
(≤150 mm Hg) and diastolic BP has been <95th percentile (≤95 mm Hg) for 2 consecutive 
treatment cycles.  If a repeat event of systolic BP ≥99th percentile (BP ≥160 mm Hg) or 
diastolic BP ≥99th percentile (BP ≥100 mm Hg) occurs, the 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 2 consecutive treatment cycles. 
The following guidelines should be followed for the management of systolic BP ≥99th 
percentile (BP ≥160 mm Hg) or diastolic BP ≥99th percentile (BP ≥100 mm Hg) confirmed 
on repeat measurements after at least 30 minutes: 

Continue lenvatinib and institute antihypertensive therapy for subjects not already 
receiving this. 

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%]) 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. 
-
If systolic BP ≥99th percentile (BP ≥160 mm Hg) or diastolic BP ≥99th percentile 
(BP ≥100 mm Hg) recurs on the first dose reduction despite optimal management 
of hypertension with antihypertensive medications (either by dose increase or the 
addition of a different class of antihypertensive), then lenvatinib administration 
should be interrupted and restarted at an additional dose reduction only when 
systolic BP <95th percentile (BP ≤150 mm Hg) and diastolic BP <95th percentile 
(BP ≤95 mm Hg) and the subject has been on a stable dose of antihypertensive 
medication for at least 48 hours. 
-
If systolic BP ≥99th percentile (BP ≥160 mm Hg) or diastolic BP ≥99th percentile 
(BP ≥100 mm Hg) recurs on the second dose reduction despite optimal 
management of hypertension with antihypertensive medications (either by dose 
increase or the addition of a different class of antihypertensive), then lenvatinib 
administration should be interrupted and restarted at a third dose reduction only 
when systolic BP <95th percentile (BP ≤150 mm Hg and diastolic BP <95th 
percentile (BP ≤95 mm Hg) and the participant has been on a stable dose of 
antihypertensive medication for at least 48 hours.
Page 195 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 48 of 121
-
Additional dose reduction should be discussed with the Sponsor. 
The following guidelines should be followed for the management of Grade 4 hypertension 
(life-threatening consequences): 

Institute appropriate medical management 

Discontinue lenvatinib
Figure 2 shows the procedures associated with the management of hypertension.
Figure 2
Management of Hypertension
BP = blood pressure, HTN = hypertension, Tx = treatment.
8.4.1.1.3
MANAGEMENT OF POSTERIOR REVERSIBLE LEUKOENCEPHALOPATHY 
SYNDROME/REVERSIBLE POSTERIOR LEUKOENCEPHALOPATHY SYNDROME
Posterior Reversible Leukoencephalopathy Syndrome (PRES)/Reversible Posterior 
Leukoencephalopathy Syndrome (RPLS) is a neurological disorder that can present with 
headache, seizure, lethargy, confusion, altered mental function, blindness, and other visual or 
neurological disturbances.  Mild to severe hypertension may be present.  An MRI is 
1 BP Assessment is defined as, the 
Mean value of 2 measurements at 
least 5 mins apart
BP mmHg ≥95th percentile on 2 assessments 30 mins apart
BP mmHg ≥99th percentile on
2 Assessments 30 mins apart
Continue study drug
Page 196 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 49 of 121
necessary to confirm the diagnosis of PRES/RPLS.  Appropriate measures should be taken to 
control BP (see Section 8.4.1.1.1 and 8.4.1.1.2), and neurologic consultation is advised.  In 
subjects with signs or symptoms of PRES/RPLS, dose modification guidelines as per Table 1
should be followed.
8.4.1.1.4
MANAGEMENT OF PROTEINURIA
Regular assessment for proteinuria should be conducted as detailed in the Schedule of 
Assessments (Table 5 and Table 6).  Guidelines for assessment and management of 
proteinuria are summarized as follows: 
Grading of Proteinuria

Grading according to CTCAE 5.0 (Cancer Therapy Evaluation Program, 2017) will be 
based on the protein-creatinine ratio or 24-hour urinary protein result, if available. For 
subjects ≥18 years of age, if the subject has 4+ proteinuria by dipstick, a 24-hour urinary 
protein result is required to confirm Grade 3 proteinuria.
Management of Proteinuria

Management of lenvatinib administration will be based on the grade of proteinuria 
according to Table 1.

In the event of nephrotic syndrome, lenvatinib must be discontinued.
Detection and Confirmation

Perform urine dipstick testing per the Schedule of Assessments (Table 5 and Table 6)

For subjects ≥18 years of age, a 24-hour urine collection initiated as soon as possible and
at least within 72 hours (or an immediate spot urine protein-to-creatinine ratio [UPCR]
test) AND for subjects <18 years of age, an immediate spot UPCR test, and if possible, a 
24-hour urine collection (initiated as soon as possible and at least within 72 hours) is 
required in the following situations:
-
The first (initial) occurrence of ≥2+ proteinuria on urine dipstick while on lenvatinib
-
A subsequent increase in severity of urine dipstick proteinuria occurring on the same 
lenvatinib dose level
-
When there has been a lenvatinib dose reduction and at the new dose level the urine 
protein dipstick result is ≥2+

For subjects ≥18 years of age, a 24-hour urine collection (initiated as soon as possible and 
at least within 72 hours) to verify the grade of proteinuria is required when UPCR is ≥2.4.
Monitoring

Urine dipstick testing for subjects with proteinuria ≥2+ should be performed on Day 15 
(or more frequently as clinically indicated) until the results have been 1+ or negative for 
2 consecutive treatment cycles.
Page 197 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 50 of 121

Proteinuria monitoring can be performed at the local laboratory or investigator site, but 
must be managed by the site physician.
8.4.1.1.5
MANAGEMENT OF HEPATOTOXICITY
Regular monitoring of liver function tests (ALT, AST, bilirubin levels) should be conducted 
as detailed in the Schedule of Assessments (Table 5 and Table 6) 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 1).  Appropriate 
supportive care should be provided together with close monitoring.  If hepatic failure occurs 
the study drug must be discontinued.
8.4.1.1.6
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 
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 1).  
Appropriate supportive care should be provided together with close monitoring.  If a subject 
experiences a Grade 3 or a life-threatening (Grade 4) thromboembolic reaction, including 
pulmonary embolism, study drug must be discontinued.
Arterial thromboembolic events (eg, new onset, worsening, or unstable angina, myocardial 
infarction, transient ischemic attack, and cerebrovascular accident) of any grade require study 
drug discontinuation.
8.4.1.1.7
MANAGEMENT OF HYPOCALCEMIA
Serum calcium should be monitored monthly per the Schedule of Assessments (Table 5 and 
Table 6). Corrected serum calcium should be used to assess the grade of hypocalcemia per 
CTCAE v5.0, using the following formula: 
Corrected calcium = ([4 – serum albumin in g/dL] ×0.8 + serum calcium)
The formula is not applicable when serum albumin concentration is normal (˃4 g/dL); in 
such situations, the total (uncorrected) serum calcium should be used instead.
Hypocalcemia should be treated per institutional guidelines (eg, using appropriate calcium, 
magnesium, and Vitamin D supplementation) until resolution.
8.4.1.1.8
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 
Page 198 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 51 of 121
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, follow 
instructions contained in Table 1 regarding study treatment dose reduction and interruption.  
For Grade 4 adverse events that result in abdominal pain, study drug must be discontinued.
Gastrointestinal symptoms including diarrhea should be managed by providing symptomatic 
treatment. If the symptoms persist (eg, diarrhea for more than 10 days), dose modification 
guidelines should be followed as per Table 1. 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. 
Lenvatinib should be discontinued in any subject who develops gastrointestinal perforation
of any grade or Grade ≥4 fistula.  
8.4.1.1.9
MANAGEMENT OF HEMORRHAGE
Dose modification guidelines as per Table 1 for lenvatinib related adverse events should be 
followed for the management of hemorrhage. Either resume lenvatinib at a reduced dose or 
discontinue lenvatinib, depending on the severity and persistence of hemorrhage.
8.4.1.2
Management of Ifosfamide-Etoposide Associated Toxicity
Blood counts should be closely monitored during and prior to the next cycle of 
chemotherapy. Chemotherapy-associated myelosuppression should be managed by 
granulocyte-colony stimulating factor (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 white blood cell (WBC) counts are 
≥1×109/L. Guidelines for dose modification for ifosfamide and etoposide associated 
toxicities are provided in the Table 2 below. 
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).
Page 199 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 52 of 121
Table 2
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
ANC = absolute neutrophil count, RBC = red blood cell, ULN = upper limit normal.
8.4.2
Identity of Investigational Product(s)
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 4
provides instructions for the preparation of the lenvatinib suspension.  
8.4.2.1
Chemical Name of E7080

Test drug code:  E7080

Generic name:  lenvatinib

Chemical name:  4-[3-Chloro-4-(N’-cyclopropylureido)phenoxy]-7-methoxyquinoline-6-
carboxamide methanesulfonate

Molecular formula:  C21H19CLN4O4•CH4O3S

Molecular weight: 522.96
Page 200 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 53 of 121
8.4.2.2
Comparator Drug
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 or 
sourced by the clinical sites.  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. 
Anti-emetic or any other prophylaxis should be administered in accordance with institutional 
guidelines.
8.4.2.3
Labeling for Study Drug
Lenvatinib and the combination chemotherapy drugs, ifosfamide and etoposide, where 
supplied by the sponsor will be labeled in accordance with text that is in full regulatory 
compliance with each participating country and is translated into the required language(s) for 
each of those countries.  
The following information will be provided (but not limited to):

For clinical trial use only

Name and address of the sponsor

Chemical name / drug identifier

Lot number/Batch number

Storage conditions, expiration date if necessary
8.4.2.4
Storage Conditions
Lenvatinib will be stored in accordance with the labeled storage conditions.  The expiry date 
for lenvatinib will be established based on manufacturing date and is based on formulation 
testing.  The expiry date of of the lenvatinib will either be on the label and in the interactive 
voice response system (IVRS) system.
Page 201 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 54 of 121
Ifosfamide and etoposide will be stored in accordance with the labeled storage conditions.  
The expiry date of the ifosfamide and etoposide will be the same as the commercial products 
provided.  
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.
8.4.3
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 8.3) will be
assigned to treatments based on a computer-generated randomization scheme that will be 
reviewed and approved by an independent statistician.  The randomization scheme and 
identification for each subject will be included in the final clinical study report for this study.
After the Baseline Period, subjects will be randomized to 1 of the following 2 treatment arms 
in a 1:1 ratio:

Arm A:  lenvatinib 14 mg/m2 (orally, once daily) plus ifosfamide 3000 mg/m2/day (IV, 
Day 1 to Day 3 of each cycle for a total of up to 5 cycles) and etoposide 100 mg/m2/day 
(IV, Day 1 to Day 3 of each cycle for a total of up to 5 cycles)

Arm B: ifosfamide 3000 mg/m2/day (IV, Day 1 to Day 3 of each cycle for a total of up to
5 cycles) and etoposide 100 mg/m2/day (IV, Day 1 to Day 3 of each cycle for a total of up 
to 5 cycles)
Randomization will be performed centrally by an IVRS.  Randomization will follow a 
predefined randomization scheme based on the following stratification factors: time to first 
relapse/refractory disease (early [<18 months] or late [≥18 months]) and age (<18 and 
≥18 years).  Time to first relapse/refractory disease will be calculated starting from date of 
initial diagnosis.
8.4.4
Selection of Doses in the Study
The dose of lenvatinib, ifosfamide and etoposide in this study is the RP2D (14 mg/m2 + 
ifosfamide 3000 mg/m2 + etoposide 100 mg/m2) established in Study 207. The dose of 
lenvatinib is the same as the RP2D for lenvatinib monotherapy, also established in 
Study 207.
Page 202 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 55 of 121
8.4.5
Selection and Timing of 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 21 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 drugs should be administered at the clinic on PK sampling days. All scheduled visits 
must be conducted as per protocol, irrespective of treatment interruption. 
8.4.6
Blinding
The study will not be blinded.
8.4.7
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.
Treatment of complications or AEs, or therapy 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.  Granulocyte colony-stimulating 
factor (g-CSF) or equivalent may be used in accordance with American Society of Clinical 
Oncology (ASCO), institutional, or national guidelines.  Erythropoietin may be used 
according to ASCO, institutional, or national guidelines, but the subject should be carefully 
monitored for increases in red blood cell (RBC) counts.
8.4.7.1
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.  There is no clinically meaningful drug-drug interaction (DDI) risk when lenvatinib 
is co-administered with CYP3A substrates such as midazolam.  Simultaneous CYP3A4/P-gp 
inhibitions by ketoconazole slightly (15% to 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 
Page 203 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 56 of 121
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.
8.4.7.2
Prohibited Concomitant Therapies and Drugs
Subjects should not receive other antitumor therapies while on study. If a subject receives 
additional antitumor therapies other than the study drug(s), such as chemotherapy, targeted 
therapies, immunotherapy, or antitumor interventions - such as surgery or palliative 
radiotherapy (other than as described below), this will be judged to represent evidence of 
disease progression, and the study medication should be discontinued.  
For further information on the prohibited concomitant therapies for ifosfamide and etoposide, 
please refer to the respective prescribing information.
8.4.7.3
Permitted Concomitant Treatment/Procedures
The following concomitant treatments/procedures are allowed:
a.
Removal of existing (not new) osteosarcoma lesion (eg, surgical, radiofrequency 
ablation, cryotherapy, thermoablation, stereotaxic ratiotherapy, etc.) after completion of 
the Week 18 tumor assessment.  Subjects in Arm A in the presence of clinical benefit, 
may continue treatment with lenvatinib after protocol permissible surgery.
b. Palliative radiotherapy is allowed for ≤2 significantly symptomatic nontarget lesions. 
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. 
Any additional procedural or subject specific particularities should be discussed with the 
investigator and the sponsor.
Page 204 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 57 of 121
8.4.8
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.
8.4.9
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

The IRB/IEC membership list and statutes or Health and Human Services Assurance 
number

A copy of the certification and a table of the normal laboratory ranges for the reference 
laboratory conducting the clinical laboratory tests required by this protocol

An investigator-signed and dated FDA Form FDA 1572, or a completed Investigator and 
Site Information Form

Financial Disclosure form(s) for the principal investigator (PI) and all subinvestigators 
listed on Form FDA 1572 or Investigator and Site Information Form

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 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 
Page 205 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 58 of 121
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, Medicines and Healthcare Products Regulatory Agency [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 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.
8.5
Study Assessments
8.5.1
Assessments
8.5.1.1
Screening/Baseline Assessments
8.5.1.1.1
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).
8.5.1.1.2
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 
Page 206 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 59 of 121
(serum or urine) within 72 hours of the first dose of study medication), Lansky play score 
(see Appendix 2) or Karnofsky performance status score (see Appendix 3), tumor-node 
metastasis (TNM) Staging (at initial diagnosis of the disease), vital signs, clinical chemistry 
and hematology, urine dipstick testing, height, Tanner’s staging (see Appendix 10), proximal 
tibial growth plates, and pharmacodynamic biomarkers (for Arm A only).
8.5.1.1.3
MEDICAL HISTORY
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 5, and Table 6).  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.
8.5.1.2
Efficacy Assessments
8.5.1.2.1
TUMOR RESPONSE ASSESSMENTS
Tumor assessment will be performed based on RECIST 1.1 (Appendix 1).  
Investigator-determined response assessments will be performed at each assessment time point 
and entered onto the appropriate CRF.  Copies of all tumor assessment scans will be sent to 
an ICL designated by the sponsor for efficacy assessment and for confirmation of PD.  
Tumor assessments will be carried out following the guidelines provided by the ICL.  
Subjects must have evaluable disease or measurable disease based on RECIST 1.1.
At Screening
During the Screening Period, 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 Cycle 1 Day 1.  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.  
Brain scans by MRI with and without contrast enhancement or CT with contrast 
enhancement will be performed at screening as clinically indicated.
Historical scans (within 28 days prior to the Cycle 1 Day 1) may be used to demonstrate 
eligibility as long as they meet minimum standards as separately defined by the ICL. 
Page 207 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 60 of 121
During Treatment Phase
CT/MRI scans of, 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 weeks ±1 week, following the start of treatment on Cycle 1 Day 1 during the chemotherapy 
treatment period until Week 18.  Following completion of the chemotherapy treatment period
(ie, after Week 18), the frequency of tumor assessments will be every 9 weeks ±1 week until 
Week 54 ±1 week.  Thereafter, they will be performed every 12 weeks ±2 weeks until 
documentation of PD.  At any point, scans should be performed earlier than the scheduled 
time point, if clinically indicated.
An initial assessment of CR or PR according to RECIST 1.1 must be confirmed by IIR 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 PD, tumor assessments 
should continue to be performed as per the tumor assessment schedule until documentation 
of progression or start of a new anticancer agent.  Screening CT scans should be performed 
with oral and iodinated intravenous contrast and MRI scans should be performed with 
intravenous gadolinium chelate.  Post-screening scans may be performed without contrast if a 
medical contraindication develops while on study treatment.  If iodinated intravenous
contrast is contraindicated, chest CT should be done without intravenous 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 
intravenous contrast, and the MRI scans should be performed with intravenous 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 5-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.
Page 208 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 61 of 121
Brain scans by MRI with and without contrast enhancement or CT with contrast 
enhancement will be performed 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, 9, or 12 weeks).  
Disease progression per RECIST 1.1 during the randomization phase must be confirmed by 
IIR prior to the investigator discontinuing study treatment for a subject.  In the event that the 
investigator considers alternative treatments must be instituted immediately for management 
of urgent medical complications of PD, study drugs may be discontinued without waiting for 
independent confirmation of radiographic evidence of PD.  Subjects who discontinue study 
treatment without PD will continue to undergo tumor assessments according to the schedule 
until PD is documented or another anticancer therapy is initiated.  If possible, before 
discontinuation of the subject from the study, the investigator should consult with the 
sponsor.
During Post-treatment Follow-up 
Subjects who discontinue treatment without PD will have tumor assessments performed as 
per the appropriate tumor assessment schedule) or sooner if clinically indicated, for
documented PD or until another anticancer therapy is initiated, whichever occurs first. 
After data cutoff for PFS-1y and OS-1y analysis, 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 2 years after end of treatment or until 
death, unless the study is terminated by the sponsor, or the subject discontinues due to 
withdrawal of consent, or is lost to follow-up.
8.5.1.2.2
PALATABILITY AND ACCEPTABILITY OF LENVATINIB SUSPENSION FORMULATION
The palatability and acceptability of lenvatinib suspension formulation will be assessed using 
the Palatability Questionnaire (see Appendix 5). All subjects who receive suspension 
formulation with the exception of subjects using a nasogastric or gastrostomy tube, 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).
8.5.1.3
Pharmacokinetic, Pharmacodynamic, and Other Biomarker Assessments
8.5.1.3.1
PHARMACOKINETIC ASSESSMENTS
Blood samples (2 mL each) will be collected from all subjects from Arm A only at the time 
points shown in Table 3.  Pharmacokinetic blood samples will also be drawn pretreatment on 
the day of tumor assessment as described in the Table 3.  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 
Page 209 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 62 of 121
model.  For the time points shown in Table 3, 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 doses of 
lenvatinib will be administered at the study site at approximately the same time of day in 
order to accommodate PK sample collection timing.  Instructions for the collection, handling, 
and shipping procedures of PK samples will be provided in a separate Laboratory Manual.
Table 3
Lenvatinib Pharmacokinetic Sampling Time Points
Time Pointa
Time (h)
Cycle 1 Day 1
Postdose:  0.5-4 and 6-10
Cycle 1 Day 15
Predose
Postdose: 0.5-4 and 6-10
Cycle 2 Day 1
Predose
Note: All predose samples are to be drawn approximately 24 hours following the dose administered on the 
previous day.
h = hour(s).
a. If dose interruption is necessary in these time points, please contact the sponsor.
Only samples from all subjects randomized to Arm A will be collected.  Lenvatinib will be 
quantified using a validated liquid chromatography/mass spectrometry/mass spectrometry 
(LC/MS/MS) method.
8.5.1.3.2
PHARMACODYNAMIC AND OTHER BIOMARKER ASSESSMENTS
Pharmacodynamic serum and archived fixed tumor tissue samples for biomarker analysis 
will be collected from study subjects randomized to Arm A (ie, lenvatinib + ifosfamide + 
etoposide), as specified in the Schedule of Procedures/Assessments. Pharmacodynamic 
serum and tumor biomarkers identified in other lenvatinib clinical studies will be assessed in 
samples collected from subjects enrolled in this study.  Pharmacodynamic biomarker analysis 
will be performed as described in an analysis plan provided separately.
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).
8.5.1.4
Safety Assessments
Safety assessments will consist of monitoring and recording all AEs, including all grades per 
National Cancer Institute (NCI) CTCAE v5.0 (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 5
and Table 6).
Clinical and laboratory toxicities/symptomatology will be graded according to CTCAE v5.0 
(Cancer Therapy Evaluation Program, 2017). 
Page 210 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 63 of 121
8.5.1.4.1
ADVERSE EVENTS
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered an investigational product.  An AE does not necessarily have a causal 
relationship with the medicinal product.  For this study, the study drug is lenvatinib. 
The criteria for identifying AEs in this study are:

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of an investigational product, 
whether or not considered related to the investigational product (Note:  Every sign or 
symptom should not be listed as a separate AE if the applicable disease [diagnosis] is 
being reported as an AE)

Any new disease or exacerbation of an existing disease. However, worsening of the 
primary disease should be captured under efficacy assessments as PD.

Any deterioration in nonprotocol-required measurements of a laboratory value or other 
clinical test (eg, ECG or x-ray) that results in symptoms, a change in treatment, or 
discontinuation of study drug

Recurrence of an intermittent medical condition (eg, headache) not present pretreatment 
(Baseline)

An abnormal laboratory test result should be considered an AE if the identified laboratory 
abnormality leads to any type of intervention, withdrawal of study drug, or withholding 
of study drug, whether prescribed in the protocol or not
All AEs, regardless of relationship to study drug or procedure, should be recorded beginning 
from the time the subject signs the study ICF through the last visit and for 30 days after the 
subject’s last dose.  Refer to Section 8.5.4.1 for the time period after the end of treatment for 
SAE collection.  
Abnormal laboratory values should not be listed as separate AEs if they are considered to be 
part of the clinical syndrome that is being reported as an AE.  It is the responsibility of the 
investigator to review all laboratory findings in all subjects and determine if they constitute 
an AE.  Medical and scientific judgment should be exercised in deciding whether an isolated 
laboratory abnormality should be classified as an AE.  Any laboratory abnormality
considered to constitute an AE should be reported on the Adverse Event CRF. 
Abnormal ECG (QTcF) results, if not otherwise considered part of a clinical symptom that is 
being reported as an AE, should be considered an AE if the QTcF interval is more than 
450 ms and there is an increase of more than 60 ms from baseline.  Any ECG abnormality 
that the investigator considers as an AE should be reported as such.
All AEs must be followed for 30 days after the subject’s last study drug dose, or until 
resolution, whichever comes first.  Subjects with onset of an AE or deterioration of a 
preexisting AE during the AE collection period will be followed until resolution to baseline, 
start of a new anticancer treatment, or death. All SAEs must be followed to resolution or, if 
resolution is unlikely, to stabilization.
Page 211 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 64 of 121
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 on a 5-point scale according to CTCAE v5.0 (Cancer Therapy 
Evaluation Program, 2017).  Investigators will report CTCAE grades for all AEs (for both 
increasing and decreasing severity).
Assessing Relationship to Study Treatment
Items to be considered when assessing the relationship of an AE to the study treatment are:

Temporal relationship of the onset of the event to the initiation of the study treatment

The course of the event, especially the effect of discontinuation of study treatment or 
reintroduction of study treatment, as applicable

Whether the event is known to be associated with the study treatment or with other 
similar treatments

The presence of risk factors in the study subject known to increase the occurrence of the 
event

The presence of nonstudy, treatment-related factors that are known to be associated with 
the occurrence of the event
Classification of Causality
The relationship of each AE to the study drug will be recorded on the CRF in response to the 
following question:
Is there a reasonable possibility that the study drug caused the AE?
Yes (related)
A causal relationship between the study drug and the AE is a reasonable 
possibility.
No (not related) A causal relationship between the study drug and the AE is not a 
reasonable possibility.
8.5.1.4.2
SERIOUS ADVERSE EVENTS AND EVENTS ASSOCIATED WITH SPECIAL SITUATIONS
An 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
Page 212 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 65 of 121

Is a congenital anomaly/birth defect (in the child of a subject who was exposed to the 
study drug)
Other important medical events that may not be immediately life-threatening or result in 
death or hospitalization but, when based on appropriate medical judgment, may jeopardize 
the subject or may require intervention to prevent one of the outcomes in the definition of 
SAE listed above should also be considered SAEs.  Medical and scientific judgment should 
be exercised in deciding whether expedited reporting is appropriate in such situations. 
In addition to the above, events associated with special situations include pregnancy or 
exposure to study drug through breastfeeding; AEs associated with study drug overdose, 
misuse, abuse, or medication error.  These events associated with special situations are to be 
captured using the SAE procedures but are to be considered as SAEs only if they meet one of 
the above criteria.  All AEs associated with special situations are to be reported on the CRF 
whether or not they meet the criteria for SAEs.  
All SAEs must be followed to resolution or, if resolution is unlikely, to stabilization.
The following hospitalizations are not considered to be SAEs because there is no “adverse 
event” (ie, there is no untoward medical occurrence) associated with the hospitalization:

Hospitalizations for respite care 

Planned hospitalizations required by the protocol

Hospitalization planned before informed consent (where the condition requiring the 
hospitalization has not changed after study drug administration)

Hospitalization for administration of study drug or insertion of access for administration 
of study drug

Hospitalization for routine maintenance of a device (eg, battery replacement) that was in 
place before study entry
8.5.1.4.3
LABORATORY MEASUREMENTS
Clinical laboratory tests to be performed, including hematology, chemistry, and urinalysis, 
are summarized in Table 4.  Subjects should be in a seated or supine position during blood 
collection.  The Schedule of Procedures/Assessments (Table 5 and Table 6) shows the visits 
and time points at which blood for clinical laboratory tests and urine for urinalysis will be 
collected in the study.
Page 213 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 66 of 121
Table 4
Clinical Laboratory Tests
Category
Parameters
Hematology
Hematocrit, hemoglobin, platelets, RBC count, and WBC count 
with differential (bands, basophils, eosinophils, lymphocytes, 
monocytes, neutrophils)
Chemistry
Electrolytes
Bicarbonate, chloride, potassium, sodium, calcium, magnesium, 
phosphorus
Liver function tests
ALT, alkaline phosphatase, AST, conjugated (direct) bilirubina, 
total bilirubin, INRb
Renal function tests
BUN or urea, creatinine
Other chemistries
Albumin, amylase, glucose, LDH, lipase, total protein 
Thyroid function testsc
Thyroid stimulating hormone, free T4 level
Urinalysis for microscopyd
RBCs
Urine dipstick testingd,e
Blood, protein, glucose
Other
Pregnancy test (serum or urine β–hCG)
ALT = alanine aminotransferase, AST = aspartate aminotransferase, BUN = blood urea nitrogen, β hCG = 
beta-human chorionic gonadotropin, INR = International Normalized ratio, LDH = lactate dehydrogenase,
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.
INR should only be performed as part of the screening assessment.  During the study, INR should be 
performed if clinically indicated.
c.
Thyroid function will be assessed every 2 cycles for all subjects.
d.
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
e.
If urine protein is ≥ 2+, then a spot test for protein-creatinine ratio and if possible, a 24-hour urine 
collection should be done to quantify the 24 hour urine protein excretion. 
All clinical laboratory tests during the study will be performed at qualified local laboratories.  
All hematology, blood chemistry (including pregnancy test, as applicable), and urinalysis 
samples are to be obtained prior to study drug administration and sent to the local laboratory 
on the day of collection unless otherwise instructed. 
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 Table 1 (study 
drug dose reduction and interruption instructions) 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 8.5.1.4.1 and the CRF Completion Guidelines.  In these instances, the 
Page 214 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 67 of 121
AE corresponding to the laboratory abnormality will be recorded on the Adverse Event CRF
(see Section 8.5.4.3.2).
8.5.1.4.4
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 5
and Table 6) 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.  On Cycle 1 Day 8, subjects will be contacted by 
telephone to assess for the development of early toxicity. Subjects will be provided with a 
BP cuff to monitor BP at home or can have the measurement done by a local healthcare 
provider, and will report the C1D8 measurement at telephone contact. An unscheduled visit 
can occur prior to C1D15 if deemed necessary by the investigator.
Only 1 BP measurement is needed for subjects with systolic BP <95th percentile (BP 
<140 mm Hg) and diastolic BP <95th percentile (BP <90 mmHg). If the subject’s initial BP 
measurement is elevated (systolic BP ≥95th percentile [≥140 mmHg] or diastolic BP ≥95th 
percentile [≥90 mmHg]), the BP measurement should be repeated at least 5 minutes later. 
The mean value of 2 measurements at least 5 minutes apart is defined as 1 BP assessment. If 
the BP assessment (ie, the mean of the 2 BP measurements obtained at least 5 minutes apart) 
is elevated (systolic BP ≥95th percentile [≥140 mm Hg] or diastolic BP ≥95th percentile
[≥90 mm Hg]), a confirmatory assessment should be obtained at least 30 minutes later by 
performing 2 measurements (at least 5 minutes apart) to yield a mean value.
8.5.1.4.5
PHYSICAL EXAMINATIONS
Physical examinations will be performed as designated in the Schedule of 
Procedures/Assessments (Table 5 and Table 6).  Documentation of the physical examination 
will be included in the source documentation at the site.  Only changes from screening 
physical examination findings that meet the definition of an AE will be recorded on the 
Adverse Events CRF.
8.5.1.4.6
ELECTROCARDIOGRAMS
Electrocardiograms will be obtained as designated in the Schedule of Assessments (Table 5
and Table 6).  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.  If possible, 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 8.5.1.4.1) and the CRF Completion Guidelines.  In these instances, the AE 
corresponding to the ECG abnormality will be recorded on the Adverse Events CRF.
Page 215 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 68 of 121
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 8.5.4.1).
8.5.1.4.7
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 8.3.1 and 8.3.2).  A serum or urine 
pregnancy test will be performed at Screening, Baseline (or within 72 hours prior to the first 
dose of study medication), on Day 1 of each cycle from Cycle 2 onwards, 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 5 and
Table 6).
Echocardiogram
An echocardiogram to assess 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.
8.5.1.5
Other Assessments
Health-related quality of life (HRQoL) assessment will be performed per the Schedule of 
Assessments (Table 5 and Table 6). Impact of treatment on HRQoL will be assessed using 
the PedsQL (including the Generic Core Scales and Cancer Module).  Data will be collected 
as parent-report for toddlers (2 to 4 years) and as self-report for subjects aged ≥5 years.  
Self-report is the preferred data collection for all subjects aged ≥5, however to improve 
adherence of participation, it is also acceptable to collect the data as proxy report by 
observers including parents and caregivers.
The PedsQL is a modular instrument designed to measure HRQoL in pediatric and adults 
population. The PedsQL 4.0 Generic Core Scales are multidimensional child self-report and 
parent proxy-report scales developed as the generic core measure to be integrated with the 
PedsQL disease specific modules. The PedsQL 3.0 Cancer Module was designed to measure 
pediatric cancer specific HRQOL.
It is best practice and strongly recommended that the PedsQL measurement modules are 
administered to randomized subjects prior to drug administration or any other interaction 
with site staff.
Page 216 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 69 of 121
8.5.2
Schedule of Procedures/Assessments
8.5.2.1
Schedule of Procedures/Assessments
Table 5 presents the schedule of procedures/assessments for the Randomization Phase of the
study.
Table 6 presents the schedule of procedures/assessments for the Extension Phase of the 
study.
Page 217 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 70 of 121
Table 5
Schedule of Assessments in Study E7080-G000-230 – Randomization Phase
Phase
Prerandomization
Randomization a
(All cycles are 21 days in duration)
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
18+
Cycle
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5
Cycle 
6-X
Day
-28 to -2
-1
1
8
15
1
8
15
1
8
15
1
8
15
1
8
15
1
Procedures/Assessments
Informed consent
X
Inclusion/exclusion
X
X
Randomization (IVRS)
X
Demographic data
X
Medical/surgical history
X
X
Prior medication/ procedures
X
X
Pregnancy testf
X
X
X
X
X
X
X
X
Lansky play score/ 
Karnofsky PSg
X
X
X
X
X
X
X
X
TNM Staging
X
Physical examinationh
X
X
X
X
X
X
X
X
X
X
X
Vital signsi
X
X
X
Xj
X
X
X
X
X
X
X
X
12-lead ECGk
X
X
X
X
X
Echocardiograml
X
Performed every 16±2 weeks following the first dose of study drug or sooner, if clinically indicated
X
Clinical chemistry and 
hematologym
X
X
X
X
X
X
X
X
X
X
Urine dipstick testingn
X
X
X
X
X
X
X
X
X
X
PK blood sampleso
X
X
X
Study treatmentp
Arm A:  Combination of lenvatinib (QD) + ifosfamide + etoposide (Days 1-3 of Cycles 1-5 only)
[based on BSA calculations at Day 1 of each Cycle]; after Cycle 5 subjects will receive lenvatinib alone.
Arm B:  Ifosfamide + etoposide (Days 1-3 of Cycles 1-5 only)
[based on BSA calculations at Day 1 of each Cycle]
Page 218 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 71 of 121
Table 5
Schedule of Assessments in Study E7080-G000-230 – Randomization Phase
Phase
Prerandomization
Randomization a
(All cycles are 21 days in duration)
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
18+
Cycle
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5
Cycle 
6-X
Day
-28 to -2
-1
1
8
15
1
8
15
1
8
15
1
8
15
1
8
15
1
Procedures/Assessments
Palatability Questionnaireq
X
Tumor assessments: 
CT/MRIr
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±1 week or sooner if clinically indicated until Week 18±1 week, 
then every 9±1 weeks until Week 54±1 week.  Thereafter, to be performed every 12±2 weeks until 
documentation of PD.
X
Brain CT/MRIs
X
Brain scans will be performed at screening as clinically indicated, and thereafter during treatment if 
clinically indicated.  For subjects with protocol-eligible, treated brain metastases at Screening, brain 
scans should be performed at all tumor assessment time points.
Heightt
X
X
X
X
X
X
Tanner Stageu
X
X
X
Proximal Tibial growth 
plates x-ray t
X
X
HRQoL
X
HRQoL will be collected on C2D1, C3D1,  Week 18, C8D1, and C18D1  
X
Pharmacodynamic 
biomarkersv
X
X
X
X
X
Archival tumor block or 
slidesw
X
Survivalx
X
X
Concomitant medicationsy
Throughout
X
AEs/SAEsz
Throughout
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, h = hour, HR = heart rate, HRQoL = Health-Related Quality of Life, IV = intravenous, IVRS = Interactive Voice 
Response System, MRI = magnetic resonance imaging, PD = progressive disease/disease progression, PK = pharmacokinetics, PR = partial response, PS = 
Page 219 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 72 of 121
Table 5
Schedule of Assessments in Study E7080-G000-230 – Randomization Phase
Phase
Prerandomization
Randomization a
(All cycles are 21 days in duration)
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
18+
Cycle
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5
Cycle 
6-X
Day
-28 to -2
-1
1
8
15
1
8
15
1
8
15
1
8
15
1
8
15
1
Procedures/Assessments
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.  
a.
During Cycle 1, efforts should be made to conduct study visits on the day scheduled (1 day); from Cycle 2 onwards, efforts should be made to conduct 
study visits on the day scheduled (±3 days).
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.
For subjects randomized to Arm A, subjects benefiting from study treatment in the opinion of the investigator will continue lenvatinib treatment until PD, 
intolerable toxicity, noncompliance with safety or efficacy assessments, voluntary discontinuation by the subject at any time, or study termination by the 
sponsor, whichever occurs first.
e.
Subjects will be followed every 12 weeks until documentation of PD 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), on 
Day 1 of each cycle from Cycle 2 onwards, if pregnancy is suspected, 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 C1D1 Visit, 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), C1D15, C2D1, C2D15, 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.  Refer to hypertension management guidelines in Section 8.4.1.1.2.
j.
On Cycle 1 Day 8, subjects will be contacted by telephone to assess for the development of early toxicity. Subjects will be provided with a BP cuff to 
monitor BP at home or can have the measurement done by a local healthcare provider, and will report the C1D8 measurement at telephone contact. An 
unscheduled visit can occur prior to C1D15 if deemed necessary by the investigator.
k.
Single 12-lead ECG.  If possible, subjects must be in the recumbent position for a period of 5 minutes prior to the ECG.  ECG should be conducted at 
Page 220 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 73 of 121
Table 5
Schedule of Assessments in Study E7080-G000-230 – Randomization Phase
Phase
Prerandomization
Randomization a
(All cycles are 21 days in duration)
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
18+
Cycle
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5
Cycle 
6-X
Day
-28 to -2
-1
1
8
15
1
8
15
1
8
15
1
8
15
1
8
15
1
Procedures/Assessments
Screening, C1D1, C2D1,  D1 of every 4th cycle (ie, C6, C10, C14, etc.). ECG at C1D1 and C2D1 should be conducted approximately 2 hours after 
lenvatinib dose.  For high risk subjects  (as defined in lenvatinib product label), conduct ECG monitoring in every cycle. 
l.
An echocardiogram is performed during screening, every 16±2 weeks, and at the Off-Treatment visit, or sooner if clinically indicated.
m. Clinical chemistry and hematology results must be reviewed by the investigator prior to administration of study drug on C1D1 and within 48 hours after 
administering any 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).  TSH should be 
assessed for all subjects.
n.
Urine dipstick testing should be performed at Screening, Baseline, C1D15, C2D1, C2D15, and Day 1 of every subsequent cycle, or more frequently as 
clinically indicated, 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 2 treatment cycles.  If a new event of proteinuria ≥2+ occurs, refer to Section 8.4.1.1.4 for further management guidelines.  
Urine glucose should be performed as part of the urine dipstick.  
o.
Sampling (one 2 mL sample per time point) for PK analysis of lenvatinib will be performed (in subjects in Arm A only) on Cycle 1 Day 1 at 0.5 to 4 hours 
and 6 to 10 hours postdose, on Cycle 1 Day 15 at predose, 0.5 to 4 hours and 6 to 10 hours postdose, and on Cycle 2 Day 1 at predose.  All predose samples 
are to be drawn approximately 24 hours following the dose administered on the previous day.  If dose interruption is necessary at  these time points, please 
contact the sponsor.
p.
Subjects randomized to Arm A will continue to receive lenvatinib only after completion of 5 cycles with lenvatinib+ifosfamide+etoposide until progressive 
disease, unacceptable toxicity, subject request, study termination by the sponsor, subject noncompliance with safety or efficacy assessments, or withdrawal 
of consent.  Subjects randomized to Arm B will be off-treatment after 5 cycles of ifosfamide+etoposide.
q.
All subjects who receive suspension formulation, with the exception of subjects using a nasogastric or gastrostomy tube, 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.  
r.
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.
Page 221 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 74 of 121
Table 5
Schedule of Assessments in Study E7080-G000-230 – Randomization Phase
Phase
Prerandomization
Randomization a
(All cycles are 21 days in duration)
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
18+
Cycle
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5
Cycle 
6-X
Day
-28 to -2
-1
1
8
15
1
8
15
1
8
15
1
8
15
1
8
15
1
Procedures/Assessments
Treatment Phase:  Tumor assessments of the chest, and other areas of known disease at Screening or newly suspected disease should be performed every 
6±1 weeks from C1D1 until Week 18±1 week, then every 9±1 weeks until Week 54±1 week, and thereafter, every 12±2 weeks until documentation of PD
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 according to the 
schedule: every 6±1 weeks until Week 18±1 week, then every 9±1 weeks until Week 54±1 week, thereafter, to be performed every 12±2 weeks until 
documentation of progression or start of a new anticancer agent. 
s.
Brain CT with contrast or MRI pre- and post- gadolinium contrast will be performed at the Screening Visit as clinically indicated, and thereafter during 
treatment as clinically indicated.  For subjects with protocol-eligible treated brain metastases, brain CT/MRI will be performed at all tumor assessment time 
points.
t.
Height will be assessed at the Baseline Visit, Day 1 of every 4 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.  If the growth plates are 
closed at baseline then the subject does not need a reassessment at the Off-treatment Visit. Tibial growth plate x-rays will be optional for Germany.
u.
Tanner Stage will be assessed at the Baseline Visit, at the Off-treatment Visit, and annually thereafter during the Post-treatment Follow-up.  
v.
Blood samples will be collected only from subjects in Arm A at the Baseline Visit, C1D15, Day 1 of Cycles 2, 4, and 6, for assessment for blood serum 
sample to measure factors implicated in angiogenesis. 
w.
An archival tumor sample from the most recent surgery or biopsy for identification of predictive biomarkers and pathology review may be collected from 
subjects in Arm A at any time during the study, unless no such material is available.
x.
Survival data will be collected every 3 months until death as per the protocol.  All anticancer therapies will be collected.
y.
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.  
z.
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.
Page 222 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 75 of 121
Table 6 presents the Schedule of Procedures/Assessments for the Extension Phase of the 
study.  
Page 223 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 76 of 121
Table 6
Schedule of Assessments in Study E7080-G000-230 – Extension Phase
Phase
Extensiona
Period
Treatment Period a
Follow-up Period
Visit 
98
99
Cycle
Cycle X +1 and beyond
Off-Tx Visit
Day
1
Procedures/Assessments
Pregnancy testb
X
X
Lansky play score/ Karnofsky PSc
X
X
Physical examinationd
X
X
Vital signse
X
X
12-lead ECGf
As clinically indicated
Echocardiogramg
As clinically indicated
Clinical chemistry and hematologyh
X
X
Urine dipstick testingi
X
X
Study treatmentj
Arm A:  Lenvatiniba
Tumor assessments: CT/MRIk
After data cutoff, tumor assessments may be performed as clinically indicated 
as per the institutional guidelines, following the prevailing local standard of 
care.
Brain CT/MRIl
After data cutoff, tumor assessments may be performed as clinically indicated 
as per the institutional guidelines, following the prevailing local standard of 
care.
Heightm
To be checked every 4 cycles
X
X
Tanner Stagen
X
X
Proximal Tibial growth plates x-rayo
X
Survivalp
X
X
Concomitant medicationsq
Throughout
X
AEs/SAEsr
Throughout
X
AE = adverse event, CT = computerized tomography, ICL = imaging core laboratory, MRI = magnetic resonance imaging, PD = disease progression, PS = 
performance status, SAE = serious adverse event.
a. Subjects benefiting from study treatment in the opinion of the investigator will continue treatment until PD, intolerable toxicity, subject request, subject 
noncompliance with safety or efficacy assessments, voluntary discontinuation by the subject at any time, or study termination by the sponsor, whichever 
occurs first.
Page 224 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 77 of 121
Table 6
Schedule of Assessments in Study E7080-G000-230 – Extension Phase
Phase
Extensiona
Period
Treatment Period a
Follow-up Period
Visit 
98
99
Cycle
Cycle X +1 and beyond
Off-Tx Visit
Day
1
b. A serum or urine pregnancy test will be performed on Day 1 of each cycle and at the Off-treatment Visit in women of childbearing potential.
c. A Lansky play score or Karnofsky performance status score will be obtained at Day 1 of every cycle visit.
d. A physical examination will be performed at Day 1 visit of each cycle, and at the Off-treatment Visit.  A symptom-directed physical examination will be 
performed at any time  as clinically indicated.
e. 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. Refer to hypertension management guidelines in Section 8.4.1.1.2.  
f.
Single 12-lead ECG.  Subjects must be in the recumbent position for a period of 5 minutes prior to the ECG.
g. An echocardiogram is performed as clinically indicated.
h. Clinical chemistry and hematology results must be reviewed within 48 hours after administering any 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).  TSH should be assessed for all subjects.
i.
Urine dipstick testing should be performed on Day 1 of every cycle, or more frequently as clinically indicated, 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 2 consecutive cycles.  If a new 
event of proteinuria ≥2+ occurs, refer to Section 8.4.1.1.4 for further management guidelines.  Urine glucose should be performed as part of the urine 
dipstick.  
j.
Subjects randomized to Arm A will continue to receive lenvatinib only until progressive disease, unacceptable toxicity, or withdrawal of consent.  
k. After data cutoff, tumor assessments may be performed as clinically indicated as per the institutional guidelines, following the prevailing local standard of 
care.  The scans will no longer be required to be sent to the ICL.
l.
Brain CT with contrast or MRI pre- and post- gadolinium contrast will be performed as per the institutional guidelines, following the prevailing local standard 
of care.
m. Height will be assessed at the Baseline Visit, Day 1 of every 4 cycles during the Treatment Phase, at the Off-treatment Visit and every 3 months during the 
Post-treatment Follow-up.  
n. Tanner Stage will be assessed at the Baseline Visit, at the Off-treatment Visit, and annually thereafter during the Post-treatment Follow-up.  
o. Proximal tibial growth plates x-rays should be conducted at baseline and at the Off-treatment Visit. If the growth plates are closed at baseline then the subject 
does not need a reassessment at the Off-treatment Visit. Tibial growth plate x-rays will be optional for Germany.
p. Survival data will be collected every 3 months until death as per the protocol.  All anticancer therapies will be collected.
q. 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.  
r.
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.
Page 225 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 78 of 121
8.5.2.2
Description of Procedures/Assessments Schedule
Refer to Table 5 for schedule and description of procedures in the Randomization Phase and 
Table 6 for the Extension Phase.
8.5.3
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).
8.5.4
Reporting of Serious Adverse Events, Pregnancy, and Events Associated 
with Special Situations
8.5.4.1
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 date the investigator becomes aware of the event.
Serious adverse events, regardless of causality assessment, must be collected for 30 days 
after the subject’s last dose.  All SAEs must be followed to resolution or, if resolution is 
unlikely, to stabilization.  Any SAE judged by the investigator to be related to the study 
treatment or any protocol-required procedure should be reported to the sponsor regardless of 
the length of time that has passed since study completion.
The detailed contact information for reporting of SAEs is provided in the Investigator Study 
File.
For urgent safety issues, please ensure all appropriate medical care is administered to the 
subject and contact the appropriate study team member listed in the Investigator Study File.
It is very important that the SAE report form be filled out as completely as possible at the 
time of the initial report.  This includes the investigator’s assessment of causality.
Any relevant follow-up information received on SAEs should be forwarded within 24 hours
of its receipt.  If the relevant 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.
Page 226 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 79 of 121
The investigator must notify his/her IRB/IEC of the occurrence of the SAE in writing, if 
required by their institution.  A copy of this communication must be forwarded to the sponsor 
and/or the designated CRO monitor to be filed in the sponsor’s Trial Master File.
8.5.4.2
Reporting of Pregnancy and Exposure to Study Drug Through Breastfeeding
Any pregnancy in a female subject 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 exposure, this 
should be reported regardless of the length of time that has passed since the exposure to study 
treatment.
A congenital anomaly, death during perinatal period, a spontaneous abortion or an induced 
abortion done due to safety concerns for either mother or fetus 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 8.5.4.1]).
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 date the investigator becomes 
aware of the pregnancy.  The contact information for the reporting of pregnancies and 
exposure to study drug through breastfeeding is provided in the Investigator Study File.  The 
Pregnancy Report Form must be used for reporting.  All pregnancies must be followed to 
outcome.  The outcome of the pregnancy must be reported as soon as possible but no later 
than 24 hours from the date the investigator becomes aware of the outcome.
A subject who becomes pregnant must be withdrawn from the study.
8.5.4.3
Reporting of Events Associated with Special Situations
8.5.4.3.1
REPORTING OF ADVERSE EVENTS ASSOCIATED WITH STUDY DRUG OVERDOSE,
MISUSE, ABUSE, OR MEDICATION ERROR
Adverse events associated with study drug overdose, misuse, abuse, and medication error 
refer to AEs associated with uses of the study drug outside of that specified by the protocol.  
Overdose, misuse, abuse, and medication error are defined as follows:
Overdose
Accidental or intentional use of the study drug in an amount higher 
than the protocol-defined dose
Misuse
Intentional and inappropriate use of study drug not in accordance with 
the protocol
Abuse
Sporadic or persistent intentional excessive use of study drug 
accompanied by harmful physical or psychological effects
Page 227 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 80 of 121
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 8.5.4.1) even if the AEs do not meet serious criteria.  Abuse 
and Intentional Overdose, even if asymptomatic, are 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.
8.5.4.3.2
REPORTING OF ABNORMAL HEPATIC TESTS OF CLINICAL INTEREST
The following combination of abnormal laboratory tests*, as determined by way of 
protocol-specified laboratory testing or unscheduled laboratory testing and whether 
nonserious or serious, should be entered on the Adverse Event CRF and reported using the 
procedures detailed in Reporting of Serious Adverse Events (Section 8.5.4.1). If the event 
does not meet serious criteria, the seriousness criteria on the SAE form should be indicated as 
“nonserious.”  

Elevated AST or ALT lab value that is greater than or equal to 3× the upper limit of 
normal 
AND

Elevated total bilirubin lab value that is greater than or equal to 2× the upper limit of 
normal 
AND AT THE SAME TIME

Alkaline phosphatase lab value that is less than 2× the upper limit of normal
*Note: These criteria are based upon available regulatory guidance documents. The purpose 
of the criteria is to specify a threshold of abnormal hepatic tests that may require additional 
evaluation for an underlying etiology. In addition to reporting the abnormal hepatic 
laboratory tests on a SAE form, the site should also consult the medical monitor for guidance 
on assessment and follow-up.  At a minimum, laboratory testing should be repeated at least 
once weekly until improvement or identification of a cause unrelated to study drug use that is 
unlikely to improve.
8.5.4.4
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.
Page 228 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 81 of 121
8.5.4.5
Breaking the Blind
Not applicable
8.5.4.6
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 
SUSARs will be reported, as required, to the competent authorities of all involved European 
member states.
8.5.5
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 PD will be followed in the post-study treatment follow-up period and continue to undergo 
regularly scheduled disease assessment until documentation of PD or start of an alternative 
anticancer treatment.  All subjects who discontinue study drug will be followed for OS 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 5 and Table 6). 
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 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.
8.5.6
Abuse or Diversion of Study Drug
Not applicable.
Page 229 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 82 of 121
8.5.7
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.
8.6
Data Quality Assurance
This study will be organized, performed, and reported in compliance with the protocol, 
SOPs, working practice documents, and applicable regulations and guidelines.  Site audits 
will be made periodically by the sponsor’s or the CRO’s qualified compliance auditing team, 
which is an independent function from the study team responsible for conduct of the study.
8.6.1
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.
8.6.2
Clinical Data Management
All software applications used in the collection of data will be properly validated following 
standard computer system validation that is compliant with all regulatory requirements.  All 
data, both CRF and external data (eg, laboratory data), will be entered into a clinical system.
8.7
Statistical Methods
All statistical analyses will be performed by the sponsor or designee after the study is 
completed, the database is locked and released, a snapshot of the database is obtained and 
released, and randomization codes have been released and applied.  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).
Page 230 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 83 of 121
8.7.1
Statistical and Analytical Plans
The statistical analyses of 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.
8.7.1.1
Study Endpoints
8.7.1.1.1
PRIMARY ENDPOINT

Progression-free survival rate at 4 months (PFS-4m rate) by IIR is defined as the 
percentage of subjects who are alive and without PD at 4 months from the randomization 
date as determined by IIR of radiological imaging using RECIST 1.1.  The PFS-4m rate 
is estimated on the full analysis set for this study using the K-M method.
8.7.1.1.2
SECONDARY ENDPOINTS

Progression-free survival rate at 1 year (PFS-1y rate) by IIR is defined as the percentage 
of subjects who are alive and without PD at 1 year from the randomization date as 
determined by IIR of radiological imaging using RECIST 1.1.  The PFS-1y rate is 
estimated on the full analysis set for this study using the K-M method.

Progression-free survival (PFS) by IIR is defined as the time from the date of 
randomization to the date of the first documentation of PD or death (whichever occurs 
first) as determined by IIR using RECIST 1.1.

Overall survival (OS) is defined as the time from the date of randomization to 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 alive, or date of 
data cutoff, whichever occurs first.  Overall survival rate at 1 year will be estimated.

Objective response rate (ORR) by IIR at 4 months is defined as the proportion of subjects 
who have best overall response of complete response (CR) or partial response (PR) as 
determined by IIR using RECIST 1.1 within the first 4 months.

Safety will be assessed summarising the incidence of TEAEs and SAEs together with all 
other safety parameters.

Assessment of population-based PK parameters of lenvatinib.

Score changes from baseline for all PedsQL scales including Generic Core Scales and 
Cancer Module. Scores will be calculated for total generic score, total cancer score, each 
physical function subscale including physical health, psychosocial health, emotional 
function, social function, school/work function in the Generic Core Scales, and each 
subscales in the cancer module.

Palatibility and acceptability of the suspension formulation of lenvatinib in subjects 
receiving the suspension formulation in the study will be assessed using the Palatability 
Questionnaire (see Appendix 5).
Page 231 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 84 of 121
8.7.1.1.3
EXPLORATORY ENDPOINTS 

Duration of response (DOR) by IIR is defined as the time from the date a response was 
first documented until the date of the first documentation of PD or date of death from any 
case.

Disease control rate (DCR) by IIR is the proportion of subjects who have a best overall 
response of CR or PR or stable disease (SD).  In this context, stable disease is defined as 
stable disease at ≥7 weeks after randomization to be considered best overall response.

Clinical benefit rate (CBR) by IIR is the proportion of subjects who have best overall 
response of CR or PR or durable SD (duration of SD ≥23 weeks after randomization).

Proportion of subjects who achieve complete removal of baseline lesions following 
completion of chemotherapy.

Blood and tumor biomarkers will be assessed for identifying potential correlation with 
clinical outcomes-related endpoints.

All efficacy endpoints above (except OS) will be evaluated by both IIR and investigator 
assessment using RECIST 1.1.
8.7.1.2
Definitions of Analysis Sets
The Full Analysis Set (Intent-to-Treat Analysis [ITT]) includes all randomized subjects 
regardless of the treatment actually received.  This is the primary analysis population used 
for the efficacy analyses which will be based on the ITT principle.
The Per Protocol Analysis Set includes those subjects from the ITT set who received at least 
1 dose of any study drug, had no major protocol deviations, and had both baseline and at 
least one postbaseline tumor assessment.  Subjects for whom death occurred prior to the first 
postbaseline tumor assessment will also be included.  The per protocol analysis set will be 
the secondary analysis set for efficacy endpoints.
The Safety Analysis Set includes subjects who received at least 1 dose of any study drug.  
This is the analysis population used for all safety analyses which will be based on as-treated 
principle.
Population Pharmacokinetic (PK) Analysis Set includes the subjects who have received at 
least 1 dose of lenvatinib with documented dosing history and have measurable plasma levels 
of lenvatinib.
The Pharmacodynamic Analysis Set includes subjects who received at least 1 dose of study 
drug and had sufficient pharmacodynamic data (eg, at least 1 evaluable/measurable
pharmacodynamic parameter).
The HRQoL Analysis Set will consist of all randomized subjects who have received at least 1
dose of study medication, and have completed at least 1 patient-reported outcome (PRO)
assessment beyond baseline. For PRO analysis, subjects will be analyzed as randomized and 
not according to treatment actually received.
Page 232 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 85 of 121
8.7.1.3
Subject Disposition
Reasons for screening failure will be summarized.
The number and percentage of subjects who completed the study will be summarized by 
treatment group, and for overall, and the number and percentage of subjects who 
discontinued prematurely will also be summarized by reason for discontinuation.
8.7.1.4
Demographic and Other Baseline Characteristics
Demographic and other baseline characteristics for the Full Analysis Set will be summarized 
using descriptive statistics.  Continuous demographic and baseline variables (including age, 
sex, race, height, and weight) will be summarized using n (number of subjects with available 
data), mean, standard deviation, median, quartiles 1 and 3, and range (minimum and 
maximum) unless otherwise specified.  Categorical variables will be summarized by number 
and percentage.
8.7.1.5
Prior and Concomitant Therapy
All investigator terms for medications recorded in the CRF will be coded to an 11-digit code 
using the World Health Organization Drug Dictionary (WHO DD).  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 started prior to the first dose of study drug and were either continued during 
the study or stopped prior to the first dose of study drug.  Concomitant medications will be 
defined as medications that (1) started before the first dose of study drug and were continuing 
at the time of the first dose of study drug, or (2) started on or after the date of the first dose of 
study drug 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 treatment arm.
8.7.1.6
Efficacy Analyses
Efficacy analyses will be based primarily on the Full Analysis Set.
All the statistical analysis will be conducted at the PFS-1y/OS-1y analysis data cutoff date
(ie, when the last subject has completed 18 cycles of treatment or discontinues before the end 
of Cycle 18, whichever occurs first), including the analysis of PFS-4m rate.  Additional 
follow-up analysis will based on the date of data cutoff for the additional follow-up analysis 
for OS or at the time of last subject last visit, whichever occurs later.  
8.7.1.6.1
PRIMARY EFFICACY ANALYSIS
The primary analysis of PFS-4m rate will be based upon data provided by IIR of tumor 
assessments.  PFS-4m rate and their Greenwood standard errors will be evaluated using the 
K-M estimates from both treatment groups.  The statistical significance of the difference in 
the 2 K-M PFS-4m rates comparing lenvatinib + chemotherapy agent (Test Arm) vs. 
chemotherapy agent alone (Control Arm) will be tested using a 2-sided 80% CI. This 2-sided 
Page 233 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 86 of 121
80% CI and a p-value will be constructed using the difference of these 2 K-M PFS-4m rates 
and the 2 corresponding Greenwood standard errors. Statistical significance of the difference 
is declared if the CI is entirely above 0. This is equivalent to a test using a 1-sided test at 
alpha=0.1. The 2-sided 95% CIs will also be provided for descriptive purposes. PFS-4m 
rate will also be analyzed using a binomial approach as a sensitivity analysis by excluding 
subjects whose PFS are censored prior to 18 weeks.
8.7.1.6.2
SECONDARY EFFICACY ANALYSES
PFS-1y rate will be analyzed using the same methods as the primary efficacy analysis.  PFS 
censoring rules will follow FDA guidance of 2007, however, removal of baseline lesions 
after completion of Week 18 without progression is not a trigger for PFS censoring after 
18 weeks. (refer to Section 8.4.7.3 for allowed concomitant treatments/procedure in the 
study).
Overall survival (OS) will be compared between treatment arm and control arm using the 
stratified logrank test with time to first relapse/refractory disease (early [<18 months] or late 
[≥18 months]) and age (<18 or ≥18 years) as strata.  Median OS with 2-sided 80% and 
95% CIs will be calculated using K-M product-limit estimates for each treatment arm, and 
the K-M estimates of OS will be plotted over time.  The Cox regression model will be used 
to estimate the hazard ratio and its 80% and 95% CIs stratified by time to first 
relapse/refractory disease (early [<18 months] or late [≥18 months]) and age (<18 or 
≥18 years).  Kaplan-Meier (K-M) estimates will also be presented for 4, 6, 9 and 12 months 
with 2-sided 80% and 95% CIs.
Overall PFS will be analyzed similarly to OS. Median PFS and 2-sided 80% and 95% (as 
exploratory) CIs will be presented, and the K-M estimates of PFS will be plotted over time.  
The Cox regression model will be used to estimate the hazard ratio and its 80% and 95% CIs 
stratified by time to first relapse/refractory disease (early [<18 months] or late [≥18 months]) 
and age (<18 or ≥18 years).  K-M estimates will also be presented for 4, 6, 9, and 12 months 
with 2-sided 80% and 95% CIs.
The ORR will be compared between the test and control groups using either a chi-square test 
or a Cochran-Mantel-Haenszel test stratified by time to first relapse/refractory disease (early 
[<18 months] or late [≥18 months]) and age (<18 or ≥18 years), as appropriate.  
Corresponding odds ratios and their 2-sided 80% and 95% CIs comparing the groups will 
also be presented.  The individual treatment group ORRs will also be calculated along with 
exact 95% confidence intervals using the Clopper and Pearson method.
8.7.1.6.3
EXPLORATORY EFFICACY ANALYSES
Median DOR among responders for each arm will be presented along with its corresponding 
2-sided 95% CIs.  Disease Control Rate (DCR) and CBR will be calculated with exact 
95% CIs using the Clopper and Pearson method.  The differences of the above rates between 
2 groups and corresponding two-sided 95% CIs will be calculated respectively.
Page 234 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 87 of 121
8.7.1.7
Pharmacokinetic, Pharmacodynamic, and Other Biomarker Analyses
8.7.1.7.1
PHARMACOKINETIC ANALYSES
Lenvatinib concentration versus time data will be tabulated and summarized and graphically 
presented.
Lenvatinib data from Arm A of the study will be pooled with available data from other 
studies and subjected to population PK analysis.  The PK model will be parameterized in 
terms of clearance and volume of distribution. Details of the population PK analysis will be 
provided in a separate analysis plan.
8.7.1.7.2
PHARMACODYNAMIC AND OTHER BIOMARKER ANALYSES
Pharmacodynamic, and other biomarker analyses may be performed and reported separately.  
Details of these analyses may be described in a separate analysis plan.
Pharmacodynamic serum and archived, fixed tumor tissue biomarkers will be collected from 
subjects in Arm A only as described in the Schedule of Assessments.  Pharmacodynamic 
serum and tumor biomarkers in this study will be identified as in other lenvatinib clinical 
studies. 
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. 
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.
Data obtained from the pharmacodynamic samples will be used for research.  The 
pharmacodynamic 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.
8.7.1.8
Safety Analyses
All safety analyses will be performed on the Safety Analysis Set.  Safety data, presented by 
treatment group, will be summarized on an “as treated” basis using descriptive statistics (eg, 
n, mean, standard deviation, median, minimum, maximum for continuous variables; n [%] 
Page 235 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 88 of 121
for categorical variables), as appropriate.  Safety variables include TEAEs, clinical laboratory 
parameters, vital signs, 12-lead ECG results, Lansky play scores or Karnofsky performance 
scores, physical examination, height, closure of proximal tibial plates, and LVEF.  Study 
Day 1 for all safety analyses will be defined as the date of the first dose of study drug.
8.7.1.8.1
EXTENT OF EXPOSURE
The number of cycles/days on treatment, quantity of study drug administered, and the 
number of subjects requiring dose reductions, treatment interruption, and treatment 
discontinuation due to adverse events will be summarized.
8.7.1.8.2
ADVERSE EVENTS
The AE verbatim descriptions (investigator terms from the CRF) will be classified into 
standardized medical terminology using the Medical Dictionary for Regulatory Activities 
(MedDRA).  Adverse events will be coded to the MedDRA (Version 20.1 or higher) lower 
level term (LLT) closest to the verbatim term.  The linked MedDRA preferred term (PT) and 
primary system organ class (SOC) are also captured in the database.
A TEAE is defined as an AE that emerges during treatment (and within 30 days of the last 
study treatment), having been absent at pretreatment (Baseline) or 

Re-emerges during treatment, having been present at pretreatment (Baseline) but 
stopped before treatment, 
or 

Worsens in severity during treatment relative to the pretreatment state, when the AE 
is continuous.
Only those AEs that are treatment-emergent will be included in summary tables.  All AEs, 
treatment-emergent or otherwise, will be presented in subject data listings.
The TEAEs will be summarized by treatment group.  The incidence of TEAEs will be 
reported as the number (percentage) of subjects with TEAEs by SOC and PT.  A subject will 
be counted only once within an SOC and PT, even if the subject experienced more than 1
TEAE within a specific SOC and PT.  The number (percentage) of subjects with TEAEs will 
also be summarized by highest CTCAE grade.
The number (percentage) of subjects with TEAEs will also be summarized by relationship to 
study drug (Yes [related] and No [not related]).
The number (percentage) of subjects with treatment-related TEAEs will be summarized by 
SOC and PT.  Treatment-related TEAEs include those events considered by the investigator 
to be related to study treatment.  The number (percentage) of subjects with treatment-related 
TEAEs will also be summarized by highest CTCAE grade.
Adverse events will be summarized using the Safety Analysis Set.  The number of AEs and 
number and incidence (%) of subjects with AEs will be summarized by treatment group and 
Page 236 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 89 of 121
overall.  To obtain the incidence (%), the number of subjects with at least 1 event and the 
percentage of subjects with AEs by SOC and by PT will be calculated.  Incidence (%) by 
causal relationship with study drug and by severity (CTCAE v5.0) will also be calculated.  
For clinically significant events, time of onset, and recovery will be reported.
Adverse events will be summarized for descriptive purposes by age (2 to <6, 6 to <18, and 
≥18), and sex.
The number (percentage) of subjects with TEAEs leading to death will be summarized by 
MedDRA SOC and PT for each treatment group.  A subject data listing of all AEs leading to 
death will be provided.  All deaths will also be summarized.
The number (percentage) of subjects with treatment-emergent SAEs will be summarized by 
MedDRA SOC and PT for each treatment group.  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 for each treatment group. A subject data 
listing of all AEs leading to discontinuation from study drug will be provided.
8.7.1.8.3
LABORATORY VALUES
Laboratory results will be summarized using Système International (SI) units, as appropriate.  
For all quantitative parameters listed in Section 8.5.1.4.3, 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 treatment group using descriptive 
statistics.  Qualitative parameters listed in Section 8.5.1.4.3 will be summarized using 
frequencies (number and percentage of subjects), and changes from baseline to each 
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.  Within-treatment comparisons for each laboratory parameter will be based 
on shift tables that compare the baseline LNH classification to the LNH classification at each 
postbaseline visit and at the end of treatment.  Similar shift tables will also compare the 
baseline LNH classification to the LNH classification for the highest and lowest value during 
the treatment period.
8.7.1.8.4
VITAL SIGNS
Descriptive statistics for vital signs parameters (ie, systolic and diastolic BP, pulse, 
respiratory rate, temperature, weight, and height) and changes from baseline will be 
presented by visit and treatment group.
Percentiles for BP values (only for subjects <18 years old) will also be summarized using a 
shift table of worst postbaseline from Baseline measurement by categories (<90th percentile, 
Page 237 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 90 of 121
90th to 95th percentile, 95th to ≤99th percentile, systolic BP or diastolic BP >99th 
percentile).  See Appendix 6 and Appendix 7 for detail on percentiles.
8.7.1.8.5
ELECTROCARDIOGRAMS
Descriptive statistics for electrocardiogram parameters (HR, PR, QRS, QT, QTcB, QTcF and 
RR) and changes from Baseline will be presented by visit. Electrocardiogram (ECG)
findings will be summarized. A shift table of worst postbaseline values from Baseline for 
ECG findings will be provided.
QTc Bazett and QTc Fridericia will be summarized.  QTc Bazett and QTc Fridericia will be 
categorized as both maximum increases from Baseline and maximum postbaseline values.
8.7.1.8.6
OTHER SAFETY ANALYSES
Descriptive summary statistics for LVEF changes from baseline will be calculated and 
summarized.
The shift of worst postbaseline proteinuria from Baseline will be summarized.
Thyroid-stimulating hormone values will be summarized in 2 categories (≤ULN and >ULN).
Lansky play scores or Karnofsky Performance Status score scores will be summarized by 
shifts from Baseline to worst postbaseline visit.
Radiographic findings of proximal tibial growth plates will be listed and analyzed if 
appropriate.
8.7.1.9
Other Analyses
8.7.1.9.1
HEALTH-RELATED QUALITY OF LIFE 
Descriptive statistics will be presented for all PedsQL endpoints at each analysis time period
by treatment arm. Baseline is defined as the later value of Day -1 or at Cycle 1 Day 1 prior 
to treatment. 
This will be collected at baseline, at C2D1, C3D1, Week 18, C8D1, C18 D1 and at the 
Off-Treatment Visit.  Score change from baseline in PedsQL at each analysis timepoint will 
be analyzed. Primary timepoint for assessment is at week 18 for all PedsQL endpoints.  
Detailed HRQoL analysis plan will be provided in a separate analysis plan and the results 
will be provided in a stand-alone report.
8.7.1.9.2
PALATABILITY AND ACCEPTABILITY QUESTIONNAIRE
Measurement of palatability will be assessed using the Hedonic scale (Guinard, 2001) which 
is a Visual Analog Scale (VAS) in subjects receiving the suspension formulation in the study.
Page 238 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 91 of 121
8.7.2
Determination of Sample Size
A binomial-based comparison of 2 proportions using correction for continuity was used for 
sample size estimation.  A total sample size of 72 subjects is estimated to achieve 80% 
statistical power at 1-sided alpha of 0.1 to detect a difference of 30% based on the 
assumption that PFS-4m for Arm A (lenvatinib arm) is 55% and for Arm B is 25%.  Alpha is 
the type 1 error probability of declaring lenvatinib arm being effective when the true 
lenvatinib arm PFS-4m rate is only 25%.
8.7.3
Interim Analysis
No interim analysis is planned for this study.
The safety monitoring will be conducted by the independent data monitoring committee 
(IDMC).  The frequency of the safety reviews will be defined in the IDMC charter.  Minutes 
from the open meetings of the IDMC will be provided if requested by regulatory agencies.  
The recommendation of whether to stop the study for safety will be reached by the IDMC 
based on their review of safety data with treatment information.  The function and 
membership of the IDMC will be described in the IDMC charter.
8.7.4
Other Statistical/Analytical Issues
Not applicable.
8.7.5
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.
Page 239 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 92 of 121
9
REFERENCE LIST
Bacci G, Briccoli A, Longhi A, Ferrari S, Mercuri M, Faggioli F, et al. Treatment and 
outcome of recurrent osteosarcoma: experience at Rizzoli in 235 patients initially treated 
with neoadjuvant chemotherapy. Acta Oncol. 2005;44(7):748-55.
Briccoli A, Rocca M, Salone M, Bacci G, Ferrari S, Balladelli A, et al. Resection of recurrent 
pulmonary metastases in patients with osteosarcoma. Cancer. 2005 Oct 15;104(8):1721-5.
Casali PG, Bielack S, Abecassis N, Aro HT, Bauer S, Biagini R, ESMO Guidelines 
Committee, PaedCan and ERN EURACAN, et al. Bone sarcomas: ESMO-PaedCan-
EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 
2018 Oct 1;29(Suppl 4):iv79-iv95.
Cancer Therapy Evaluation Program, Common Terminology Criteria for Adverse Events 
(CTCAE) version 5.0 [published 27 November 2017. Available from:  
https://ctep.cancer.gov/protocoldevelopment/.../ctcae_v5_quick_reference_5x7.pdf.
Chou AJ, Merola PR, Wexler LH, Gorlick RG, Vyas YM, Healey JH, et al. Treatment of 
osteosarcoma at first recurrence after contemporary therapy: the Memorial Sloan-Kettering 
Cancer Center experience. Cancer. 2005 Nov 15;104(10):2214-21.
Cole TJ., Bellizzi MC., Flegal KM, Dietz WH: Establishing a standard definition for child 
overweight and obesity worldwide: international survey. BMJ. 2000;320:1240.
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.
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New 
response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J 
Cancer. 2009;45(2):228-47.
ESMO/European Sarcoma Network Working Group. Bone sarcomas: ESMO Clinical 
Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2014;25(3):113–23.
Ferrari S, Briccoli A, Mercuri M, Bertoni F, Picci P, Tienghi A, et al. Postrelapse survival in 
osteosarcoma of the extremities: Prognostic factors for long-term survival. J Clin Oncol. 
2003;21(4):710-5.
Ferrari S, Serra M. An update on chemotherapy for osteosarcoma. Expert Opin 
Pharmacother. 2015;16(18):2727-36.
Gaspar N, Casanova M, Bautista Sirvent FJ, Venkatramani R, Morland B, Gambart M, et al. 
Single agent expansion cohort of lenvatinib (LEN) and combination dose-finding cohort of 
LEN + etoposide (ETP) + ifosfamide (IFM) in patients (pts) aged 2 to ≤ 25 years with 
relapsed/refractory osteosarcoma (OS). Poster presented at the International Society for 
Paediatric Oncology (SIOP); 2018 Nov 16–19; Kyoto, Japan.
Page 240 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 93 of 121
Gaspar N, Bautista Sirvent FJ, Venkatramani R, Longhi L, Lervat C, Casanova M, et al.  
Phase 1 combination dose-finding/phase 2 expansion cohorts of lenvatinib + etoposide + 
ifosfamide in patients (pts) aged 2 to ≤25 years with relapsed/refractory (r/r) osteosarcoma. 
Poster presented at the: European Society for Medical Oncology (ESMO) meeting; 
September 27 to October 1, 2019; Barcelona, Spain 2019.
Gorlick R, Khanna C. Osteosarcoma. J Bone and Mineral Research. 2010;25(4): 683–691.
Guinard FX. Sensory and consumer testing with children. Trends Food Sci Technol
2001;11:273–83.
Hawkins DS, Arndt CA. Pattern of disease recurrence and prognostic factors in patients with 
osteosarcoma treated with contemporary chemotherapy. Cancer. 2003 Dec 1;98(11):2447-56.
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.
Howlader N, Noone AM, Krapcho M, Miller D, Brest A, Yu M, Ruhl J, Tatalovich Z, 
Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA (eds). SEER Cancer Statistics 
Review, 1975-2016, National Cancer Institute. Bethesda, MD. Available from: 
https://seer.cancer.gov/csr/1975_2016/, based on November 2018 SEER data submission, 
posted to the SEER web site, April 2019.
Isakoff MS, Bielack SS, Meltzer P, Gorlick R. Osteosarcoma: Current treatment and a 
collaborative pathway to success. J Clin Oncol. 2015;33(27):3029-35.
Kaatsch P. Epidemiology of childhood cancer. Cancer Treat Rev. 2010;36(4):277-85.
Kato Y, Tabata K, Kimura T, Yachie-Kinoshita A, Ozawa Y, Yamada K, et al. Lenvatinib 
plus anti-PD-1 antibody combination treatment activates CD8+ T cells through reduction of 
tumor-associated macrophage and activation of the interferon pathway. PLoS ONE. 
2019;14(2):e0212513.
Kempf-Bielack B, Bielack SS, Jürgens H, Branscheid D, Berdel WE, Exner GU, et al. 
Osteosarcoma relapse after combined modality therapy: an analysis of unselected patients in 
the Cooperative Osteosarcoma Study Group (COSS). J Clin Oncol. 2005;23(3):559-68.
Kimura T, Kato Y, Ozawa Y, et al. Immunomodulatory activity of lenvatinib contributes to
antitumor activity in the Hepa1-6 hepatocellular carcinoma model. Cancer Sci. 
2018;109:3993–4002.
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.
Page 241 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 94 of 121
Leary SE, Wozniak AW, Billups CA, Wu J, McPherson V, Neel MD, et al. Survival of 
pediatric patients after relapsed osteosarcoma: the St. Jude Children's Research Hospital 
experience. Cancer. 2013;119(14):2645-53.
Le Vu B, de Vathaire F, Shamsaldin A, Hawkins MM, Grimaud E, Hardiman C, Diallo I, 
Vassal G, Bessa E, Campbell S, Panis X, Daly-Schveitzer N, Lagrange JL, Zucker JM, 
Eschwège F, Chavaudra J, Lemerle J. Radiation dose, chemotherapy and risk of 
osteosarcoma after solid tumours during childhood. Int. J. Cancer. 1998;77:370–377.
Meazza C, Scanagatta P. Metastatic osteosarcoma: a challenging multidisciplinary treatment. 
Expert Rev Anticancer Ther. 2016 May;16(5):543-56. 
Mirabello L, Troisi RJ, Savage SA: Osteosarcoma incidence and survival rates from 1973 to 
2004: data from the Surveillance, Epidemiology, and End Results Program. Cancer. 
2009;115(7):1531-43.
Morris NM, Udry JR. Validation of a self-administered instrument to assess stage of 
adolescent development. J Youth Adolesc. 1980;9(3):271-80.
NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) Bone Cancer. 
Version 1.2020 – August 12, 2019.  
Ogden CL, Flegal KM, Carroll MD, Johnson CL. Prevalence and trends in overweight 
among US children and adolescents, 1999-2000. JAMA. 2002;288:1728–32.
O'Toole DM, Golden AM. Evaluating cancer patients for rehabilitation potential. West J 
Med. 1991;155:384-7.
Schwartz GJ, Gauthier B. A simple estimate of glomerular filtration rate in adolescent boys. J 
Pediatr. 1985 Mar;106(3):522-6.
Tuettenberg J, Friedel C, Vajkoczy P. Angiogenesis in malignant glioma--a target for 
antitumor therapy? Crit Rev Oncol Hematol. 2006;59(3):181-93.
Ward E, DeSantis C, Robbins A, Kohler B, Jemal A. Childhood and adolescent cancer 
statistics. 2014. Cancer J Clin. 2014 Mar-Apr;64(2):83-103.
Page 242 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 95 of 121
10 PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE 
PROCEDURES)
10.1
Changes to the Protocol
Any change to the protocol requires a written protocol amendment or administrative change 
that must be approved by the sponsor before implementation.  Amendments specifically 
affecting the safety of subjects, the scope of the investigation, or the scientific quality of the 
study require submission to health or regulatory authorities as well as additional approval by 
the applicable IRBs/IECs.  These requirements should in no way prevent any immediate 
action from being taken by the investigator, or by the sponsor, in the interest of preserving 
the safety of all subjects included in the study.  If the investigator determines that an 
immediate change to or deviation from the protocol is necessary for safety reasons to 
eliminate an immediate hazard to the subjects, the sponsor’s medical monitor and the 
IRB/IEC for the site must be notified immediately.  The sponsor must notify the health or 
regulatory authority as required per local regulations.
Protocol amendments that affect only administrative aspects of the study may not require 
submission to health or regulatory authority or the IRB/IEC, but the health or regulatory 
authority and IRB/IEC (or if regionally required, the head of the medical institution) should 
be kept informed of such changes as required by local regulations.  In these cases, the 
sponsor may be required to send a letter to the IRB/IEC and the Competent Authorities (or, if 
regionally required, the head of the medical institution) detailing such changes.
10.2
Adherence to the Protocol
The investigator will conduct the study in strict accordance with the protocol (refer to 
ICH E6, Section 4.5).
10.3
Monitoring Procedures
The sponsor’s/CRO’s CRA will maintain contact with the investigator and designated staff 
by telephone, letter, or email between study visits.  Monitoring visits to each site will be 
conducted by the assigned CRA as described in the monitoring plan.  The investigator (or if 
regionally required, the head of the medical institution) will allow the CRA to inspect the 
clinical, laboratory, and pharmacy facilities to assure compliance with GCP and local 
regulatory requirements.  The CRFs and subject’s corresponding original medical records 
(source documents) are to be fully available for review by the sponsor’s representatives at 
regular intervals.  These reviews verify adherence to study protocol and data accuracy in 
accordance with local regulations.  All records at the site are subject to inspection by the 
local auditing agency and to IRB/IEC review.
In accordance with ICH E6, Section 1.52, source documents include, but are not limited to,
the following:

Clinic, office, or hospital charts
Page 243 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 96 of 121

Copies or transcribed health care provider notes that have been certified for accuracy 
after production

Recorded data from automated instruments such as IVRS, 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

Electronic Patient-Reported Outcome by self-reported measures
10.4
Recording of Data
A CRF is required and must be completed for each subject by qualified and authorized 
personnel.  All data on the CRF must reflect the corresponding source document, except 
when a section of the CRF itself is used as the source document.  Any correction to entries 
made on the CRF must be documented in a valid audit trail where the correction is dated, the 
individual making the correct is identified, the reason for the change is stated, and the 
original data are not obscured.  Only data required by the protocol for the purposes of the 
study should be collected.
The investigator must sign each CRF.  The investigator will report the CRFs to the sponsor 
and retain a copy of the CRFs.
10.5
Identification of Source Data
All data to be recorded on the CRF must reflect the corresponding source documents.  
10.6
Retention of Records
The circumstances of completion or termination of the study notwithstanding, the 
investigator (or if regionally required, the head of the medical institution or the designated 
representative) is responsible for retaining all study documents, including but not limited to 
the protocol, copies of CRFs, the Investigator’s Brochure, and regulatory agency registration 
documents (eg, Form FDA 1572 for US sites), Investigator and Site Information Form (for 
non-US sites), ICFs, and IRB/IEC correspondence). The site should plan to retain study 
Page 244 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 97 of 121
documents, as directed by the sponsor, for at least 15 years following the completion of the 
study.
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.
10.7
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.
10.8
Handling of Study Drug
All study drug will be supplied to the principal investigator (or a designated pharmacist) by 
the sponsor.  Drug supplies must be kept in an appropriate secure area (eg, locked cabinet) 
and stored according to the conditions specified on the drug labels.  The investigator (or a 
designated pharmacist) must maintain an accurate record of the shipment and dispensing of 
the study drug in a drug accountability ledger, a copy of which must be given to the sponsor 
at the end of the study.  An accurate record of the date and amount of study drug dispensed to 
each subject must be available for inspection at any time.  The CRA will visit the site and 
review these documents along with all other study conduct documents at appropriate 
intervals once study drug has been received by the site.
All drug supplies are to be used only for this study and not for any other purpose.  The 
investigator (or site personnel) must not destroy any drug labels or any partly used or unused 
drug supply before approval to do so by the sponsor.  At the conclusion of the study and as 
appropriate during the study, the investigator (or a designated pharmacist) will return all used 
and unused drug containers, drug labels, and a copy of the completed drug disposition form 
to the sponsor’s CRA (or designated contractor) or, when approval is given by the sponsor, 
will destroy supplies and containers at the site.
10.9
Publication of Results
All manuscripts, abstracts, or other modes of presentation arising from the results of the 
study must be reviewed and approved in writing by the sponsor in advance of submission 
pursuant to the terms and conditions set forth in the executed Clinical Trial Agreement 
between the sponsor/CRO and the institution/investigator.  The review is aimed at protecting 
the sponsor's proprietary information existing either at the date of the commencement of the 
study or generated during the study.
Page 245 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 98 of 121
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.
10.10 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.
10.11 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.
10.12 Subject Insurance and Indemnity
The sponsor will provide insurance for any subjects participating in the study in accordance 
with all applicable laws and regulations.
Page 246 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 99 of 121
11 APPENDICES
Appendix 1
Response Evaluation Criteria in Solid Tumors 
(RECIST) 1.1
Tumor response assessments in this clinical study 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 study 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.
Page 247 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 100 of 121
Appendix 2
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.
Page 248 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 101 of 121
Appendix 3
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.
Page 249 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 102 of 121
Appendix 4
Preparation of Lenvatinib suspension
Preparation of suspension Prepare the suspension as illustrated by either method. Prepare the suspension 
with water or apple juice. The suspension should be directly injected into the mouth of the subjects and should 
not be washed down with additional fluid.  The suspension should be taken immediately after preparation.
a.
Procedure for suspension administration by syringe
 
A: Water or apple juice
B: Cap
C: Syringe (20 mL, Baxa preferred)
D: Syringe for rinse (20 mL, Baxa preferred)
Place one capsule* into a syringe. The tip port of the syringe needs 
to be closed with a cap.
* One to five capsules are allowed to be placed in a syringe.
Three (3) mL of water or apple juice is added into the syringe using 
another (new) syringe.
Insert a piston into the syringe (cylinder) about 2 cm from the end. 
Leave the syringe for not less than 10 minutes.
Page 250 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 103 of 121
After 10 minutes leaving, shake the syringe for not less than 3 
minutes to dissolve the capsule shell completely and to suspend 
granules (capsule shell needs to be dissolved. It is fine as long 
as granules are well suspended).
Remove the cap from the syringe. 
By sliding the piston, push air out from the syringe, and then 
administer the 3mL of suspension from the syringe.
Rinse step
After the administration of 3mL suspension from the syringe, 
the cap (reuse) is to be connected with the syringe.
2 mL of water or apple juice is to be taken by another (new) 
syringe.
2 mL of water or apple juice is to be poured into the syringe 
(which was used for the 3mL suspension).
Page 251 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 104 of 121
After connecting the cap (reuse), the syringe is to be shaken 
for 10 times.
After removing the cap from the syringe, push air out from the 
syringe, and then 2 mL of rinse liquid is to be administered.
Total volume of suspension to be administrated is 5 ml (=3mL for suspension + 2mL for rinse) for one to 
five capsules.
b. Procedure of suspension administering by syringe with NG 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 one capsule* into a syringe. The tip port of the syringe 
needs to be closed with a cap.
* One to five capsules are allowed to be placed in a syringe.
Page 252 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 105 of 121
The 3 mL of water or apple juice is to be poured into the syringe 
using another (new) syringe.
Insert a piston into the syringe (cylinder) about 2 cm from the 
end. 
Leave the syringe for is not less than 10 minutes.
After 10 minutes leaving, shake the syringe for not less than 3 
minutes to dissolve the capsule shell completely and to suspend 
granules (capsule shell needs to be dissolved, but it is fine as long 
as granules are well suspended).
Remove the cap from the syringe. 
By sliding the piston, push air out from the syringe.
After connecting a NG tube with the syringe, administrate the 3 
mL of suspension through the NG tube.
Page 253 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 106 of 121
Rinse step
After pouring the suspension, the NG tube is to be taken off from 
the syringe.
The cap (reuse) is connected with the syringe
Two 2 mL of water or apple juice is to be poured into the syringe 
by using another (new) syringe.
After inserting the piston to the syringe (about 2cm from the end), 
shake the syringe for 10 times.
By sliding the piston, push out air from the syringe. 
After connecting a NG tube, the 2 mL of rinse liquid is to be 
administered from the syringe through the NG tube.
Total volume of suspension to be administrated is 5 ml (=3mL 
for suspension + 2mL for rinse) for one to five capsules.
Page 254 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 107 of 121
Appendix 5
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-G000-230- Palatability Questionnaire
Page 255 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 108 of 121
(Please circle according to your experience)
Mouth Feel (how does it 
feel in your mouth?)
(Please circle according to your experience)
Overall Acceptability
Page 256 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 109 of 121
Appendix 6
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
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
Page 257 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 110 of 121
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
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/
Page 258 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 111 of 121
Appendix 7
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
11
50th
100
101
102
103
105
106
107
60
60
60
61
62
63
63
Page 259 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 112 of 121
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
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/
Page 260 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 113 of 121
Appendix 8
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
Page 261 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 114 of 121
Appendix 9
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.ht
Page 262 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 115 of 121
Appendix 10
Tanner’s Staging
Boys Tanner Stage progression scale*
Genitalia:
1= The testes, scrotum and penis are about the same size and shape as they were when you were 
a child
2= The testes and scrotum are bigger.  The skin of the scrotum has changed.  The scrotum, the 
sack holding the testes, has gotten lower.  The penis has gotten only a little bigger.
3= The penis has grown in length.  The testes and scrotum have grown and dropped lower.
4= The penis has gotten even bigger.  It is sider.  The glans (the head of the penis) is bigger.  The 
scrotum is darker than before. It is bigger because the testes are bigger.
5= The penis, scrotum, and testes are the size and shape of an adult man.
Pubic Hair:
1= There is no pubic hair at all.
2= There is a little soft, long, lightly-colored hair. Most of the hair is at the base of the penis.
This hair may be straight or a little curly.
3= The hair is darker in this stage. It is more curled. It has spread out and thinly covers a bigger 
area.
4= the hair is now as dark, curly, and course as that of an adult man.  The area that the hair 
covers is not as big as that of an adult man.  The hair has NOT spread out to the legs.
5= The hair has spread out to the legs.  The hair is now like that of an adult man. It covers the 
same area as that of an adult man.
Girls Tanner Stage progression scale
Breast:
1= The nipple is raised a little. The rest of the breast is still flat.
2= This is the breast bud stage.  In this stage, the nipple is raised more than in stage 1.  The 
breast is a small mound.  The areola is larger than stage 1.
3= The breast and areola are both larger than in stage 2.  The areola does not stick out away from 
the breast.
Page 263 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 116 of 121
4= The areola and the nipple make up a mound that sticks up above the shape of the breast.  
NOTE:  This stage may not happen at all for some girls.  Some girls develop from stage 3 to 
stage 5 with no stage 4
5= This is the mature adult stage.  The breasts are fully developed. Only the nipple sticks out in 
this stage.  The areola has moved back in the general shape of the breast.
Pubic Hair:
1= There is no pubic hair at all.
2= There is a little soft, long lightly-colored hair.  This hair may be straight or a little curly.
3= The hair is darker in this stage. It is coarser more curled. It has spread out and thinly covers 
a bigger area.
4= the hair is now as dark, curly, and course as that of an adult female. The area that the hair 
covers is not as big as that of an adult female. The hair has NOT spread out to the legs.
5= The hair is now like that of an adult female. It covers the same area as that of an adult 
female. The hair usually forms a triangular (V) pattern as it spreads out to the legs.
*Adapted from: Morris, N.M., and Udry, J.R., (1980).  Validation of a Self-Administered Instrument to Assess 
Stage of Adolescent Development. Journal of Youth and Adolescence, Vol. 9, No. 3: 271-80.
Page 264 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 117 of 121
Appendix 11
Pharmacodynamic, and Other Biomarker Research
Subjects enrolled in this clinical study will have biologic samples collected for 
pharmacodynamic (PD), 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.
Collection of the PD, and other biomarker samples will be bound by the sample principles and 
processes outlined in the main study protocol.  Sample collection for PD, 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.
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 
Page 265 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 118 of 121
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 study 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.
Given the research nature of the PD, 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, 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 
Page 266 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 119 of 121
should only occur when data have been validated by multiple studies and testing has been done 
in CLIA-approved laboratories.
Page 267 of 388


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 120 of 121
PROTOCOL SIGNATURE PAGE
Study Protocol Number:
E7080-G000-230
Study Protocol Title:
A Multicenter, Open-label, Randomized Phase 2 Study to 
Compare the Efficacy and Safety of Lenvatinib in Combination 
with Ifosfamide and Etoposide versus Ifosfamide and Etoposide 
in Children, Adolescents and Young Adults with Relapsed or 
Refractory Osteosarcoma (OLIE)
Investigational Product 
Name:
E7080/Lenvatinib 
IND Number:
146642
EudraCT Number:
2019-003696-19
SIGNATURES
Authors:
Oncology Business Group, Eisai Inc.  
Date
Oncology Business Group, Eisai Inc.  
Date
Oncology Business Group, Eisai Inc.
Date
Page 268 of 388
PPD
PPD
PPD
PPD


Clinical Study Protocol
incorporating Amendment 01
E7080-G000-230
Eisai
FINAL: 09 Mar 2020
Confidential
Page 121 of 121
INVESTIGATOR SIGNATURE PAGE
Study Protocol Number:
E7080-G000-230
Study Protocol Title:
A Multicenter, Open-label, Randomized Phase 2 Study to 
Compare the Efficacy and Safety of Lenvatinib in Combination 
with Ifosfamide and Etoposide versus Ifosfamide and Etoposide 
in Children, Adolescents and Young Adults with Relapsed or 
Refractory Osteosarcoma (OLIE)
Investigational Product
Name:
E7080/Lenvatinib 
IND Number:
146642
EudraCT Number:
2019-003696-19
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
.
Page 269 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 1 of 119
TITLE PAGE
Clinical Study Protocol
Study Protocol 
Number:
E7080-G000-230
Study Protocol 
Title:
A Multicenter, Open-label, Randomized Phase 2 Study to Compare 
the Efficacy and Safety of Lenvatinib in Combination with Ifosfamide 
and Etoposide versus Ifosfamide and Etoposide in Children,
Adolescents and Young Adults with Relapsed or Refractory 
Osteosarcoma (OLIE)
Sponsor:
Eisai Inc.
155 Tice Boulevard
Woodcliff Lake, 
New Jersey 07677
US
Eisai Ltd. 
European Knowledge 
Centre
Mosquito Way 
Hatfield, Hertfordshire 
AL10 9SN UK
Eisai Co., Ltd. 
4-6-10 Koishikawa
Bunkyo-Ku, 
Tokyo 112 8088
JP
Sponsor’s 
Investigational 
Product Name:
E7080/Lenvatinib
Indication:
Osteosarcoma
Phase:
2
Approval Date:
Original Protocol
08 Oct 2019
IND Number:
146642
EudraCT Number:
2019-003696-19
GCP Statement:
This study is to be performed in full compliance with International 
Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) and all applicable local Good 
Clinical Practice (GCP) and regulations.  All required study 
documentation will be archived as required by regulatory authorities.
Confidentiality 
Statement:
This document is confidential.  It contains proprietary information of 
Eisai (the sponsor).  Any viewing or disclosure of such information 
that is not authorized in writing by the sponsor is strictly prohibited.  
Such information may be used solely for the purpose of reviewing or 
performing this study.
Page 270 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 2 of 119
1
CLINICAL PROTOCOL SYNOPSIS
Compound No.  E7080
Name of Active Ingredient:  Lenvatinib
Study Protocol Title
A Multicenter, Open-label, Randomized Phase 2 Study to Compare the Efficacy and Safety of 
Lenvatinib in Combination with Ifosfamide and Etoposide versus Ifosfamide and Etoposide in 
Children, Adolescents and Young Adults with Relapsed or Refractory Osteosarcoma (OLIE)
Investigator
Principal Investigator:  Dr Nathalie Gaspar
Sites
Approximately 70 sites worldwide 
Study Period and Phase of Development
Approximately 36 months
Phase 2
Objectives
Primary Objective
To evaluate whether lenvatinib in combination with ifosfamide and etoposide (Arm A) is superior to 
ifosfamide and etoposide (Arm B) in improving progression-free survival (PFS) rate at 4 months
(PFS-4m) (by independent imaging review [IIR] using Response Evaluation Criteria In Solid Tumors
[RECIST 1.1]), in children, adolescents, and young adults with relapsed or refractory osteosarcoma.
Secondary Objectives
The secondary objectives of the study are to:
1.
Compare differences in PFS rate at 1 year (PFS-1y) between the 2 treatment arms 
2.
Compare differences in PFS Kaplan-Meier (K-M) survival curves and median PFS between the 
2 treatment arms
3.
Compare differences in overall survival (OS) and OS rate at 1 year (OS-1y) between the 
2 treatment arms
4.
Compare differences in objective response rate (ORR) at 4 months between the 2 treatment arms
5.
Compare differences in safety and tolerability between the 2 treatment arms
6.
Characterize the pharmacokinetics (PK) of lenvatinib, when administered in combination with 
ifosfamide and etoposide 
7.
Compare differences in health-related quality of life (HRQoL) as assessed by using the the 
Pediatric Quality of Life Inventory (PedsQL) Generic Core Scales and Cancer Module between
the 2 treatment arms
8.
Assess the palatability and acceptability of the suspension formulation of lenvatinib in pediatric 
subjects receiving the suspension formulation in the study
Exploratory Objectives
The exploratory objectives of the study are to: 
1.
Explore differences in duration of response (DOR), disease control rate (DCR), and clinical 
benefit rate (CBR) between the 2 treatment arms
Page 271 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 3 of 119
2.
Compare the proportion of subjects who achieve complete removal of baseline lesion(s) 
following completion of chemotherapy between the 2 treatment arms
3.
Investigate the relationship between subject tumor biomarkers and clinical response and toxicity 
of lenvatinib in combination with ifosfamide and etoposide
Study Design
E7080-G000-230 is a multicenter, randomized, open-label, parallel-group, Phase 2 study to compare 
the efficacy and safety of lenvatinib in combination with ifosfamide and etoposide versus ifosfamide 
and etoposide in children, adolescents, and young adults with relapsed or refractory osteosarcoma.  
Approximately 72 eligible subjects will be randomized to 1 of the following 2 treatment arms in a 1:1 
ratio within the strata:

Arm A:  lenvatinib 14 mg/m2 (orally, once daily) plus ifosfamide 3000 mg/m2/day (intravenously 
[IV], Day 1 to Day 3 of each cycle for a total of up to 5 cycles) and etoposide 100 mg/m2/day 
(IV, Day 1 to Day 3 of each cycle for a total of up to 5 cycles)

Arm B:  ifosfamide 3000 mg/m2/day (IV, Day 1 to Day 3 of each cycle for a total of up to 
5 cycles) and etoposide 100 mg/m2/day (IV, Day 1 to Day 3 of each cycle for a total of up to 5 
cycles)
Randomization will follow a predefined randomization scheme based on the following stratification 
factors: time to first relapse/refractory disease (early [<18 months] or late [≥18 months]) and age 
(<18 and ≥18 years).  
Eisai will closely monitor enrolment, to ensure that at least 32 subjects <18 years of age at the time of 
informed consent are randomized.  
The study will be conducted in 3 Phases: a Prerandomization Phase, a Randomization Phase, and an 
Extension Phase.  
The Prerandomization Phase will consist of 2 periods: Screening and Baseline. The 
Prerandomization Phase will last no longer than 28 days. The Screening Period will establish 
protocol eligibility and the Baseline Period will confirm eligibility. 
The Randomization Phase will consist of 2 periods: Treatment Period and Follow-up Period. The 
Randomization Phase will begin at the time of randomization of the first subject and will end on the 
data cutoff date for the PFS-1y and OS-1y analysis.  After the data cutoff date for the PFS-1y and 
OS-1y has occurred, all subjects who are still on study treatment will enter the Extension Phase. 
Data cutoff (for PFS-1y and OS-1y analysis) will occur when the last subject has completed 
18 cycles of treatment or discontinues before the end of Cycle 18, whichever occurs first. 
The Treatment Period for each subject will begin at the time of randomization and will end at the 
completion of the Off-Treatment Visit which will occur within 30 days after the final dose of study 
treatment  
Subjects will receive study treatment as continuous 21-day cycles in both treatment arms. Treatment 
cycles will be counted continuously regardless of dose interruptions. If chemotherapy administration 
is precluded on Day 1 of a treatment cycle, the subject may resume treatment once recovered at the 
discretion of investigator. Subsequent chemotherapy will be administered every 21 (±1) days starting 
from the timepoint it was resumed.
Subjects will undergo safety and efficacy assessments as defined in the Schedule of 
Procedures/Assessments.  Subjects randomized to Arm A will continue to receive lenvatinib until 
disease progression (PD) confirmed by IIR, development of unacceptable toxicity, subject request, 
withdrawal of consent, or study termination by the sponsor, whichever occurs first.
Disease progression (PD) must be confirmed by IIR prior to the investigator discontinuing study 
treatment for a subject.  In situations where the investigator judges that alternative treatments must be 
Page 272 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 4 of 119
instituted immediately for a subject’s safety, study drugs may be discontinued without waiting for IIR
confirmation of radiographic evidence of PD.  If possible, before discontinuation of the subject from 
the study, the investigator should consult with the sponsor.
The Follow-up Period begins the day after the Off-Treatment Visit and will continue as long as the 
subject is alive, unless the subject withdraws consent, or the sponsor terminates the study.  
Subjects may at any time withdraw consent for further study participation.  No further data will be 
collected on subjects once consent has been withdrawn, however, an investigator may consult public 
records to establish survival status if permitted by local regulations.
All adverse events (AEs) will be captured for 30 days after the last dose of study drug.  
All subjects who discontinue study treatment early for reasons other than PD, will continue to 
undergo tumor assessments every 6 weeks until Week 18, then every 9 weeks until Week 54, 
thereafter, every 12 weeks until confirmation of disease progression by IIR as described in the tumor 
assessments in the assessment schedule, or until another anticancer therapy is initiated.
Subjects in both Arm A and Arm B will be followed for survival every 12 weeks (±1 week) and all 
subsequent anticancer treatments received will be recorded.  Subjects who are being followed for 
survival at the time of data cutoff for the for PFS-1y and OS-1y analysis (ie, at the end of the 
Randomization Phase) will continue to be followed for survival during the Follow-up Period of the 
Extension Phase.
Extension Phase:  The Extension Phase will consist of 2 periods: Treatment Period and Follow-up 
Period.  
In the Treatment Period, subjects still on lenvatinib in Arm A following the completion of the 
PFS-1y and OS-1y analysis (ie, at the end of the Randomization Phase) will continue to receive 
lenvatinib in 21-day cycles until disease progression, development of unacceptable toxicity, subject 
request, withdrawal of consent, or discontinuation of study by the sponsor.  Tumor assessments will 
be performed according to the local standard of care.  Independent imaging review (IIR) review and 
confirmation of radiographic evidence of PD will not be required, and scans will no longer be 
required to be sent to the imaging core laboratory (ICL).  The Off-Treatment Visit will occur within 
30 days after the final dose of study treatment. All AEs will be captured up to 30 days after last dose 
of study drug.  In case the study is discontinued by the sponsor, the sponsor will continue to provide 
study drug (outside the study) for subjects requiring continuation of treatment. 
The Follow-up Period will begin the day after the Off-Treatment Visit and will last until death or for 
2 years after end of treatment for a subject, unless the study is terminated by the sponsor, or the 
subject discontinues due to withdrawal of consent, or is lost to follow-up.  Subjects will be treated by 
the investigator according to the prevailing local standard of care. Subjects will be followed every 
12 weeks (±1week) for survival and all subsequent anticancer treatments received will be recorded.   
The definition of end of the study, as required by certain regulatory agencies, will be the date of data 
cutoff for the final analysis or the time of last subject last visit, whichever occurs later.
Number of Subjects
Approximately 72 subjects will be randomised (36 subjects in each arm).
For the primary endpoint (intent–to-treat analysis), at least 32 subjects 18 years old (at the time of 
informed consent) will be randomized.
Inclusion Criteria
1.
Histologically or cytologically confirmed diagnosis of high grade osteosarcoma.
2.
Refractory or relapsed osteosarcoma after 1 to 2 prior systemic treatments. 
3.
Measurable or evaluable disease per RECIST 1.1 that meets the following criteria:
Page 273 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 5 of 119
-
Must be accurately measurable with a minimum size (by long axis) of 10 mm using 
computed tomography/magnetic resonance imaging (CT/MRI) (lymph nodes must be 
accurately measurable with a minimum size [by short axis] of 15 mm). 
-
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.
Aged 2 years to ≤25 years at the time of informed consent.
5.
Life expectancy of 12 weeks or more.
6.
Lansky play score ≥50% or Karnofsky Performance Status score ≥50%.  Use Karnofsky for 
subjects ≥16 years of age and Lansky for subjects <16 years of age.  Subjects who are unable to 
walk because of paralysis, but who are up in wheelchair, will be considered ambulatory for the 
purpose of assessing the performance score.
7.
Adequate bone marrow function as evidenced by:
a.
absolute neutrophil count (ANC) ≥1.0×109/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 of <8.0 g/dL is acceptable if it is corrected by growth 
factor or transfusion before Cycle 1 Day 1).
c.
platelet count ≥75×109/L.
8.
Adequate blood coagulation function defined by International Normalized ratio (INR) ≤1.5 
unless participant is receiving anticoagulant therapy, as long as INR is within therapeutic range 
of intended use of anticoagulants.
9.
Adequate liver function as evidenced by:
a.
bilirubin ≤1.5 times the upper limit of normal (ULN).
b.
Alanine aminotransferase (ALT), and aspartate aminotransferase (AST) ≤3×ULN (in the case 
of liver metastases ≤5×ULN).
10. 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.
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 
Page 274 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 6 of 119
Common Terminology Criteria for Adverse Events (CTCAE) v5.0 and if possible perform a 
24-hour urine collection (children and adolescents ≤12 years of age must have ≤500 mg of 
protein/24 hours and subjects >12 years of age must have ≤1 g of protein/24 hours).
c.
No clinical evidence of nephrotic syndrome. 
11. Adequate cardiac function as evidenced by left ventricular ejection fraction ≥50% at baseline as 
determined by echocardiography.
12. 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 guidelines) and no change in antihypertensive medications within 1 week 
prior to Cycle 1 Day 1. Subjects >18 years of age should have BP ≤150/90 mm Hg at 
screening and no change in antihypertensive therapy within 1 week prior to Cycle 1 Day 1.
13. Washout before Cycle 1 Day 1 of 3 weeks in case of prior chemotherapy, 6 weeks if treatment 
included nitrosoureas; 4 weeks for definitive radiotherapy, 2 weeks for palliative radiotherapy; 
and 3 months from high-dose chemotherapy and stem cell rescue.  Subjects must have recovered 
(to Grade ≤1, except for alopecia, ototoxicity, and Grade ≤2 peripheral neuropathy, per CTCAE 
v5.0) from the acute toxic effects of all prior anticancer therapy before Cycle 1 Day 1.
14. 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.
15. Willing and able to comply with the protocol, scheduled follow-up, and management of toxicity 
as judged by the investigator.
Exclusion Criteria
1. Any active infection or infectious illness unless fully recovered  prior to Cycle 1 Day 1 (ie, no 
longer requiring systemic treatment).
2. Subjects with central nervous system metastases are not eligible, unless they have completed 
local therapy (eg, whole brain radiation therapy, surgery, or radiosurgery) and have discontinued 
the use of corticosteroids for this indication for at least 2 weeks before Cycle 1 Day 1.  
3. Active second malignancy within 2 years prior to enrollment ([in addition to osteosarcoma], but 
not including definitively treated superficial melanoma, carcinoma-in-situ, basal or squamous 
cell carcinoma of the skin).
4. Any medical or other condition that in the opinion of the investigator(s) would preclude the 
subject’s participation in a clinical study.  
5. Has had major surgery within 3 weeks prior to Cycle 1 Day 1. Note: Adequate wound healing 
after major surgery must be assessed clinically, independent of time elapsed for eligibility.
6. Known hypersensitivity to any component(s) of the study drugs (lenvatinib, ifosfamide, and 
etoposide, or their ingredients).
7. Currently receiving any investigational drug or device in another clinical study or within 28 days 
prior to Cycle 1 Day 1.
8. A clinically significant ECG abnormality, including a marked baseline prolonged QT or QTc 
interval (eg, a repeated demonstration of a QTc interval >480 msec).
9. Gastrointestinal malabsorption, gastrointestinal anastomosis, or any other condition that in the 
opinion of the investigator might affect the absorption of lenvatinib.
10. Pre-existing Grade ≥3 gastrointestinal or non-gastrointestinal fistula.
11. Gastrointestinal bleeding or active hemoptysis (bright red blood of at least ½ teaspoon) within 
Page 275 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 7 of 119
3 weeks prior to Cycle 1 Day 1.
12. Radiographic evidence of intratumoral cavitation, encasement, or invasion of a major blood 
vessel. Additionally, the degree of proximity to major blood vessels should be considered for 
exclusion because of the potential risk of severe hemorrhage associated with tumor 
shrinkage/necrosis after lenvatinib therapy.
13. History of ifosfamide-related Grade ≥3 nephrotoxicity or encephalopathy.
14. Evidence of clinically significant disease (eg, cardiac, respiratory, gastrointestinal, renal disease) 
that in the opinion of the investigator(s) could affect the subject’s safety or interfere with the 
study assessments.
15. Known to be human immunodeficiency virus (HIV) positive.  Note:  HIV testing is required at 
screening only when mandated by local health authority.
16. Active viral hepatitis (B or C) as demonstrated by positive serology.  Note:  Testing for Hepatitis 
B or Hepatitis C is required at screening only when mandated by local health authority.
17. 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.
18. Females of childbearing potential* who:
-
Do not agree to use a highly effective method of contraception for the entire study period and 
for 28 days after lenvatinib discontinuation or 12 months after etoposide and ifosfamide 
discontinuation, ie:
◦
total abstinence (if it is their preferred and usual lifestyle)
◦
an intrauterine device (IUD) or intrauterine hormone-releasing system (IUS)
◦
a contraceptive implant
◦
an oral contraceptive.  Subject must be on a stable dose of the same oral contraceptive 
product for at least 28 days before dosing with study drug and throughout the study and 
for 28 days after lenvatinib discontinuation or 12 months after etoposide and ifosfamide 
discontinuation
OR
-
Do not have a vasectomized partner with confirmed azoospermia.
For sites outside of the EU, it is permissible that if a highly effective method of contraception is 
not appropriate or acceptable to the subject, or the subject has changed oral hormonal 
contraceptive product/dose within 4 weeks prior to study drug administration, 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. 
* All post pubertal females will be considered to be of childbearing potential unless they have 
early menopause (amenorrheic for at least 12 consecutive months, in the appropriate age group, 
and without other known or suspected cause) or have been sterilized surgically (ie, bilateral tubal 
ligation, total hysterectomy, or bilateral oophorectomy, all with surgery at least 1 month before 
dosing), or are pre-menarcheal (Tanner Stage 1-3).
19. Males who have not had a successful vasectomy (confirmed azoospermia) or if they and their 
female partners do not meet the criteria above (ie, not of childbearing potential or practicing 
highly effective contraception throughout the study period and for 28 days after lenvatinib 
discontinuation or 6 months after discontinuation of etoposide and ifosfamide).  No sperm 
Page 276 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 8 of 119
donation is allowed during the study period and for 28 days after lenvatinib discontinuation or 
6 months after discontinuation of etoposide and ifsofamide.  
Study Treatments
Body surface area (BSA) will be used to determine the amount of study drugs administered, and must 
be calculated on Day 1 of each cycle based on the subject’s current height and body weight. The 
dose should be rounded to the nearest whole number. 
Test Arm (Arm A): Lenvatinib + Ifosfamide + Etoposide
Lenvatinib 14 mg/m2, orally administered once daily in each 21-day cycle.
Lenvatinib is provided as hard capsules containing 1 mg, 4 mg, or 10 mg lenvatinib. An 
extemporaneous suspension of lenvatinib capsules should be used for subjects unable to swallow 
capsules. After adjustment for BSA, the daily dose cannot exceed 24 mg QD.
Ifosfamide 3000 mg/m2/day, IV, for 3 consecutive days (Day 1 to 3), every 21 days, for a maximum 
of 5 cycles.
Etoposide 100 mg/m2/day, IV, for 3 consecutive days (Day 1 to 3) , every 21 days, for a maximum of 
5 cycles. 
Treatment with lenvatinib will continue in 21-day cycles after chemotherapy is discontinued, until 
disease progression, development of unacceptable toxicity, subject request, withdrawal of consent, or 
discontinuation of study by the sponsor.
In case the study is discontinued by the sponsor, the sponsor will continue to provide study drug 
(outside the study) for subjects requiring continuation of treatment.
Control Arm (Arm B):  Ifosfamide + Etoposide
Ifosfamide 3000 mg/m2/day, IV, daily for 3 consecutive days (Day 1 to 3), every 21 days, for a 
maximum of 5 cycles.
Etoposide 100 mg/m2/day, IV, daily for 3 consecutive days (Day 1 to 3), every 21 days, for a 
maximum of 5 cycles.
Duration of Treatment
A subject will remain on study treatment until 1 or more of the following events occur(s):

Progressive disease (as confirmed by IIR)

Unacceptable toxicity

Subject request

Withdrawal of consent 

Termination of the study by the Sponsor
Concomitant Drug/Therapy
Prohibited Concomitant Therapies and Drugs
Subjects should not receive other antitumor therapies while on study. If a subject receives additional 
antitumor therapies other than the study drug(s), such as chemotherapy, targeted therapies, 
immunotherapy, or antitumor interventions - such as surgery or palliative radiotherapy (other than as 
described below), this will be judged to represent evidence of disease progression, and continuation 
of the study medication and further participation in the study must be discussed and agreed upon with 
the sponsor.  
For further information on the prohibited concomitant therapies for ifosfamide and etoposide, please 
refer to the respective prescribing information.
Granulocyte-colony stimulating factor (G-CSF) may be used to mitigate the toxicity of ifosfamide 
Page 277 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 9 of 119
and etoposide.
The following concomitant treatments/procedures are allowed:
a.
Removal of existing (not new) osteosarcoma lesion (eg, surgical, radiofrequency ablation,
cryotherapy, thermoablation, stereotaxic ratiotherapy, etc.) after completion of the Week 18 
tumor assessment.  Subjects in Arm A in the presence of clinical benefit, may continue treatment 
with lenvatinib after protocol permissible surgery.
b.
Palliative radiotherapy is allowed for ≤2 significantly symptomatic nontarget lesions. 
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.
Any additional procedural or subject specific particularities should be discussed with the sponsor.  
Assessments
Efficacy Assessments
Tumor assessment will be performed based on RECIST 1.1. Investigator–determined response 
assessments will be performed at each assessment time point and entered onto the case report form 
(CRF). Copies of all tumor assessment scans will be sent to an imaging core laboratory (ICL)
designated by the sponsor for efficacy assessment and for confirmation of PD.  Tumor assessments 
will be carried out following the guidelines provided by the ICL.  
During the Screening Period, 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 Cycle 1
Day 1.  A brain scan (CT scan with contrast or MRI pre- and post-gadolinium) will be performed at 
screening as clinically indicated, and thereafter during the study as clinically indicated.  Historical 
CT or MRI scans performed within 28 days prior to Cycle 1 Day 1 may be used as screening scans 
(baseline scans) to demonstrate eligibility, as long as they meet minimum standards as separately 
defined by the ICL.  
Tumor assessments will then be performed every 6 weeks ±1 week following the start of treatment 
on Cycle 1 Day 1 during the chemotherapy treatment period until Week 18.  Following completion of 
the chemotherapy treatment period (ie, after Week 18), the frequency of tumor assessments will be 
every 9 weeks ±1 week until Week 54 ±1 week.  Thereafter, they will be performed every 12 weeks 
±2 weeks until documentation of PD (please see schedule of assessments for details).  At any point, 
the CT/MRI scan should be performed earlier than the scheduled time point, if clinically indicated.  
After data cutoff for PFS-1y and OS-1y analysis, tumor assessments should be performed following 
the prevailing local standard of care.
Disease progression per RECIST 1.1 during the randomization phase must be confirmed by IIR prior 
to the investigator discontinuing study treatment.
In the event that the investigator considers alternative treatments must be instituted immediately for 
management of urgent medical complications of PD, study drugs may be discontinued without 
waiting for independent confirmation of radiographic evidence of PD.  Subjects who discontinue 
study treatment without PD will continue to undergo tumor assessments according to the schedule 
until PD is documented or another anticancer therapy is initiated. 
Pharmacokinetic Assessments
Blood samples for plasma concentrations of lenvatinib will be collected from all subjects from 
Page 278 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 10 of 119
Arm A only as described in the Schedule of Assessments.
Pharmacodynamic and Other Biomarker Assessments
Pharmacodynamic serum and archived fixed tumor tissue samples for biomarker analysis will be 
collected from subjects randomized to Arm A only, as described in the Schedule of Assessments.  
Pharmacodynamic serum and tumor biomarkers assessed in this study will be based on those
identified in other lenvatinib clinical studies.  Pharmacodynamic biomarker analysis will be 
performed as described in a separate analysis plan. 
Safety Assessments
Safety assessments will consist of monitoring and recording all adverse events (AEs), including all 
grades per National Cancer Institute (NCI) CTCAE v5.0 (for both increasing and decreasing 
severity), and serious adverse events (SAEs); regular laboratory evaluation for hematology, blood 
chemistry, and urine values; periodic measurement of vital signs and ECGs; and physical 
examinations.
Progression of osteosarcoma and signs and symptoms clearly related to the progression of the 
osteosarcoma should not be captured as an AE.  Disease progression is a study endpoint and should 
be captured in the CRF as per the guidelines for reporting disease progression.
Other Assessments
HRQoL assessment will be performed per the Schedule of Assessments.  Impact of treatment on 
HRQoL will be assessed using the PedsQL (including the Generic Core Scales and Cancer Module).  
Bioanalytical Methods
Lenvatinib in plasma will be quantified using a validated liquid chromatography tandem mass
spectrometry (LC-MS/MS) method.  Pharmacodynamic biomarker analysis will be performed as 
described in a separate analysis plan.  Clinical laboratory tests will be performed at qualified local 
laboratories.
Statistical Methods
Primary Endpoint

PFS-4m rate (progression-free survival rate at 4 months) by IIR is defined as the percentage 
of subjects who are alive and without PD at 4 months from the randomization date as determined 
by IIR of radiological imaging using RECIST 1.1.  The PFS-4m rate is estimated on the full 
analysis set for this study using the K-M method.  
Secondary Endpoints

PFS-1y rate (progression-free survival rate at 1 year) by IIR is defined as the percentage of 
subjects who are alive and without PD at 1 year from the randomization date as determined by 
IIR of radiological imaging using RECIST 1.1.  The PFS-1y rate is estimated on the full analysis 
set for this study using the K-M method.  

Progression-free survival (PFS) by IIR is defined as the time from the date of randomization to 
the date of the first documentation of PD or death (whichever occurs first) as determined by IIR 
using RECIST 1.1.  

Overall survival (OS) is defined as the time from the date of randomization to 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 alive, or date of data cutoff, 
whichever occurs first.  Overall survival rate at 1 year will be estimated.

Objective response rate (ORR) by IIR at 4 months is defined as the proportion of subjects who 
have best overall response of complete response (CR) or partial response (PR) as determined by 
IIR using RECIST 1.1 within the first 4 months.
Page 279 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 11 of 119

Safety will be assessed summarizing the incidence of treatment-emergent adverse events 
(TEAEs) and SAEs together with all other safety parameters.  

Assessment of population-based PK parameters of lenvatinib.

Score changes from baseline for all PedsQL scales including Generic Core Scales and Cancer 
Module.  Scores will be calculated for total generic score, total cancer score, each physical 
function subscale including physical health, psychosocial health, emotional function, social 
function, school/work function in the Generic Core Scales, and each subscales in the cancer 
module.  

Palatibility and acceptability of the suspension formulation of lenvatinib in subjects receiving the 
suspension formulation in the study will be assessed using the Palatability Questionnaire (see 
Appendix 5).
Exploratory Endpoints

Duration of response (DOR) by IIR is defined as the time from the date a response was first 
documented until the date of the first documentation of PD or date of death from any case.

Disease control rate (DCR) by IIR is the proportion of subjects who have a best overall 
response of CR or PR or stable disease (SD).  In this context, stable disease is defined as stable 
disease at ≥7 weeks after randomization to be considered best overall response.

Clinical benefit rate (CBR) by IIR is the proportion of subjects who have best overall response 
of CR or PR or durable SD (duration of SD ≥23 weeks after randomization).

Proportion of subjects who achieve complete removal of baseline lesions following completion 
of chemotherapy.

Blood and tumor biomarkers will be assessed for identifying potential correlation with clinical 
outcomes-related endpoints.

All efficacy endpoints listed above (except OS) evaluated based on investigator 
assessment using RECIST 1.1.
Analysis Sets
The Full Analysis Set (Intent-to-Treat Analysis [ITT]) includes all randomized subjects regardless
of the treatment actually received. This is the primary analysis population used for the efficacy 
analyses which will be based on the ITT principle.
The Per Protocol Analysis Set includes those subjects from the ITT set who received at least 1 dose 
of any study drug, had no major protocol deviations and had both baseline and at least one 
postbaseline tumor assessment. Subjects for whom death occurred prior to the first postbaseline 
tumor assessment will also be included. The per protocol analysis set will be the secondary analysis 
set for efficacy endpoints.
The Safety Analysis Set includes subjects who received at least 1 dose of any study drug. This is 
the analysis population used for all safety analyses which will be based on as-treated principle.
Population Pharmacokinetic (PK) Analysis Set includes the subjects who have received at least 1
dose of lenvatinib with documented dosing history and have measurable plasma levels of lenvatinib.
The Pharmacodynamic Analysis Set includes subjects who received at least 1 dose of study drug 
and had sufficient pharmacodynamic data (eg, at least 1 evaluable/measurable pharmacodynamic
parameter).
The HRQoL Analysis Set will consist of all randomized subjects who have received at least 1 dose 
of study medication, and have completed at least 1 patient-reported outcome (PRO) assessment 
beyond baseline.  For PRO analysis, subjects will be analyzed as randomized and not according to 
treatment actually received.
Page 280 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 12 of 119
Efficacy Analyses
Efficacy analyses will be based primarily on the Full Analysis Set.
All the statistical analysis will be conducted at the PFS-1y/OS-1y analysis data cutoff date (ie, 
when the last subject has completed 18 cycles of treatment or discontinues before the end of 
Cycle 18, whichever occurs first), including the analysis of PFS-4m rate.  Additional follow-up 
analysis will be based on the date of data cutoff for the additional follow-up analysis for OS or at the 
time of last subject last visit, whichever occurs later.  
Primary Analysis
The primary analysis of PFS-4m rate will be based upon data provided by IIR of tumor assessments.  
PFS-4m rate and their Greenwood standard errors will be evaluated using the K-M estimates from 
both treatment groups.  The statistical significance of the difference in the 2 K-M PFS-4m rates 
comparing lenvatinib + chemotherapy agent (Test Arm) vs. chemotherapy agent alone (Control Arm) 
will be tested using a 2-sided 80% CI. This 2-sided 80% CI and a p-value will be constructed using 
the difference of these 2 K-M PFS-4m rates and the 2 corresponding Greenwood standard errors. 
Statistical significance of the difference is declared if the CI is entirely above 0. This is equivalent to 
a test using a 1-sided test at alpha=0.1. The 2-sided 95% CIs will also be provided for descriptive 
purposes. PFS-4m rate will also be analyzed using a binomial approach as a sensitivity analysis by 
excluding subjects whose PFS are censored prior to 18 weeks.
Secondary Analyses
PFS-1y rate will be analyzed using the same methods as the primary efficacy analysis. PFS 
censoring rules will follow FDA guidance of 2007, however, removal of baseline lesions after 
completion of Week 18 without progression is not a trigger for PFS censoring after 18 weeks (refer to 
Concomitant Drug/Therapy – allowed concomitant treatment/procedures).
Overall survival (OS) will be compared between treatment arm and control arm using the stratified 
logrank test with time to first relapse/refractory disease (early [<18 months] or late [≥18 months]) 
and age (<18 or ≥18 years) as strata.  Median OS with 2-sided 80% and 95% CIs will be calculated 
using K-M product-limit estimates for each treatment arm, and the K-M estimates of OS will be 
plotted over time. The Cox regression model will be used to estimate the hazard ratio and its 80% 
and 95% CIs stratified by time to first relapse/refractory disease (early [<18 months] or late 
[≥18 months]) and age (<18 or ≥18 years).  K-M estimates will also be presented for 4, 6, 9, and 
12 months with 2-sided 80% and 95% CIs.
Median PFS and 2-sided 80% and 95% (as exploratory) CIs will be presented, and the K-M estimates 
of PFS will be plotted over time. The Cox regression model will be used to estimate the hazard ratio 
and its 80% and 95% CIs stratified by time to first relapse/refractory disease (early [<18 months] or 
late [≥18 months]) and age (<18 or ≥18 years).  Kaplan-Meier (K-M) estimates will also be presented 
for 4, 6, 9, and 12 months with 2-sided 80% and 95% CIs.
The ORR will be compared between the test and control groups using either a chi-square test or a 
Cochran-Mantel-Haenszel test stratified by time to first relapse/refractory disease (early 
[<18 months] or late [≥18 months]) and age (<18 or ≥18 years), as appropriate.  Corresponding odds 
ratios and their 2-sided 80% and 95% CIs comparing the groups will also be presented.  The 
individual treatment group ORRs will also be calculated along with exact 95% confidence intervals 
using the Clopper and Pearson method.
Exploratory Analyses
Median DOR among responders for each arm will be presented along with its corresponding 2-sided 
95% CIs. Disease Control Rate (DCR) and CBR will be calculated with exact 95% CIs using the 
Clopper and Pearson method. The differences of the above rates between 2 groups and 
corresponding two-sided 95% CIs will be calculated respectively.
Page 281 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 13 of 119
Pharmacodynamic and Other Biomarker Analyses
Pharmacodynamic, and other biomarker analyses may be performed and reported separately.  Details 
of these analyses may be described in a separate analysis plan.
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. 
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.
Data obtained from the pharmacodynamic samples will be used for research.  The pharmacodynamic
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 informed consent forms (ICFs) to continue on the study.
Pharmacokinetic Analyses
Lenvatinib concentration versus time data will be tabulated and summarized and graphically 
presented.
Lenvatinib data from Arm A of the study will be pooled with available data from other studies and 
subjected to population PK analysis.  The PK model will be parameterized in terms of clearance and 
volume of distribution. Details of the population PK analysis will be provided in a separate analysis 
plan. 
Other Analyses
Health-Related Quality of Life (HRQoL):
The PedsQL for all subjects(self- and proxy-rating) will be collected at baseline, at C2D1, C3D1, 
Week 18, C8D1, C18 D1, and at the Off-Treatment visit.
Interim Analyses
No interim analysis is planned for this study.
The safety monitoring will be conducted by the independent data monitoring committee (IDMC).
The frequency of safety reviews will be defined in the IDMC charter. Minutes from the open 
meetings of the IDMC will be provided if requested by regulatory agencies. The recommendation 
whether to stop the study for safety will be reached by the IDMC based on their review of safety data 
with treatment information. The function and membership of the IDMC will be described in the 
IDMC charter.
Sample Size Rationale
A binomial-based comparison of 2 proportions using correction for continuity was used for sample 
size estimation.  A total sample size of 72 subjects is estimated to achieve 80% statistical power at 
1-sided alpha of 0.1 to detect a difference of 30% based on the assumption that PFS-4m for Arm A 
(lenvatinib arm) is 55% and for Arm B is 25%.  Alpha is the type 1 error probability of declaring 
lenvatinib arm being effective when the true lenvatinib arm PFS-4m rate is only 25%. 
Page 282 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 14 of 119
2
TABLE OF CONTENTS
TITLE PAGE........................................................................................................................1
1
CLINICAL PROTOCOL SYNOPSIS............................................................................2
2
TABLE OF CONTENTS.............................................................................................14
3
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................20
4
ETHICS.......................................................................................................................23
4.1
Institutional Review Boards/Independent Ethics Committees.............................23
4.2
Ethical Conduct of the Study..............................................................................23
4.3
Subject Information and Informed Consent ........................................................24
5
INVESTIGATORS AND STUDY PERSONNEL .......................................................25
6
INTRODUCTION.......................................................................................................25
6.1
Osteosarcoma.....................................................................................................25
6.2
Current Therapeutic Options ..............................................................................26
6.3
Lenvatinib..........................................................................................................27
6.3.1
Clinical Data on Lenvatinib in Combination with Ifosfamide and 
Etoposide for Treatment of Relapsed or Refractory Osteosarcoma............28
6.4
Study Rationale..................................................................................................29
7
STUDY OBJECTIVES................................................................................................29
7.1
Primary Objective ..............................................................................................29
7.2
Secondary Objectives.........................................................................................29
7.3
Exploratory Objective(s)....................................................................................30
8
INVESTIGATIONAL PLAN ......................................................................................30
8.1
Overall Study Design and Plan...........................................................................30
8.1.1
Prerandomization Phase ...........................................................................31
8.1.1.1
Screening Period...............................................................................31
8.1.1.2
Baseline Period.................................................................................32
8.1.2
Randomization Phase ...............................................................................32
8.1.2.1
Treatment Period ..............................................................................32
8.1.2.2
Follow-Up Period .............................................................................33
8.1.3
Extension Phase .......................................................................................33
8.1.3.1
Treatment Period ..............................................................................33
8.1.3.2
Follow-Up Period .............................................................................34
8.2
Discussion of Study Design, Including Choice of Control Groups......................34
8.3
Selection of Study Population ............................................................................35
8.3.1
Inclusion Criteria......................................................................................35
8.3.2
Exclusion Criteria.....................................................................................37
8.3.3
Removal of Subjects From Therapy or Assessment ..................................39
Page 283 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 15 of 119
8.4
Treatment(s).......................................................................................................39
8.4.1
Treatment(s) Administered.......................................................................39
8.4.1.1
Lenvatinib Dose Reduction and Interruption Instructions..................40
8.4.1.1.1
Blood Pressure............................................................................42
8.4.1.1.2
Management of Hypertension .....................................................43
8.4.1.1.3
Management of Posterior Reversible Leukoencephalopathy 
Syndrome/Reversible Posterior Leukoencephalopathy 
Syndrome ...................................................................................45
8.4.1.1.4
Management of Proteinuria.........................................................46
8.4.1.1.5
Management of Hepatotoxicity ...................................................47
8.4.1.1.6
Management of Thromboembolic Events....................................47
8.4.1.1.7
Management of Hypocalcemia....................................................47
8.4.1.1.8
Management of Gastrointestinal Symptoms and Acute 
Abdominal Pain ..........................................................................47
8.4.1.1.9
Management of Hemorrhage.......................................................48
8.4.1.2
Management of Ifosfamide-Etoposide Associated Toxicity...............48
8.4.2
Identity of Investigational Product(s)........................................................49
8.4.2.1
Chemical Name of E7080.................................................................49
8.4.2.2
Comparator Drug..............................................................................50
8.4.2.3
Labeling for Study Drug ...................................................................50
8.4.2.4
Storage Conditions ...........................................................................50
8.4.3
Method of Assigning Subjects to Treatment Groups.................................51
8.4.4
Selection of Doses in the Study ................................................................51
8.4.5
Selection and Timing of Dose for Each Subject........................................52
8.4.6
Blinding ...................................................................................................52
8.4.7
Prior and Concomitant Therapy................................................................52
8.4.7.1
Drug-Drug Interactions.....................................................................52
8.4.7.2
Prohibited Concomitant Therapies and Drugs ...................................53
8.4.7.3
Permitted Concomitant Treatment/Procedures ..................................53
8.4.8
Treatment Compliance .............................................................................54
8.4.9
Drug Supplies and Accountability ............................................................54
8.5
Study Assessments.............................................................................................55
8.5.1
Assessments .............................................................................................55
8.5.1.1
Screening/Baseline Assessments.......................................................55
8.5.1.1.1
Demography ...............................................................................55
8.5.1.1.2
Baseline Assessments .................................................................55
8.5.1.1.3
Medical History ..........................................................................56
8.5.1.2
Efficacy Assessments .......................................................................56
Page 284 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 16 of 119
8.5.1.2.1
Tumor Response Assessments.....................................................56
8.5.1.2.2
Palatability and Acceptability of Lenvatinib Suspension 
Formulation ................................................................................58
8.5.1.3
Pharmacokinetic, Pharmacodynamic, and Other Biomarker 
Assessments .....................................................................................58
8.5.1.3.1
Pharmacokinetic Assessments.....................................................58
8.5.1.3.2
Pharmacodynamic and Other Biomarker Assessments ................59
8.5.1.4
Safety Assessments...........................................................................59
8.5.1.4.1
Adverse Events...........................................................................60
8.5.1.4.2
Serious Adverse Events and Events Associated with Special 
Situations....................................................................................61
8.5.1.4.3
Laboratory Measurements...........................................................62
8.5.1.4.4
Vital Signs and Weight Measurements........................................64
8.5.1.4.5
Physical Examinations ................................................................64
8.5.1.4.6
Electrocardiograms .....................................................................64
8.5.1.4.7
Other Safety Assessments ...........................................................65
8.5.1.5
Other Assessments............................................................................65
8.5.2
Schedule of Procedures/Assessments........................................................65
8.5.2.1
Schedule of Procedures/Assessments................................................65
8.5.2.2
Description of Procedures/Assessments Schedule .............................76
8.5.3
Appropriateness of Measurements............................................................76
8.5.4
Reporting of Serious Adverse Events, Pregnancy, and Events 
Associated with Special Situations ...........................................................76
8.5.4.1
Reporting of Serious Adverse Events................................................76
8.5.4.2
Reporting of Pregnancy and Exposure to Study Drug Through 
Breastfeeding....................................................................................77
8.5.4.3
Reporting of Events Associated with Special Situations....................77
8.5.4.3.1
Reporting of Adverse Events Associated With Study Drug 
Overdose, Misuse, Abuse, or Medication Error...........................77
8.5.4.3.2
Reporting of Abnormal Hepatic Tests of Clinical Interest ...........78
8.5.4.4
Expedited Reporting .........................................................................78
8.5.4.5
Breaking the Blind............................................................................79
8.5.4.6
Regulatory Reporting of Adverse Events ..........................................79
8.5.5
Completion/Discontinuation of Subjects...................................................79
8.5.6
Abuse or Diversion of Study Drug............................................................79
8.5.7
Confirmation of Medical Care by Another Physician................................80
8.6
Data Quality Assurance......................................................................................80
8.6.1
Data Collection.........................................................................................80
8.6.2
Clinical Data Management .......................................................................80
Page 285 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 17 of 119
8.7
Statistical Methods.............................................................................................80
8.7.1
Statistical and Analytical Plans.................................................................81
8.7.1.1
Study Endpoints................................................................................81
8.7.1.1.1
Primary Endpoint........................................................................81
8.7.1.1.2
Secondary Endpoints...................................................................81
8.7.1.1.3
Exploratory Endpoints ................................................................82
8.7.1.2
Definitions of Analysis Sets..............................................................82
8.7.1.3
Subject Disposition...........................................................................83
8.7.1.4
Demographic and Other Baseline Characteristics..............................83
8.7.1.5
Prior and Concomitant Therapy ........................................................83
8.7.1.6
Efficacy Analyses.............................................................................83
8.7.1.6.1
Primary Efficacy Analysis...........................................................83
8.7.1.6.2
Secondary Efficacy Analyses......................................................84
8.7.1.6.3
Exploratory Efficacy Analyses....................................................84
8.7.1.7
Pharmacokinetic, Pharmacodynamic, and Other Biomarker 
Analyses...........................................................................................85
8.7.1.7.1
Pharmacokinetic Analyses ..........................................................85
8.7.1.7.2
Pharmacodynamic and Other Biomarker Analyses......................85
8.7.1.8
Safety Analyses ................................................................................85
8.7.1.8.1
Extent of Exposure......................................................................86
8.7.1.8.2
Adverse Events...........................................................................86
8.7.1.8.3
Laboratory Values.......................................................................87
8.7.1.8.4
Vital Signs ..................................................................................87
8.7.1.8.5
Electrocardiograms .....................................................................88
8.7.1.8.6
Other Safety Analyses.................................................................88
8.7.1.9
Other Analyses .................................................................................88
8.7.1.9.1
Health-Related Quality of Life....................................................88
8.7.1.9.2
Palatability and Acceptability Questionnaire ...............................88
8.7.2
Determination of Sample Size ..................................................................89
8.7.3
Interim Analysis.......................................................................................89
8.7.4
Other Statistical/Analytical Issues ............................................................89
8.7.5
Procedure for Revising the Statistical Analysis Plan.................................89
9
REFERENCE LIST.....................................................................................................90
10
PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE PROCEDURES).......93
10.1
Changes to the Protocol......................................................................................93
10.2
Adherence to the Protocol..................................................................................93
10.3
Monitoring Procedures.......................................................................................93
10.4
Recording of Data..............................................................................................94
Page 286 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 18 of 119
10.5
Identification of Source Data..............................................................................94
10.6
Retention of Records..........................................................................................94
10.7
Auditing Procedures and Inspection ...................................................................95
10.8
Handling of Study Drug .....................................................................................95
10.9
Publication of Results ........................................................................................95
10.10 Disclosure and Confidentiality ...........................................................................96
10.11 Discontinuation of Study....................................................................................96
10.12 Subject Insurance and Indemnity........................................................................96
11
APPENDICES.............................................................................................................97
LIST OF IN-TEXT TABLES
Table 1
Criteria for Temporary Discontinuation of Study Drug, Dose 
Reduction, and Resumption of Treatment ...............................................42
Table 2
Criteria for Dose Modification of Chemotherapy Dose...........................49
Table 3
Lenvatinib Pharmacokinetic Sampling Time Points................................59
Table 4
Clinical Laboratory Tests........................................................................63
Table 5
Schedule of Assessments in study E7080-G000-230 – Randomization 
Phase......................................................................................................67
Table 6
Schedule of Assessments in study E7080-G000-230 – Extension Phase..73
LIST OF IN-TEXT FIGURES
Figure 1
Overall Study Design..............................................................................31
Figure 2
Management of Hypertension.................................................................45
LIST OF APPENDICES
Appendix 1
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 .................97
Appendix 2
Lansky Score..........................................................................................98
Appendix 3
Karnofsky Performance Status Scale Definitions Rating (%) Criteria .....99
Appendix 4
Preparation of Lenvatinib suspension ...................................................100
Appendix 5
Palatability Questionnaire.....................................................................105
Appendix 6
Blood Pressure Levels for Boys by Age and Height Percentile .............107
Appendix 7
Blood Pressure Levels for Girls by Age and Height Percentile..............109
Appendix 8
Body Mass Index-For-Age Percentiles..................................................111
Appendix 9
Body Mass Index-For-Age Percentiles..................................................112
Appendix 10
Tanner’s Staging ..................................................................................113
Page 287 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 19 of 119
Appendix 11
Pharmacodynamic, and Other Biomarker Research...............................115
Page 288 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 20 of 119
3
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
ANC
absolute neutrophil count
β-hCG
beta-human chorionic gonadotropin
BP
blood pressure
BSA
body surface area
CA
Competent Authorities
CBR
clinical benefit rate
CFR
Code of Federal Regulations
Cmax
maximum drug or metabolite concentration
CR
complete response
CRA
clinical research associate
CRF
case report form
CRO
contract research organization
CT
computerized tomography
CTCAE
Common Terminology Criteria for Adverse Events
CYP/CYP3A4
Cytochrome P450/cytochrome P4503A4
DCR
disease control rate
DOR
duration of response
DTC
differentiated thyroid cancer
ESMO
European Society for Medical Oncology
FGFR
fibroblast growth factor receptor
FGF
fibroblast growth factor
GFR
glomerular filtration rate 
G-CSF
granulocyte-colony stimulating factor
HRQoL
health-related quality of life 
HR
heart rate
ICF
informed consent form
Page 289 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 21 of 119
ICH
International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use
ICL
imaging core laboratory 
ID
identification
IDMC
independent data monitoring committee 
IEC
Independent Ethics Committee
IIR
independent imaging review 
IRB
Institutional Review Board
ITT
intent-to-treat
IV
intravenously
IVRS
interactive voice response system
KDR
kinase insert domain receptor
K-M
Kaplan-Meier
LVEF
left ventricular ejection fraction
MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
ORR
objective response rate
OS
overall survival
OS-1y
overall survival rate at 1 year
PD
progressive disease/disease progression
PDGFR
platelet-derived growth factor receptor
PedsQL
Pediatric Quality of Life Inventory 
PFS
progression-free survival
PFS-4m
progression-free survival rate at 4 months
PFS-1y
progression-free survival rate at 1 year
PK
pharmacokinetic(s)
PR
partial  response
PRES 
posterior reversible leukoencephalopathy syndrome 
PT
preferred term
QD
once daily
Page 290 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 22 of 119
QTc
QT interval corrected for heart rate
RECIST
Response Evaluation Criteria in Solid Tumors
RET
rearranged during transfection
RP2D
recommended Phase 2 dose 
RPLS
reversible posterior leukoencephalopathy syndrome
RTK
receptor tyrosine kinase
RTKI
receptor tyrosine kinase inhibitor
SAE
serious adverse event
SAP
statistical analysis plan 
SD
stable disease
SmPC
summary of product characteristics
SOC
system organ class
SOP
standard operating procedure
SUSARs
suspected unexpected serious adverse reactions
TEAEs
treatment-emergent adverse events
TKI
tyrosine kinase inhibitors
TNM
tumor-node metastasis
TSH
thyroid stimulating hormone
ULN
upper limit of normal
UPCR
urine protein-to-creatinine ratio 
VEGF
vascular endothelial growth factor 
VEGFR
vascular endothelial growth factor receptor
WHO DD
World Health Organization Drug Dictionary
Page 291 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 23 of 119
4
ETHICS
4.1
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 the International Council 
for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (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(s) [CRAs], 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.
Documented study approval from the IRB/IEC chairman must be sent to the principal 
investigator (or if regionally required, the head of the medical institution) 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 (or if regionally required, the head of the medical institution) 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 of the end of the study is the date of the data cutoff for 
the final analysis or last subject/last visit, including discontinuation from the study for any 
reason, whichever occurs later.
In the case of early termination/temporary halt of the study, the investigator should notify the 
IRB/IEC and CA within 15 calendar days, and a detailed written explanation of the reasons 
for the termination/halt should be given.
4.2
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:
Page 292 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 24 of 119

Principles of the World Medical Association Declaration of Helsinki 2013

ICH E6 Guideline for GCP (CPMP/ICH/135/95) of the European Agency for the 
Evaluation of Medicinal Products, Committee for Proprietary Medicinal Products, 
International Council for Harmonisation of Technical Requirements for Pharmaceuticals 
for Human Use

Title 21 of the United States Code of Federal Regulations (US 21 CFR) regarding clinical 
studies, including Part 50 and Part 56 concerning informed subject consent and IRB 
regulations and applicable sections of US 21 CFR Part 312

An IRB waiver request will be submitted before study initiation for non-US sites 
conducted under an Investigational New Drug (IND) application.

European Good Clinical Practice Directive 2005/28/EC and Clinical Trial Directive 
2001/20/EC for studies conducted within any EU country.  All suspected unexpected 
serious adverse reactions (SUSARs) will be reported, as required, to the Competent 
Authorities of all involved EU member states.

Other applicable regulatory authorities’ requirements or directives
4.3
Subject Information and Informed Consent
As part of administering the informed consent document, the investigator must explain to 
each subject or guardian, in accordance with applicable professional standards and local 
laws/regulations or legally acceptable 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 should be given by means of a standard written statement, written in 
nontechnical language.  The subject or the subject’s legally acceptable representative should 
understand the statement before signing and dating it and will be given a copy of the signed 
document.  If a subject is unable to read or if a legally acceptable representative is unable to 
read, an impartial witness should be present during the entire informed consent discussion.  
In countries where specific laws for children are established for informed consent, those local 
laws will be applied.  After the ICF and/or assent form and any other written information to 
be provided to subjects is read and explained to the subject or the subject’s 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 and/or assent form, 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 ICF and/or assent form before any study-
Page 293 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 25 of 119
specific procedures are performed.  No subject can enter the study before his/her informed 
consent has been obtained.
An unsigned copy of an IRB/IEC-approved ICF 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).  Each subject and the 
subject’s parent(s) or legally acceptable representative must sign an approved ICF before 
study participation.  The form must be signed and dated by the appropriate parties.  The 
original, signed ICF for each subject will be verified by the sponsor and kept on file 
according to local procedures at the site.
The subject and/or the subject’s parent(s) or the subject’s legally acceptable representative 
should be informed in a timely manner if new information becomes available that may be 
relevant to the subject’s willingness to continue participation in the 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 
ICF to continue on the study.
5
INVESTIGATORS AND STUDY PERSONNEL
This study will be conducted by qualified investigators under the sponsorship of Eisai (the 
sponsor) at approximately 70 investigational sites worldwide.
The name, telephone and fax numbers of the medical monitor and other contact personnel at 
the sponsor and of the contract research organization(s) (CRO[s]) are listed in the Regulatory 
Binder provided to each site.
6
INTRODUCTION
6.1
Osteosarcoma
Cancer is a relatively uncommon diagnosis in the pediatric population, and the overall 
incidence is low (18.6 cases per 100,000 children [Howlader, et al., 2019]).  Solid tumors 
constitute approximately 60% of childhood malignancies (Howlader, et al., 2019).  
Malignant bone tumors are the fifth most common solid tumor type accounting for about 5% 
of childhood tumors (Howlader, et al., 2019; Kaatsch, 2010). 
Osteosarcoma is the most commonly diagnosed primary malignancy of the bone in children 
and young adults, and accounts for approximately 5% of childhood tumors, with an estimated
annual incidence of 4.4 cases per 1 million in people younger than 24 years (Mirabello, et al., 
2009).  Osteosarcoma occurs predominantly in adolescents and young adults.  The median 
age at diagnosis is 20 years, with the incidence peaking at 15 to 19 years of age (ESMO, 
guidelines, 2014).  According to the American Cancer Society, osteosarcoma in this age 
group is 8 per 1 million (Ward, et al., 2014).  
Page 294 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 26 of 119
There are both intrinsic and extrinsic factors that have been shown to contribute to the 
development of osteosarcoma. Studies have demonstrated that several genetic abnormalities, 
including the overexpression of vascular endothelial growth factor (VEGF) receptor 
(VEGFR), platelet-derived growth factor (PDGF) receptor (PDGFR), and c-fos, are
associated with the development of osteosarcoma in laboratory models as well as humans 
(Gorlick and Khanna, 2010).  However, osteosarcoma is not characterized by a single 
oncogenic driver.  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).  Extrinsic factors such as ionizing radiation, which is used for the treatment 
of childhood solid tumors, have 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).
The management of osteosarcoma is multimodal; patients not amenable to surgery or patients 
at second or third relapse have a poor prognosis.  Metastatic osteosarcoma is common (10% 
to 20%) (NCCN, Bone cancer guidelines, 2020, Casali, et al., 2018), with the most frequent 
site being the lung (>85%).  In the case of isolated lung metastases, more than a third of 
patients with a second surgical remission survive for >5 years (Casali, et al., 2018).
Approximately 25% of all patients with primary metastatic osteosarcoma and >40% of those 
who achieve a complete surgical remission may become long-term survivors (Casali, et al., 
2018) as compared with 65% to 70% of patients with localized disease (Meazza and 
Scanagatta, 2016).
About 30% to 40% of patients with localized disease and 80% of those with metastatic 
disease experience relapse (Casali, et al., 2018; NCCN, Bone cancer guidelines, 2020; 
Ferrari, 2003).  The presence of solitary metastasis, time to first relapse, and complete 
resectability of disease at first recurrence are the most significant prognostic indicators for 
improved survival.  Patients whose tumor is not amenable to surgery, or with second or third 
recurrence, or who have metastases to the bone, have a poor prognosis.  In general, despite 
second-line treatment, the prognosis of recurrent disease in osteosarcoma has remained poor, 
with long-term postrelapse survival of <20% (Casali, et al., 2018; NCCN Bone Cancer 
Guidelines, 2020).  
6.2
Current Therapeutic Options
There has been no substantial progress in the treatment of osteosarcoma since the 1980s. 
Current treatment utilizes multi-agent chemotherapy and surgical resection of all clinically 
detectable disease.  
Treatment of Newly Diagnosed Disease
Newly diagnosed osteosarcoma is typically managed with neoadjuvant chemotherapy 
followed by surgical removal of the primary tumor and all clinically evident metastatic 
disease, followed by adjuvant chemotherapy.  Surgical resection of all clinically detectable 
sites of disease is vital, regardless of number and site, as complete resection is predictive of 
Page 295 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 27 of 119
survival (Meazza and Scanagatta, 2016).  For patients with unresectable disease at multiple 
sites, experimental therapy is also considered, due to the poor prognosis for these patients. 
The most effective chemotherapy regimens include the combination of high-dose 
methotrexate, doxorubicin, and cisplatin and has become the standard treatment for 
high-grade osteosarcoma (Ferrari and Serra, 2015; Isakoff, et al., 2015; NCCN Bone Cancer 
Guidelines, 2020).
Treatment of Relapsed, Refractory, and Progressive Disease
Second-line treatment for relapsed disease consists of chemotherapy and/or surgical resection
(Casali, et al., 2018; NCCN Bone Cancer Guidelines, 2020). The role of second-line 
chemotherapy for recurrent osteosarcoma is much less well defined than that of surgery, and 
there is no accepted standard regimen (Casali, et al., 2018). For patients with resectable 
solitary metastasis to the lung, surgical resection only may be adequate. For those with 
recurrent pulmonary metastases that are resectable, surgery is advised in addition to 
neoadjuvant or adjuvant chemotherapy, regardless of the number of previous lung relapses 
and the number of secondary pulmonary lesions (Briccoli, et al., 2005). Aggressive surgical 
resection of metastases and the ability to achieve a second surgical remission have 
consistently been shown essential for long-term survival following relapse (Kempf-Bielack,
et al., 2005; Leary, et al., 2013; Bacci, et al., 2005; Chou, et al., 2005; Hawkins and Arndt, 
2003). 
As per the European Society for Medical Oncology (ESMO) guidelines for bone sarcoma, 
treatment options for recurrent osteosarcoma include ifosfamide ± etoposide ± carboplatin, 
and other active drugs (Casali, et al., 2018). Preferred regimens for second-line therapy per 
the National Comprehensive Cancer Network (NCCN) bone sarcoma guidelines include
ifosfamide (high dose) with or without etoposide, regorafenib, sorafenib, and sorafenib plus 
everolimus (NCCN Bone Cancer Guidelines, 2020).
In the event of subsequent relapse, the NCCN guidelines (NCCN Bone Cancer Guidelines,
2020) and ESMO guidelines (Casali, et al., 2018) strongly encourage participation in clinical 
studies.  Otherwise, patients with disease progression or relapse after second-line therapy are 
managed with surgical resection, palliative radiotherapy, or best supportive care.
6.3
Lenvatinib
E7080 (lenvatinib) is a potent multiple receptor tyrosine kinase (RTK) inhibitor (RTKI) that 
selectively inhibits VEGF receptors, VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 
(FLT4), in addition to other pro-angiogenic and oncogenic pathway-related RTKs, including 
fibroblast growth factor (FGF) receptor (FGFR) 1-4, PDGF receptor alpha (PDGFRα), KIT, 
and RET.  Therefore, lenvatinib exerts it’s in vivo antitumoural activity based on multiple 
mechanisms involved in and through effects related to angiogenesis (including reversion of 
resistance) and the tumor microenvironment, as well as direct inhibitory action on the tumour 
cells.  Recent studies have also demonstrated lenvatinib’s immunomodulatory activity in the 
tumor microenvironment.  This includes decreases in immunosuppressive tumor-associated 
Page 296 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 28 of 119
macrophages, activated cytotoxic T cell increases, and activation of interferon-gamma  
signaling.  These all contribute to lenvatinib’s antitumor activity in immunocompetent mice 
(Kato, et al., 2019; Kimura, et al., 2018).
6.3.1
Clinical Data on Lenvatinib in Combination with Ifosfamide and Etoposide
for Treatment of Relapsed or Refractory Osteosarcoma
The safety, tolerability and activity of single-agent lenvatinib, and lenvatinib in combination 
with chemotherapy (ifosfamide and etoposide), have been assessed in E7080-G000-207 
(Study 207), a phase 1/2, multicenter, open-label study in children, adolescents and young 
adults with solid tumors, including relapsed or refractory osteosarcoma, and
radioiodine- refractory differentiated thyroid carcinoma. The recommended phase 2 dose 
(RP2D) of lenvatinib was determined in the phase 1b portion as 14 mg/m2 orally once daily 
when given as single-agent as well as in combination with etoposide (100 mg/m2 IV once 
daily for 3 days) + ifosfamide (3000 mg/m2 IV once daily for 3 days), administered on days 1
to 3 of each 21-day cycle, for 5 cycles. Safety and efficacy is being assessed in the Phase 2 
portion of the study.
Data from Study 207 have shown that patients with osteosarcoma may benefit from treatment 
with lenvatinib. In the single agent expansion cohort in relapsed/refractory osteosarcoma,
(n=31; Cohort 2B), 9 of 28 evaluable patients (32.1%) achieved progression-free survival 
(PFS) at 4 months (PFS-4m), median PFS was 3.0 months (95% CI: 1.8, 5.5). Two out of 
29 subjects (6.9%) with measurable disease had a partial response (PR) (Gaspar, et al., 2018).  
Among the 31 subjects included in the safety analysis set for the single-agent lenvatinib 
expansion cohort, the most common adverse events were: headache (48%), vomiting (45%), 
decreased appetite, diarrhea, and hypothyroidism (42% each), proteinuria (39%), increased 
blood TSH, hypertension, nausea, pyrexia, and weight decreased (36% each).  Five subjects 
(16.1%) discontinued treatment due to TEAEs, and 8 subjects (25.8%) reported TEAEs 
leading to study drug dose reduction.  There were no treatment-related fatal TEAEs (Gaspar, 
et al., 2018).  
In a pooled analysis of subjects from Phase 1b and 2 receiving lenvatinib 14 mg/m2 in 
combination with ifosfamide plus etoposide (N=35; full analysis set), the primary efficacy 
endpoint, PFS-4 rate based on RECIST 1.1 by investigator assessment, was 67.9% (95% CI: 
47.6, 84.1). As of the data cutoff date of 23 Jul 2019, the objective response rate (ORR) was 
12.5%, including 4 subjects with PR. Median PFS was 11.1 months (95% CI: 4.5, 12.6), and 
median overall survival (OS) was 16.3 months (95% CI: 12.6, NE) (Gaspar, et al., 2019).
Overall treatment with lenvatinib in combination with ifosfamide and etoposide in this 
patient population was associated with a manageable safety profile, and no unexpected 
toxicities were observed. Among the 31 subjects included in the safety analysis set, the most 
frequent treatment-emergent adverse events (TEAEs) were anemia (71%), nausea and 
vomiting (61% each), diarrhea (52%), neutropenia, platelet count decreased, and white blood 
cell count decreased (48% each).  The most common treatment-related grade ≥3 TEAEs were 
anemia (52%), neutropenia (48%), platelet count decreased and white blood cell count 
Page 297 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 29 of 119
decreased (42% each), neutrophil count decreased (32%), and thrombocytopenia (29%).  
Eight subjects (25.8%) discontinued treatment due to TEAEs, and 15 subjects (48.4%) 
reported TEAEs leading to study drug dose reduction. There were no treatment-related fatal
TEAEs (Gaspar, et al., 2019).
6.4
Study Rationale
Study 230, a randomized, controlled Phase 2 study, will evaluate the efficacy and safety of 
lenvatinib in combination with ifosfamide and etoposide in children, adolescents, and young 
adults with relapsed or refractory osteosarcoma. Eligible patients aged 2 to 25 years old will 
receive ifosfamide and etoposide with or without lenvatinib (14 mg/m2; RP2D from 
Study 207). Subjects randomized to Arm A can continue to receive lenvatinib until disease 
progression, intolerable toxicity, or withdrawal of consent. Approximately 72 subjects will 
be treated in the study.  The primary objective of the study is to demonstrate that lenvatinib 
in combination with ifosfamide and etoposide has superior efficacy compared to ifosfamide 
and etoposide based on the PFS-4m rate in children, adolescents and young adults with 
relapsed or refractory osteosarcoma.
Pediatric solid tumors are highly vascularized.  Angiogenesis and vasculogenesis are the 
fundamental processes by which new blood vessels are formed.  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. Thus, inhibition of angiogenesis is a viable target for 
anticancer therapy.  Moreover, vascular normalisation allows reoxygenation, hence the 
addition of an anti-VEGF to chemotherapy may result in increased uptake of drugs into 
tumor tissue (Tuettenberg, et al., 2006).
7
STUDY OBJECTIVES
7.1
Primary Objective
To evaluate whether lenvatinib in combination with ifosfamide and etoposide (Arm A) is 
superior to ifosfamide and etoposide (Arm B) in improving PFS-4m rate (by independent 
imaging review [IIR] using Response Evaluation Criteria In Solid Tumors [RECIST 1.1]), in 
children, adolescents, and young adults with relapsed or refractory osteosarcoma.
7.2
Secondary Objectives
The secondary objectives of the study are to:
1. Compare differences in PFS rate at 1 year (PFS-1y) between the 2 treatment arms 
2. Compare differences in PFS Kaplan-Meier (K-M) survival curves and median PFS 
between the 2 treatment arms
3. Compare differences in OS and OS rate at 1 year (OS-1y) between the 2 treatment arms
Page 298 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 30 of 119
4. Compare differences in objective response rate (ORR) at 4 months between the 
2 treatment arms
5. Compare differences in safety and tolerability between the 2 treatment arms
6. Characterize the pharmacokinetics (PK) of lenvatinib, when administered in combination 
with ifosfamide and etoposide 
7. Compare differences in health-related quality of life (HRQoL) as assessed by using the 
the Pediatric Quality of Life Inventory (PedsQL) Generic Core Scales and Cancer 
Module between the 2 treatment arms
8. Assess the palatability and acceptability of the suspension formulation of lenvatinib in 
pediatric subjects receiving the suspension formulation in the study
7.3
Exploratory Objective(s)
The exploratory objectives of the study are to:
1. Explore differences in duration of response (DOR), disease control rate (DCR), and 
clinical benefit rate (CBR) between the 2 treatment arms
2. Compare the proportion of subjects who achieve complete removal of baseline lesion(s) 
following completion of chemotherapy between the 2 treatment arms 
3. Investigate the relationship between subject tumor biomarkers and clinical response and 
toxicity of lenvatinib in combination with ifosfamide and etoposide
8
INVESTIGATIONAL PLAN
8.1
Overall Study Design and Plan
This is a multicenter, randomized, open-label, parallel-group, Phase 2 study to compare the 
efficacy and safety of lenvatinib in combination with ifosfamide and etoposide versus 
ifosfamide and etoposide in children, adolescents, and young adults with relapsed or 
refractory osteosarcoma.
Approximately 72 eligible subjects will be randomized to 1 of the following 2 treatment arms 
in a 1:1 ratio within the strata:

Arm A:  lenvatinib 14 mg/m2 (orally, once daily) plus ifosfamide 3000 mg/m2/day 
(intravenously [IV], Day 1 to Day 3 of each cycle for a total of up to 5 cycles) and 
etoposide 100 mg/m2/day (IV, Day 1 to Day 3 of each cycle for a total of up to 5 cycles)

Arm B:  ifosfamide 3000 mg/m2/day (IV, Day 1 to Day 3 of each cycle for a total of up to 
5 cycles) and etoposide 100 mg/m2/day (IV, Day 1 to Day 3 of each cycle for a total of up 
to 5 cycles)
Randomization will follow a predefined randomization scheme based on the following 
stratification factors: time to first relapse/refractory disease (early [<18 months] or late 
[≥18 months]) and age (<18 and ≥18 years).
Eisai will closely monitor enrolment, to ensure that at least 32 subjects <18 years of age at 
the time of informed consent are randomized.  
Page 299 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 31 of 119
The study will be conducted in 3 Phases: a Pre-randomization Phase, a Randomization 
Phase, and an Extension Phase.  
The end of the study will be the date of data cutoff for the final analysis or the time of last 
subject last visit, whichever occurs later.
An overview of the study design is presented in Figure 1.
Figure 1 Overall Study Design
Follow-up can occur during the Randomization Phase (if the subject discontinued treatment during 
the Randomization Phase), or during the Extension Phase, after the termination of study treatment.
Arm A = lenvatinib+ifosfamide+ etoposide (ifosfamide+etoposide for maximum of 5 cycles; 
lenvatinib to be continued until disease progression, intolerable toxicity, subject request,
withdrawal of consent, or study termination by the sponsor, whichever occurs first.
Arm B = ifosfamide+ etoposide (maximum of 5 cycles)
R = randomization
8.1.1
Prerandomization Phase
The Prerandomization Phase will consist of 2 periods: Screening and Baseline. The 
Prerandomization Phase will last no longer than 28 days. The Screening Period will establish 
protocol eligibility and the Baseline Period will confirm eligibility.
8.1.1.1
Screening Period
Screening will occur between Day –28 and Day –2.  The purpose of the Screening Period is 
to obtain informed consent and to establish protocol eligibility.  Informed consent will be 
obtained after the study has been fully explained to each subject and before the conduct of 
any screening procedures or assessments.  Procedures to be followed when obtaining 
informed consent are detailed in Section 4.3.
Period:
Screening
Baseline
R
Arm A
Day -28 to -2
Day 1
Treatment
Follow-up
Arm B
Phase:
Treatment
Follow-up
Day -1
Randomization
Prerandomization
Randomization
Prerandomization
Extension
Page 300 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 32 of 119
Subjects must have a histologically or cytologically confirmed diagnosis of high grade 
refractory or relapsed osteosarcoma as detailed in the Inclusion Criteria (Section 8.3.1).
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.
8.1.1.2
Baseline Period
The purpose of the Baseline Period is to confirm protocol eligibility as specified in the 
inclusion/exclusion criteria (as detailed in Section 8.3.1 and Section 8.3.2).  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 4), 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 8.3.1 and Section 8.3.2) will begin the 
Randomization Phase of this study.
8.1.2
Randomization Phase
The Randomization Phase will consist of 2 periods: Treatment Period and Follow-up Period. 
The Randomization Phase will begin at the time of randomization of the first subject and will 
end on the data cutoff date for the PFS-1y and OS-1y analysis.  Data cutoff for PFS-1y and 
OS-1y analysis will occur when the last subject has completed 18 cycles of treatment or 
discontinues before the end of Cycle 18, whichever occurs first.
After the data cutoff date for the PFS-1y and OS-1y analysis has occurred, all subjects who 
are still on study treatment will enter the Extension Phase.  
8.1.2.1
Treatment Period
The Treatment Period for each subject will begin at the time of randomization and will end at 
the completion of the Off-Treatment Visit which will occur within 30 days after the final 
dose of study treatment.
Subjects will receive study treatment as continuous 21-day cycles in both treatment arms.
Treatment cycles will be counted continuously regardless of dose interruptions.  If 
chemotherapy administration is precluded on Day 1 of a treatment cycle, the subject may 
resume treatment once recovered at the discretion of investigator.  Subsequent chemotherapy 
will be administered every 21 (±1) days starting from the timepoint it was resumed.  Subjects 
will undergo safety and efficacy assessments as defined in the Schedule of 
Procedures/Assessments (Table 5).  Subjects randomized to Arm A will continue to receive
lenvatinib until disease progression (PD) confirmed by IIR, development of unacceptable 
toxicity, subject request, withdrawal of consent, or study termination by the sponsor, 
whichever occurs first.
Page 301 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 33 of 119
Disease progression (PD) must be confirmed by IIR prior to the investigator discontinuing 
study treatment for a subject.  In situations where the investigator judges that alternative 
treatments must be instituted immediately for a subject’s safety, study drugs may be 
discontinued without waiting for IIR confirmation of radiographic evidence of PD.  If 
possible, before discontinuation of the subject from the study, the investigator should consult 
with the sponsor.
8.1.2.2
Follow-Up Period
The Follow-up Period begins the day after the Off-Treatment Visit and will continue as long 
as the subject is alive, unless the subject withdraws consent or the sponsor terminates the 
study.  
Subjects may at any time withdraw consent for further study participation.  No further data 
will be collected on subjects once consent has been withdrawn, however, an investigator may 
consult public records to establish survival status if permitted by local regulations.
All adverse events (AEs) will be captured for 30 days after the last dose of study drug.  
All subjects who discontinue study treatment early for reasons other than PD, will continue 
to undergo tumor assessments every 6 weeks until Week 18, then every 9 weeks until 
Week 54, thereafter, every 12 weeks until IIR confirmation of radiographic evidence of PD 
as described in the tumor assessments in the assessment schedule, or until another anticancer 
therapy is initiated.
Subjects in both Arm A and Arm B will be followed for survival every 12 weeks (±1 week) 
and all subsequent anticancer treatments received will be recorded.  Subjects who are being 
followed for survival at the time of data cutoff for the for PFS-1y and OS-1y analysis (ie, at 
the end of the Randomization Phase) will continue to be followed for survival during the 
Follow-up Period of the Extension Phase.
8.1.3
Extension Phase
The Extension Phase will consist of 2 periods: Treatment Period and Follow-up Period.  
8.1.3.1
Treatment Period
In the Treatment Period, subjects still on lenvatinib in Arm A following the completion of the 
PFS-1y and OS-1y analysis (ie, at the end of the Randomization Phase) will continue to 
receive lenvatinib in 21-day cycles until disease progression, development of unacceptable 
toxicity, subject request, withdrawal of consent, or discontinuation of study by the sponsor.  
Tumor assessments will be performed according to the local standard of care.  Independent 
imaging review (IIR) review and confirmation of radiographic evidence of PD will not be 
required, and scans will no longer be required to sent to the imaging core laboratory (ICL).  
The Off-Treatment Visit will occur within 30 days after the final dose of study treatment. 
All AEs will be captured up to 30 days after last dose of study drug.  In case the study is 
Page 302 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 34 of 119
discontinued by the sponsor, the sponsor will continue to provide study drug (outside the 
study) for subjects requiring continuation of treatment.
8.1.3.2
Follow-Up Period
The Follow-up Period will begin the day after the Off-Treatment Visit and will last until 
death or for 2 years after end of treatment for a subject, unless the study is terminated by the 
sponsor, or the subject discontinues due to withdrawal of consent, or is lost to follow-up.  
Subjects will be treated by the investigator according to the prevailing local standard of care. 
Subjects will be followed every 12 weeks (±1week) for survival and all subsequent 
anticancer treatments received will be recorded.  
8.2
Discussion of Study Design, Including Choice of Control Groups
The study has been designed as an open-label, randomized study to compare the safety and 
efficacy of lenvatinib in combination with the ifosfamide and etoposide with ifosfamide and 
etoposide alone in children, adolescents, and young adults with relapsed or refractory 
osteosarcoma. Ifosfamide and etoposide will be used as the control group since it is a 
recognized treatment option for patients with relapsed osteosarcoma.
Progression-free survival (PFS) rate at 4 months (PFS-4m) as compared to control, with 
blinded IIR of radiological imaging using RECIST 1.1 criteria will be evaluated as the 
primary endpoint.  The endpoint was determined as appropriate for the study, given the 
unique biology of the osteosarcoma (bone lesions do not shrink) and the vital role of surgical 
resection of metastatic lesions, where possible, in the management of patients with this 
tumor.  Pulmonary metastases are most common in osteosarcoma, and the ability to achieve a 
second surgical remission has consistently been shown essential for long-term survival 
following relapse (Kempf Bielack, et al., 2005; Leary, et al., 2013; Bacci, et al., 2005; Chou,
et al., 2005; Hawkins and Arndt, 2003).  The protocol allows for surgical resection of 
baseline lesions after completion of the Week 18 tumor assessment.  This timepoint allows
for surgical resection after completion of chemotherapy without confounding data due to 
subjects undergoing surgery. To avoid bias in efficacy assessment, the analysis for primary 
endpoint is based on tumor assessment by IIR, a central independent blinded assessment. 
Progression-free survival at 1 year (PFS-1y), PFS, and OS will also be evaluated in the study
as secondary endpoints.
Pharmacodynamic serum and tumor biomarkers identified in other lenvatinib clinical studies
will be assessed in samples collected from subjects enrolled in this study in the test arm only 
(Arm A: lenvatinib + ifosfamide + etoposide) and may be used for exploratory analysis for 
evaluation of response-related and/or safety-related outcomes.
The study will also assess health related quality of life (HRQoL) using validated 
questionnaires.
Randomization will be used in this study to avoid bias in the assignment of subjects to 
treatment, to increase the likelihood that known and unknown subject attributes (eg, 
Page 303 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 35 of 119
demographics and baseline characteristics) are balanced across treatment groups, and to 
ensure the validity of statistical comparisons across treatment groups.
8.3
Selection of Study Population
Approximately 72 subjects between 2 and ≤25 years of age will be randomised (36 subjects 
in each arm). 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.
For evaluation of the primary endpoint (intent–to-treat analysis), at least 32 subjects 
18 years old (at the time of informed consent) will be randomized.
8.3.1
Inclusion Criteria
Subjects must meet all of the following criteria to be included in this study:
1. Histologically or cytologically confirmed diagnosis of high grade osteosarcoma.
2. Refractory or relapsed osteosarcoma after 1 to 2 prior systemic treatments.   
3. Measurable or evaluable disease per RECIST 1.1 that meets the following criteria:
-
Must be accurately measurable with a minimum size (by long axis) of 10 mm using 
computed tomography/magnetic resonance imaging (CT/MRI) (lymph nodes must be 
accurately measurable with a minimum size [by short axis] of 15 mm). 
-
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. Aged 2 years to ≤25 years at the time of informed consent.
5. Life expectancy of 12 weeks or more.
6. Lansky play score ≥50% or Karnofsky Performance Status score ≥50%.  Use Karnofsky 
for subjects ≥16 years of age and Lansky for subjects <16 years of age.  Subjects who are 
unable to walk because of paralysis, but who are up in a wheelchair, will be considered 
ambulatory for the purpose of assessing the performance score.
7. Adequate bone marrow function as evidenced by:
a.
absolute neutrophil count (ANC) ≥1.0×109/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 of <8.0 g/dL is acceptable if it is corrected by 
growth factor or transfusion before Cycle 1 Day 1).
c.
platelet count ≥75×109/L. 
8. Adequate blood coagulation function defined by International Normalized ratio (INR) 
≤1.5 unless participant is receiving anticoagulant therapy, as long as INR is within 
therapeutic range of intended use of anticoagulants.
9. Adequate liver function as evidenced by:
a.
bilirubin ≤1.5 times the upper limit of normal (ULN).
Page 304 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 36 of 119
b. Alanine aminotransferase (ALT), and aspartate aminotransferase (AST) ≤3×ULN (in 
the case of liver metastases ≤5×ULN).
10. 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.
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 Common Terminology Criteria for Adverse Events (CTCAE) v5.0 and 
if possible perform a 24-hour urine collection (children and adolescents ≤12 years of 
age must have ≤500 mg of protein/24 hours and subjects >12 years of age must have 
≤1 g of protein/24 hours).
c.
No clinical evidence of nephrotic syndrome. 
11. Adequate cardiac function as evidenced by left ventricular ejection fraction (LVEF)
≥50% at baseline as determined by echocardiography.
12. 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 guidelines) and no change in antihypertensive 
medications within 1 week prior to Cycle 1 Day 1.  Subjects >18 years of age should 
have BP ≤150/90 mm Hg at screening and no change in antihypertensive therapy 
within 1 week prior to Cycle 1 Day 1.
13. Washout before Cycle 1 Day 1 of 3 weeks in case of prior chemotherapy, 6 weeks if 
treatment included nitrosoureas; 4 weeks for definitive radiotherapy, 2 weeks for 
palliative radiotherapy; and 3 months from high-dose chemotherapy and stem cell rescue.  
Subjects must have recovered (to Grade ≤1, except for alopecia, ototoxicity, and Grade 
≤2 peripheral neuropathy, per CTCAE v5.0) from the acute toxic effects of all prior 
anticancer therapy before Cycle 1 Day 1.
14. 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.
Page 305 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 37 of 119
15. Willing and able to comply with the protocol, scheduled follow-up, and management of 
toxicity as judged by the investigator.
8.3.2
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 Cycle 1 Day 1
(ie, no longer requiring systemic treatment).
2. Subjects with central nervous system metastases are not eligible, unless they have 
completed local therapy (eg, whole brain radiation therapy, surgery or radiosurgery) and 
have discontinued the use of corticosteroids for this indication for at least 2 weeks before
Cycle 1 Day 1. 
3. Active second malignancy within 2 years prior to enrollment ([in addition to 
osteosarcoma], but not including definitively treated superficial melanoma, 
carcinoma-in-situ, basal or squamous cell carcinoma of the skin).
4. Any medical or other condition that in the opinion of the investigator(s) would preclude 
the subject’s participation in a clinical study. 
5. Has had major surgery within 3 weeks prior to Cycle 1 Day 1.  Note: Adequate wound 
healing after major surgery must be assessed clinically, independent of time elapsed for 
eligibility.
6. Known hypersensitivity to any component(s) of the study drugs (lenvatinib, ifosfamide,
and etoposide, or their ingredients).
7. Currently receiving any investigational drug or device in another clinical study or within 
28 days prior to Cycle 1 Day 1.
8. A clinically significant ECG abnormality, including a marked baseline prolonged QT or 
QTc interval (eg, a repeated demonstration of a QTc interval >480 msec).
9. Gastrointestinal malabsorption, gastrointestinal anastomosis, or any other condition that 
in the opinion of the investigator might affect the absorption of lenvatinib.
10. Pre-existing Grade ≥3 gastrointestinal or non-gastrointestinal fistula.
11. Gastrointestinal bleeding or active hemoptysis (bright red blood of at least ½ teaspoon) 
within 3 weeks prior to Cycle 1 Day 1.
12. Radiographic evidence of intratumoral cavitation, encasement, or invasion of a major 
blood vessel. Additionally, the degree of proximity to major blood vessels should be 
considered for exclusion because of the potential risk of severe hemorrhage associated 
with tumor shrinkage/necrosis after lenvatinib therapy.
13. History of ifosfamide-related Grade ≥3 nephrotoxicity or encephalopathy.
14. Evidence of clinically significant disease (eg, cardiac, respiratory, gastrointestinal, renal 
disease) that in the opinion of the investigator(s) could affect the subject’s safety or 
interfere with the study assessments.
15. Known to be human immunodeficiency virus (HIV) positive.  Note: HIV testing is 
required at screening only when mandated by local health authority.
Page 306 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 38 of 119
16. Active viral hepatitis (B or C) as demonstrated by positive serology.  Note: Testing for 
Hepatitis B or Hepatitis C is required at screening only when mandated by local health 
authority.
17. 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 any study drug.
18. Females of childbearing potential* who:
-
Do not agree to use a highly effective method of contraception for the entire study 
period and for 28 days after lenvatinib discontinuation or 12 months after etoposide 
and ifosfamide discontinuation, ie:
◦
total abstinence (if it is their preferred and usual lifestyle)
◦
an intrauterine device (IUD) or intrauterine hormone-releasing system (IUS)
◦
A contraceptive implant
◦
an oral contraceptive.  Subject must be on a stable dose of the same oral 
contraceptive product for at least 28 days before dosing with study drug and 
throughout the study and for 28 days after lenvatinib discontinuation or 12 months 
after etoposide and ifosfamide discontinuation .
OR
-
Do not have a vasectomized partner with confirmed azoospermia.
For sites outside of the EU, it is permissible that if a highly effective method of 
contraception is not appropriate or acceptable to the subject, or the subject has changed 
oral hormonal contraceptive product/dose within 4 weeks prior to study drug 
administration, 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. 
* All post pubertal females will be considered to be of childbearing potential unless they 
have early menopause (amenorrheic for at least 12 consecutive months, in the appropriate 
age group, and without other known or suspected cause) or have been sterilized surgically 
(ie, bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, all with surgery 
at least 1 month before dosing), or are pre-menarcheal (Tanner Stage 1-3).
19. Males who have not had a successful vasectomy (confirmed azoospermia) or if they and 
their female partners do not meet the criteria above (ie, not of childbearing potential or 
practicing highly effective contraception throughout the study period and for 28 days 
after lenvatinib discontinuation or 6 months after discontinuation of etoposide and 
ifosfamide). No sperm donation is allowed during the study period and for 28 days after 
lenvatinib discontinuation or 6 months after discontinuation of etoposide and ifosfamide.
Page 307 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 39 of 119
8.3.3
Removal of Subjects From Therapy or Assessment
Subjects will continue to receive study treatment until any of the following occur:  

Progressive disease (as confirmed by IIR)

Unacceptable toxicity

Subject request

Withdrawal of consent 

Termination of the study by the Sponsor
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 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.
During the Follow-Up Period, subjects who have discontinued study treatment without 
progression should have disease assessments as per the appropriate tumor assessment 
schedule in Table 5 and Table 6 from the date of the last assessment until PD is documented 
or another anticancer therapy is initiated.  After data cutoff of PFS-1y and OS-1y, tumor 
assessments may be performed as clinically indicated per institutional guidelines, following 
the prevailing local standard of care, and IIR confirmation of radiographic evidence of PD
will not be required.
All subjects will be followed for survival until death or for 2 years after end of treatment for 
a subject, except where a subject withdraws consent or the sponsor chooses to halt survival 
follow-up after completion of the primary study analysis.
8.4
Treatment(s)
8.4.1
Treatment(s) Administered
Lenvatinib will be provided by Eisai as hard capsules containing 1, 4, or 10 mg lenvatinib. A 
extemporaneous suspension of lenvatinib capsules should be used for subjects unable to 
swallow capsules, as detailed in Appendix 4.
Test Arm (Arm A): Lenvatinib + Ifosfamide + Etoposide
Lenvatinib 14 mg/m2, orally administered once daily in each 21-day cycle.
Lenvatinib is provided as hard capsules containing 1 mg, 4 mg, or 10 mg lenvatinib. An 
extemporaneous suspension of lenvatinib capsules should be used for subjects unable to 
Page 308 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 40 of 119
swallow capsules. After adjustment for body surface area (BSA), the daily dose can not 
exceed 24 mg QD.
Ifosfamide 3000 mg/m2/day, IV, for 3 consecutive days (Day 1 to 3), every 21 days, for a 
maximum of 5 cycles.
Etoposide 100 mg/m2/day, IV, for 3 consecutive days (Day 1 to 3) , every 21 days, for a 
maximum of 5 cycles. 
Treatment with lenvatinib will continue in 21-day cycles after chemotherapy is discontinued, 
until disease progression, development of unacceptable toxicity, subject request, withdrawal 
of consent, or discontinuation of study by the sponsor.  In case the study is discontinued by 
the sponsor, the sponsor will continue to provide study drug (outside the study) for subjects 
requiring continuation of treatment.
Control Arm (Arm B):  Ifosfamide + Etoposide
Ifosfamide 3000 mg/m2/day, IV, daily for 3 consecutive days (Day 1 to 3), every 21 days, for 
a maximum of 5 cycles.
Etoposide 100 mg/m2/day, IV, daily for 3 consecutive days (Day 1 to 3), every 21 days, for a 
maximum of 5 cycles.
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) × body surface area (BSA) (m2) = lenvatinib dose (mg)
Body surface area (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.
Subjects will receive study treatment as continuous 21-day cycles in both treatment arms. 
Treatment cycles will be counted continuously regardless of dose interruptions.  If 
chemotherapy administration is precluded on Day 1 of a treatment cycle, the subject may 
resume treatment once recovered at the discretion of investigator.  Subsequent chemotherapy 
will be administered every 21 (±1) days starting from the timepoint it was resumed.
8.4.1.1
Lenvatinib Dose Reduction and Interruption Instructions
Adverse events will be graded using CTCAE version 5.0.
Dose reduction and interruptions for subjects who experience lenvatinib related toxicity will 
be managed as described in Table 1.  
Page 309 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 41 of 119
The starting dose of lenvatinib is 14 mg/m2. 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 study drug dose level has been reduced, it may not be increased at a later date, 
unless the dose was mistakenly decreased; in this situation, the sponsor’s approval is required 
to increase the dose.
Refer to the subsections below for management of hypertension, posterior reversible 
encephalopathy syndrome/reversible posterior leukoencephalopathy syndrome 
(PRES/RPLS), proteinuria, hepatotoxicity, thromboembolic events, hypocalcemia,
gastrointestinal symptoms and acute abdominal pain, and hemorrhage, as appropriate, before 
consulting the dose modification table below.
Page 310 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 42 of 119
Table 1
Criteria for Temporary Discontinuation of Study Drug, Dose 
Reduction, and Resumption of Treatment
Dose Modification Guidelines for Lenvatinib Related Toxicity
Treatment-Related Toxicitya,b
Management
Dose Adjustment
Grade 1 or Tolerable Grade 2
Continue treatment
No change
Intolerable Grade 2c, dor Grade 3e
First occurrence
Interrupt lenvatinib until 
resolved to Grade 0-1, or 
tolerable Grade 2
11.2 mg/m2 (or 20% 
reduction of the starting 
dose) orally QD (one-level 
reduction)
Second occurrence
(same toxicity or new toxicity)
Interrupt lenvatinib until 
resolved to Grade 0-1, or 
tolerable Grade 2
9.0 mg/m2 (or 20% 
reduction of the previous 
dose) orally QD (one-level 
reduction)
Third occurrence
(same toxicity or new toxicity)
Interrupt lenvatinib until 
resolved to Grade 0-1, or 
tolerable Grade 2
7.2 mg/m2 (or 20% 
reduction of the previous 
dose) orally QD (one-level 
reduction)  
Fourth occurrence
(same toxicity or new toxicity)
Interrupt lenvatinib
Discuss with sponsor
Grade 4f: Discontinue Study Treatment
Note: For grading see CTCAE version 5.0. Collect all CTC grades of adverse events, decreasing and 
increasing grade. 
BMI =  body mass index, CTCAE = Common Terminology Criteria for Adverse Events
a: An interruption of study treatment for more than 28 days will require sponsor`s approval before treatment 
can be resumed.
b: Initiate optimal medical management for nausea, vomiting, hypertension, hypothyroidism, and/or diarrhea 
prior to any study treatment interruption or dose reduction. 
c: Applicable only to Grade 2 toxicities judged by the subject and/or physician to be intolerable.
d: Obese subjects with weight loss do not need to return to the baseline weight or 10% of baseline weight (ie, 
Grade 1 weight loss).  These subjects will restart the study drug(s) at a lower dose once their weight 
remains stable for at least 1 week and they reached the normal BMI (if the weight loss occurred but it is 
still above normal BMI, they can restart the study treatment at a lower dose once the weight has been 
stable for at least 1 week).  Normal BMI should be used as the new baseline for further dose reductions.   
Obesity is defined as body mass index (BMI) percentiles corresponding to 30 kg/m², related to the age of 
the children (Cole, et al., 2000) or BMI ≥ the 95th percentile for children and teens of the same age and sex 
(Ogden, et al., 2002) (Appendix 8 and Appendix 9).   
e: For asymptomatic laboratory abnormalities, such as Grade ≥3 elevations of amylase and lipase that are not 
considered clinically relevant by the investigator, continuation of treatment should be discussed with the 
Sponsor. 
f: Excluding laboratory abnormalities judged to be non-life-threatening, in which case manage as Grade 3.
8.4.1.1.1
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 are
provided in Appendix 6 and Appendix 7.  Blood pressure that is consistently above the 95th 
percentile [for subjects age 18 to 25 years BP ≤140/90 mm Hg] for age and height/length 
Page 311 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 43 of 119
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.
8.4.1.1.2
MANAGEMENT OF HYPERTENSION
Hypertension is a recognized side-effect of treatment with drugs inhibiting VEGF signaling.
Investigators should therefore ensure that subjects enrolled to receive treatment with 
lenvatinib have BP <95th percentile [BP ≤150/90 mm Hg] for sex, age, and height/length at 
the time of study entry and, if known to be hypertensive, have been on a stable dose of 
antihypertensive therapy for at least 1 week before Cycle 1 Day 1. Early detection and 
effective management of hypertension are important to minimize the need for lenvatinib dose 
interruptions and reductions.  
Regular assessment of BP should be conducted as detailed in the Schedule of Procedures/
Assessments (Table 5 and Table 6).  Hypertension will be graded using CTCAE v5.0, based 
on BP measurements only (and not on the number of antihypertensive medications).
If the subject’s initial BP measurement is elevated (systolic BP ≥95th percentile [BP 
≥140 mm Hg] or diastolic BP ≥95th percentile [BP ≥90 mm Hg]), the BP measurement 
should be repeated at least 5 minutes later. The mean value of 2 measurements at least 
5 minutes apart is defined as 1 BP assessment. If the BP assessment (ie, the mean of the 
2 BP measurements obtained at least 5 minutes apart) is elevated (systolic BP ≥140 mm Hg 
or diastolic BP ≥90 mm Hg), a confirmatory assessment should be obtained at least 
30 minutes later by performing 2 measurements (at least 5 minutes apart) to yield a mean 
value.
Antihypertensive agents should be started as soon as elevated BP (systolic BP ≥95th 
percentile [BP ≥140 mm Hg] or diastolic BP ≥95th percentile [BP ≥90 mm Hg]) is confirmed 
on 2 assessments obtained 30 minutes apart.  The choice of antihypertensive treatment should 
be individualized to the 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 
30 minutes apart.  For those subjects already on antihypertensive medication, treatment 
modification may be necessary if hypertension persists.
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 
Page 312 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 44 of 119
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 on Day 15 
(or more frequently as clinically indicated) until systolic BP has been <95th percentile 
(≤150 mm Hg) and diastolic BP has been <95th percentile (≤95 mm Hg) for 2 consecutive 
treatment cycles.  If a repeat event of systolic BP ≥99th percentile (BP ≥160 mm Hg) or 
diastolic BP ≥99th percentile (BP ≥100 mm Hg) occurs, the 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 2 consecutive treatment cycles. 
The following guidelines should be followed for the management of systolic BP ≥99th 
percentile (BP ≥160 mm Hg) or diastolic BP ≥99th percentile (BP ≥100 mm Hg) confirmed 
on repeat measurements after at least 30 minutes: 

Continue lenvatinib and institute antihypertensive therapy for subjects not already 
receiving this. 

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%]) 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. 
-
If systolic BP ≥99th percentile (BP ≥160 mm Hg) or diastolic BP ≥99th percentile 
(BP ≥100 mm Hg) recurs on the first dose reduction despite optimal management 
of hypertension with antihypertensive medications (either by dose increase or the 
addition of a different class of antihypertensive), then lenvatinib administration 
should be interrupted and restarted at an additional dose reduction only when 
systolic BP <95th percentile (BP ≤150 mm Hg) and diastolic BP <95th percentile 
(BP ≤95 mm Hg) and the subject has been on a stable dose of antihypertensive 
medication for at least 48 hours. 
-
If systolic BP ≥99th percentile (BP ≥160 mm Hg) or diastolic BP ≥99th percentile 
(BP ≥100 mm Hg) recurs on the second dose reduction despite optimal 
management of hypertension with antihypertensive medications (either by dose 
increase or the addition of a different class of antihypertensive), then lenvatinib 
administration should be interrupted and restarted at a third dose reduction only 
when systolic BP <95th percentile (BP ≤150 mm Hg and diastolic BP <95th 
percentile (BP ≤95 mm Hg) and the participant has been on a stable dose of 
antihypertensive medication for at least 48 hours.
Page 313 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 45 of 119
-
Additional dose reduction should be discussed with the Sponsor. 
The following guidelines should be followed for the management of Grade 4 hypertension 
(life-threatening consequences): 

Institute appropriate medical management 

Discontinue lenvatinib
Figure 2 shows the procedures associated with the management of hypertension.
Figure 2
Management of Hypertension
BP = blood pressure, HTN = hypertension, Tx = treatment.
8.4.1.1.3
MANAGEMENT OF POSTERIOR REVERSIBLE LEUKOENCEPHALOPATHY 
SYNDROME/REVERSIBLE POSTERIOR LEUKOENCEPHALOPATHY SYNDROME
Posterior Reversible Leukoencephalopathy Syndrome (PRES)/Reversible Posterior 
Leukoencephalopathy Syndrome (RPLS) is a neurological disorder that can present with 
headache, seizure, lethargy, confusion, altered mental function, blindness, and other visual or 
neurological disturbances.  Mild to severe hypertension may be present.  An MRI is 
1 BP Assessment is defined as, the 
Mean value of 2 measurements at 
least 5 mins apart
BP mmHg ≥95th percentile on 2 assessments 30 mins apart
BP mmHg ≥99th percentile on
2 Assessments 30 mins apart
Continue study drug
Page 314 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 46 of 119
necessary to confirm the diagnosis of PRES/RPLS.  Appropriate measures should be taken to 
control BP (see Section 8.4.1.1.1 and 8.4.1.1.2), and neurologic consultation is advised.  In 
subjects with signs or symptoms of PRES/RPLS, dose modification guidelines as per Table 1
should be followed.
8.4.1.1.4
MANAGEMENT OF PROTEINURIA
Regular assessment for proteinuria should be conducted as detailed in the Schedule of 
Assessments (Table 5 and Table 6).  Guidelines for assessment and management of 
proteinuria are summarized as follows: 
Grading of Proteinuria

Grading according to CTCAE 5.0 (Cancer Therapy Evaluation Program, 2017) will be 
based on the protein-creatinine ratio or 24-hour urinary protein result, if available. For 
subjects ≥18 years of age, if the subject has 4+ proteinuria by dipstick, a 24-hour urinary 
protein result is required to confirm Grade 3 proteinuria.
Management of Proteinuria

Management of lenvatinib administration will be based on the grade of proteinuria 
according to Table 1.

In the event of nephrotic syndrome, lenvatinib must be discontinued.
Detection and Confirmation

Perform urine dipstick testing per the Schedule of Assessments (Table 5 and Table 6)

For subjects ≥18 years of age, a 24-hour urine collection initiated as soon as possible and
at least within 72 hours (or an immediate spot urine protein-to-creatinine ratio [UPCR]
test) AND for subjects <18 years of age, an immediate spot UPCR test, and if possible, a 
24-hour urine collection (initiated as soon as possible and at least within 72 hours) is 
required in the following situations:
-
The first (initial) occurrence of ≥2+ proteinuria on urine dipstick while on lenvatinib
-
A subsequent increase in severity of urine dipstick proteinuria occurring on the same 
lenvatinib dose level
-
When there has been a lenvatinib dose reduction and at the new dose level the urine 
protein dipstick result is ≥2+

For subjects ≥18 years of age, a 24-hour urine collection (initiated as soon as possible and 
at least within 72 hours) to verify the grade of proteinuria is required when UPCR is ≥2.4.
Monitoring

Urine dipstick testing for subjects with proteinuria ≥2+ should be performed on Day 15 
(or more frequently as clinically indicated) until the results have been 1+ or negative for 
2 consecutive treatment cycles.
Page 315 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 47 of 119

Proteinuria monitoring can be performed at the local laboratory or investigator site, but 
must be managed by the site physician.
8.4.1.1.5
MANAGEMENT OF HEPATOTOXICITY
Regular monitoring of liver function tests (ALT, AST, bilirubin levels) should be conducted 
as detailed in the Schedule of Assessments (Table 5 and Table 6) 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 1).  Appropriate 
supportive care should be provided together with close monitoring.  If hepatic failure occurs 
the study drug must be discontinued.
8.4.1.1.6
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 
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 1).  
Appropriate supportive care should be provided together with close monitoring.  If a subject 
experiences a Grade 3 or a life-threatening (Grade 4) thromboembolic reaction, including 
pulmonary embolism, study drug must be discontinued.
Arterial thromboembolic events (eg, new onset, worsening, or unstable angina, myocardial 
infarction, transient ischemic attack, and cerebrovascular accident) of any grade require study 
drug discontinuation.
8.4.1.1.7
MANAGEMENT OF HYPOCALCEMIA
Serum calcium should be monitored monthly per the Schedule of Assessments (Table 5 and 
Table 6). Corrected serum calcium should be used to assess the grade of hypocalcemia per 
CTCAE v5.0, using the following formula: 
Corrected calcium = ([4 – serum albumin in g/dL] ×0.8 + serum calcium)
The formula is not applicable when serum albumin concentration is normal (˃4 g/dL); in 
such situations, the total (uncorrected) serum calcium should be used instead.
Hypocalcemia should be treated per institutional guidelines (eg, using appropriate calcium, 
magnesium, and Vitamin D supplementation) until resolution.
8.4.1.1.8
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 
Page 316 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 48 of 119
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, follow 
instructions contained in Table 1 regarding study treatment dose reduction and interruption.  
For Grade 4 adverse events that result in abdominal pain, study drug must be discontinued.
Gastrointestinal symptoms including diarrhea should be managed by providing symptomatic 
treatment. If the symptoms persist (eg, diarrhea for more than 10 days), dose modification 
guidelines should be followed as per Table 1. 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. 
Lenvatinib should be discontinued in any subject who develops gastrointestinal perforation
of any grade or Grade ≥4 fistula.  
8.4.1.1.9
MANAGEMENT OF HEMORRHAGE
Dose modification guidelines as per Table 1 for lenvatinib related adverse events should be 
followed for the management of hemorrhage. Either resume lenvatinib at a reduced dose or 
discontinue lenvatinib, depending on the severity and persistence of hemorrhage.
8.4.1.2
Management of Ifosfamide-Etoposide Associated Toxicity
Blood counts should be closely monitored during and prior to the next cycle of 
chemotherapy. Chemotherapy-associated myelosuppression should be managed by 
granulocyte-colony stimulating factor (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 white blood cell (WBC) counts are 
≥1×109/L. Guidelines for dose modification for ifosfamide and etoposide associated 
toxicities are provided in the Table 2 below. 
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).
Page 317 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 49 of 119
Table 2
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
ANC = absolute neutrophil count, RBC = red blood cell, ULN = upper limit normal.
8.4.2
Identity of Investigational Product(s)
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 4
provides instructions for the preparation of the lenvatinib suspension.  
8.4.2.1
Chemical Name of E7080

Test drug code:  E7080

Generic name:  lenvatinib

Chemical name:  4-[3-Chloro-4-(N’-cyclopropylureido)phenoxy]-7-methoxyquinoline-6-
carboxamide methanesulfonate

Molecular formula:  C21H19CLN4O4•CH4O3S

Molecular weight: 522.96
Page 318 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 50 of 119
8.4.2.2
Comparator Drug
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 or 
sourced by the clinical sites.  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. 
Anti-emetic or any other prophylaxis should be administered in accordance with institutional 
guidelines.
8.4.2.3
Labeling for Study Drug
Lenvatinib and the combination chemotherapy drugs, ifosfamide and etoposide, where 
supplied by the sponsor will be labeled in accordance with text that is in full regulatory 
compliance with each participating country and is translated into the required language(s) for 
each of those countries.  
The following information will be provided (but not limited to):

For clinical trial use only

Name and address of the sponsor

Chemical name / drug identifier

Lot number/Batch number

Storage conditions, expiration date if necessary
8.4.2.4
Storage Conditions
Lenvatinib will be stored in accordance with the labeled storage conditions.  The expiry date 
for lenvatinib will be established based on manufacturing date and is based on formulation 
testing.  The expiry date of of the lenvatinib will either be on the label and in the interactive 
voice response system (IVRS) system.
Page 319 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 51 of 119
Ifosfamide and etoposide will be stored in accordance with the labeled storage conditions.  
The expiry date of the ifosfamide and etoposide will be the same as the commercial products 
provided.  
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.
8.4.3
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 8.3) will be
assigned to treatments based on a computer-generated randomization scheme that will be 
reviewed and approved by an independent statistician.  The randomization scheme and 
identification for each subject will be included in the final clinical study report for this study.
After the Baseline Period, subjects will be randomized to 1 of the following 2 treatment arms 
in a 1:1 ratio:

Arm A:  lenvatinib 14 mg/m2 (orally, once daily) plus ifosfamide 3000 mg/m2/day (IV, 
Day 1 to Day 3 of each cycle for a total of up to 5 cycles) and etoposide 100 mg/m2/day 
(IV, Day 1 to Day 3 of each cycle for a total of up to 5 cycles)

Arm B: ifosfamide 3000 mg/m2/day (IV, Day 1 to Day 3 of each cycle for a total of up to
5 cycles) and etoposide 100 mg/m2/day (IV, Day 1 to Day 3 of each cycle for a total of up 
to 5 cycles)
Randomization will be performed centrally by an IVRS.  Randomization will follow a 
predefined randomization scheme based on the following stratification factors: time to first 
relapse/refractory disease (early [<18 months] or late [≥18 months]) and age (<18 and 
≥18 years).  Time to first relapse/refractory disease will be calculated starting from date of 
initial diagnosis.
8.4.4
Selection of Doses in the Study
The dose of lenvatinib, ifosfamide and etoposide in this study is the RP2D (14 mg/m2 + 
ifosfamide 3000 mg/m2 + etoposide 100 mg/m2) established in Study 207. The dose of 
lenvatinib is the same as the RP2D for lenvatinib monotherapy, also established in 
Study 207.
Page 320 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 52 of 119
8.4.5
Selection and Timing of 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 21 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 drugs should be administered at the clinic on PK sampling days. All scheduled visits 
must be conducted as per protocol, irrespective of treatment interruption. 
8.4.6
Blinding
The study will not be blinded.
8.4.7
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.
Treatment of complications or AEs, or therapy 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.  Granulocyte colony-stimulating 
factor (g-CSF) or equivalent may be used in accordance with American Society of Clinical 
Oncology (ASCO), institutional, or national guidelines.  Erythropoietin may be used 
according to ASCO, institutional, or national guidelines, but the subject should be carefully 
monitored for increases in red blood cell (RBC) counts.
8.4.7.1
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.  There is no clinically meaningful drug-drug interaction (DDI) risk when lenvatinib 
is co-administered with CYP3A substrates such as midazolam.  Simultaneous CYP3A4/P-gp 
inhibitions by ketoconazole slightly (15% to 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 
Page 321 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 53 of 119
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.
8.4.7.2
Prohibited Concomitant Therapies and Drugs
Subjects should not receive other antitumor therapies while on study. If a subject receives 
additional antitumor therapies other than the study drug(s), such as chemotherapy, targeted 
therapies, immunotherapy, or antitumor interventions - such as surgery or palliative 
radiotherapy (other than as described below), this will be judged to represent evidence of 
disease progression, and continuation of the study medication and further participation in the 
study must be discussed and agreed upon with the sponsor.  
For further information on the prohibited concomitant therapies for ifosfamide and etoposide, 
please refer to the respective prescribing information.
8.4.7.3
Permitted Concomitant Treatment/Procedures
The following concomitant treatments/procedures are allowed:
a.
Removal of existing (not new) osteosarcoma lesion (eg, surgical, radiofrequency 
ablation, cryotherapy, thermoablation, stereotaxic ratiotherapy, etc.) after completion of 
the Week 18 tumor assessment.  Subjects in Arm A in the presence of clinical benefit, 
may continue treatment with lenvatinib after protocol permissible surgery.
b. Palliative radiotherapy is allowed for ≤2 significantly symptomatic nontarget lesions. 
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. 
Any additional procedural or subject specific particularities should be discussed with the 
investigator and the sponsor.
Page 322 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 54 of 119
8.4.8
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.
8.4.9
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

The IRB/IEC membership list and statutes or Health and Human Services Assurance 
number

A copy of the certification and a table of the normal laboratory ranges for the reference 
laboratory conducting the clinical laboratory tests required by this protocol

An investigator-signed and dated FDA Form FDA 1572, or a completed Investigator and 
Site Information Form

Financial Disclosure form(s) for the principal investigator (PI) and all subinvestigators 
listed on Form FDA 1572 or Investigator and Site Information Form

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 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 
Page 323 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 55 of 119
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, Medicines and Healthcare Products Regulatory Agency [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 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.
8.5
Study Assessments
8.5.1
Assessments
8.5.1.1
Screening/Baseline Assessments
8.5.1.1.1
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).
8.5.1.1.2
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 
Page 324 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 56 of 119
(serum or urine) within 72 hours of the first dose of study medication), Lansky play score 
(see Appendix 2) or Karnofsky performance status score (see Appendix 3), tumor-node 
metastasis (TNM) Staging (at initial diagnosis of the disease), vital signs, clinical chemistry 
and hematology, urine dipstick testing, height, Tanner’s staging (see Appendix 10), proximal 
tibial growth plates, and pharmacodynamic biomarkers (for Arm A only).
8.5.1.1.3
MEDICAL HISTORY
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 5, and Table 6).  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.
8.5.1.2
Efficacy Assessments
8.5.1.2.1
TUMOR RESPONSE ASSESSMENTS
Tumor assessment will be performed based on RECIST 1.1 (Appendix 1).  
Investigator-determined response assessments will be performed at each assessment time point 
and entered onto the appropriate CRF.  Copies of all tumor assessment scans will be sent to 
an ICL designated by the sponsor for efficacy assessment and for confirmation of PD.  
Tumor assessments will be carried out following the guidelines provided by the ICL.  
Subjects must have evaluable disease or measurable disease based on RECIST 1.1.
At Screening
During the Screening Period, 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 Cycle 1 Day 1.  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.  
Brain scans by MRI with and without contrast enhancement or CT with contrast 
enhancement will be performed at screening as clinically indicated.
Historical scans (within 28 days prior to the Cycle 1 Day 1) may be used to demonstrate 
eligibility as long as they meet minimum standards as separately defined by the ICL. 
Page 325 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 57 of 119
During Treatment Phase
CT/MRI scans of, 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 weeks ±1 week, following the start of treatment on Cycle 1 Day 1 during the chemotherapy 
treatment period until Week 18.  Following completion of the chemotherapy treatment period
(ie, after Week 18), the frequency of tumor assessments will be every 9 weeks ±1 week until 
Week 54 ±1 week.  Thereafter, they will be performed every 12 weeks ±2 weeks until 
documentation of PD.  At any point, scans should be performed earlier than the scheduled 
time point, if clinically indicated.
An initial assessment of CR or PR according to RECIST 1.1 must be confirmed by IIR 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 PD, tumor assessments 
should continue to be performed as per the tumor assessment schedule until documentation 
of progression or start of a new anticancer agent.  Screening CT scans should be performed 
with oral and iodinated intravenous contrast and MRI scans should be performed with 
intravenous gadolinium chelate.  Post-screening scans may be performed without contrast if a 
medical contraindication develops while on study treatment.  If iodinated intravenous
contrast is contraindicated, chest CT should be done without intravenous 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 
intravenous contrast, and the MRI scans should be performed with intravenous 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 5-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.
Page 326 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 58 of 119
Brain scans by MRI with and without contrast enhancement or CT with contrast 
enhancement will be performed 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, 9, or 12 weeks).  
Disease progression per RECIST 1.1 during the randomization phase must be confirmed by 
IIR prior to the investigator discontinuing study treatment for a subject.  In the event that the 
investigator considers alternative treatments must be instituted immediately for management 
of urgent medical complications of PD, study drugs may be discontinued without waiting for 
independent confirmation of radiographic evidence of PD.  Subjects who discontinue study 
treatment without PD will continue to undergo tumor assessments according to the schedule 
until PD is documented or another anticancer therapy is initiated.  If possible, before 
discontinuation of the subject from the study, the investigator should consult with the 
sponsor.
During Post-treatment Follow-up 
Subjects who discontinue treatment without PD will have tumor assessments performed as 
per the appropriate tumor assessment schedule) or sooner if clinically indicated, for
documented PD or until another anticancer therapy is initiated, whichever occurs first. 
After data cutoff for PFS-1y and OS-1y analysis, 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 2 years after end of treatment or until 
death, unless the study is terminated by the sponsor, or the subject discontinues due to 
withdrawal of consent, or is lost to follow-up.
8.5.1.2.2
PALATABILITY AND ACCEPTABILITY OF LENVATINIB SUSPENSION FORMULATION
The palatability and acceptability of lenvatinib suspension formulation will be assessed using 
the Palatability Questionnaire (see Appendix 5). All subjects who receive suspension 
formulation with the exception of subjects using a nasogastric or gastrostomy tube, 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).
8.5.1.3
Pharmacokinetic, Pharmacodynamic, and Other Biomarker Assessments
8.5.1.3.1
PHARMACOKINETIC ASSESSMENTS
Blood samples (2 mL each) will be collected from all subjects from Arm A only at the time 
points shown in Table 3.  Pharmacokinetic blood samples will also be drawn pretreatment on 
the day of tumor assessment as described in the Table 3.  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 
Page 327 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 59 of 119
model.  For the time points shown in Table 3, 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 doses of 
lenvatinib will be administered at the study site at approximately the same time of day in 
order to accommodate PK sample collection timing.  Instructions for the collection, handling, 
and shipping procedures of PK samples will be provided in a separate Laboratory Manual.
Table 3
Lenvatinib Pharmacokinetic Sampling Time Points
Time Pointa
Time (h)
Cycle 1 Day 1
Postdose:  0.5-4 and 6-10
Cycle 1 Day 15
Predose
Postdose: 0.5-4 and 6-10
Cycle 2 Day 1
Predose
Note: All predose samples are to be drawn approximately 24 hours following the dose administered on the 
previous day.
h = hour(s).
a. If dose interruption is necessary in these time points, please contact the sponsor.
Only samples from all subjects randomized to Arm A will be collected.  Lenvatinib will be 
quantified using a validated liquid chromatography/mass spectrometry/mass spectrometry 
(LC/MS/MS) method.
8.5.1.3.2
PHARMACODYNAMIC AND OTHER BIOMARKER ASSESSMENTS
Pharmacodynamic serum and archived fixed tumor tissue samples for biomarker analysis 
will be collected from study subjects randomized to Arm A (ie, lenvatinib + ifosfamide + 
etoposide), as specified in the Schedule of Procedures/Assessments. Pharmacodynamic 
serum and tumor biomarkers identified in other lenvatinib clinical studies will be assessed in 
samples collected from subjects enrolled in this study.  Pharmacodynamic biomarker analysis 
will be performed as described in an analysis plan provided separately.
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).
8.5.1.4
Safety Assessments
Safety assessments will consist of monitoring and recording all AEs, including all grades per 
National Cancer Institute (NCI) CTCAE v5.0 (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 5
and Table 6).
Clinical and laboratory toxicities/symptomatology will be graded according to CTCAE v5.0 
(Cancer Therapy Evaluation Program, 2017). 
Page 328 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 60 of 119
8.5.1.4.1
ADVERSE EVENTS
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered an investigational product.  An AE does not necessarily have a causal 
relationship with the medicinal product.  For this study, the study drug is lenvatinib. 
The criteria for identifying AEs in this study are:

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of an investigational product, 
whether or not considered related to the investigational product (Note:  Every sign or 
symptom should not be listed as a separate AE if the applicable disease [diagnosis] is 
being reported as an AE)

Any new disease or exacerbation of an existing disease. However, worsening of the 
primary disease should be captured under efficacy assessments as PD.

Any deterioration in nonprotocol-required measurements of a laboratory value or other 
clinical test (eg, ECG or x-ray) that results in symptoms, a change in treatment, or 
discontinuation of study drug

Recurrence of an intermittent medical condition (eg, headache) not present pretreatment 
(Baseline)

An abnormal laboratory test result should be considered an AE if the identified laboratory 
abnormality leads to any type of intervention, withdrawal of study drug, or withholding 
of study drug, whether prescribed in the protocol or not
All AEs, regardless of relationship to study drug or procedure, should be recorded beginning 
from the time the subject signs the study ICF through the last visit and for 30 days after the 
subject’s last dose.  Refer to Section 8.5.4.1 for the time period after the end of treatment for 
SAE collection.  
Abnormal laboratory values should not be listed as separate AEs if they are considered to be 
part of the clinical syndrome that is being reported as an AE.  It is the responsibility of the 
investigator to review all laboratory findings in all subjects and determine if they constitute 
an AE.  Medical and scientific judgment should be exercised in deciding whether an isolated 
laboratory abnormality should be classified as an AE.  Any laboratory abnormality
considered to constitute an AE should be reported on the Adverse Event CRF. 
Abnormal ECG (QTcF) results, if not otherwise considered part of a clinical symptom that is 
being reported as an AE, should be considered an AE if the QTcF interval is more than 
450 ms and there is an increase of more than 60 ms from baseline.  Any ECG abnormality 
that the investigator considers as an AE should be reported as such.
All AEs must be followed for 30 days after the subject’s last study drug dose, or until 
resolution, whichever comes first.  Subjects with onset of an AE or deterioration of a 
preexisting AE during the AE collection period will be followed until resolution to baseline, 
start of a new anticancer treatment, or death. All SAEs must be followed to resolution or, if 
resolution is unlikely, to stabilization.
Page 329 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 61 of 119
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 on a 5-point scale according to CTCAE v5.0 (Cancer Therapy 
Evaluation Program, 2017).  Investigators will report CTCAE grades for all AEs (for both 
increasing and decreasing severity).
Assessing Relationship to Study Treatment
Items to be considered when assessing the relationship of an AE to the study treatment are:

Temporal relationship of the onset of the event to the initiation of the study treatment

The course of the event, especially the effect of discontinuation of study treatment or 
reintroduction of study treatment, as applicable

Whether the event is known to be associated with the study treatment or with other 
similar treatments

The presence of risk factors in the study subject known to increase the occurrence of the 
event

The presence of nonstudy, treatment-related factors that are known to be associated with 
the occurrence of the event
Classification of Causality
The relationship of each AE to the study drug will be recorded on the CRF in response to the 
following question:
Is there a reasonable possibility that the study drug caused the AE?
Yes (related)
A causal relationship between the study drug and the AE is a reasonable 
possibility.
No (not related) A causal relationship between the study drug and the AE is not a 
reasonable possibility.
8.5.1.4.2
SERIOUS ADVERSE EVENTS AND EVENTS ASSOCIATED WITH SPECIAL SITUATIONS
An 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
Page 330 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 62 of 119

Is a congenital anomaly/birth defect (in the child of a subject who was exposed to the 
study drug)
Other important medical events that may not be immediately life-threatening or result in 
death or hospitalization but, when based on appropriate medical judgment, may jeopardize 
the subject or may require intervention to prevent one of the outcomes in the definition of 
SAE listed above should also be considered SAEs.  Medical and scientific judgment should 
be exercised in deciding whether expedited reporting is appropriate in such situations. 
In addition to the above, events associated with special situations include pregnancy or 
exposure to study drug through breastfeeding; AEs associated with study drug overdose, 
misuse, abuse, or medication error.  These events associated with special situations are to be 
captured using the SAE procedures but are to be considered as SAEs only if they meet one of 
the above criteria.  All AEs associated with special situations are to be reported on the CRF 
whether or not they meet the criteria for SAEs.  
All SAEs must be followed to resolution or, if resolution is unlikely, to stabilization.
The following hospitalizations are not considered to be SAEs because there is no “adverse 
event” (ie, there is no untoward medical occurrence) associated with the hospitalization:

Hospitalizations for respite care 

Planned hospitalizations required by the protocol

Hospitalization planned before informed consent (where the condition requiring the 
hospitalization has not changed after study drug administration)

Hospitalization for administration of study drug or insertion of access for administration 
of study drug

Hospitalization for routine maintenance of a device (eg, battery replacement) that was in 
place before study entry
8.5.1.4.3
LABORATORY MEASUREMENTS
Clinical laboratory tests to be performed, including hematology, chemistry, and urinalysis, 
are summarized in Table 4.  Subjects should be in a seated or supine position during blood 
collection.  The Schedule of Procedures/Assessments (Table 5 and Table 6) shows the visits 
and time points at which blood for clinical laboratory tests and urine for urinalysis will be 
collected in the study.
Page 331 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 63 of 119
Table 4
Clinical Laboratory Tests
Category
Parameters
Hematology
Hematocrit, hemoglobin, platelets, RBC count, and WBC count 
with differential (bands, basophils, eosinophils, lymphocytes, 
monocytes, neutrophils)
Chemistry
Electrolytes
Bicarbonate, chloride, potassium, sodium, calcium, magnesium, 
phosphorus
Liver function tests
ALT, alkaline phosphatase, AST, conjugated (direct) bilirubina, 
total bilirubin, INRb
Renal function tests
BUN or urea, creatinine
Other chemistries
Albumin, amylase, glucose, LDH, lipase, total protein 
Thyroid function testsc
Thyroid stimulating hormone, free T4 level
Urinalysis for microscopyd
RBCs
Urine dipstick testingd,e
Blood, protein, glucose
Other
Pregnancy test (serum or urine β–hCG)
ALT = alanine aminotransferase, AST = aspartate aminotransferase, BUN = blood urea nitrogen, β hCG = 
beta-human chorionic gonadotropin, INR = International Normalized ratio, LDH = lactate dehydrogenase,
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.
INR should only be performed as part of the screening assessment.  During the study, INR should be 
performed if clinically indicated.
c.
Thyroid function will be assessed every 2 cycles for all subjects.
d.
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
e.
If urine protein is ≥ 2+, then a spot test for protein-creatinine ratio and if possible, a 24-hour urine 
collection should be done to quantify the 24 hour urine protein excretion. 
All clinical laboratory tests during the study will be performed at qualified local laboratories.  
All hematology, blood chemistry (including pregnancy test, as applicable), and urinalysis 
samples are to be obtained prior to study drug administration and sent to the local laboratory 
on the day of collection unless otherwise instructed. 
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 Table 1 (study 
drug dose reduction and interruption instructions) 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 8.5.1.4.1 and the CRF Completion Guidelines.  In these instances, the 
Page 332 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 64 of 119
AE corresponding to the laboratory abnormality will be recorded on the Adverse Event CRF
(see Section 8.5.4.3.2).
8.5.1.4.4
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 5
and Table 6) 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.  
Only 1 BP measurement is needed for subjects with systolic BP <95th percentile (BP 
<140 mm Hg) and diastolic BP <95th percentile (BP <90 mmHg). If the subject’s initial BP 
measurement is elevated (systolic BP ≥95th percentile [≥140 mmHg] or diastolic BP ≥95th 
percentile [≥90 mmHg]), the BP measurement should be repeated at least 5 minutes later. 
The mean value of 2 measurements at least 5 minutes apart is defined as 1 BP assessment. If 
the BP assessment (ie, the mean of the 2 BP measurements obtained at least 5 minutes apart) 
is elevated (systolic BP ≥95th percentile [≥140 mm Hg] or diastolic BP ≥95th percentile
[≥90 mm Hg]), a confirmatory assessment should be obtained at least 30 minutes later by 
performing 2 measurements (at least 5 minutes apart) to yield a mean value.
8.5.1.4.5
PHYSICAL EXAMINATIONS
Physical examinations will be performed as designated in the Schedule of 
Procedures/Assessments (Table 5 and Table 6).  Documentation of the physical examination 
will be included in the source documentation at the site.  Only changes from screening 
physical examination findings that meet the definition of an AE will be recorded on the 
Adverse Events CRF.
8.5.1.4.6
ELECTROCARDIOGRAMS
Electrocardiograms will be obtained as designated in the Schedule of Assessments (Table 5
and Table 6).  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.  If possible, 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 8.5.1.4.1) 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 8.5.4.1).
Page 333 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 65 of 119
8.5.1.4.7
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 8.3.1 and 8.3.2).  A serum or urine 
pregnancy test will be performed at Screening, Baseline (or within 72 hours prior to the first 
dose of study medication), on Day 1 of each cycle from Cycle 2 onwards, 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 5 and
Table 6).
Echocardiogram
An echocardiogram to assess 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.
8.5.1.5
Other Assessments
Health-related quality of life (HRQoL) assessment will be performed per the Schedule of 
Assessments (Table 5 and Table 6). Impact of treatment on HRQoL will be assessed using 
the PedsQL (including the Generic Core Scales and Cancer Module).  Data will be collected 
as parent-report for toddlers (2 to 4 years) and as self-report for subjects aged ≥5 years.  
Self-report is the preferred data collection for all subjects aged ≥5, however to improve 
adherence of participation, it is also acceptable to collect the data as proxy report by 
observers including parents and caregivers.
The PedsQL is a modular instrument designed to measure HRQoL in pediatric and adults 
population. The PedsQL 4.0 Generic Core Scales are multidimensional child self-report and 
parent proxy-report scales developed as the generic core measure to be integrated with the 
PedsQL disease specific modules. The PedsQL 3.0 Cancer Module was designed to measure 
pediatric cancer specific HRQOL.
It is best practice and strongly recommended that the PedsQL measurement modules are 
administered to randomized subjects prior to drug administration or any other interaction 
with site staff.
8.5.2
Schedule of Procedures/Assessments
8.5.2.1
Schedule of Procedures/Assessments
Table 5 presents the schedule of procedures/assessments for the Randomization Phase of the
study.
Page 334 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 66 of 119
Table 6 presents the schedule of procedures/assessments for the Extension Phase of the 
study.
Page 335 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 67 of 119
Table 5
Schedule of Assessments in study E7080-G000-230 – Randomization Phase
Phase
Prerandomization
Randomization a
(All cycles are 21 days in duration)
Period
Screeningb Baselin
ec
Treatmentd
Off-
Tx
Follow-
upe
Visit 
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18+
Cycle
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5
Cycle 
6-X
Day
-28 to -2
-1
1
8
15
1
8
15
1
8
15
1
8
15
1
8
15
1
Procedures/Assessments
Informed consent
X
Inclusion/exclusion
X
X
Randomization (IVRS)
X
Demographic data
X
Medical/surgical history
X
X
Prior medication/ procedures
X
X
Pregnancy testf
X
X
X
X
X
X
X
X
Lansky play score/ 
Karnofsky PSg
X
X
X
X
X
X
X
X
TNM Staging
X
Physical examinationh
X
X
X
X
X
X
X
X
X
X
X
Vital signsi
X
X
X
X
X
X
X
X
X
X
X
12-lead ECGj
X
X
X
X
X
Echocardiogramk
X
Performed every 16±2 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
Urine dipstick testingm
X
X
X
X
X
X
X
X
X
X
PK blood samplesn
X
X
X
Study treatmento
Arm A:  Combination of lenvatinib (QD) + ifosfamide + etoposide (Days 1-3 of Cycles 1-5 only)
[based on BSA calculations at Day 1 of each Cycle]; after Cycle 5 subjects will receive lenvatinib alone.
Arm B:  Ifosfamide + etoposide (Days 1-3 of Cycles 1-5 only)
[based on BSA calculations at Day 1 of each Cycle]
Page 336 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 68 of 119
Table 5
Schedule of Assessments in study E7080-G000-230 – Randomization Phase
Phase
Prerandomization
Randomization a
(All cycles are 21 days in duration)
Period
Screeningb Baselin
ec
Treatmentd
Off-
Tx
Follow-
upe
Visit 
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18+
Cycle
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5
Cycle 
6-X
Day
-28 to -2
-1
1
8
15
1
8
15
1
8
15
1
8
15
1
8
15
1
Procedures/Assessments
Palatability Questionnairep
X
Tumor assessments: 
CT/MRIq
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±1 week or sooner if clinically indicated until Week 18±1 week, then 
every 9±1 weeks until Week 54±1 week.  Thereafter, to be performed every 12±2 weeks until 
documentation of PD.
X
Brain CT/MRIr
X
Brain scans will be performed at screening as clinically indicated, and thereafter during treatment if 
clinically indicated.  For subjects with protocol-eligible, treated brain metastases at Screening, brain scans 
should be performed at all tumor assessment time points.
Heights
X
X
X
X
X
X
Tanner Staget
X
X
X
Proximal Tibial growth 
plates x-ray s
X
X
HRQoL
X
HRQoL will be collected on C2D1, C3D1,  Week 18, C8D1, and C18D1  
X
Pharmacodynamic 
biomarkersu
X
X
X
X
X
Archival tumor block or 
slidesv
X
Survivalw
X
X
Concomitant medicationsx
Throughout
X
AEs/SAEsy
Throughout
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, h = hour, HR = heart rate, HRQoL = Health-Related Quality of Life, IV = intravenous, IVRS = Interactive Voice 
Response System, MRI = magnetic resonance imaging, PD = progressive disease/disease progression, PK = pharmacokinetics, PR = partial response, PS = 
Page 337 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 69 of 119
Table 5
Schedule of Assessments in study E7080-G000-230 – Randomization Phase
Phase
Prerandomization
Randomization a
(All cycles are 21 days in duration)
Period
Screeningb Baselin
ec
Treatmentd
Off-
Tx
Follow-
upe
Visit 
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18+
Cycle
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5
Cycle 
6-X
Day
-28 to -2
-1
1
8
15
1
8
15
1
8
15
1
8
15
1
8
15
1
Procedures/Assessments
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.  
a.
During Cycle 1, efforts should be made to conduct study visits on the day scheduled (1 day); from Cycle 2 onwards, efforts should be made to conduct 
study visits on the day scheduled (±3 days).
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.
For subjects randomized to Arm A, subjects benefiting from study treatment in the opinion of the investigator will continue lenvatinib treatment until PD, 
intolerable toxicity, noncompliance with safety or efficacy assessments, voluntary discontinuation by the subject at any time, or study termination by the 
sponsor, whichever occurs first.
e.
Subjects will be followed every 12 weeks until documentation of PD 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), on 
Day 1 of each cycle from Cycle 2 onwards, if pregnancy is suspected, 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 C1D1 Visit, 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), C1D15, C2D1, C2D15, 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.  Refer to hypertension management guidelines in Section 8.4.1.1.2.    
j.
Single 12-lead ECG.  If possible, subjects must be in the recumbent position for a period of 5 minutes prior to the ECG.  ECG should be conducted at 
Screening, C1D1, C2D1,  D1 of every 4th cycle (ie, C6, C10, C14, etc.). ECG at C1D1 and C2D1 should be conducted approximately 2 hours after 
lenvatinib dose.  For high risk subjects  (as defined in lenvatinib product label), conduct ECG monitoring in every cycle. 
k.
An echocardiogram is performed during screening, every 16±2 weeks, and at the Off-Treatment visit, or sooner if clinically indicated.
Page 338 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 70 of 119
Table 5
Schedule of Assessments in study E7080-G000-230 – Randomization Phase
Phase
Prerandomization
Randomization a
(All cycles are 21 days in duration)
Period
Screeningb Baselin
ec
Treatmentd
Off-
Tx
Follow-
upe
Visit 
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18+
Cycle
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5
Cycle 
6-X
Day
-28 to -2
-1
1
8
15
1
8
15
1
8
15
1
8
15
1
8
15
1
Procedures/Assessments
l.
Clinical chemistry and hematology results must be reviewed by the investigator prior to administration of study drug on C1D1 and within 48 hours after 
administering any 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).  TSH should be 
assessed for all subjects.
m. Urine dipstick testing should be performed at Screening, Baseline, C1D15, C2D1, C2D15, and Day 1 of every subsequent cycle, or more frequently as 
clinically indicated, 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 2 treatment cycles.  If a new event of proteinuria ≥2+ occurs, refer to Section 8.4.1.1.4 for further management guidelines.  
Urine glucose should be performed as part of the urine dipstick.  
n.
Sampling (one 2 mL sample per time point) for PK analysis of lenvatinib will be performed (in subjects in Arm A only) on Cycle 1 Day 1 at 0.5 to 4 hours 
and 6 to 10 hours postdose, on Cycle 1 Day 15 at predose, 0.5 to 4 hours and 6 to 10 hours postdose, and on Cycle 2 Day 1 at predose.  All predose samples 
are to be drawn approximately 24 hours following the dose administered on the previous day.  If dose interruption is necessary at  these time points, please 
contact the sponsor.
o.
Subjects randomized to Arm A will continue to receive lenvatinib only after completion of 5 cycles with lenvatinib+ifosfamide+etoposide until progressive 
disease, unacceptable toxicity, subject request, study termination by the sponsor, subject noncompliance with safety or efficacy assessments, or withdrawal 
of consent.  Subjects randomized to Arm B will be off-treatment after 5 cycles of ifosfamide+etoposide.
p.
All subjects who receive suspension formulation, with the exception of subjects using a nasogastric or gastrostomy tube, 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.  
q.
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±1 weeks from C1D1 until Week 18±1 week, then every 9±1 weeks until Week 54±1 week, and thereafter, every 12±2 weeks until documentation of PD
during the Treatment Phase (or sooner if there is evidence of progressive disease) and should utilize the same methodology (CT or MRI) and scan 
Page 339 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 71 of 119
Table 5
Schedule of Assessments in study E7080-G000-230 – Randomization Phase
Phase
Prerandomization
Randomization a
(All cycles are 21 days in duration)
Period
Screeningb Baselin
ec
Treatmentd
Off-
Tx
Follow-
upe
Visit 
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18+
Cycle
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5
Cycle 
6-X
Day
-28 to -2
-1
1
8
15
1
8
15
1
8
15
1
8
15
1
8
15
1
Procedures/Assessments
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 according to the 
schedule: every 6±1 weeks until Week 18±1 week, then every 9±1 weeks until Week 54±1 week, thereafter, to be performed every 12±2 weeks until 
documentation of progression or start of a new anticancer agent. 
r.
Brain CT with contrast or MRI pre- and post- gadolinium contrast will be performed at the Screening Visit as clinically indicated, and thereafter during 
treatment as clinically indicated.  For subjects with protocol-eligible treated brain metastases, brain CT/MRI will be performed at all tumor assessment time 
points.
s.
Height will be assessed at the Baseline Visit, Day 1 of every 4 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.  If the growth plates are 
closed at baseline then the subject does not need a reassessment at the Off-treatment Visit. Tibial growth plate x-rays will be optional for Germany.
t.
Tanner Stage will be assessed at the Baseline Visit, at the Off-treatment Visit, and annually thereafter during the Post-treatment Follow-up.  
u.
Blood samples will be collected only from subjects in Arm A at the Baseline Visit, C1D8, Day 1 of Cycles 2, 4, and 6, for assessment for blood serum 
sample to measure factors implicated in angiogenesis. 
v.
An archival tumor sample from the most recent surgery or biopsy for identification of predictive biomarkers and pathology review may be collected from 
subjects in Arm A at any time during the study, unless no such material is available.
w.
Survival data will be collected every 3 months until death as per the protocol.  All anticancer therapies will be collected.
x.
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.  
y.
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.
Page 340 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 72 of 119
Table 6 presents the Schedule of Procedures/Assessments for the Extension Phase of the 
study.  
Page 341 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 73 of 119
Table 6
Schedule of Assessments in study E7080-G000-230 – Extension Phase
Phase
Extensiona
Period
Treatment Period a
Follow-up Period
Visit 
98
99
Cycle
Cycle X +1 and beyond
Off-Tx Visit
Day
1
Procedures/Assessments
Pregnancy testb
X
X
Lansky play score/ Karnofsky PSc
X
X
Physical examinationd
X
X
Vital signse
X
X
12-lead ECGf
As clinically indicated
Echocardiogramg
As clinically indicated
Clinical chemistry and hematologyh
X
X
Urine dipstick testingi
X
X
Study treatmentj
Arm A:  Lenvatiniba
Tumor assessments: CT/MRIk
After data cutoff, tumor assessments may be performed as clinically indicated 
as per the institutional guidelines, following the prevailing local standard of 
care.
Brain CT/MRIl
After data cutoff, tumor assessments may be performed as clinically indicated 
as per the institutional guidelines, following the prevailing local standard of 
care.
Heightm
To be checked every 4 cycles
X
X
Tanner Stagen
X
X
Proximal Tibial growth plates x-rayo
X
Survivalp
X
X
Concomitant medicationsq
Throughout
X
AEs/SAEsr
Throughout
X
AE = adverse event, CT = computerized tomography, ICL = imaging core laboratory, MRI = magnetic resonance imaging, PD = disease progression, PS = 
performance status, SAE = serious adverse event.
a. Subjects benefiting from study treatment in the opinion of the investigator will continue treatment until PD, intolerable toxicity, subject request, subject 
Page 342 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 74 of 119
Table 6
Schedule of Assessments in study E7080-G000-230 – Extension Phase
Phase
Extensiona
Period
Treatment Period a
Follow-up Period
Visit 
98
99
Cycle
Cycle X +1 and beyond
Off-Tx Visit
Day
1
noncompliance with safety or efficacy assessments, voluntary discontinuation by the subject at any time, or study termination by the sponsor, whichever 
occurs first.
b. A serum or urine pregnancy test will be performed on Day 1 of each cycle and at the Off-treatment Visit in women of childbearing potential.
c. A Lansky play score or Karnofsky performance status score will be obtained at Day 1 of every cycle visit.
d. A physical examination will be performed at Day 1 visit of each cycle, and at the Off-treatment Visit.  A symptom-directed physical examination will be 
performed at any time  as clinically indicated.
e. 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. Refer to hypertension management guidelines in Section 8.4.1.1.2.  
f.
Single 12-lead ECG.  Subjects must be in the recumbent position for a period of 5 minutes prior to the ECG.
g. An echocardiogram is performed as clinically indicated.
h. Clinical chemistry and hematology results must be reviewed within 48 hours after administering any 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).  TSH should be assessed for all subjects.
i.
Urine dipstick testing should be performed on Day 1 of every cycle, or more frequently as clinically indicated, 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 2 consecutive cycles.  If a new 
event of proteinuria ≥2+ occurs, refer to Section 8.4.1.1.4 for further management guidelines.  Urine glucose should be performed as part of the urine 
dipstick.  
j.
Subjects randomized to Arm A will continue to receive lenvatinib only until progressive disease, unacceptable toxicity, or withdrawal of consent.  
k. After data cutoff, tumor assessments may be performed as clinically indicated as per the institutional guidelines, following the prevailing local standard of 
care.  The scans will no longer be required to be sent to the ICL.
l.
Brain CT with contrast or MRI pre- and post- gadolinium contrast will be performed as per the institutional guidelines, following the prevailing local standard 
of care.
m. Height will be assessed at the Baseline Visit, Day 1 of every 4 cycles during the Treatment Phase, at the Off-treatment Visit and every 3 months during the 
Post-treatment Follow-up.  
n. Tanner Stage will be assessed at the Baseline Visit, at the Off-treatment Visit, and annually thereafter during the Post-treatment Follow-up.  
o. Proximal tibial growth plates x-rays should be conducted at baseline and at the Off-treatment Visit. If the growth plates are closed at baseline then the subject 
does not need a reassessment at the Off-treatment Visit. Tibial growth plate x-rays will be optional for Germany.
p. Survival data will be collected every 3 months until death as per the protocol.  All anticancer therapies will be collected.
q. 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.  
Page 343 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 75 of 119
Table 6
Schedule of Assessments in study E7080-G000-230 – Extension Phase
Phase
Extensiona
Period
Treatment Period a
Follow-up Period
Visit 
98
99
Cycle
Cycle X +1 and beyond
Off-Tx Visit
Day
1
r.
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.
Page 344 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 76 of 119
8.5.2.2
Description of Procedures/Assessments Schedule
Refer to Table 5 for schedule and description of procedures in the Randomization Phase and 
Table 6 for the Extension Phase.
8.5.3
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).
8.5.4
Reporting of Serious Adverse Events, Pregnancy, and Events Associated 
with Special Situations
8.5.4.1
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 date the investigator becomes aware of the event.
Serious adverse events, regardless of causality assessment, must be collected for 30 days 
after the subject’s last dose.  All SAEs must be followed to resolution or, if resolution is 
unlikely, to stabilization.  Any SAE judged by the investigator to be related to the study 
treatment or any protocol-required procedure should be reported to the sponsor regardless of 
the length of time that has passed since study completion.
The detailed contact information for reporting of SAEs is provided in the Investigator Study 
File.
For urgent safety issues, please ensure all appropriate medical care is administered to the 
subject and contact the appropriate study team member listed in the Investigator Study File.
It is very important that the SAE report form be filled out as completely as possible at the 
time of the initial report.  This includes the investigator’s assessment of causality.
Any relevant follow-up information received on SAEs should be forwarded within 24 hours
of its receipt.  If the relevant 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.
Page 345 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 77 of 119
The investigator must notify his/her IRB/IEC of the occurrence of the SAE in writing, if 
required by their institution.  A copy of this communication must be forwarded to the sponsor 
and/or the designated CRO monitor to be filed in the sponsor’s Trial Master File.
8.5.4.2
Reporting of Pregnancy and Exposure to Study Drug Through Breastfeeding
Any pregnancy in a female subject 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 exposure, this 
should be reported regardless of the length of time that has passed since the exposure to study 
treatment.
A congenital anomaly, death during perinatal period, a spontaneous abortion or an induced 
abortion done due to safety concerns for either mother or fetus 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 8.5.4.1]).
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 date the investigator becomes 
aware of the pregnancy.  The contact information for the reporting of pregnancies and 
exposure to study drug through breastfeeding is provided in the Investigator Study File.  The 
Pregnancy Report Form must be used for reporting.  All pregnancies must be followed to 
outcome.  The outcome of the pregnancy must be reported as soon as possible but no later 
than 24 hours from the date the investigator becomes aware of the outcome.
A subject who becomes pregnant must be withdrawn from the study.
8.5.4.3
Reporting of Events Associated with Special Situations
8.5.4.3.1
REPORTING OF ADVERSE EVENTS ASSOCIATED WITH STUDY DRUG OVERDOSE,
MISUSE, ABUSE, OR MEDICATION ERROR
Adverse events associated with study drug overdose, misuse, abuse, and medication error 
refer to AEs associated with uses of the study drug outside of that specified by the protocol.  
Overdose, misuse, abuse, and medication error are defined as follows:
Overdose
Accidental or intentional use of the study drug in an amount higher 
than the protocol-defined dose
Misuse
Intentional and inappropriate use of study drug not in accordance with 
the protocol
Abuse
Sporadic or persistent intentional excessive use of study drug 
accompanied by harmful physical or psychological effects
Page 346 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 78 of 119
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 8.5.4.1) even if the AEs do not meet serious criteria.  Abuse 
and Intentional Overdose, even if asymptomatic, are 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.
8.5.4.3.2
REPORTING OF ABNORMAL HEPATIC TESTS OF CLINICAL INTEREST
The following combination of abnormal laboratory tests*, as determined by way of 
protocol-specified laboratory testing or unscheduled laboratory testing and whether 
nonserious or serious, should be entered on the Adverse Event CRF and reported using the 
procedures detailed in Reporting of Serious Adverse Events (Section 8.5.4.1). If the event 
does not meet serious criteria, the seriousness criteria on the SAE form should be indicated as 
“nonserious.”  

Elevated AST or ALT lab value that is greater than or equal to 3× the upper limit of 
normal 
AND

Elevated total bilirubin lab value that is greater than or equal to 2× the upper limit of 
normal 
AND AT THE SAME TIME

Alkaline phosphatase lab value that is less than 2× the upper limit of normal
*Note: These criteria are based upon available regulatory guidance documents. The purpose 
of the criteria is to specify a threshold of abnormal hepatic tests that may require additional 
evaluation for an underlying etiology. In addition to reporting the abnormal hepatic 
laboratory tests on a SAE form, the site should also consult the medical monitor for guidance 
on assessment and follow-up.  At a minimum, laboratory testing should be repeated at least 
once weekly until improvement or identification of a cause unrelated to study drug use that is 
unlikely to improve.
8.5.4.4
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.
Page 347 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 79 of 119
8.5.4.5
Breaking the Blind
Not applicable
8.5.4.6
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 
SUSARs will be reported, as required, to the competent authorities of all involved European 
member states.
8.5.5
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 PD will be followed in the post-study treatment follow-up period and continue to undergo 
regularly scheduled disease assessment until documentation of PD or start of an alternative 
anticancer treatment.  All subjects who discontinue study drug will be followed for OS 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 5 and Table 6). 
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 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.
8.5.6
Abuse or Diversion of Study Drug
Not applicable.
Page 348 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 80 of 119
8.5.7
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.
8.6
Data Quality Assurance
This study will be organized, performed, and reported in compliance with the protocol, 
SOPs, working practice documents, and applicable regulations and guidelines.  Site audits 
will be made periodically by the sponsor’s or the CRO’s qualified compliance auditing team, 
which is an independent function from the study team responsible for conduct of the study.
8.6.1
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.
8.6.2
Clinical Data Management
All software applications used in the collection of data will be properly validated following 
standard computer system validation that is compliant with all regulatory requirements.  All 
data, both CRF and external data (eg, laboratory data), will be entered into a clinical system.
8.7
Statistical Methods
All statistical analyses will be performed by the sponsor or designee after the study is 
completed, the database is locked and released, a snapshot of the database is obtained and 
released, and randomization codes have been released and applied.  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).
Page 349 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 81 of 119
8.7.1
Statistical and Analytical Plans
The statistical analyses of 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.
8.7.1.1
Study Endpoints
8.7.1.1.1
PRIMARY ENDPOINT

Progression-free survival rate at 4 months (PFS-4m rate) by IIR is defined as the 
percentage of subjects who are alive and without PD at 4 months from the randomization 
date as determined by IIR of radiological imaging using RECIST 1.1.  The PFS-4m rate 
is estimated on the full analysis set for this study using the K-M method.
8.7.1.1.2
SECONDARY ENDPOINTS

Progression-free survival rate at 1 year (PFS-1y rate) by IIR is defined as the percentage 
of subjects who are alive and without PD at 1 year from the randomization date as 
determined by IIR of radiological imaging using RECIST 1.1.  The PFS-1y rate is 
estimated on the full analysis set for this study using the K-M method.

Progression-free survival (PFS) by IIR is defined as the time from the date of 
randomization to the date of the first documentation of PD or death (whichever occurs 
first) as determined by IIR using RECIST 1.1.

Overall survival (OS) is defined as the time from the date of randomization to 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 alive, or date of 
data cutoff, whichever occurs first.  Overall survival rate at 1 year will be estimated.

Objective response rate (ORR) by IIR at 4 months is defined as the proportion of subjects 
who have best overall response of complete response (CR) or partial response (PR) as 
determined by IIR using RECIST 1.1 within the first 4 months.

Safety will be assessed summarising the incidence of TEAEs and SAEs together with all 
other safety parameters.

Assessment of population-based PK parameters of lenvatinib.

Score changes from baseline for all PedsQL scales including Generic Core Scales and 
Cancer Module. Scores will be calculated for total generic score, total cancer score, each 
physical function subscale including physical health, psychosocial health, emotional 
function, social function, school/work function in the Generic Core Scales, and each 
subscales in the cancer module.

Palatibility and acceptability of the suspension formulation of lenvatinib in subjects 
receiving the suspension formulation in the study will be assessed using the Palatability 
Questionnaire (see Appendix 5).
Page 350 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 82 of 119
8.7.1.1.3
EXPLORATORY ENDPOINTS 

Duration of response (DOR) by IIR is defined as the time from the date a response was 
first documented until the date of the first documentation of PD or date of death from any 
case.

Disease control rate (DCR) by IIR is the proportion of subjects who have a best overall 
response of CR or PR or stable disease (SD).  In this context, stable disease is defined as 
stable disease at ≥7 weeks after randomization to be considered best overall response.

Clinical benefit rate (CBR) by IIR is the proportion of subjects who have best overall 
response of CR or PR or durable SD (duration of SD ≥23 weeks after randomization).

Proportion of subjects who achieve complete removal of baseline lesions following 
completion of chemotherapy.

Blood and tumor biomarkers will be assessed for identifying potential correlation with 
clinical outcomes-related endpoints.

All efficacy endpoints above (except OS) will be evaluated by both IIR and investigator 
assessment using RECIST 1.1.
8.7.1.2
Definitions of Analysis Sets
The Full Analysis Set (Intent-to-Treat Analysis [ITT]) includes all randomized subjects 
regardless of the treatment actually received.  This is the primary analysis population used 
for the efficacy analyses which will be based on the ITT principle.
The Per Protocol Analysis Set includes those subjects from the ITT set who received at least 
1 dose of any study drug, had no major protocol deviations, and had both baseline and at 
least one postbaseline tumor assessment.  Subjects for whom death occurred prior to the first 
postbaseline tumor assessment will also be included.  The per protocol analysis set will be 
the secondary analysis set for efficacy endpoints.
The Safety Analysis Set includes subjects who received at least 1 dose of any study drug.  
This is the analysis population used for all safety analyses which will be based on as-treated 
principle.
Population Pharmacokinetic (PK) Analysis Set includes the subjects who have received at 
least 1 dose of lenvatinib with documented dosing history and have measurable plasma levels 
of lenvatinib.
The Pharmacodynamic Analysis Set includes subjects who received at least 1 dose of study 
drug and had sufficient pharmacodynamic data (eg, at least 1 evaluable/measurable
pharmacodynamic parameter).
The HRQoL Analysis Set will consist of all randomized subjects who have received at least 1
dose of study medication, and have completed at least 1 patient-reported outcome (PRO)
assessment beyond baseline. For PRO analysis, subjects will be analyzed as randomized and 
not according to treatment actually received.
Page 351 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 83 of 119
8.7.1.3
Subject Disposition
Reasons for screening failure will be summarized.
The number and percentage of subjects who completed the study will be summarized by 
treatment group, and for overall, and the number and percentage of subjects who 
discontinued prematurely will also be summarized by reason for discontinuation.
8.7.1.4
Demographic and Other Baseline Characteristics
Demographic and other baseline characteristics for the Full Analysis Set will be summarized
using descriptive statistics.  Continuous demographic and baseline variables (including age, 
sex, race, height, and weight) will be summarized using n (number of subjects with available 
data), mean, standard deviation, median, quartiles 1 and 3, and range (minimum and 
maximum) unless otherwise specified.  Categorical variables will be summarized by number 
and percentage.
8.7.1.5
Prior and Concomitant Therapy
All investigator terms for medications recorded in the CRF will be coded to an 11-digit code 
using the World Health Organization Drug Dictionary (WHO DD).  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 started prior to the first dose of study drug and were either continued during 
the study or stopped prior to the first dose of study drug.  Concomitant medications will be 
defined as medications that (1) started before the first dose of study drug and were continuing 
at the time of the first dose of study drug, or (2) started on or after the date of the first dose of 
study drug 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 treatment arm.
8.7.1.6
Efficacy Analyses
Efficacy analyses will be based primarily on the Full Analysis Set.
All the statistical analysis will be conducted at the PFS-1y/OS-1y analysis data cutoff date
(ie, when the last subject has completed 18 cycles of treatment or discontinues before the end 
of Cycle 18, whichever occurs first), including the analysis of PFS-4m rate.  Additional 
follow-up analysis will based on the date of data cutoff for the additional follow-up analysis 
for OS or at the time of last subject last visit, whichever occurs later.  
8.7.1.6.1
PRIMARY EFFICACY ANALYSIS
The primary analysis of PFS-4m rate will be based upon data provided by IIR of tumor 
assessments.  PFS-4m rate and their Greenwood standard errors will be evaluated using the 
K-M estimates from both treatment groups.  The statistical significance of the difference in 
the 2 K-M PFS-4m rates comparing lenvatinib + chemotherapy agent (Test Arm) vs. 
chemotherapy agent alone (Control Arm) will be tested using a 2-sided 80% CI. This 2-sided 
Page 352 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 84 of 119
80% CI and a p-value will be constructed using the difference of these 2 K-M PFS-4m rates 
and the 2 corresponding Greenwood standard errors. Statistical significance of the difference 
is declared if the CI is entirely above 0. This is equivalent to a test using a 1-sided test at 
alpha=0.1. The 2-sided 95% CIs will also be provided for descriptive purposes. PFS-4m 
rate will also be analyzed using a binomial approach as a sensitivity analysis by excluding 
subjects whose PFS are censored prior to 18 weeks.
8.7.1.6.2
SECONDARY EFFICACY ANALYSES
PFS-1y rate will be analyzed using the same methods as the primary efficacy analysis.  PFS 
censoring rules will follow FDA guidance of 2007, however, removal of baseline lesions 
after completion of Week 18 without progression is not a trigger for PFS censoring after 
18 weeks. (refer to Section 8.4.7.3 for allowed concomitant treatments/procedure in the 
study).
Overall survival (OS) will be compared between treatment arm and control arm using the 
stratified logrank test with time to first relapse/refractory disease (early [<18 months] or late 
[≥18 months]) and age (<18 or ≥18 years) as strata.  Median OS with 2-sided 80% and 
95% CIs will be calculated using K-M product-limit estimates for each treatment arm, and 
the K-M estimates of OS will be plotted over time.  The Cox regression model will be used 
to estimate the hazard ratio and its 80% and 95% CIs stratified by time to first 
relapse/refractory disease (early [<18 months] or late [≥18 months]) and age (<18 or 
≥18 years).  Kaplan-Meier (K-M) estimates will also be presented for 4, 6, 9 and 12 months 
with 2-sided 80% and 95% CIs.
Overall PFS will be analyzed similarly to OS. Median PFS and 2-sided 80% and 95% (as 
exploratory) CIs will be presented, and the K-M estimates of PFS will be plotted over time.  
The Cox regression model will be used to estimate the hazard ratio and its 80% and 95% CIs 
stratified by time to first relapse/refractory disease (early [<18 months] or late [≥18 months]) 
and age (<18 or ≥18 years).  K-M estimates will also be presented for 4, 6, 9, and 12 months 
with 2-sided 80% and 95% CIs.
The ORR will be compared between the test and control groups using either a chi-square test 
or a Cochran-Mantel-Haenszel test stratified by time to first relapse/refractory disease (early 
[<18 months] or late [≥18 months]) and age (<18 or ≥18 years), as appropriate.  
Corresponding odds ratios and their 2-sided 80% and 95% CIs comparing the groups will 
also be presented.  The individual treatment group ORRs will also be calculated along with 
exact 95% confidence intervals using the Clopper and Pearson method.
8.7.1.6.3
EXPLORATORY EFFICACY ANALYSES
Median DOR among responders for each arm will be presented along with its corresponding 
2-sided 95% CIs.  Disease Control Rate (DCR) and CBR will be calculated with exact 
95% CIs using the Clopper and Pearson method.  The differences of the above rates between 
2 groups and corresponding two-sided 95% CIs will be calculated respectively.
Page 353 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 85 of 119
8.7.1.7
Pharmacokinetic, Pharmacodynamic, and Other Biomarker Analyses
8.7.1.7.1
PHARMACOKINETIC ANALYSES
Lenvatinib concentration versus time data will be tabulated and summarized and graphically 
presented.
Lenvatinib data from Arm A of the study will be pooled with available data from other 
studies and subjected to population PK analysis.  The PK model will be parameterized in 
terms of clearance and volume of distribution. Details of the population PK analysis will be 
provided in a separate analysis plan.
8.7.1.7.2
PHARMACODYNAMIC AND OTHER BIOMARKER ANALYSES
Pharmacodynamic, and other biomarker analyses may be performed and reported separately.  
Details of these analyses may be described in a separate analysis plan.
Pharmacodynamic serum and archived, fixed tumor tissue biomarkers will be collected from 
subjects in Arm A only as described in the Schedule of Assessments.  Pharmacodynamic 
serum and tumor biomarkers in this study will be identified as in other lenvatinib clinical 
studies. 
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. 
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.
Data obtained from the pharmacodynamic samples will be used for research.  The 
pharmacodynamic 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.
8.7.1.8
Safety Analyses
All safety analyses will be performed on the Safety Analysis Set.  Safety data, presented by 
treatment group, will be summarized on an “as treated” basis using descriptive statistics (eg, 
n, mean, standard deviation, median, minimum, maximum for continuous variables; n [%] 
Page 354 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 86 of 119
for categorical variables), as appropriate.  Safety variables include TEAEs, clinical laboratory 
parameters, vital signs, 12-lead ECG results, Lansky play scores or Karnofsky performance 
scores, physical examination, height, closure of proximal tibial plates, and LVEF.  Study 
Day 1 for all safety analyses will be defined as the date of the first dose of study drug.
8.7.1.8.1
EXTENT OF EXPOSURE
The number of cycles/days on treatment, quantity of study drug administered, and the 
number of subjects requiring dose reductions, treatment interruption, and treatment 
discontinuation due to adverse events will be summarized.
8.7.1.8.2
ADVERSE EVENTS
The AE verbatim descriptions (investigator terms from the CRF) will be classified into 
standardized medical terminology using the Medical Dictionary for Regulatory Activities 
(MedDRA).  Adverse events will be coded to the MedDRA (Version 20.1 or higher) lower 
level term (LLT) closest to the verbatim term.  The linked MedDRA preferred term (PT) and 
primary system organ class (SOC) are also captured in the database.
A TEAE is defined as an AE that emerges during treatment (and within 30 days of the last 
study treatment), having been absent at pretreatment (Baseline) or 

Re-emerges during treatment, having been present at pretreatment (Baseline) but 
stopped before treatment, 
or 

Worsens in severity during treatment relative to the pretreatment state, when the AE 
is continuous.
Only those AEs that are treatment-emergent will be included in summary tables.  All AEs, 
treatment-emergent or otherwise, will be presented in subject data listings.
The TEAEs will be summarized by treatment group.  The incidence of TEAEs will be 
reported as the number (percentage) of subjects with TEAEs by SOC and PT.  A subject will 
be counted only once within an SOC and PT, even if the subject experienced more than 1
TEAE within a specific SOC and PT.  The number (percentage) of subjects with TEAEs will 
also be summarized by highest CTCAE grade.
The number (percentage) of subjects with TEAEs will also be summarized by relationship to 
study drug (Yes [related] and No [not related]).
The number (percentage) of subjects with treatment-related TEAEs will be summarized by 
SOC and PT.  Treatment-related TEAEs include those events considered by the investigator 
to be related to study treatment.  The number (percentage) of subjects with treatment-related 
TEAEs will also be summarized by highest CTCAE grade.
Adverse events will be summarized using the Safety Analysis Set.  The number of AEs and 
number and incidence (%) of subjects with AEs will be summarized by treatment group and 
Page 355 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 87 of 119
overall.  To obtain the incidence (%), the number of subjects with at least 1 event and the 
percentage of subjects with AEs by SOC and by PT will be calculated.  Incidence (%) by 
causal relationship with study drug and by severity (CTCAE v5.0) will also be calculated.  
For clinically significant events, time of onset, and recovery will be reported.
Adverse events will be summarized for descriptive purposes by age (2 to <6, 6 to <18, and 
≥18), and sex.
The number (percentage) of subjects with TEAEs leading to death will be summarized by 
MedDRA SOC and PT for each treatment group.  A subject data listing of all AEs leading to 
death will be provided.  All deaths will also be summarized.
The number (percentage) of subjects with treatment-emergent SAEs will be summarized by 
MedDRA SOC and PT for each treatment group.  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 for each treatment group. A subject data 
listing of all AEs leading to discontinuation from study drug will be provided.
8.7.1.8.3
LABORATORY VALUES
Laboratory results will be summarized using Système International (SI) units, as appropriate.  
For all quantitative parameters listed in Section 8.5.1.4.3, 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 treatment group using descriptive 
statistics.  Qualitative parameters listed in Section 8.5.1.4.3 will be summarized using 
frequencies (number and percentage of subjects), and changes from baseline to each 
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.  Within-treatment comparisons for each laboratory parameter will be based 
on shift tables that compare the baseline LNH classification to the LNH classification at each 
postbaseline visit and at the end of treatment.  Similar shift tables will also compare the 
baseline LNH classification to the LNH classification for the highest and lowest value during 
the treatment period.
8.7.1.8.4
VITAL SIGNS
Descriptive statistics for vital signs parameters (ie, systolic and diastolic BP, pulse, 
respiratory rate, temperature, weight, and height) and changes from baseline will be 
presented by visit and treatment group.
Percentiles for BP values (only for subjects <18 years old) will also be summarized using a 
shift table of worst postbaseline from Baseline measurement by categories (<90th percentile, 
Page 356 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 88 of 119
90th to 95th percentile, 95th to ≤99th percentile, systolic BP or diastolic BP >99th 
percentile).  See Appendix 6 and Appendix 7 for detail on percentiles.
8.7.1.8.5
ELECTROCARDIOGRAMS
Descriptive statistics for electrocardiogram parameters (HR, PR, QRS, QT, QTcB, QTcF and 
RR) and changes from Baseline will be presented by visit. Electrocardiogram (ECG)
findings will be summarized. A shift table of worst postbaseline values from Baseline for 
ECG findings will be provided.
QTc Bazett and QTc Fridericia will be summarized.  QTc Bazett and QTc Fridericia will be 
categorized as both maximum increases from Baseline and maximum postbaseline values.
8.7.1.8.6
OTHER SAFETY ANALYSES
Descriptive summary statistics for LVEF changes from baseline will be calculated and 
summarized.
The shift of worst postbaseline proteinuria from Baseline will be summarized.
Thyroid-stimulating hormone values will be summarized in 2 categories (≤ULN and >ULN).
Lansky play scores or Karnofsky Performance Status score scores will be summarized by 
shifts from Baseline to worst postbaseline visit.
Radiographic findings of proximal tibial growth plates will be listed and analyzed if 
appropriate.
8.7.1.9
Other Analyses
8.7.1.9.1
HEALTH-RELATED QUALITY OF LIFE 
Descriptive statistics will be presented for all PedsQL endpoints at each analysis time period
by treatment arm. Baseline is defined as the later value of Day -1 or at Cycle 1 Day 1 prior 
to treatment. 
This will be collected at baseline, at C2D1, C3D1, Week 18, C8D1, C18 D1 and at the 
Off-Treatment Visit.  Score change from baseline in PedsQL at each analysis timepoint will 
be analyzed. Primary timepoint for assessment is at week 18 for all PedsQL endpoints.  
Detailed HRQoL analysis plan will be provided in a separate analysis plan and the results 
will be provided in a stand-alone report.
8.7.1.9.2
PALATABILITY AND ACCEPTABILITY QUESTIONNAIRE
Measurement of palatability will be assessed using the Hedonic scale (Guinard, 2001) which 
is a Visual Analog Scale (VAS) in subjects receiving the suspension formulation in the study.
Page 357 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 89 of 119
8.7.2
Determination of Sample Size
A binomial-based comparison of 2 proportions using correction for continuity was used for 
sample size estimation.  A total sample size of 72 subjects is estimated to achieve 80% 
statistical power at 1-sided alpha of 0.1 to detect a difference of 30% based on the 
assumption that PFS-4m for Arm A (lenvatinib arm) is 55% and for Arm B is 25%.  Alpha is 
the type 1 error probability of declaring lenvatinib arm being effective when the true 
lenvatinib arm PFS-4m rate is only 25%.
8.7.3
Interim Analysis
No interim analysis is planned for this study.
The safety monitoring will be conducted by the independent data monitoring committee 
(IDMC).  The frequency of the safety reviews will be defined in the IDMC charter.  Minutes 
from the open meetings of the IDMC will be provided if requested by regulatory agencies.  
The recommendation of whether to stop the study for safety will be reached by the IDMC 
based on their review of safety data with treatment information.  The function and 
membership of the IDMC will be described in the IDMC charter.
8.7.4
Other Statistical/Analytical Issues
Not applicable.
8.7.5
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.
Page 358 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 90 of 119
9
REFERENCE LIST
Bacci G, Briccoli A, Longhi A, Ferrari S, Mercuri M, Faggioli F, et al. Treatment and 
outcome of recurrent osteosarcoma: experience at Rizzoli in 235 patients initially treated 
with neoadjuvant chemotherapy. Acta Oncol. 2005;44(7):748-55.
Briccoli A, Rocca M, Salone M, Bacci G, Ferrari S, Balladelli A, et al. Resection of recurrent 
pulmonary metastases in patients with osteosarcoma. Cancer. 2005 Oct 15;104(8):1721-5.
Casali PG, Bielack S, Abecassis N, Aro HT, Bauer S, Biagini R, ESMO Guidelines 
Committee, PaedCan and ERN EURACAN, et al. Bone sarcomas: ESMO-PaedCan-
EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 
2018 Oct 1;29(Suppl 4):iv79-iv95.
Cancer Therapy Evaluation Program, Common Terminology Criteria for Adverse Events 
(CTCAE) version 5.0 [published 27 November 2017. Available from:  
https://ctep.cancer.gov/protocoldevelopment/.../ctcae_v5_quick_reference_5x7.pdf.
Chou AJ, Merola PR, Wexler LH, Gorlick RG, Vyas YM, Healey JH, et al. Treatment of 
osteosarcoma at first recurrence after contemporary therapy: the Memorial Sloan-Kettering 
Cancer Center experience. Cancer. 2005 Nov 15;104(10):2214-21.
Cole TJ., Bellizzi MC., Flegal KM, Dietz WH: Establishing a standard definition for child 
overweight and obesity worldwide: international survey. BMJ. 2000;320:1240.
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.
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New 
response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J 
Cancer. 2009;45(2):228-47.
ESMO/European Sarcoma Network Working Group. Bone sarcomas: ESMO Clinical 
Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2014;25(3):113–23.
Ferrari S, Briccoli A, Mercuri M, Bertoni F, Picci P, Tienghi A, et al. Postrelapse survival in 
osteosarcoma of the extremities: Prognostic factors for long-term survival. J Clin Oncol. 
2003;21(4):710-5.
Ferrari S, Serra M. An update on chemotherapy for osteosarcoma. Expert Opin 
Pharmacother. 2015;16(18):2727-36.
Gaspar N, Casanova M, Bautista Sirvent FJ, Venkatramani R, Morland B, Gambart M, et al. 
Single agent expansion cohort of lenvatinib (LEN) and combination dose-finding cohort of 
LEN + etoposide (ETP) + ifosfamide (IFM) in patients (pts) aged 2 to ≤ 25 years with 
relapsed/refractory osteosarcoma (OS). Poster presented at the International Society for 
Paediatric Oncology (SIOP); 2018 Nov 16–19; Kyoto, Japan.
Page 359 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 91 of 119
Gaspar N, Bautista Sirvent FJ, Venkatramani R, Longhi L, Lervat C, Casanova M, et al.  
Phase 1 combination dose-finding/phase 2 expansion cohorts of lenvatinib + etoposide + 
ifosfamide in patients (pts) aged 2 to ≤25 years with relapsed/refractory (r/r) osteosarcoma. 
Poster presented at the: European Society for Medical Oncology (ESMO) meeting; 
September 27 to October 1, 2019; Barcelona, Spain 2019.
Gorlick R, Khanna C. Osteosarcoma. J Bone and Mineral Research. 2010;25(4): 683–691.
Guinard FX. Sensory and consumer testing with children. Trends Food Sci Technol
2001;11:273–83.
Hawkins DS, Arndt CA. Pattern of disease recurrence and prognostic factors in patients with 
osteosarcoma treated with contemporary chemotherapy. Cancer. 2003 Dec 1;98(11):2447-56.
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.
Howlader N, Noone AM, Krapcho M, Miller D, Brest A, Yu M, Ruhl J, Tatalovich Z, 
Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA (eds). SEER Cancer Statistics 
Review, 1975-2016, National Cancer Institute. Bethesda, MD. Available from: 
https://seer.cancer.gov/csr/1975_2016/, based on November 2018 SEER data submission, 
posted to the SEER web site, April 2019.
Isakoff MS, Bielack SS, Meltzer P, Gorlick R. Osteosarcoma: Current treatment and a 
collaborative pathway to success. J Clin Oncol. 2015;33(27):3029-35.
Kaatsch P. Epidemiology of childhood cancer. Cancer Treat Rev. 2010;36(4):277-85.
Kato Y, Tabata K, Kimura T, Yachie-Kinoshita A, Ozawa Y, Yamada K, et al. Lenvatinib 
plus anti-PD-1 antibody combination treatment activates CD8+ T cells through reduction of 
tumor-associated macrophage and activation of the interferon pathway. PLoS ONE. 
2019;14(2):e0212513.
Kempf-Bielack B, Bielack SS, Jürgens H, Branscheid D, Berdel WE, Exner GU, et al. 
Osteosarcoma relapse after combined modality therapy: an analysis of unselected patients in 
the Cooperative Osteosarcoma Study Group (COSS). J Clin Oncol. 2005;23(3):559-68.
Kimura T, Kato Y, Ozawa Y, et al. Immunomodulatory activity of lenvatinib contributes to
antitumor activity in the Hepa1-6 hepatocellular carcinoma model. Cancer Sci. 
2018;109:3993–4002.
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.
Page 360 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 92 of 119
Leary SE, Wozniak AW, Billups CA, Wu J, McPherson V, Neel MD, et al. Survival of 
pediatric patients after relapsed osteosarcoma: the St. Jude Children's Research Hospital 
experience. Cancer. 2013;119(14):2645-53.
Le Vu B, de Vathaire F, Shamsaldin A, Hawkins MM, Grimaud E, Hardiman C, Diallo I, 
Vassal G, Bessa E, Campbell S, Panis X, Daly-Schveitzer N, Lagrange JL, Zucker JM, 
Eschwège F, Chavaudra J, Lemerle J. Radiation dose, chemotherapy and risk of 
osteosarcoma after solid tumours during childhood. Int. J. Cancer. 1998;77:370–377.
Meazza C, Scanagatta P. Metastatic osteosarcoma: a challenging multidisciplinary treatment. 
Expert Rev Anticancer Ther. 2016 May;16(5):543-56. 
Mirabello L, Troisi RJ, Savage SA: Osteosarcoma incidence and survival rates from 1973 to 
2004: data from the Surveillance, Epidemiology, and End Results Program. Cancer. 
2009;115(7):1531-43.
Morris NM, Udry JR. Validation of a self-administered instrument to assess stage of 
adolescent development. J Youth Adolesc. 1980;9(3):271-80.
NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) Bone Cancer. 
Version 1.2020 – August 12, 2019.  
Ogden CL, Flegal KM, Carroll MD, Johnson CL. Prevalence and trends in overweight 
among US children and adolescents, 1999-2000. JAMA. 2002;288:1728–32.
O'Toole DM, Golden AM. Evaluating cancer patients for rehabilitation potential. West J 
Med. 1991;155:384-7.
Schwartz GJ, Gauthier B. A simple estimate of glomerular filtration rate in adolescent boys. J 
Pediatr. 1985 Mar;106(3):522-6.
Tuettenberg J, Friedel C, Vajkoczy P. Angiogenesis in malignant glioma--a target for 
antitumor therapy? Crit Rev Oncol Hematol. 2006;59(3):181-93.
Ward E, DeSantis C, Robbins A, Kohler B, Jemal A. Childhood and adolescent cancer 
statistics. 2014. Cancer J Clin. 2014 Mar-Apr;64(2):83-103.
Page 361 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 93 of 119
10 PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE 
PROCEDURES)
10.1
Changes to the Protocol
Any change to the protocol requires a written protocol amendment or administrative change 
that must be approved by the sponsor before implementation.  Amendments specifically 
affecting the safety of subjects, the scope of the investigation, or the scientific quality of the 
study require submission to health or regulatory authorities as well as additional approval by 
the applicable IRBs/IECs.  These requirements should in no way prevent any immediate 
action from being taken by the investigator, or by the sponsor, in the interest of preserving 
the safety of all subjects included in the study.  If the investigator determines that an 
immediate change to or deviation from the protocol is necessary for safety reasons to 
eliminate an immediate hazard to the subjects, the sponsor’s medical monitor and the 
IRB/IEC for the site must be notified immediately.  The sponsor must notify the health or 
regulatory authority as required per local regulations.
Protocol amendments that affect only administrative aspects of the study may not require 
submission to health or regulatory authority or the IRB/IEC, but the health or regulatory 
authority and IRB/IEC (or if regionally required, the head of the medical institution) should 
be kept informed of such changes as required by local regulations.  In these cases, the 
sponsor may be required to send a letter to the IRB/IEC and the Competent Authorities (or, if 
regionally required, the head of the medical institution) detailing such changes.
10.2
Adherence to the Protocol
The investigator will conduct the study in strict accordance with the protocol (refer to 
ICH E6, Section 4.5).
10.3
Monitoring Procedures
The sponsor’s/CRO’s CRA will maintain contact with the investigator and designated staff 
by telephone, letter, or email between study visits.  Monitoring visits to each site will be 
conducted by the assigned CRA as described in the monitoring plan.  The investigator (or if 
regionally required, the head of the medical institution) will allow the CRA to inspect the 
clinical, laboratory, and pharmacy facilities to assure compliance with GCP and local 
regulatory requirements.  The CRFs and subject’s corresponding original medical records 
(source documents) are to be fully available for review by the sponsor’s representatives at 
regular intervals.  These reviews verify adherence to study protocol and data accuracy in 
accordance with local regulations.  All records at the site are subject to inspection by the 
local auditing agency and to IRB/IEC review.
In accordance with ICH E6, Section 1.52, source documents include, but are not limited to,
the following:

Clinic, office, or hospital charts
Page 362 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 94 of 119

Copies or transcribed health care provider notes that have been certified for accuracy 
after production

Recorded data from automated instruments such as IVRS, 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

Electronic Patient-Reported Outcome by self-reported measures
10.4
Recording of Data
A CRF is required and must be completed for each subject by qualified and authorized 
personnel.  All data on the CRF must reflect the corresponding source document, except 
when a section of the CRF itself is used as the source document.  Any correction to entries 
made on the CRF must be documented in a valid audit trail where the correction is dated, the 
individual making the correct is identified, the reason for the change is stated, and the 
original data are not obscured.  Only data required by the protocol for the purposes of the 
study should be collected.
The investigator must sign each CRF.  The investigator will report the CRFs to the sponsor 
and retain a copy of the CRFs.
10.5
Identification of Source Data
All data to be recorded on the CRF must reflect the corresponding source documents.  
10.6
Retention of Records
The circumstances of completion or termination of the study notwithstanding, the 
investigator (or if regionally required, the head of the medical institution or the designated 
representative) is responsible for retaining all study documents, including but not limited to 
the protocol, copies of CRFs, the Investigator’s Brochure, and regulatory agency registration 
documents (eg, Form FDA 1572 for US sites), Investigator and Site Information Form (for 
non-US sites), ICFs, and IRB/IEC correspondence). The site should plan to retain study 
Page 363 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 95 of 119
documents, as directed by the sponsor, for at least 15 years following the completion of the 
study.
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.
10.7
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.
10.8
Handling of Study Drug
All study drug will be supplied to the principal investigator (or a designated pharmacist) by 
the sponsor.  Drug supplies must be kept in an appropriate secure area (eg, locked cabinet) 
and stored according to the conditions specified on the drug labels.  The investigator (or a 
designated pharmacist) must maintain an accurate record of the shipment and dispensing of 
the study drug in a drug accountability ledger, a copy of which must be given to the sponsor 
at the end of the study.  An accurate record of the date and amount of study drug dispensed to 
each subject must be available for inspection at any time.  The CRA will visit the site and 
review these documents along with all other study conduct documents at appropriate 
intervals once study drug has been received by the site.
All drug supplies are to be used only for this study and not for any other purpose.  The 
investigator (or site personnel) must not destroy any drug labels or any partly used or unused 
drug supply before approval to do so by the sponsor.  At the conclusion of the study and as 
appropriate during the study, the investigator (or a designated pharmacist) will return all used 
and unused drug containers, drug labels, and a copy of the completed drug disposition form 
to the sponsor’s CRA (or designated contractor) or, when approval is given by the sponsor, 
will destroy supplies and containers at the site.
10.9
Publication of Results
All manuscripts, abstracts, or other modes of presentation arising from the results of the 
study must be reviewed and approved in writing by the sponsor in advance of submission 
pursuant to the terms and conditions set forth in the executed Clinical Trial Agreement 
between the sponsor/CRO and the institution/investigator.  The review is aimed at protecting 
the sponsor's proprietary information existing either at the date of the commencement of the 
study or generated during the study.
The detailed obligations regarding the publication of any data, material results, or other 
information generated or created in relation to the study shall be set out in the agreement 
between each investigator and the sponsor or CRO, as appropriate.
Page 364 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 96 of 119
10.10 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.
10.11 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.
10.12 Subject Insurance and Indemnity
The sponsor will provide insurance for any subjects participating in the study in accordance 
with all applicable laws and regulations.
Page 365 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 97 of 119
11 APPENDICES
Appendix 1
Response Evaluation Criteria in Solid Tumors 
(RECIST) 1.1
Tumor response assessments in this clinical study 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 study 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.
Page 366 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 98 of 119
Appendix 2
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.
Page 367 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 99 of 119
Appendix 3
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.
Page 368 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 100 of 119
Appendix 4
Preparation of Lenvatinib suspension
Preparation of suspension Prepare the suspension as illustrated by either method. Prepare the suspension 
with water or apple juice. The suspension should be directly injected into the mouth of the subjects and should 
not be washed down with additional fluid.  The suspension should be taken immediately after preparation.
a.
Procedure for suspension administration by syringe
 
A: Water or apple juice
B: Cap
C: Syringe (20 mL, Baxa preferred)
D: Syringe for rinse (20 mL, Baxa preferred)
Place one capsule* into a syringe. The tip port of the syringe needs 
to be closed with a cap.
* One to five capsules are allowed to be placed in a syringe.
Three (3) mL of water or apple juice is added into the syringe using 
another (new) syringe.
Insert a piston into the syringe (cylinder) about 2 cm from the end. 
Leave the syringe for not less than 10 minutes.
Page 369 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 101 of 119
After 10 minutes leaving, shake the syringe for not less than 3 
minutes to dissolve the capsule shell completely and to suspend 
granules (capsule shell needs to be dissolved. It is fine as long 
as granules are well suspended).
Remove the cap from the syringe. 
By sliding the piston, push air out from the syringe, and then 
administer the 3mL of suspension from the syringe.
Rinse step
After the administration of 3mL suspension from the syringe, 
the cap (reuse) is to be connected with the syringe.
2 mL of water or apple juice is to be taken by another (new) 
syringe.
2 mL of water or apple juice is to be poured into the syringe 
(which was used for the 3mL suspension).
Page 370 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 102 of 119
After connecting the cap (reuse), the syringe is to be shaken 
for 10 times.
After removing the cap from the syringe, push air out from the 
syringe, and then 2 mL of rinse liquid is to be administered.
Total volume of suspension to be administrated is 5 ml (=3mL for suspension + 2mL for rinse) for one to 
five capsules.
b. Procedure of suspension administering by syringe with NG 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 one capsule* into a syringe. The tip port of the syringe 
needs to be closed with a cap.
* One to five capsules are allowed to be placed in a syringe.
Page 371 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 103 of 119
The 3 mL of water or apple juice is to be poured into the syringe 
using another (new) syringe.
Insert a piston into the syringe (cylinder) about 2 cm from the 
end. 
Leave the syringe for is not less than 10 minutes.
After 10 minutes leaving, shake the syringe for not less than 3 
minutes to dissolve the capsule shell completely and to suspend 
granules (capsule shell needs to be dissolved, but it is fine as long 
as granules are well suspended).
Remove the cap from the syringe. 
By sliding the piston, push air out from the syringe.
After connecting a NG tube with the syringe, administrate the 3 
mL of suspension through the NG tube.
Page 372 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 104 of 119
Rinse step
After pouring the suspension, the NG tube is to be taken off from 
the syringe.
The cap (reuse) is connected with the syringe
Two 2 mL of water or apple juice is to be poured into the syringe 
by using another (new) syringe.
After inserting the piston to the syringe (about 2cm from the end), 
shake the syringe for 10 times.
By sliding the piston, push out air from the syringe. 
After connecting a NG tube, the 2 mL of rinse liquid is to be 
administered from the syringe through the NG tube.
Total volume of suspension to be administrated is 5 ml (=3mL 
for suspension + 2mL for rinse) for one to five capsules.
Page 373 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 105 of 119
Appendix 5
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-G000-230- Palatability Questionnaire
Page 374 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 106 of 119
(Please circle according to your experience)
Mouth Feel (how does it 
feel in your mouth?)
(Please circle according to your experience)
Overall Acceptability
Page 375 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 107 of 119
Appendix 6
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
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
Page 376 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 108 of 119
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
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/
Page 377 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 109 of 119
Appendix 7
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
11
50th
100
101
102
103
105
106
107
60
60
60
61
62
63
63
Page 378 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 110 of 119
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
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/
Page 379 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 111 of 119
Appendix 8
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
Page 380 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 112 of 119
Appendix 9
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.ht
Page 381 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 113 of 119
Appendix 10
Tanner’s Staging
Boys Tanner Stage progression scale*
Genitalia:
1= The testes, scrotum and penis are about the same size and shape as they were when you were 
a child
2= The testes and scrotum are bigger.  The skin of the scrotum has changed.  The scrotum, the 
sack holding the testes, has gotten lower.  The penis has gotten only a little bigger.
3= The penis has grown in length.  The testes and scrotum have grown and dropped lower.
4= The penis has gotten even bigger.  It is sider.  The glans (the head of the penis) is bigger.  The 
scrotum is darker than before. It is bigger because the testes are bigger.
5= The penis, scrotum, and testes are the size and shape of an adult man.
Pubic Hair:
1= There is no pubic hair at all.
2= There is a little soft, long, lightly-colored hair. Most of the hair is at the base of the penis.
This hair may be straight or a little curly.
3= The hair is darker in this stage. It is more curled. It has spread out and thinly covers a bigger 
area.
4= the hair is now as dark, curly, and course as that of an adult man.  The area that the hair 
covers is not as big as that of an adult man.  The hair has NOT spread out to the legs.
5= The hair has spread out to the legs.  The hair is now like that of an adult man. It covers the 
same area as that of an adult man.
Girls Tanner Stage progression scale
Breast:
1= The nipple is raised a little. The rest of the breast is still flat.
2= This is the breast bud stage.  In this stage, the nipple is raised more than in stage 1.  The 
breast is a small mound.  The areola is larger than stage 1.
3= The breast and areola are both larger than in stage 2.  The areola does not stick out away from 
the breast.
Page 382 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 114 of 119
4= The areola and the nipple make up a mound that sticks up above the shape of the breast.  
NOTE:  This stage may not happen at all for some girls.  Some girls develop from stage 3 to 
stage 5 with no stage 4
5= This is the mature adult stage.  The breasts are fully developed. Only the nipple sticks out in 
this stage.  The areola has moved back in the general shape of the breast.
Pubic Hair:
1= There is no pubic hair at all.
2= There is a little soft, long lightly-colored hair.  This hair may be straight or a little curly.
3= The hair is darker in this stage. It is coarser more curled. It has spread out and thinly covers 
a bigger area.
4= the hair is now as dark, curly, and course as that of an adult female. The area that the hair 
covers is not as big as that of an adult female. The hair has NOT spread out to the legs.
5= The hair is now like that of an adult female. It covers the same area as that of an adult 
female. The hair usually forms a triangular (V) pattern as it spreads out to the legs.
*Adapted from: Morris, N.M., and Udry, J.R., (1980).  Validation of a Self-Administered Instrument to Assess 
Stage of Adolescent Development. Journal of Youth and Adolescence, Vol. 9, No. 3: 271-80.
Page 383 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 115 of 119
Appendix 11
Pharmacodynamic, and Other Biomarker Research
Subjects enrolled in this clinical study will have biologic samples collected for 
pharmacodynamic (PD), 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.
Collection of the PD, and other biomarker samples will be bound by the sample principles and 
processes outlined in the main study protocol.  Sample collection for PD, 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.
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 
Page 384 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 116 of 119
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 study 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.
Given the research nature of the PD, 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, 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 
Page 385 of 388


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 117 of 119
should only occur when data have been validated by multiple studies and testing has been done 
in CLIA-approved laboratories.
Page 386 of 388


Page 387 of 388
PPD
PPD
PPD
PPD


Clinical Study Protocol
E7080-G000-230
Eisai
FINAL: 08 Oct 2019
Confidential
Page 119 of 119
INVESTIGATOR SIGNATURE PAGE
Study Protocol Number:
E7080-G000-230
Study Protocol Title:
A Multicenter, Open-label, Randomized Phase 2 Study to 
Compare the Efficacy and Safety of Lenvatinib in Combination 
with Ifosfamide and Etoposide versus Ifosfamide and Etoposide 
in Children, Adolescents and Young Adults with Relapsed or 
Refractory Osteosarcoma (OLIE)
Investigational Product
Name:
E7080/Lenvatinib 
IND Number:
146642
EudraCT Number:
2019-003696-19
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
.
Page 388 of 388

SAP_005.pdf: 
Statistical Analysis Plan 
E7080-G000-230 
 
Eisai 
Confidential 
Page 1 of 40 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
Study Protocol 
Number: 
E7080-G000-230 
 
 
Study Protocol 
Title: 
A Multicenter, Open-label, Randomized Phase 2 Study to Compare the 
Efficacy and Safety of Lenvatinib in Combination with Ifosfamide and 
Etoposide versus Ifosfamide and Etoposide in Children, Adolescents and 
Young Adults with Relapsed or Refractory Osteosarcoma (OLIE) 
 
Date:  
15 June 2022 
 
 
Version: 
Final Version 3.0 
 
 
 
 
 
 


Statistical Analysis Plan 
E7080-G000-230 
 
 
Eisai 
Confidential 
Page 2 of 40 
 
1 
TABLE OF CONTENTS 
1 
TABLE OF CONTENTS ...................................................................................................2 
2 
VERSION HISTORY ........................................................................................................5 
3 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ....................................7 
4 
INTRODUCTION .............................................................................................................9 
4.1 
Study Objectives ......................................................................................................9 
4.1.1 
Primary Objective ..........................................................................................9 
4.1.2 
Secondary Objectives .....................................................................................9 
4.1.3 
Exploratory Objectives ..................................................................................9 
4.2 
Overall Study Design and Plan ..............................................................................10 
4.2.1 
Prerandomization Phase ...............................................................................11 
4.2.1.1 
Screening Period ................................................................................11 
4.2.1.2 
Baseline Period ..................................................................................11 
4.2.2 
Randomization Phase ...................................................................................11 
4.2.2.1 
Treatment Period ................................................................................12 
4.2.2.2 
Follow-up Period ...............................................................................12 
4.2.3 
Extension Phase ...........................................................................................13 
4.2.3.1 
Treatment Period ................................................................................13 
4.2.3.2 
Follow-Up Period...............................................................................13 
4.2.4 
Optional Lenvatinib Crossover (for Subjects in Arm B Only) ....................13 
5 
DETERMINATION OF SAMPLE SIZE ........................................................................14 
6 
STATISTICAL METHODS ............................................................................................14 
6.1 
Study Endpoints .....................................................................................................15 
6.1.1 
Primary Endpoint .........................................................................................15 
6.1.2 
Secondary Endpoints ...................................................................................15 
6.1.3 
Exploratory Endpoints .................................................................................16 
6.2 
Study Subjects ........................................................................................................16 
6.2.1 
Definitions of Analysis Sets.........................................................................16 
6.2.2 
Subject Disposition ......................................................................................17 
6.2.3 
Protocol Deviations ......................................................................................18 
6.2.4 
Demographic and Other Baseline Characteristics .......................................18 
6.2.4.1 
Medical History .................................................................................19 
6.2.5 
Prior and Concomitant Therapy ...................................................................20 
6.2.6 
Treatment Compliance .................................................................................20 
6.3 
Data Analysis General Considerations ..................................................................20 
6.3.1 
Pooling of Centers........................................................................................20 
6.3.2 
Adjustments for Covariates..........................................................................20 
6.3.3 
Multiple Comparisons/Multiplicity .............................................................21 
6.3.4 
Examination of Subgroups ...........................................................................21 


Statistical Analysis Plan 
E7080-G000-230 
 
 
Eisai 
Confidential 
Page 3 of 40 
 
6.3.5 
Handling of Missing Data, Dropouts, and Outliers .....................................22 
6.4 
Efficacy Analyses ..................................................................................................22 
6.4.1 
Primary Efficacy Analysis ...........................................................................22 
6.4.2 
Secondary Efficacy Analyses ......................................................................25 
6.4.2.1 
PFS-4m and PFS-1y Rate by IIR .......................................................25 
6.4.2.2 
Overall Survival .................................................................................25 
6.4.2.3 
Overall Response Rate (ORR) and ORR-4m by IIR .........................26 
6.4.2.4 
Duration of Response, Disease Control Rate, and Clinical Benefit 
Rate by IIR .........................................................................................26 
6.4.2.5 
PFS, PFS-4m, PFS-1y, ORR-4m, ORR, DOR, DCR, and CBR by 
Investigator Assessment .....................................................................26 
6.4.2.6 
Subjects Achieving Complete Resection ...........................................26 
6.4.2.7 
Maximum Tumor Shrinkage ..............................................................26 
6.5 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other 
Biomarker Analyses ...............................................................................................27 
6.5.1 
Pharmacokinetic Analyses ...........................................................................27 
6.5.2 
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Analyses ....27 
6.6 
Safety Analyses ......................................................................................................27 
6.6.1 
Extent of Exposure .......................................................................................27 
6.6.1.1 
Extent of Exposure of Study Drug .....................................................27 
6.6.1.2 
Study Drug Administration ................................................................28 
6.6.1.3 
Study Drug Dose Modifications ........................................................28 
6.6.2 
Adverse Events ............................................................................................29 
6.6.2.1 
Overview of TEAEs ...........................................................................30 
6.6.2.2 
All TEAEs ..........................................................................................30 
6.6.2.3 
Treatment-related TEAEs ..................................................................30 
6.6.2.4 
Treatment-emergent SAEs .................................................................30 
6.6.2.5 
TEAEs Leading to Treatment Discontinuation ..................................31 
6.6.2.6 
TEAEs Leading to Dose Reductions and Dose Interruptions ............31 
6.6.2.7 
Grade 3 or Higher TEAEs ..................................................................31 
6.6.2.8 
TEAEs with Fatal Outcome ...............................................................31 
6.6.2.9 
Deaths ................................................................................................31 
6.6.2.10 
Adverse Events of Clinical Interest ...................................................31 
6.6.3 
Laboratory Values ........................................................................................32 
6.6.3.1 
Hematology and Clinical Chemistry ..................................................32 
6.6.3.2 
Thyroid-Stimulating Hormone ...........................................................33 
6.6.3.3 
Urinalysis ...........................................................................................33 
6.6.4 
Vital Signs ....................................................................................................33 
6.6.5 
Other Safety Analyses ..................................................................................33 
6.6.5.1 
Electrocardiograms ............................................................................33 
6.6.5.2 
Left Ventricular Ejection Fraction .....................................................34 
6.6.5.3 
Lansky Play Scores or Karnofsky Performance Status Scores ..........34 
6.6.5.4 
Proximal Tibial Growth Plates...........................................................34 
6.6.5.5 
Tanner Stage ......................................................................................34 


Statistical Analysis Plan 
E7080-G000-230 
 
 
Eisai 
Confidential 
Page 4 of 40 
 
6.6.5.6 
Dental Examination ...........................................................................34 
6.6.5.7 
New Anticancer Therapies During Follow-up Period .......................35 
6.7 
Other Analyses .......................................................................................................35 
6.7.1 
Palatability ...................................................................................................35 
6.7.2 
Health-Related Quality of Life ....................................................................35 
6.8 
Exploratory Analyses .............................................................................................35 
7 
INTERIM ANALYSES ...................................................................................................35 
8 
CHANGES IN THE PLANNED ANALYSES ...............................................................35 
9 
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING ...............................36 
9.1 
Visit Windows .......................................................................................................36 
9.2 
Baseline Definitions ...............................................................................................36 
9.3 
Imputation of Missing Data ...................................................................................36 
9.4 
Variable Derivations ..............................................................................................37 
9.4.1 
Duration of Events Prior to Randomization.................................................37 
9.5 
Pharmacokinetics/Pharmacodynamics Data Handling ..........................................37 
10 PROGRAMMING SPECIFICATIONS ..........................................................................37 
11 STATISTICAL SOFTWARE ..........................................................................................37 
12 MOCK TABLES, LISTINGS, AND GRAPHS ..............................................................37 
13 REFERENCES ................................................................................................................38 
14 APPENDICES .................................................................................................................39 
 
 
 


Statistical Analysis Plan 
E7080-G000-230 
 
 
Eisai 
Confidential 
Page 5 of 40 
 
2 
VERSION HISTORY 
Version 
Description 
Date 
1.0 
Initial Version 
15Apr2020 
2.0 
Version based on Protocol Amendment 02 
- 
Revised primary objective and efficacy endpoint to 
progression-free survival (PFS), and changed PFS rate at 4 
months (PFS-4m) from primary to secondary objective and 
endpoint 
- 
The primary efficacy endpoint of PFS per IIR will be 
analyzed by the stratified log-rank test adjusting for the 
randomization stratification factors of “Age (<18 vs ≥18 
years)” and “Time to first relapse/refractory disease (early 
[<18 months] vs late [≥18 months])”. 
- 
Clarify that tumor efficacy endpoint(s) will be based on 
investigator and IIR evaluations. 
- 
Revised sample size calculation based on PFS, with the 
primary analysis being performed after 38 PFS events occur. 
- 
Add objective response rate (ORR) as a secondary endpoint. 
- 
Add 2 sensitivity analyses:  1) baseline tumor removal is 
considered part of the drug therapy, 2) PD or death after two 
or more missing assessments, or after receiving a new 
anticancer therapy will be considered as a PFS event.  
- 
Clarify exploratory endpoints 
- 
Revise the definition of the Randomization Phase to: 
The Randomization Phase will begin at the time of 
randomization of the first subject and will end on the data 
cutoff date for the primary analysis (ie, when approximately 
38 PFS events, as determined by IIR, are observed). 
- 
Revise the length of follow-up from “will continue as long as 
the subject is alive” to “will continue for up to 2 years after 
end of treatment for a subject” unless the subject withdraws 
consent, or is lost to follow-up, or the sponsor terminates the 
study. 
- 
Added Optional Lenvatinib Crossover Treatment for 
Subjects in Arm B who experience progressive disease. 
13Dec2021 
3.0 
- 
Updates to handling of subjects with removal of baseline 
lesions within 1) primary efficacy endpoint, 2) sensitivity 
analysis 1. 
- 
The primary efficacy endpoint of PFS per IIR will be 
analyzed by the stratified log-rank test with randomization 
06Jun2022 


Statistical Analysis Plan 
E7080-G000-230 
 
 
Eisai 
Confidential 
Page 6 of 40 
 
stratification factor of Age (<18 vs ≥18 years). Stratification 
factor of time to first relapse/refractory disease (early [<18 
months] vs late [≥18 months]) is removed due to small 
subject numbers for stratum ≥ 18 months based on blinded 
data review. 
- 
Addition of subgroup analyses for the primary efficacy 
endpoint, PFS: 
- 
Age (<18 years, ≥18 years)  
- 
Time to first relapse (<18 months, ≥18 months) 
- 
Sites of metastasis [Lung only, Others (+/- lung)] 
- 
Prior Ifosfamide +/- Etoposide (Yes, No) 
- 
Measurable disease [Yes (Subjects with at least 1 target 
lesion), No (Subjects with only non-target lesions)] 
- 
Multiple editorial updates 
- 
For DCR, change SD minimum duration period to 5 weeks 
from 7 weeks after randomization.  The change was made 
due to the tumor assessment schedule of every 6 weeks until 
Week 18. 
 
 
 


Statistical Analysis Plan 
E7080-G000-230 
 
 
Eisai 
Confidential 
Page 7 of 40 
 
3 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Term 
AE 
adverse event 
ATC 
anatomical therapeutic class 
BLQ  
below limit of quantification  
BMI 
body mass index 
BSA 
body surface area 
CBR  
clinical benefit rate  
CMQ  
customized MedDRA queries  
CR  
complete response  
CRF 
case report form 
CSAEs  
clinically significant adverse events  
CTCAE  
Common Terminology Criteria for Adverse Events 
DCR 
disease control rate 
DOR 
duration of response 
DBP 
diastolic blood pressure 
EMA  
European Medicines Agency  
HRQoL  
Health-Related Quality of Life  
IIR  
independent imaging review  
IRT 
interactive response technology 
ITT 
intent-to-treat 
K-M 
Kaplan-Meier 
KPS  
Karnofsky performance status  
LLT  
lower level term  
LVEF  
left ventricular ejection fraction  
MedDRA 
Medical Dictionary for Regulatory Activities 
NA  
not applicable  
NE  
not evaluable  
ORR  
objective response rate  
OS  
overall survival  
OS-1y 
overall survival rate at 1 year 


Statistical Analysis Plan 
E7080-G000-230 
 
 
Eisai 
Confidential 
Page 8 of 40 
 
Abbreviation 
Term 
PD 
pharmacodynamic(s) or progressive disease/disease progression 
PedsQL 
Pediatric Quality of Life Inventory 
PFS 
progression-free survival 
PFS-4m 
progression-free survival rate at 4 months 
PFS-1y 
progression-free survival rate at 1 year 
PK 
pharmacokinetic(s) 
PR 
partial response 
PRO 
patient-reported outcome 
PT 
preferred term 
QTc 
corrected QT interval 
QTcB 
corrected QT interval using Bazett’s correction factor 
QTcF 
corrected QT interval using Fridericia’s correction factor 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SBP 
systolic blood pressure 
SD 
standard deviation or stable disease  
SI 
Système International 
SMQs  
standardized MedDRA queries  
SOC  
system organ class  
TEAE 
treatment-emergent adverse event 
TLG 
tables, listings, and graphs 
TNM  
tumor-node-metastasis  
TSH 
thyroid stimulating hormone 
WHO DD 
World Health Organization Drug Dictionary 


Statistical Analysis Plan 
E7080-G000-230 
 
 
Eisai 
Confidential 
Page 9 of 40 
 
4 
INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to describe the procedures and the 
statistical methods that will be used to analyze and report results of the primary analysis for 
Eisai Protocol E7080-G000-230 Amendment 02.  Analyses on subjects’ Health-Related 
Quality of Life (HRQoL) data, pharmacokinetic (PK)/pharmacodynamics (PD), biomarkers, 
and relationships between PK and efficacy/safety will be included in separate statistical 
analysis plans. 
4.1 
Study Objectives 
4.1.1 
Primary Objective 
To evaluate whether lenvatinib in combination with ifosfamide and etoposide (Arm A) is 
superior to ifosfamide and etoposide (Arm B) in improving progression-free survival (PFS) 
by independent imaging review (IIR) using Response Evaluation Criteria In Solid Tumors 
(RECIST 1.1 [Eisenhauer, et al., 2009]), in children, adolescents, and young adults with 
relapsed or refractory osteosarcoma. 
4.1.2 
Secondary Objectives 
The secondary objectives of the study are to: 
1. Compare difference in PFS rate at 4 months (PFS-4m) between the 2 treatment arms per 
IIR 
2. Compare difference in PFS rate at 1 year (PFS-1y) between the 2 treatment arms per IIR 
3. Compare differences in overall survival (OS) and OS rate at 1 year (OS-1y) between the 
2 treatment arms 
4. Compare difference in objective response rate (ORR) at 4 months (ORR-4m) between the 
2 treatment arms per IIR 
5. Compare difference in objective response rate (ORR) between the 2 treatment arms per 
IIR  
6. Compare differences in safety and tolerability between the 2 treatment arms 
7. Characterize the PK of lenvatinib, when administered in combination with ifosfamide and 
etoposide 
8. Compare differences in HRQoL as assessed by using the Pediatric Quality of Life 
Inventory (PedsQL) Generic Core Scales and Cancer Module between the 2 treatment 
arms 
9. Assess the palatability and acceptability of the suspension formulation of lenvatinib in 
subjects receiving the suspension formulation in the study 
  
4.1.3 
Exploratory Objectives 
The exploratory objectives of the study are to: 


Statistical Analysis Plan 
E7080-G000-230 
 
 
Eisai 
Confidential 
Page 10 of 40 
 
1. Explore differences in duration of response (DOR), disease control rate (DCR), and 
clinical benefit rate (CBR) between the 2 treatment arms per IIR and investigator 
assessment+ 
2. Explore differences in PFS, PFS-4m, PFS-1y, ORR-4m, and ORR between the 2 
treatment arms per investigator assessment  
3. Compare between the 2 treatment arms: 
- the proportion of subjects who achieve complete removal of baseline lesion(s) 
- the proportion of subjects with unresectable baseline lesion(s) that are converted to 
resectable  
4. Investigate the relationship between subject tumor biomarkers and clinical response and 
toxicity of lenvatinib in combination with ifosfamide and etoposide 
 
4.2 
Overall Study Design and Plan 
This is a multicenter, randomized, open-label, parallel-group, Phase 2 study to compare the 
efficacy and safety of lenvatinib in combination with ifosfamide and etoposide versus 
ifosfamide and etoposide in children, adolescents, and young adults with relapsed or 
refractory osteosarcoma. 
Approximately 72 eligible subjects will be randomized to 1 of the following 2 treatment arms 
in a 1:1 ratio within the strata: 
• 
Arm A:  lenvatinib 14 mg/m2 (orally, once daily) plus ifosfamide 3000 mg/m2/day 
(intravenously [IV], Day 1 to Day 3 of each cycle for a total of up to 5 cycles) and 
etoposide 100 mg/m2/day (IV, Day 1 to Day 3 of each cycle for a total of up to 5 cycles) 
• 
Arm B:  ifosfamide 3000 mg/m2/day (IV, Day 1 to Day 3 of each cycle for a total of up to 
5 cycles) and etoposide 100 mg/m2/day (IV, Day 1 to Day 3 of each cycle for a total of up 
to 5 cycles) 
Randomization will follow a predefined randomization scheme based on the following 
stratification factors:  time to first relapse/refractory disease (early [<18 months] or late [≥18 
months]) and age (<18 and ≥18 years). 
Eisai will closely monitor enrolment, to ensure that at least 36 subjects are <17 years of age 
at the time of informed consent per regulatory requirement. 
The study will be conducted in 3 Phases:  a Prerandomization Phase, a Randomization Phase, 
and an Extension Phase. 
The end of the study will be the date of data cutoff for the final analysis or the time of last 
subject last visit, whichever occurs later. 
An overview of the study design is presented in Figure 1 in the Protocol. 


Statistical Analysis Plan 
E7080-G000-230 
 
 
Eisai 
Confidential 
Page 11 of 40 
 
4.2.1 
Prerandomization Phase 
The Prerandomization Phase will consist of 2 periods:  Screening and Baseline.  The 
Prerandomization Phase will last no longer than 28 days.  The Screening Period will establish 
protocol eligibility and the Baseline Period will confirm eligibility. 
4.2.1.1 
Screening Period 
Screening will occur between Day –28 and Day –2.  The purpose of the Screening Period is 
to obtain informed consent and to establish protocol eligibility.  Informed consent will be 
obtained after the study has been fully explained to each subject and before the conduct of 
any screening procedures or assessments.  Procedures to be followed when obtaining 
informed consent are detailed in Section 5.3 of the Protocol. 
Subjects must have a histologically or cytologically confirmed diagnosis of high grade 
refractory or relapsed osteosarcoma as detailed in the Inclusion Criteria (Section 9.3.1 of the 
Protocol). 
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. 
4.2.1.2 
Baseline Period 
The purpose of the Baseline Period is to confirm protocol eligibility as specified in the 
inclusion/exclusion criteria (as detailed in Section 9.3.1 and Section 9.3.2 of the Protocol).  
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 4 of the Protocol), 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 of the Protocol) will begin 
the Randomization Phase of this study. 
4.2.2 
Randomization Phase 
The Randomization Phase will consist of 2 periods:  Treatment Period and Follow-up Period.  
The Randomization Phase will begin at the time of randomization of the first subject and will 
end on the data cutoff date for the primary analysis (ie, when approximately 38 PFS events, 
as determined by IIR, are observed).  
After the data cutoff date for the primary analysis has occurred, all subjects who are still on 
study treatment will enter the Extension Phase. 


Statistical Analysis Plan 
E7080-G000-230 
 
 
Eisai 
Confidential 
Page 12 of 40 
 
4.2.2.1 
Treatment Period 
The Treatment Period for each subject will begin at the time of randomization and will end at 
the completion of the Off-Treatment Visit which will occur within 30 days after the final 
dose of study treatment. 
Subjects will receive study treatment as continuous 21-day cycles in both treatment arms.  
Treatment cycles will be counted continuously regardless of dose interruptions.  If 
chemotherapy administration is precluded on Day 1 of a treatment cycle, the subject may 
resume treatment once recovered at the discretion of the investigator.  Subsequent 
chemotherapy will be administered every 21 (±1) days starting from the timepoint it was 
resumed.  Subjects will undergo safety and efficacy assessments as defined in the Schedule 
of Procedures/Assessments (Table 5 of the Protocol).  Subjects randomized to Arm A will 
continue to receive lenvatinib until disease progression (PD) confirmed by IIR, development 
of unacceptable toxicity, subject request, withdrawal of consent, or study termination by the 
sponsor, whichever occurs first. 
Disease progression (PD) must be confirmed by IIR prior to the investigator discontinuing 
study treatment for a subject.  In situations where the investigator judges that alternative 
treatments must be instituted immediately for a subject’s safety, study drugs may be 
discontinued without waiting for IIR confirmation of radiographic evidence of PD.  If 
possible, before discontinuation of the subject from the study, the investigator should consult 
with the sponsor. 
4.2.2.2 
Follow-up Period 
The Follow-up Period begins the day after the Off-Treatment Visit and will continue for up 
to 2 years after end of treatment for a subject, unless the subject withdraws consent, or is lost 
to follow-up, or the sponsor terminates the study. 
Subjects may at any time withdraw consent for further study participation.  No further data 
will be collected on subjects once consent has been withdrawn; however, an investigator may 
consult public records to establish survival status if permitted by local regulations. 
All adverse events (AEs), including serious adverse events (SAEs), will be captured for 30 
days after the last dose of study drug. 
All subjects who end study treatment without IIR confirmed PD will continue to undergo 
tumor assessments every 6 weeks until Week 18, then every 9 weeks until Week 54, 
thereafter, every 12 weeks until IIR confirmation of radiographic evidence of PD as 
described in the tumor assessments in the assessment schedule, or until another anticancer 
therapy is initiated. 
 
Subjects in both Arm A and Arm B will be followed for survival every 12 weeks (±1 week) 
and all subsequent anticancer treatments received will be recorded.  Subjects who are being 


Statistical Analysis Plan 
E7080-G000-230 
 
 
Eisai 
Confidential 
Page 13 of 40 
 
followed for survival at the primary analysis (ie, at the end of the Randomization Phase) will 
continue to be followed for survival during the Follow-up Period of the Extension Phase. 
4.2.3 
Extension Phase 
The Extension Phase starts after completion of the Randomization Phase (data cutoff for 
primary analysis).  The Extension Phase will consist of 2 periods:  Treatment Period and 
Follow-up Period. 
4.2.3.1 
Treatment Period 
In the Treatment Period, subjects still on study treatment following the completion of the 
Randomization Phase will continue study treatment as outlined in Protocol Section 9.4.1 until 
disease progression, development of unacceptable toxicity, subject request, withdrawal of 
consent, or discontinuation of study by the sponsor.  Tumor assessments will be performed 
according to the local standard of care.  Independent imaging review (IIR) and confirmation 
of radiographic evidence of PD will not be required, and scans will no longer be required to 
be sent to the imaging core laboratory.  The Off-Treatment Visit will occur within 30 days 
after the final dose of study treatment.  All AEs, including SAEs will be captured up to 30 
days after last dose of study drug.  In case the study is discontinued by the sponsor, the 
sponsor will continue to provide study drug (outside the study) for subjects who have not met 
the criteria for study drug discontinuation. 
4.2.3.2 
Follow-Up Period 
The Follow-up Period will begin the day after the Off-Treatment Visit and will last for up to 
2 years after end of treatment for a subject, unless the study is terminated by the sponsor, or 
the subject discontinues due to withdrawal of consent, or is lost to follow-up.  Subjects will 
be treated by the investigator according to the prevailing local standard of care.  Subjects will 
be followed every 12 weeks (±1week) for survival and all subsequent anticancer treatments 
received will be recorded. 
4.2.4 
Optional Lenvatinib Crossover (for Subjects in Arm B Only) 
Subjects in Arm B with disease progression per RECIST 1.1 may be eligible for optional 
treatment with lenvatinib alone (after 5 cycles of chemotherapy) or lenvatinib plus 
chemotherapy (before 5 cycles of chemotherapy).  Note:  subjects may only receive a 
maximum of 5 cycles of chemotherapy for the duration of the study.  Optional Lenvatinib 
crossover treatment must be initiated within 30 days of documented disease progression. 
Optional lenvatinib crossover treatment is only available if the following conditions are met: 
- 
Subject experiences disease progression per RECIST 1.1 (as confirmed by IIR for all 
subjects who cross over prior to the start of the Extension Phase); and 
- 
No new systemic anticancer medication was administered after the last dose of study 
drugs; and 
- 
The subject meets all of the safety parameters listed in the inclusion criteria and none 
of the safety parameters listed in the exclusion criteria; and 


Statistical Analysis Plan 
E7080-G000-230 
 
 
Eisai 
Confidential 
Page 14 of 40 
 
- 
The study is ongoing. 
Treatment with lenvatinib alone or lenvatinib plus chemotherapy will continue until the next 
disease progression (per RECIST 1.1 as assessed by investigator only), development of 
unacceptable toxicity, subject request, or withdrawal of consent, whichever occurs first.  
Prior to optional lenvatinib crossover treatment, baseline tumor assessment must be re-
established (ie, new tumor assessment scans performed), unless the last tumor assessment 
scans were performed within 4 weeks prior to Cycle 1 Day 1 of the crossover treatment. 
Subjects who qualify to receive optional lenvatinib crossover treatment will be followed 
according to the schedule of procedures/assessments in Table 7 of the Protocol. 
5 
DETERMINATION OF SAMPLE SIZE 
A total sample size of 72 subjects is estimated for the primary efficacy endpoint of PFS.  A 
median PFS of 3.5 months for Arm B (control arm) has been assumed by comparing 
available PFS data from clinically active agents in this patient population (Davis, et al., 2019; 
Palmerini, et al, 2016; Grignani, et al., 2012).  With respect to Arm A (lenvatinib plus 
chemotherapy arm), a median PFS of 8.75 months is assumed based on the results from 
Study E7080-G000-207. 
Therefore, assuming a hazard ratio of 0.4, a 1-sided type 1 error rate of 0.025, and power of 
80%, the required number of PFS events for the study is 38.  The primary PFS analysis is 
estimated to occur at approximately 32 months after the first subject is randomized 
(assuming a 20-month enrollment period), and accounts for an overall dropout rate of up to 
40%.  This dropout rate includes the potential early dropouts and subjects who are censored 
before the data cutoff. 
6 
STATISTICAL METHODS 
In general, continuous variables will be summarized using descriptive statistics such as mean, 
SD, median, first quartile (Q1), third quartile (Q3), and range (minimum and maximum).  
Categorical variables will be summarized using frequency and percentage.  For time-to-event 
variables, the Kaplan-Meier (K-M) method will be used for descriptive summaries.  For the 
calculation of time-to-event or duration-of-event variables, the difference between the start 
date and the end date plus 1 day will be used.  For events (eg, baseline disease characteristics 
or prior therapies) prior to randomization, the durations will be calculated as the date of 
randomization minus the date of the event; the details are specified in Section 9.4.1. 
For any efficacy endpoint that involves complete response (CR) or partial response (PR), the 
endpoint will be calculated using the confirmed CR/PR, i.e., any CR or PR must be 
confirmed not less than 4 weeks following the initial achievement of the response. 


Statistical Analysis Plan 
E7080-G000-230 
 
 
Eisai 
Confidential 
Page 15 of 40 
 
6.1 
Study Endpoints 
Efficacy endpoints related to tumor assessments will be evaluated by IIR and investigator 
assessment during the randomization phase and investigator assessment only during the 
extension phase.  
6.1.1 
Primary Endpoint 
Progression-free survival (PFS) by IIR is defined as the time from the date of randomization 
to the date of the first documentation of PD or death (whichever occurs first) as determined 
by IIR using RECIST 1.1.   
 
6.1.2 
Secondary Endpoints 
1. Progression-free survival rate at 4 months (PFS-4m) by IIR is defined as the percentage 
of subjects who are alive and without PD at 4 months from the randomization date as 
determined by IIR of radiological imaging using RECIST 1.1.  The PFS-4m rate is 
estimated using the Kaplan-Meier (K-M) method. 
2. Progression-free survival rate at 1 year (PFS-1y rate) by IIR is defined as the percentage 
of subjects who are alive and without PD at 1 year from the randomization date as 
determined by IIR of radiological imaging using RECIST 1.1.  The PFS-1y rate is 
estimated using the K-M method. 
3. Overall survival (OS) is defined as the time from the date of randomization to 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 for the primary analysis, will be censored at the date the subject was 
last known to be alive, or date of data cutoff for the primary analysis, whichever occurs 
first.  Overall survival rate at 1 year (OS-1y) will be estimated using the K-M method. 
4. Objective response rate by IIR at 4 months (ORR-4m) is defined as the proportion of 
subjects who have best overall response of complete response (CR) or partial response 
(PR) as determined by IIR using RECIST 1.1 within the first 4 months. 
5. Objective response rate (ORR) by IIR is defined as the proportion of subjects who have 
best overall response of CR or PR as determined by IIR using RECIST 1.1. 
6. Safety will be assessed by summarizing the incidence of treatment-emergent adverse 
events (TEAEs) and SAEs together with all other safety parameters. 
7. Assessment of population-based PK parameters of lenvatinib. 
8. Score changes from baseline for all PedsQL scales including Generic Core Scales and 
Cancer Module.  Scores will be calculated for total generic score, total cancer score, each 
physical function subscale including physical health, psychosocial health, emotional 
function, social function, school/work function in the Generic Core Scales, and each 
subscale in the cancer module. 
9. Palatability and acceptability of the suspension formulation of lenvatinib in subjects 
receiving the suspension formulation in the study will be assessed by using the 
Palatability Questionnaire (see Appendix 4 of the Protocol). 
 


Statistical Analysis Plan 
E7080-G000-230 
 
 
Eisai 
Confidential 
Page 16 of 40 
 
6.1.3 
Exploratory Endpoints 
1. Duration of response (DOR) by IIR and investigator assessment is defined as the time 
from the date a response was first documented until the date of the first documentation of 
PD or date of death from any cause. 
2. Disease control rate (DCR) by IIR and investigator is the proportion of subjects who have 
a best overall response of CR or PR or stable disease (SD).  In this context, stable disease 
is defined as stable disease at ≥5 weeks after randomization to be considered best overall 
response. 
3. Clinical benefit rate (CBR) by IIR and investigator is the proportion of subjects who have 
best overall response of CR or PR or durable SD (duration of SD ≥23 weeks after 
randomization).  
4. Efficacy endpoints (PFS, PFS-4m, PFS-1y, ORR-4m, and ORR) evaluated based on 
investigator assessment. 
5. Proportion of subjects who achieve complete removal of baseline lesions and the 
proportion of subjects with unresectable baseline lesions(s) that are converted to 
resectable between the 2 treatment arms. 
6. Blood and tumor biomarkers will be assessed for identifying potential correlation with 
clinical outcomes-related endpoints. 
6.2 
Study Subjects 
6.2.1 
Definitions of Analysis Sets 
• 
The Full Analysis Set (Intent-to-Treat Analysis [ITT]) includes all randomized subjects 
regardless of the treatment actually received.  This is the primary analysis population 
used for the efficacy analyses which will be based on the ITT principle. 
• 
The Per Protocol Analysis Set includes those subjects from the ITT set who received at 
least 1 dose of any study drug, had no important protocol deviations, and had both 
baseline and at least one postbaseline tumor assessment. Subjects for whom death 
occurred prior to the first postbaseline tumor assessment will also be included. The per 
protocol analysis set will be the secondary analysis set for the primary efficacy endpoint. 
• 
The Safety Analysis Set includes subjects who received at least 1 dose of any study drug.  
This is the analysis population used for all safety analyses which will be based on the as-
treated principle. 
• 
Population Pharmacokinetic (PK) Analysis Set includes the subjects who have received 
at least 1 dose of lenvatinib with documented dosing history and have measurable plasma 
levels of lenvatinib. 
• 
The Pharmacodynamic Analysis Set includes subjects who received at least 1 dose of 
study drug and had sufficient pharmacodynamic data (eg, at least 1 evaluable/measurable 
pharmacodynamic parameter). 
• 
The HRQoL Analysis Set will consist of all randomized subjects who have received at 
least 1 dose of study medication, and have completed at least 1 patient-reported outcome 
(PRO) assessment beyond baseline.  For the analysis, subjects will be analyzed as 
randomized and not according to treatment actually received. 


Statistical Analysis Plan 
E7080-G000-230 
 
 
Eisai 
Confidential 
Page 17 of 40 
 
Analysis sets in data analyses are tabulated below. 
Table 1 
Analysis Sets in Data Analysis 
Tables 
All 
Screened 
Subjects 
Full 
Analysis 
Set 
Per-
Protocol 
Analysis 
Set 
Safety 
Analysis 
Set 
PK 
Analysis 
Set 
PD 
Analysis 
Set 
HRQOL 
Analysis 
Set 
Protocol 
Deviations 
 
● 
 
 
 
 
 
Disposition 
● 
● 
 
 
 
 
 
Demography & 
Baseline 
Characteristics  
 
● 
 
 
 
 
 
Disease History  
 
● 
 
 
 
 
 
Prior and 
concomitant 
medication 
 
● 
 
 
 
 
 
New anticancer 
therapy 
 
● 
 
 
 
 
 
Efficacy analysis 
 
● 
● 
 
 
 
 
Safety analysis 
(including drug 
exposure, AEs, 
laboratory tests, 
vital signs, etc.) 
 
 
 
● 
 
 
 
Pharmacokinetics 
 
 
 
 
● 
 
 
Pharmacodynamics 
 
 
 
 
 
● 
 
HRQoL 
 
 
 
 
 
 
● 
AEs = adverse events, HRQoL = Health-Related Quality of Life, PD = pharmacodynamic, 
PK = pharmacokinetic.  
 
6.2.2 
Subject Disposition 
All subjects who were screened for the study will be reported.  The number of subjects who 
failed screening and the reasons for screen failures will be summarized. 
The summary of subject disposition will be conducted on the Full Analysis Set.   
The number of subjects who were randomized, treated, discontinued study treatment, and the 
reasons for discontinuation of study treatment will be summarized. 
The end of study status (Alive, Death, Withdrew Consent, Lost to Follow-up, etc.) at the data 
cutoff date will also be summarized by treatment arm and overall. 


Statistical Analysis Plan 
E7080-G000-230 
 
 
Eisai 
Confidential 
Page 18 of 40 
 
6.2.3 
Protocol Deviations 
Protocol deviations will be identified and documented prior to database lock. 
Important protocol deviations will be appropriately grouped into different categories.  They 
will be summarized by treatment arm within the Full Analysis Set if necessary.  A list of 
subjects with important protocol deviations will be provided. 
In addition, a listing of all protocol deviations due to COVID-19 will be provided. 
6.2.4 
Demographic and Other Baseline Characteristics 
Demographic and baseline characteristics will be summarized for the Full Analysis Set. 
The following demographic and baseline characteristics will be summarized: 
• 
Age (years) 
• 
Age group (≥2 years to <6 years, ≥6 years to <17 years [≥6 years to <12 years, ≥12 
years to <17 years], ≥17 years) 
• 
Age group (≥2 years to <12 years, ≥12 years to <18 years, ≥18 years) 
• 
Age group from interactive response technology (IRT) (<18 and ≥18 years) 
• 
Gender (Male, Female) 
• 
Race (White, Black, Asian, American Indian or Alaska Native, Native Hawaiian or 
Other Pacific Islander, Other); Asian subcategories:  Chinese, Japanese, Other. 
• 
Race group (White, Non-White) 
• 
Ethnicity (Hispanic or Latino, Not Hispanic or Latino) 
• 
Region (North America, Europe, and Asia Pacific) 
• 
Pregnancy test results (Positive, Negative) in females 
• 
Tanner stage 
• 
Height (cm)  
• 
Baseline weight (kg) 
• 
Baseline body mass index (BMI) (kg/m2) 
• 
Baseline body surface area (BSA) (m2) 
• 
Karnofsky performance status (KPS) or Lansky play scores (LPS) 
• 
Strata will be summarized based on IRT and CRF data.  Strata are defined by the two 
stratification factors of time to first relapse/refractory disease and age: 
o Early (<18 months) and age group (<18 years) 
o Early (<18 months) and age group (≥18 years) 
o Late (≥18 months) and age group (<18 years) 
o Late (≥18 months) and age group (≥18 years) 
 
The following disease history and characteristics at study entry will also be summarized: 


Statistical Analysis Plan 
E7080-G000-230 
 
 
Eisai 
Confidential 
Page 19 of 40 
 
• 
Time since first diagnosis of osteosarcoma to randomization date (months) 
• 
Time since metastatic diagnosis to randomization date (months) 
• 
Time since last progression to randomization date (months) 
• 
Age at diagnosis (in years) 
• 
Osteosarcoma subtypes  
• 
Location of the primary tumor 
• 
TNM staging and grades 
• 
Measurable disease [Yes (Subjects with at least 1 target lesion), No (Subjects with 
only non-target lesions)] 
• 
Resectable Lesions at Baseline 
• 
Sites of metastasis at baseline (bone, lung, bone AND lung, brain, liver, lymph, and 
other) 
The following previous anticancer therapies/medications will also be summarized: 
• 
Number of previous medication regimens 
• 
Duration of most recent medication (months) 
• 
Best response for most recent medication [complete response (CR), partial response 
(PR), stable disease (SD), progressive disease (PD), not evaluable (NE), not 
applicable (NA), unknown] 
• 
Time from end of most recent medication to date of randomization (months) 
• 
Therapeutic setting (Adjuvant, Maintenance, Neo-adjuvant, and Therapeutic)  
• 
Previous radiotherapy (Yes, No) 
o Time from end of most recent radiotherapy to date of randomization (months) 
o Site of previous radiotherapy 
o Tumor lesion at the site progressed since most recent radiotherapy (Yes, No, Not 
evaluable) 
• 
Previous anthracycline therapy (Yes, No)  
• 
Previous receptor tyrosine kinase inhibitor (RTKI) therapy (Yes, No) 
• 
Previous ifosfamide monotherapy (Yes, No) 
• 
Previous ifosfamide plus etoposide (Yes, No) 
• 
Previous Anticancer Procedures (Procedure Name; Site/Organ; Has tumor lesion at 
the site progressed since the procedure? (Yes, No); Post Op Result:  Complete 
Resection, Incomplete Resection). 
Demographic and baseline disease characteristics, prior anticancer therapies/medications will 
also be listed for each subject. 
6.2.4.1 
Medical History 
General medical history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) Version 25.0 and summarized by body system organ class (SOC) and preferred 
term (PT) for each treatment group and overall. 


Statistical Analysis Plan 
E7080-G000-230 
 
 
Eisai 
Confidential 
Page 20 of 40 
 
A subject data listing of medical history will be provided, including SOC and PT, current 
medical condition, date of diagnosis or surgical procedure or onset of symptoms, and end 
date/ongoing. 
6.2.5 
Prior and Concomitant Therapy 
All investigator terms for medications recorded on the CRF will be coded using the World 
Health Organization Drug Dictionary (WHO DD) Version of March 2022. 
Prior medications will be defined as the medications that were started prior to the first dose 
of study drug.  Concomitant medications will be defined as the medications that (i) started 
before the first dose of study drug and were continuing at the time of the first dose of study 
drug, or (ii) started on or after the date of the first dose of study drug up to 30 days after the 
subject’s last dose.  Medications that cannot be determined to be prior/concomitant due to 
missing or incomplete dates will be regarded as concomitant. 
Prior medications will be summarized by anatomical class (Anatomical Therapeutic 
Chemical [ATC] Level 1), pharmacologic class (ATC Level 3), and WHO DD preferred 
term.  A similar summary will also be provided for concomitant medications except 
antidiarrheal therapy and antihypertensive therapy.  Concomitant antidiarrheal therapy and 
antihypertensive therapy will be summarized separately. 
Prior anticancer therapies including anticancer medications, anticancer procedures and 
anthracycline therapy will be summarized and listed.  
Prior and concomitant medications/therapies will be summarized for the Full Analysis Set. 
6.2.6 
Treatment Compliance 
Records of treatment compliance for each subject will be kept during the study, including the 
Follow-up Period.  Clinical research associates will review treatment compliance during 
investigational site visits and at the completion of the study.  Received dose as percent of 
planned dose per subject (ie, relative dose intensity) will be summarized as described in 
Section 6.6.1.2; no other analysis of treatment compliance is planned. 
6.3 
Data Analysis General Considerations 
6.3.1 
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. 
6.3.2 
Adjustments for Covariates 
The stratified log-rank test for the primary efficacy endpoint, PFS as assessed by IIR, the 
secondary efficacy endpoint, OS, the stratified Miettinen and Nurminen’s method for the 
secondary efficacy endpoint of ORR, and the stratified Cox regression analyses to estimate 


Statistical Analysis Plan 
E7080-G000-230 
 
 
Eisai 
Confidential 
Page 21 of 40 
 
hazard ratios (time-to-event efficacy endpoints) will be performed using the following 
randomization stratification factors from IRT.  
• 
Time to first relapse/refractory disease (early [<18 months] or late [≥18 months])  
• 
Age (<18 and ≥18 years) 
In case of low numbers of subjects enrolled within any combination of stratification factors, 
subjects from the low enrollment combination(s) of the stratification factors may be pooled 
for analysis.  
Based on a blinded review of the data, the number of subjects in the level of the stratum 
“time to first relapse/refractory disease ≥18 months” is approximately 11 subjects out of 81 
subjects in the ITT population.  To ensure a sufficient number of participants in each stratum 
within each treatment arm, “time to first relapse/refractory disease” has been removed as a 
stratification factor in the analyses.  Thus, only the stratification factor “age at 
randomization” will be included in any stratified analyses.  
Other demographic and baseline variables may be included and adjusted in the statistical 
models as sensitivity analyses if deemed necessary. 
6.3.3 
Multiple Comparisons/Multiplicity 
No multiplicity adjustment will be made for this study. 
6.3.4 
Examination of Subgroups 
For the primary efficacy endpoint PFS as assessed by IIR, the median PFS, hazard ratio, and 
corresponding 95% confidence intervals may be generated for the following subgroups, as 
appropriate. 
• Age (<18 years, ≥18 years)  
• Time to first relapse (<18 months, ≥18 months) 
• Sites of metastasis [Lung only, Others (+/- lung)] 
• Prior Ifosfamide +/- Etoposide (Yes, No) 
• Measurable disease [Yes (Subjects with at least 1 target lesion), No (Subjects with only 
non-target lesions)] 
For the safety endpoints, the following TEAE tables will be provided by age group (years) 
category (<18 years, ≥18 years) and gender. 
• 
Overall summary of TEAE  
• 
TEAEs in decreasing frequency of PT  
• 
Serious TEAEs in decreasing frequency of PT  
Other exploratory subgroup analyses may be conducted if appropriate. 


Statistical Analysis Plan 
E7080-G000-230 
 
 
Eisai 
Confidential 
Page 22 of 40 
 
6.3.5 
Handling of Missing Data, Dropouts, and Outliers 
For efficacy endpoints related to ORR, which summarize the percentage of responders, 
missing responses will not be imputed. 
For incomplete dates involving efficacy and safety data such as adverse events (see below), 
concomitant medications, laboratory assessments, vital signs, and ECG data, a conservative 
imputation will be used for calculation if needed.  The imputation rules will be specified in 
study analysis dataset specifications with more details. 
Adverse events with incomplete 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 
HRQoL analysis will follow the FDA and the European Medicines Agency (EMA) PRO 
guidelines.  Handling of missing values for HRQoL analyses will be detailed in a separate 
SAP and HRQoL report. 
6.4 
Efficacy Analyses 
Efficacy analyses will be based primarily on the Full Analysis Set.  The per protocol analysis 
set will be the secondary analysis set for efficacy endpoints.  All tumor assessment analyses 
using the IIR assessments will be considered primary; all tumor assessment analyses using 
investigator assessments will be considered supportive analyses.  The randomization strata 
based on IRT will be used in the analyses unless otherwise specified. 
All primary statistical analyses will be conducted at the data cutoff date for the analysis of 
the primary efficacy endpoint, PFS by IIR (ie, when approximately 38 PFS events, as 
determined by IIR, are observed).  Additional analyses will be based on the date of data 
cutoff for the additional follow-up analysis of OS or at the time of the last subject last visit, 
whichever occurs later. 
6.4.1 
Primary Efficacy Analysis 
The primary efficacy endpoint of PFS per IIR will be analyzed and compared between the 2 
treatment arms by the stratified log-rank test adjusted for the randomization stratification 
factor (refer to Section 6.3.2).  Median PFS will be calculated using the K-M product-limit 
estimates for each treatment arm along with 2-sided 95% CIs (estimated with a generalized 
Brookmeyer and Crowley method [Brookmeyer and Crowley, 1982]).  The K-M estimates of 
PFS will be plotted over time.  The stratified Cox regression model will be used to estimate 
the hazard ratio and its 95% CI.    


Statistical Analysis Plan 
E7080-G000-230 
 
 
Eisai 
Confidential 
Page 23 of 40 
 
The PFS by IIR is defined as the time from the date of randomization to the date of first 
documentation of disease progression based on IIR assessments using RECIST 1.1 or date of 
death, whichever occurs first.   
Determination of the date of PFS event or censoring is summarized in Table 2 below.  The 
table is based on the FDA clinical trial endpoints guidance of 2007 (FDA, 2007).  In this 
study, removal of baseline lesion(s) is permitted after completion of the Week 18 tumor 
assessment, and palliative radiotherapy of non-target lesions is allowed (see protocol 9.4.7.3).  
For the primary efficacy endpoint analysis, PFS will be censored according to censoring rules 
in Table 2.  In this analysis, assessments after removal of baseline lesion(s) (considered as a 
new anticancer therapy) before or after Week 18 will be censored. 
Table 2 
PFS Event and Primary Censoring Rules 
No. 
Situation 
Date of Progression or 
Censoring 
Outcome 
1 
No baseline or post-
baseline adequate tumor 
assessments*  
Date of randomization  
Censored  
2 
Progression documented 
between scheduled visits, 
on or prior to new 
anticancer therapy 
Date of first radiologic PD 
assessment  
PFS Event  
3 
No progression at the 
time of data cutoff  
Date of last adequate 
radiologic assessment on or 
prior to data cutoff  
Censored  
4 
New anticancer therapy 
started+ 
Date of last adequate 
radiologic assessment on or 
prior to the start of new 
anticancer therapy  
Censored  
5 
Death without disease 
progression or any new 
anticancer therapy  
Date of death  
PFS Event  
6 
Death between adequate 
assessment*  
(Death before next 
scheduled assessment or 
after exactly one missing 
assessment) 
 
Date of death  
PFS Event  
7 
Death or progression after 
more than one 
consecutive missed 
visit/tumor assessment**  
Date of last adequate 
radiologic assessment 
before missed tumor 
assessments  
Censored 


Statistical Analysis Plan 
E7080-G000-230 
 
 
Eisai 
Confidential 
Page 24 of 40 
 
Note:  
+ Assessments after removal of baseline lesion(s) (eg, surgical, radiofrequency ablation, 
cryotherapy, thermoablation, stereotactic radiotherapy, etc.) before or after Week 18 will be 
censored.  Palliative radiotherapy of nontarget lesions is permitted per protocol and will not 
be considered as a new anticancer therapy.  
* Adequate tumor assessment is radiologic assessment at regular intervals as defined in the 
protocol.  Any tumor assessments occurring after the start of a new anticancer treatment will 
be censored per the FDA censoring rules. 
** More than one consecutive missed visit/adequate tumor assessment is defined as the 
duration between two consecutive tumor assessments or the duration between the last 
adequate tumor assessment and death/PD is longer than (>) 97 days [ = ((6+1) x 2 x 7) – 1] 
for subjects on every 6 weeks tumor assessment schedule in the first 18 weeks (6 cycles) of 
treatment; longer than (>) 139 days [= ((9+1) x 2 x 7) – 1)] for subjects on every 9 weeks 
tumor assessment schedule from weeks 18 to 54 (Cycle 7 to Cycle 18); longer than (>) 195 days 
[=((12+2) x 2 x 7) – 1)] for subjects on every 12 weeks tumor assessment schedule after Week 
54 in this study.  
For subjects moving from one schedule to another: 
Missed Week 18 and Week 27 assessments: (>)118 days [= ([(6+1) + (9+1)] x 7) – 1)] 
Missed Week 54 and Week 66 assessments: (>)167 days [= ([(9+1) + (12+2)] x 7) – 1)] 
If a subject had PFS event (#2, #5 or #6), the earliest event date will be used.  
The priority of the censoring rules is described as follows: 
• If a subject missed two or more consecutive tumor assessments before PD or death 
(#7), the subject will be censored at the date of the last adequate tumor assessment 
before the missed tumor assessments.   
Note that if a subject is censored by both this criterion and start of new anticancer 
therapy criterion, the earliest censoring date will be used. 
• If a subject did not have PD or death, the censoring date will be the earliest censoring 
date if the subject met multiple censoring criteria (#1, #3, #4, #7). 
Sensitivity Analysis of PFS 
Sensitivity analyses of PFS will be based on the Full Analysis Set using censoring rules from 
Table 2, along with the following exceptions listed below: 
Sensitivity Analysis 1:  In this analysis, baseline tumor removal before or after completion of 
the Week 18 tumor assessment will be evaluated as part of the study drug therapy and will 
not be considered as a new anticancer therapy (see difference in Table 2, rule 4).  
Sensitivity Analysis 2 (EMA guidance [Reference 11]):  In this analysis, PD or death after 
two or more missing assessments, or after receiving a new anticancer therapy will be 
considered as a PFS event (see differences in Table 2, rules 4 and 7). The removal of baseline 
lesion(s) before or after completion of the Week 18 tumor assessment will be considered as a 
new anticancer therapy.  


Statistical Analysis Plan 
E7080-G000-230 
 
 
Eisai 
Confidential 
Page 25 of 40 
 
6.4.2 
Secondary Efficacy Analyses 
6.4.2.1 
PFS-4m and PFS-1y Rate by IIR 
The PFS-4m rate and PFS-1y rate per IIR will be estimated using the K-M method for the 
primary efficacy endpoint PFS per IIR.  PFS-4m/PFS-1y rate and their Greenwood standard 
errors will be evaluated using the K-M estimates from both treatment groups.  The statistical 
significance of the difference in the 2 K-M PFS-4m/PFS-1y rates will be based on the 2-
sided 95% CI.  This 2-sided 95% CI and a p-value will be constructed using the difference of 
these 2 K-M PFS-4m/PFS-1y rates and the 2 corresponding Greenwood standard errors.   
6.4.2.2 
Overall Survival 
Overall survival is defined as the time from the date of randomization to the date of death.  
All deaths during the study will be considered as OS events. 
Subjects who were lost to follow-up or who withdrew consent will be censored at the date the 
subject was last known to be alive.  Subjects who are still alive at the data cut-off date will be 
censored at the data cut-off date. 
Determination of date of OS event or censoring is summarized in Table 3 below.  
Table 3 
OS Event and Censoring Method 
Situation  
Date of Event or 
Censoring  
Outcome  
Death during study  
Date of death  
OS Event  
Subject still alive at data cut-off 
(including death after data cut-off) 
Date of data cut-off  
Censored  
Subject lost to follow-up or 
withdrawal of consent before data 
cut-off  
Date of last known to 
be alive  
Censored  
OS = overall survival. 
Overall survival (OS) will be compared between the treatment arm and control arm using the 
stratified log-rank test adjusted for the randomization stratification factor (refer to Section 
6.3.2). 
Median will be calculated using the K-M [Kaplan and Meier, 1958] product-limit estimates 
for each treatment arm along with 2-sided 95% CIs (estimated with a generalized 
Brookmeyer and Crowley method [Brookmeyer and Crowley,1982]).  The K-M estimates of 
OS will be plotted over time. 
The Cox regression model will be used to estimate the hazard ratio and the corresponding 
95% CIs stratified by the randomization stratification factor (refer to Section 6.3.2).  For all 


Statistical Analysis Plan 
E7080-G000-230 
 
 
Eisai 
Confidential 
Page 26 of 40 
 
analyses using Cox regression, Efron’s method will be used for handling “ties” in the failure 
time. 
K-M estimates will also be presented for 4, 6, 9 and 12 months (ie, OS-1y) along with 2-
sided 95% CIs (estimated with the Greenwood formula using the log-log transformation 
[Greenwood (1926) and Kalbfleisch and Prentice (2002)]).  The OS-1y will be analyzed 
using the same approach as for the PFS-4m. 
6.4.2.3 
Overall Response Rate (ORR) and ORR-4m by IIR 
The ORR by IIR is the proportion of subjects with a best overall response of CR or PR 
determined by IIR using RECIST 1.1.  The ORR by IIR will be summarized and compared 
between the two treatment arms.  The raw difference in ORR will be reported. The 2-sided 
95% confidence interval of ORR difference will be generated from SAS using Miettinen-
Nurminen (Score) Confidence Limits.   
The ORR-4m by IIR will be summarized and compared between arms using the same 
approach as for ORR by IIR. 
6.4.2.4 
Duration of Response, Disease Control Rate, and Clinical Benefit Rate by IIR 
Median DOR by IIR among responders for each arm will be presented along with the 
corresponding 2-sided 95% CI; 95% CI will be estimated with the Brookmeyer and Crowley 
method.  
Disease Control Rate (DCR) and CBR by IIR will be summarized and compared between 
arms using the same approach as for ORR.  
6.4.2.5 
PFS, PFS-4m, PFS-1y, ORR-4m, ORR, DOR, DCR, and CBR by Investigator 
Assessment 
Efficacy endpoints PFS, PFS-4m, PFS-1y, ORR-4m, ORR, DOR, DCR, and CBR evaluated 
based on investigator assessment will be analyzed using the same approach as for the 
endpoints assessed by IIR.  
6.4.2.6 
Subjects Achieving Complete Resection 
The difference in the proportion of subjects who achieve complete removal of baseline 
lesion(s) between the 2 treatment arms will be compared and corresponding two-sided 95% 
CIs will be calculated using the Clopper and Pearson method (Clopper and Pearson, 1934).  
The proportion of subjects with unresectable baseline lesions(s) that are converted to 
resectable lesions will be compared between the 2 treatment arms in the same way.  
6.4.2.7 
Maximum Tumor Shrinkage 
Graphical displays (waterfall plot) will be prepared for the maximum tumor shrinkage in 
target lesions, defined as the maximum percentage change from baseline in the sum of the 
diameters of the target lesions at data cutoff. 


Statistical Analysis Plan 
E7080-G000-230 
 
 
Eisai 
Confidential 
Page 27 of 40 
 
6.5 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Analyses 
6.5.1 
Pharmacokinetic Analyses 
Lenvatinib plasma concentration data will be summarized across timepoints using n, mean, 
SD, median, Q1, Q3, minimum, and maximum.  Graphical displays will present scatter plots 
and box plots of lenvatinib plasma concentration over time.  Plasma concentration of 
lenvatinib versus time data will be listed. 
Plasma concentration data of lenvatinib will be analyzed using a population PK approach to 
estimate population PK parameters.  The analysis will be detailed in a separate analysis plan. 
6.5.2 
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Analyses 
Analyses related to PD, pharmacogenomics, and biomarkers will be detailed in separate 
analysis plans. 
 
6.6 
Safety Analyses 
All safety analyses will be performed on the Safety Analysis Set.  Safety data, presented by 
treatment group, will be summarized on an “as treated” basis using descriptive statistics (eg, 
n, mean, standard deviation, median, minimum, maximum, Q1, and Q3 for continuous 
variables; n [%] for categorical variables), as appropriate.  All safety data will be summarized 
up to the last dose + 30 days or the data cutoff date, whichever occurs earlier.  Optional 
lenvatinib crossover treatment is permitted by protocol.  For subjects in Arm B who crossed 
over to optional treatment with lenvatinib alone or lenvatinib plus chemotherapy, data 
records occurring on or after the date of the crossover (date of first administration of 
lenvatinib) will be excluded from this analysis.  In addition, for these subjects, data occurring 
on or after the date of the crossover will be summarized and listed separately for selected 
parameters as appropriate.   
Safety variables include TEAEs, clinical laboratory parameters, vital signs, 12-lead ECG 
results, Lansky play scores or Karnofsky performance scores, physical examination, height, 
tooth formation abnormalities, closure of proximal tibial plates, Tanner Stage, and left 
ventricular ejection fraction (LVEF).  Study Day 1 for all safety analyses will be defined as 
the date of the first dose of study drug. 
6.6.1 
Extent of Exposure 
Extent of exposure to study treatment, study drug administered, and study drug modifications 
will be summarized and presented for each individual drug and overall as appropriate. 
6.6.1.1 
Extent of Exposure of Study Drug 
Treatment duration and the total number of treatment cycles will be summarized 
descriptively.  The maximum number of treatment cycles for each subject is the largest cycle 


Statistical Analysis Plan 
E7080-G000-230 
 
 
Eisai 
Confidential 
Page 28 of 40 
 
number in which a subject receives any non-zero dose of study drug(s).  The number and 
percentage of subjects treated within each cycle will also be summarized for each treatment 
arm. 
Treatment duration will be summarized descriptively for each individual drug and overall.  
The dosing end date for lenvatinib will be imputed to the analysis cutoff date if the subject is 
still on treatment at the time of the data cutoff, and the dose will be imputed with the last 
dose recorded in the database for that subject.  However, the dosing end date/dose for 
chemotherapy (ifosfamide and etoposide) will be imputed as the last dose date/dose recorded 
in the database prior to or on the analysis cutoff date. 
The duration of each individual drug in days will be calculated (as Date of the last non-zero 
dose – Date of the first non-zero dose + 1) for the specific drug, including drug interruption 
days.  For overall treatment duration, it is defined as the duration between the earliest first 
dose start date of study drugs and the latest last dose end date of study drugs. 
In this study, study drugs refer to any of the following:  lenvatinib 14 mg/m2, ifosfamide 
3000 mg/m2, and etoposide 100 mg/m2. 
6.6.1.2 
Study Drug Administration 
The total dose received per subject, dose intensity, and relative dose intensity will be 
summarized with descriptive statistics for each individual study drug. 
For each individual study drug, the total dose per subject (mg) will be calculated as the sum 
of all doses that subject has received during the study.  The dose intensity (mg/m2/day) will 
be calculated as the total dose (mg) received during the study divided by BSA on Cycle 1 
Day 1 and the treatment duration of the specific drug (days).  The relative dose intensity, 
which is defined as the ratio (%) of total dose received and total planned dose (ie, received 
dose as a percentage of planned dose), will be calculated as the dose intensity divided by the 
planned dose level. 
6.6.1.3 
Study Drug Dose Modifications 
DOSE REDUCTIONS 
Dose reduction refers to a situation where a dose level was reduced from the previous dose 
level without going back.  Dose reduction could apply to any of the study drugs. 
DOSE INTERRUPTIONS 
Dose interruption refers to a situation where a subject had a planned temporary break from 
taking the study drug for a short period (ie, interruption period).  Dose interruptions will only 
be determined for lenvatinib. 
Dose interruption only refers to the scenario where the dose levels or dosing frequencies 
before and after interruption period (defined as the period with dose=0) are the same.  For 
example:  14 mg/m2 lenvatinib followed by 0 mg and followed by 14 mg/m2 lenvatinib.  If 


Statistical Analysis Plan 
E7080-G000-230 
 
 
Eisai 
Confidential 
Page 29 of 40 
 
the dose level after dose interruption period was reduced from the dose level before the 
interruption period, it should be counted as dose reduction and should not be counted as dose 
interruption.  An example of dose reduction instead of dose interruption: 
• 
14 mg/m2 lenvatinib followed by 0 mg followed by 11.2 mg/m2 lenvatinib. 
Please note, for the scenario above, the period with dose=0 should be counted as dose 
reduction period and not dose interruption (ie, the dose reduction date should be the date of 
dose=0).  If the subject discontinued from treatment permanently after dose interruption with 
dose=0, it should be counted as treatment discontinuation instead of dose interruption. 
The number of subjects with dose reductions for each individual study drug and with dose 
interruptions for lenvatinib will be summarized.  The number (ie, frequency) of dose 
reductions per subject will also be summarized. 
Time to first dose reduction is defined as the time period from the first dose date to the date 
of first dose reduction, or the time period from the first dose date to the date of first dose 
interruption for those subjects who had dose interruption first and then followed by dose 
reduction.  Time to first dose reduction will be derived and summarized descriptively for 
lenvatinib for those subjects who had at least one dose reduction during the treatment period.  
6.6.2 
Adverse Events 
Adverse events will be graded according to the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI-CTCAE), Version 5.0.  The AE verbatim 
descriptions (investigator terms from the CRF) will be classified into standardized medical 
terminology using the MedDRA Version 25.0.  Adverse events will be coded to the 
MedDRA lower level term (LLT) closest to the verbatim term.  The linked MedDRA PT and 
primary SOC are also captured in the database. 
A 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 
• 
Re-emerges 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 by treatment 
group.  Exposure-adjusted analyses will be presented for selected AE summaries.  For subjects 
in Arm B who received optional lenvatinib only or lenvatinib plus chemotherapy, adverse 
events occurring on or after the date of the crossover will be summarized separately by PT in 
order of decreasing frequency.  All AEs, treatment-emergent or otherwise, will be presented in 
subject data listings. 


Statistical Analysis Plan 
E7080-G000-230 
 
 
Eisai 
Confidential 
Page 30 of 40 
 
6.6.2.1 
Overview of TEAEs 
An overview of TEAEs reported through the study will be provided for each treatment arm.  
Overall summary of TEAE will include: 
• 
 the number and percentage of subjects with TEAEs 
• 
Treatment-emergent SAEs,  
• 
Treatment-related TEAEs,  
• 
TEAEs of Grade 3 or higher 
• 
TEAEs leading to treatment discontinuation (discontinuation in each study arm and 
discontinuation of all 3 study drugs individually in each treatment arm) 
• 
TEAEs leading to dose reductions 
• 
TEAEs leading to dose interruptions  
• 
TEAEs with fatal outcomes 
6.6.2.2 
All TEAEs 
The following summaries will be provided for all TEAEs: 
• 
TEAEs by SOC and PT 
• 
TEAEs by decreasing frequency of PT 
• 
Most common (eg, ≥10%) TEAEs by SOC and PT 
• 
TEAEs by SOC, PT, and worst toxicity grade 
6.6.2.3 
Treatment-related TEAEs 
The following treatment-related TEAEs will be summarized: 
• 
Treatment-related TEAEs by decreasing frequency of PT 
• 
Most common (eg, ≥10%) treatment-related TEAEs by SOC and PT 
• 
Treatment-related TEAEs by SOC, PT and worst toxicity grade 
6.6.2.4 
Treatment-emergent SAEs 
The incidence of treatment-emergent SAEs will be summarized as below: 
• 
Treatment-emergent SAEs by SOC and PT  
• 
Treatment-related treatment-emergent SAEs by SOC and PT  
• 
Treatment-emergent SAEs by decreasing frequency of PT  
• 
Most common (eg, ≥5%) treatment-emergent SAEs by SOC and PT  
In addition, a listing of serious AEs will be provided. 


Statistical Analysis Plan 
E7080-G000-230 
 
 
Eisai 
Confidential 
Page 31 of 40 
 
6.6.2.5 
TEAEs Leading to Treatment Discontinuation 
The TEAEs leading to treatment discontinuation (discontinuation in each study arm and 
discontinuation of all 3 study drugs individually in each treatment arm) will be summarized 
by SOC and PT.  
A listing of TEAEs leading to any study drug discontinuation will be provided. 
6.6.2.6 
TEAEs Leading to Dose Reductions and Dose Interruptions 
The TEAEs leading to dose reductions and dose interruptions will be summarized by SOC 
and PT for each treatment arm.  The TEAEs leading to dose reductions and dose 
interruptions will be summarized for each individual drug and overall. 
A listing of TEAEs leading to dose reductions and/or dose interruptions of any study drug 
will be provided. 
6.6.2.7 
Grade 3 or Higher TEAEs 
The following Grade 3 or higher TEAEs will be summarized: 
• 
Grade 3 or higher TEAEs by SOC and PT 
• 
Most common (eg, ≥5%) Grade 3 or higher TEAEs by SOC and PT 
In addition, a listing of Grade 3 or higher AEs will be provided. 
6.6.2.8 
TEAEs with Fatal Outcome 
The TEAEs with fatal outcome will be summarized by SOC and PT for each treatment arm. 
Treatment-related TEAEs with fatal outcome will also be summarized. 
A listing of AEs with fatal outcome will be provided. 
6.6.2.9 
Deaths 
The number of subjects who died during the study will be summarized. 
A listing of subjects who died during the study will be provided. 
6.6.2.10 
Adverse Events of Clinical Interest 
Clinically significant adverse events (CSAEs) for lenvatinib have been identified based on a 
thorough review of safety data from existing clinical and pharmacovigilance databases. 
Evaluations of CSAEs are based on standardized MedDRA queries (SMQs), customized 
MedDRA queries (CMQ), or sponsor-generated queries (SGQs), which include sponsor-
specified PT either alone or in addition to those listed for an SMQ or CMQ.  
CSAEs will be summarized by CTCAE grade.   


Statistical Analysis Plan 
E7080-G000-230 
 
 
Eisai 
Confidential 
Page 32 of 40 
 
The subjects with CSAEs leading to dose reductions, dose interruptions, and treatment 
discontinuations will also be provided. 
6.6.3 
Laboratory Values 
Laboratory results will be summarized using Système International (SI) units.  Laboratory 
values that are non-missing and reported as ‘below the detectable limit’ of an assay will be 
replaced by half the detectable limit in the summary tables.   
On-treatment laboratory tests will be defined as the laboratory tests conducted from the start 
of treatment to no more than 30 days after the last dose of study treatment. 
6.6.3.1 
Hematology and Clinical Chemistry 
Laboratory parameters will be graded based on CTCAE Version 5.0.  In the summary of 
laboratory parameters by CTCAE grade, for parameters with CTCAE grading in both high 
and low directions (eg, calcium, glucose, magnesium, potassium, sodium), CTCAE grades in 
both high and low directions will be summarized separately. 
The evaluation of clinical laboratory tests will focus on the following selected laboratory 
analytes: 
Hematology Panel: 
• 
hematocrit, hemoglobin, red blood cell (RBC) count, white blood cell (WBC) count, 
absolute neutrophil count, absolute lymphocyte count, platelet count. 
Chemistry Panel: 
• 
Electrolytes:  bicarbonate, calcium, chloride, magnesium, phosphate, potassium, 
sodium 
• 
Liver function tests:  alanine aminotransferase (ALT), alkaline phosphatase, aspartate 
aminotransferase (AST), direct bilirubin, total bilirubin 
• 
Renal function tests:  blood urea/blood urea nitrogen (BUN), creatinine 
• 
Thyroid function tests:  thyroid stimulating hormone (TSH), free T4 level 
• 
Other:  albumin, glucose, lactate dehydrogenase (LDH), amylase, lipase, total protein 
Descriptive statistics for values and changes from baseline at each scheduled visit for 
hematology and chemistry laboratory parameters will be provided.   
In addition, the worst CTCAE grade during the treatment will be summarized by treatment 
arm and CTCAE grade for hematology and chemistry parameters.  Shift tables from baseline 
to the worst CTCAE grade during treatment will be generated.  


Statistical Analysis Plan 
E7080-G000-230 
 
 
Eisai 
Confidential 
Page 33 of 40 
 
6.6.3.2 
Thyroid-Stimulating Hormone  
Thyroid-stimulating hormone values will be summarized by category according to 
standardized reference ranges. 
6.6.3.3 
Urinalysis 
The shift of worst postbaseline proteinuria from baseline will be summarized.  All urinalysis 
parameters (RBCs/high-power-field [HPF], blood, and protein [dipstick], and 24-hour urine 
protein) will be presented in by-subject listings. 
6.6.4 
Vital Signs 
Descriptive statistics for vital sign parameters (systolic blood pressure (SBP) and diastolic 
blood pressure (DBP), pulse, respiratory rate, temperature, height and weight) and changes 
from baseline at each scheduled visit will be presented.  
Shifts from baseline will be presented overall and by subgroups of subjects <18 and ≥18.  In 
addition, percentiles for values of height and blood pressure (only for subjects <18 years old 
[see Protocol Appendices 5 and 6]) will be summarized as a shift from baseline to end of 
treatment by category for height:  5th, 10th, 25th, 50th, 75th, 90th and 95th percentiles; and 
as a shift from baseline to worst (of SBP or DBP) postbaseline measurement by category:  
<90th, 90th to 95th, 95th to ≤99th, and >99th percentiles. 
6.6.5 
Other Safety Analyses 
6.6.5.1 
Electrocardiograms 
Descriptive statistics for ECG parameters (HR, PR, QRS, QT, QTcB, QTcF and RR) and 
changes from baseline at each scheduled visit will be presented. 
Shift tables of worst postbaseline values from baseline will be presented for ECG findings 
(categorized as normal; abnormal, not clinically significant; and abnormal, clinically 
significant). 
Clinically abnormal ECG results in QTc (QTc Fridericia and QTc Bazett) will be categorized 
using the following analyses. 
Absolute QTc interval prolongation will be summarized for the number (percentage) of 
subjects with at least 1 postbaseline ECG result during treatment: 
◦ 
QTc interval ≤450 msec 
◦ 
QTc interval >450 - 480 msec 
◦ 
QTc interval >480 - 500 msec 
◦ 
QTc interval >500 msec 
 


Statistical Analysis Plan 
E7080-G000-230 
 
 
Eisai 
Confidential 
Page 34 of 40 
 
Change from baseline in QTc interval will be summarized for the number (percentage) of 
subjects with at least one Baseline and postbaseline ECG result during treatment: 
◦ 
QTc interval increases from baseline >0 - 30 msec 
◦ 
QTc interval increases from baseline >30 - 60 msec 
◦ 
QTc interval increases from baseline >60 msec 
Subject listings will also be provided. 
6.6.5.2 
Left Ventricular Ejection Fraction 
The LVEF (%) assessed on echocardiogram or multiple gated acquisition (MUGA) scans will be 
summarized.  The lowest postbaseline value and the change from baseline will be summarized 
descriptively.   
Categorical summaries will also be presented as follows:  
• 
Percentage reduction from baseline (> 0 to ≤10%, >10 to ≤15%, >15%) 
• 
Occurrence of subjects having a lowest postbaseline value of <50%.  
A subject data listing will be provided. 
6.6.5.3 
Lansky Play Scores or Karnofsky Performance Status Scores 
Lansky play scores or KPS scores will be presented as a figure showing results over time.  A 
subject listing of Lansky play scores or KPS scores will be provided. 
6.6.5.4 
Proximal Tibial Growth Plates 
Radiographic findings of proximal tibial growth plates will be summarized at baseline and 
end of treatment.   
A subject listing will be provided. 
6.6.5.5 
Tanner Stage 
Tanner Stage will be summarized across time by visit, and as a shift from baseline to end of 
treatment. 
A subject listing will be provided. 
6.6.5.6 
Dental Examination 
Tooth formation abnormalities will be summarized and listed. 


Statistical Analysis Plan 
E7080-G000-230 
 
 
Eisai 
Confidential 
Page 35 of 40 
 
6.6.5.7 
New Anticancer Therapies During Follow-up Period 
The new anticancer medications and procedures during Follow-up Period will be reported 
and listed. 
6.7 
Other Analyses 
6.7.1 
Palatability 
Each question in the Palatability and Acceptability Questionnaire will be summarized and 
listed. 
6.7.2 
Health-Related Quality of Life 
Health-related quality of life will be collected at baseline (Day -1 or at Cycle 1 Day 1 prior to 
treatment) and C2D1, C3D1, Week 18, C8D1, C18 D1 and at the Off-Treatment Visit.  Score 
change from baseline in PedsQL at each analysis timepoint will be analyzed.  The primary 
timepoint for assessment is at Week 18 for all PedsQL endpoints. 
Descriptive statistics will be presented for all PedsQL endpoints at each analysis time period 
by treatment arm.  Baseline is defined as the later value of Day -1 or at Cycle 1 Day 1 prior 
to treatment. 
A detailed HRQoL analysis plan will be provided in a separate document and the results will 
be provided in a stand-alone report. 
6.8 
Exploratory Analyses 
Other exploratory analyses may be conducted as appropriate. 
7 
INTERIM ANALYSES 
No interim analysis is planned for this study. 
8 
CHANGES IN THE PLANNED ANALYSES 
Based on the blinded review of the data, the number of subjects in the level of the stratum 
“time to first relapse/refractory disease ≥18 months” is only about 11 subjects out of the ITT 
total size of 81 subjects.  To ensure a sufficient number of participants in each stratum within 
each treatment arm, “time to first relapse/refractory disease” stratification factor was removed 
from the analyses.  Only the stratification factor “age at randomization” will be included in 
any stratified analyses.  
For DCR, the SD minimum duration period is changed from 7 weeks to 5 weeks after 
randomization. The change was made due to the tumor assessment schedule of every 6 weeks 
until Week 18. 


Statistical Analysis Plan 
E7080-G000-230 
 
 
Eisai 
Confidential 
Page 36 of 40 
 
9 
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING 
9.1 
Visit Windows 
Visit windows will be defined to be within upper and lower bounds of 3 days of the 
scheduled visit, according to the protocol, which states that efforts should be made to conduct 
study visits (and safety assessments) on the day scheduled (± 1 day for Cycle 1 and within 3 
days for Cycle 2 onward). 
Tumor assessments should be performed at screening and every 6±1weeks after the date of 
randomization or sooner if clinically indicated until Week 18±1 week.  Then every 9±1weeks 
until Week 54±1 week, and thereafter, every 12±2 weeks until documentation of PD.  If a 
subject discontinues from study treatment without disease progression, tumor assessments 
should continue to be performed using this schedule. 
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 two or more observations have the same distance to the target visit 
day, the one that has the highest CTCAE grade or is furthest away from 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 per scheduled visit and change from baseline per visit.  
Other safety analyses (eg, worst grade laboratory results and shift tables) will include all 
postbaseline assessments, including scheduled and unscheduled visits. 
9.2 
Baseline Definitions 
For safety assessments, the baseline value is defined as the last non-missing measurement 
taken on or prior to the first dose date.  The first dose date is defined as the earliest date of 
non-zero dose administration of any study drug (ie, lenvatinib, ifosfamide, or etoposide). 
Study day is defined as date of assessment – first dosing date + 1 for any assessment done on 
or after first dosing date; otherwise, study day is defined as date of assessment – first dosing 
date. 
9.3 
Imputation of Missing Data 
Unless specified otherwise, no data imputation will be applied for missing safety and efficacy 
evaluations.  For analysis and reporting purposes, partial dates for adverse events, prior and 
concomitant therapies, disease diagnosis date, and start date of new anticancer therapy will 
be imputed if needed.  Partial dates for laboratory values, vital signs, and ECGs will not be 
imputed. 
The imputation rules will be specified in study analysis dataset specifications with more 
details. 


Statistical Analysis Plan 
E7080-G000-230 
 
 
Eisai 
Confidential 
Page 37 of 40 
 
9.4 
Variable Derivations 
9.4.1 
Duration of Events Prior to Randomization 
For the following disease characteristics and prior therapies, the duration in months will be 
calculated as the date of randomization minus the date of event (disease diagnosis, disease 
progression, prior therapies, etc.) and then divided by 30.4375. 
The duration in years will be calculated as:  (date of randomization – date of event)/365.25. 
• 
Time since the first osteosarcoma diagnosis to date of randomization (months) 
• 
Time since last disease progression to date of randomization (months) 
• 
Time from end of most recent therapy to date of randomization (months) 
• 
Time from previous surgery to date of randomization (months) 
• 
Time from most recent radiotherapy to date of randomization (months) 
 
9.5 
Pharmacokinetics/Pharmacodynamics Data Handling 
Details on calculating PK parameters, the way that the values of below limit of quantification 
(BLQ) are to be treated, and the analyses to be conducted on PK/PD and exposure-response 
relationships will be specified in a separate document. 
When calculating the mean or median value for the concentration at a given time point, the 
BLQ values will be assigned to 0.  If the proportion of values reported as BLQ is more than 
50%, no summary statistics should be presented at that time point, and the value will be 
treated as missing in mean or median concentration profiles. 
10 PROGRAMMING SPECIFICATIONS 
The rules for programming derivations and dataset specifications are provided in separate 
documents. 
11 STATISTICAL SOFTWARE 
Statistical programming and analyses will be performed using SAS® (SAS Institute, Inc., 
Cary, NC, USA), version 9.0 or higher, and/or other validated statistical software as required. 
12 MOCK TABLES, LISTINGS, AND GRAPHS 
The study tables, listings, and graphs (TLGs) shells will be provided in a separate document, 
which will show the content and format of all the TLGs in detail. 
 
 


Statistical Analysis Plan 
E7080-G000-230 
 
 
Eisai 
Confidential 
Page 38 of 40 
 
13 REFERENCES 
1. Brookmeyer R, Crowley JJ. A confidence interval for the median survival time. 
Biometrics. 1982:38:29-41. 
2. Clopper CJ Pearson ES. The Use of Confidence or Fiducial Limits Illustrated in the Case 
of the Binomial. Biometrika. 1934;26:404–13. 
3. Common Terminology Criteria for Adverse Events (CTCAE). Version 5.0. United States 
Department of Health and Human Services, National Institutes of Health. National 
Cancer Institute, Washington, DC, USA, November 27, 2017. 
4. Davis LE, Bolejack V, Ryan CW, Ganjoo KN, Loggers ET, Chawla S, et al. Randomized 
double-blind phase II study of regorafenib in patients with metastatic osteosarcoma. J 
Clin Oncol. 2019 Jun 1;37(16):1424-31. 
5. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New 
response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). 
Eur J Cancer. 2009;45(2):228-47. 
5. Greenwood, M. The natural duration of cancer. Reports on Public Health and Medical 
Subjects. 1926:33:1-26. Her Majesty's Stationery Office, London. 
6. 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. 
7. Grignani G, Palmerini E, Dileo P, Asaftei SD, D’Ambrosio L, Pignochino Y, et al. A 
phase II trial of sorafenib in relapsed and unresectable high-grade osteosarcoma after 
failure of standard multimodal therapy: an Italian Sarcoma Group study. Ann Oncol. 
2012;23(2):508-16. 
8. Kalbfleisch JD, Prentice RL. The Statistical Analysis of Failure Time Data.  
2nd Edition. John Wiley & Sons, Inc. New York. 2002. 
9. Kaplan E, Meier P. Nonparametric Estimation from Incomplete Observations. J Am Stat 
Assoc. 1958;53:457-81. 
10. Palmerini E, Jones RL, Marchesi E, Paioli A, Cesari M, Longhi A, et al. Gemcitabine and 
docetaxel in relapsed and unresectable high-grade osteosarcoma abd spindle cell sarcoma 
of bone. BioMed Centr Cancer. 2016;16:280. 
11. Guideline on the evaluation of anticancer medicinal products in man - methodological 
consideration for using progression-free survival (PFS) or disease-free survival (DFS) in 
confirmatory trials, 13 December 2012. Available from: 
https://www.ema.europa.eu/en/documents/scientific-guideline/appendix-1-guideline-
evaluation-anticancer-medicinal-products-man-methodological-consideration-
using_en.pdf. 


Statistical Analysis Plan 
E7080-G000-230 
 
 
Eisai 
Confidential 
Page 39 of 40 
 
14 APPENDICES  
Not applicable for this report. 
 
 


Statistical Analysis Plan 
E7080-G000-230 
 
 
Eisai 
Confidential 
Page 40 of 40 
 
SIGNATURE PAGE 
Author: 
 
 
 
 
 
 
Oncology Business Group, Eisai Inc. 
 
Date 
Approval: 
 
 
 
Oncology Business Group, Eisai Inc. 
 
 
Date 
 
Oncology Business Group, Eisai Ltd. 
 
 
Date 
 
  
PPD
PPD
PPD