Clinical trial NCT03441360
Conditions: Relapsed/Refractory Rhabdomyosarcoma Non-rhabdomyosarcoma Soft Tissue Sarcoma Ewing Sarcoma
Keywords: eribulin mesylate pediatric
Sponsor: Eisai Inc.
Start date: 2018-04-17; Completion date: 2022-01-21
Enrollment: 23 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will be conducted as an assessment of the safety and preliminary activity of eribulin mesylate in pediatric participants with relapsed/refractory rhabdomyosarcoma (RMS), non-rhabdomyosarcoma soft tissue sarcoma (NRSTS), or Ewing sarcoma (EWS) to determine whether each cohort warrants further investigation.

Detailed description:

Arms: arm 1: Pediatric participants with relapsed/refractory rhabdomyosarcoma (RMS) will receive eribulin mesylate administered as an intravenous (IV) infusion on Days 1 and 8 of each 21-day cycle at a dose of 1.4 milligrams per meters squared (mg/m\^2). Participants will continue study therapy until progression of disease (per Response Evaluation Criteria In Solid Tumors \[RECIST\] 1.1), intolerable toxicity, or withdrawal of consent. arm 2: Pediatric participants with non-rhabdomyosarcoma soft tissue sarcoma (NRSTS) will receive eribulin mesylate administered as an IV infusion on Days 1 and 8 of each 21-day cycle at a dose of 1.4 mg/m\^2. Participants will continue study therapy until progression of disease (per RECIST 1.1), intolerable toxicity, or withdrawal of consent. arm 3: Pediatric participants with Ewing sarcoma (EWS) will receive eribulin mesylate administered as an IV infusion on Days 1 and 8 of each 21-day cycle at a dose of 1.4 mg/m\^2. Participants will continue study therapy until progression of disease (per RECIST 1.1), intolerable toxicity, or withdrawal of consent.
Interventions: intervention 1: Eribulin mesylate
Intervention descriptions: intervention 1: Intravenous infusion

Protocol documents:
SAP_002.pdf: 
Statistical Analysis Plan 
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STATISTICAL ANALYSIS PLAN 
Study Protocol 
Number: 
E7389-G000-223 
Study Protocol 
Title: 
A Phase 2, multicenter, open-label study to assess safety and 
preliminary activity of eribulin mesylate in pediatric subjects with 
relapsed/refractory rhabdomyosarcoma (RMS), non-
rhabdomyosarcoma soft tissue sarcoma (NRSTS) and Ewing 
sarcoma (EWS) 
Date: 
08 Apr 2021 
Version: 
Final Version 1.0 


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1 
TABLE OF CONTENTS 
1 
TABLE OF CONTENTS ...................................................................................................2 
2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ....................................4 
3 
INTRODUCTION .............................................................................................................6 
3.1 
Study Objectives ......................................................................................................6 
3.1.1 
Primary Objective ..........................................................................................6 
3.1.2 
Secondary Objectives .....................................................................................6 
3.1.3 
Exploratory Objectives ..................................................................................6 
3.2 
Overall Study Design and Plan ................................................................................6 
4 
DETERMINATION OF SAMPLE SIZE ..........................................................................7 
5 
STATISTICAL METHODS ..............................................................................................8 
5.1 
Study Endpoints .......................................................................................................8 
5.1.1 
Primary Endpoint ...........................................................................................8 
5.1.2 
Secondary Endpoints .....................................................................................8 
5.1.3 
Exploratory Endpoint .....................................................................................8 
5.2 
Study Subjects ..........................................................................................................8 
5.2.1 
Definitions of Analysis Sets...........................................................................8 
5.2.2 
Subject Disposition ........................................................................................9 
5.2.3 
Protocol Deviations ........................................................................................9 
5.2.4 
Demographic and Other Baseline Characteristics .........................................9 
5.2.4.1 
Medical History ...................................................................................9 
5.2.4.2 
Disease History and Characteristics .....................................................9 
5.2.5 
Prior and Concomitant Therapy ...................................................................10 
5.2.6 
Treatment Compliance .................................................................................10 
5.3 
Data Analysis General Considerations ..................................................................11 
5.3.1 
Pooling of Centers........................................................................................11 
5.3.2 
Adjustments for Covariates..........................................................................11 
5.3.3 
Multiple Comparisons/Multiplicity .............................................................11 
5.3.4 
Examination of Subgroups ...........................................................................11 
5.3.5 
Handling of Missing Data, Dropouts, and Outliers .....................................11 
5.3.6 
Other Considerations ...................................................................................11 
5.4 
Efficacy Analyses ..................................................................................................11 
5.4.1 
Primary Efficacy Analyses ..........................................................................11 
5.4.2 
Secondary Efficacy Analyses ......................................................................12 
5.4.3 
Other Efficacy Analyses ..............................................................................12 
5.5 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other 
Biomarker Analyses ...............................................................................................12 


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5.5.1 
Pharmacokinetic Analyses ...........................................................................12 
5.5.2 
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Analyses ....12 
5.6 
Safety Analyses ......................................................................................................13 
5.6.1 
Extent of Exposure .......................................................................................13 
5.6.2 
Adverse Events ............................................................................................13 
5.6.3 
Laboratory Values ........................................................................................14 
5.6.4 
Vital Signs ....................................................................................................14 
5.6.5 
Electrocardiograms ......................................................................................15 
5.6.6 
Other Safety Analyses ..................................................................................15 
5.7 
Other Analyses .......................................................................................................15 
5.8 
Exploratory Analyses .............................................................................................15 
6 
INTERIM ANALYSES ...................................................................................................16 
7 
CHANGES IN THE PLANNED ANALYSES ...............................................................16 
8 
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING ...............................16 
9 
PROGRAMMING SPECIFICATIONS ..........................................................................17 
10 STATISTICAL SOFTWARE ..........................................................................................17 
11 MOCK TABLES, LISTINGS, AND GRAPHS ..............................................................17 
12 REFERENCES ................................................................................................................17 
13 APPENDICES .................................................................................................................17 
SIGNATURE PAGE ...............................................................................................................18 
 


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2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Term 
AE 
adverse event 
ATC 
anatomical therapeutic chemical 
BOR 
best overall response 
BSA 
body surface area 
CI 
confidence interval 
CR 
complete response 
CRF 
case report form 
CTCAE 
Common Terminology Criteria for Adverse Events 
DOR 
duration of response 
ECG 
electrocardiogram 
EWS 
Ewing sarcoma 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
IV 
intravenous 
LLT 
lower level term 
MedDRA 
Medical Dictionary for Regulatory Activities 
NRSTS 
non-rhabdomyosarcoma soft tissue sarcoma 
ORR 
objective response rate 
OS 
overall survival 
PAS 
pharmacokinetic analysis set 
PD 
progressive disease 
PFS 
progression-free survival 
PK 
pharmacokinetic 
PR 
partial response 
PT 
preferred term 
QT 
QT interval is the time between the start of the Q wave and the 
end of the T wave in the heart's electrical cycle 
QTc 
QT interval corrected for heart rate  
QTcB 
QT interval corrected for heart rate using Bazett's formula 


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Abbreviation 
Term 
QTcF 
QT interval corrected for heart rate using Fridericia's formula 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RMS 
rhabdomyosarcoma 
RP2D 
recommended phase 2 dose 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD  
stable disease 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
TLG 
tables, listings, and graphs 
WHODD 
World Health Organization Drug Dictionary 
 


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3 
INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to describe the procedures and the 
statistical methods that will be used to analyze and report results for Eisai Protocol E7389-
G000-223 titled “A Phase 2, multicenter, open-label study to assess safety and preliminary 
activity of eribulin mesylate in pediatric subjects with relapsed/refractory rhabdomyosarcoma 
(RMS), non-rhabdomyosarcoma soft tissue sarcoma (NRSTS) and Ewing sarcoma (EWS)”.  
3.1 
Study Objectives 
3.1.1 
Primary Objective 
• To conduct a preliminary assessment of activity of eribulin mesylate in pediatric subjects 
with relapsed/refractory RMS, NRSTS or EWS to determine whether each cohort 
warrants further investigation. 
3.1.2 
Secondary Objectives 
• To evaluate the progression-free survival (PFS), using Response Evaluation Criteria in 
Solid Tumors (RECIST) 1.1, of eribulin mesylate in pediatric subjects with 
relapsed/refractory RMS, NRSTS, or EWS in all cohorts combined. 
• To evaluate the safety and tolerability of eribulin in the pediatric subjects with 
relapsed/refractory RMS, NRSTS, or EWS in all cohorts combined. 
• To evaluate the duration of response (DOR) of eribulin mesylate in pediatric subjects 
with relapsed/refractory RMS, NRSTS, or EWS. 
• To evaluate the overall survival (OS) of pediatric subjects with relapsed/refractory RMS, 
NRSTS and EWS. 
3.1.3 
Exploratory Objectives 
• To evaluate the exposure of eribulin mesylate in pediatric subjects with 
relapsed/refractory RMS, NRSTS, or EWS. 
• To explore the relationship between exposure to eribulin mesylate and adverse events 
(AEs) and efficacy. 
3.2 
Overall Study Design and Plan 
E7389-G000-223 is a Phase 2, multicenter, open-label study to conduct a preliminary 
assessment of the safety and activity of eribulin mesylate in pediatric subjects with 
relapsed/refractory RMS, NRSTS, or EWS. 
Up to forty-five pediatric subjects, with approximately 15 subjects each with RMS, NRSTS, 
or EWS, will be enrolled to receive eribulin mesylate as an intravenous (IV) infusion at a dose 


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of 1.4 mg/m2 (Recommended Phase 2 Dose [RP2D]) on Days 1 and 8 of each 21-day cycle as 
determined by the dose finding study ADVL1314 (Eisai Study E7389-A001-113). 
Outline 
• Pediatric subjects with relapsed/refractory RMS, NRSTS or EWS will be enrolled to 
receive therapy with eribulin mesylate. 
• For each histology type, approximately 15 subjects will be treated.  Data will be 
monitored on an ongoing basis; depending on evaluation by the investigators and 
sponsor, if sufficient responses (PRs or CRs) are observed, then this histology type will 
be recommended for inclusion in the subsequent study. 
• Subjects will continue study therapy until progression of disease (per RECIST 1.1), 
intolerable toxicity or withdrawal of consent. 
Pre-study Phase: 
Day -28 to -1, computed tomography (CT) / magnetic resonance imaging (MRI) scans must 
be performed within 28 days prior to study drug administration.  All clinical and laboratory 
test results to determine eligibility must be performed within 7 days prior to study drug 
administration, unless otherwise indicated. 
Treatment Phase: 
The treatment phase will start on Day 1 of Cycle 1. 
Follow-up:  
The follow-up period will begin immediately after the End of Treatment visit until death or 
informed consent is withdrawn, unless the study is terminated by the sponsor.  Subjects will 
be followed for survival approximately every 12 weeks for 1 year and then annually thereafter.  
As well as follow-up for survival, the annual surveillance will also assess any long-term effects 
of the study treatment. 
During the follow-up period, subjects who have gone off study treatment without progression 
should have tumor assessments every 6 - 12 weeks, at the investigator’s discretion, from the 
date of last tumor assessment until disease progression is documented, death, or initiation of 
another anticancer therapy, whichever occurs first, unless the study is terminated by the 
sponsor.  Follow-up data will be required unless consent is withdrawn. 
The schedules of procedures/assessments are presented in Table 9 of the protocol. 
4 
DETERMINATION OF SAMPLE SIZE 
A total of up to 45 subjects will be enrolled.  In each of the histology groups of RMS, NRSTS, 
and EWS, approximately 15 subjects will be enrolled and treated with eribulin mesylate.  The 


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sample size is considered sufficient based on clinical judgment and is not obtained from 
statistical calculation. 
5 
STATISTICAL METHODS 
All descriptive statistics for continuous variables will be reported using n, mean, standard 
deviation, median, 25th percentile (Q1), 75th percentile (Q3), minimum, and maximum.  
Categorical variables will be summarized as number and percentage of subjects. 
All summary tables will be presented by histology type and overall. 
5.1 
Study Endpoints 
5.1.1 
Primary Endpoint 
• Objective response:  number of subjects achieving a best overall response of partial or 
complete response (PR or CR), by up to 24 weeks after all subjects have completed 
response assessment.  Response assessment will be determined by investigators. 
5.1.2 
Secondary Endpoints 
• PFS:  defined as the time from the first dose date to the date of disease progression or 
date of death (whichever occurs first). 
• Safety and tolerability:  AEs, SAEs, clinical laboratory values, ECG parameters, vital 
sign measurements, and performance status. 
• DOR:  defined as the time from the first date of documented PR or CR to the date of 
disease progression or date of death (whichever occurs first). 
• OS:  defined as the time from the first dose date to the date of death. 
5.1.3 
Exploratory Endpoint 
• Exposure of eribulin mesylate. 
5.2 
Study Subjects 
5.2.1 
Definitions of Analysis Sets 
The Full Analysis Set (FAS) will consist of all subjects who receive at least 1 dose of study 
drug. 
The Safety Analysis Set will consist of all subjects who receive at least 1 dose of study drug. 
The Pharmacokinetic Analysis Set (PAS) will include subjects who have at least 1 
evaluable plasma concentration and sufficient dosing information. 


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5.2.2 
Subject Disposition 
Screening disposition will be summarized by number and percentage of subjects with reasons. 
Study treatment disposition will be summarized by number and percentage of subjects with 
reasons for treatment discontinuation. 
5.2.3 
Protocol Deviations 
Protocol deviations will be determined prior to database lock.  The protocol deviations data 
as collected in the clinical database will be presented in tables and/or listings as appropriate. 
5.2.4 
Demographic and Other Baseline Characteristics 
Demographic and other baseline characteristics for the Full Analysis Set will be summarized 
for each histology group and overall using descriptive statistics.  Continuous demographic 
and baseline variables include age (years), height (cm), weight (kg), BSA (m2), and vital 
signs, categorical variables include country, sex, age group, ethnicity, race, Karnofsky (for 
age>16) / Lansky (for age<=16) performance status score. 
For continuous variables, the number of non-missing observations, mean, standard deviation, 
median, 25th percentile (Q1), 75th percentile (Q3), minimum, and maximum will be 
presented.  For categorical variables, the number and percentage of patients will be 
presented. 
5.2.4.1 
Medical History 
Medical history will be coded by MedDRA (Version 21.1 or higher), the linked MedDRA 
preferred term (PT) and primary system organ class (SOC) will also be captured in the 
database.  The number (percentage) of subjects in the Full Analysis Set reporting a history of 
any medical condition, will be summarized by SOC and PT for each histology group and 
overall.  A subject data listing of medical history will be provided. 
5.2.4.2 
Disease History and Characteristics 
Disease history and characteristics for the Full Analysis Set will be summarized for each 
histology group and overall using descriptive statistics.  
Continuous variables include: 
• Time from first diagnosis to first dose (months); 
• Age at first diagnosis (years); 
• Time from last disease progression to first dose (days); 
Categorical variables include: 
• Location of primary tumor; 


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• Target lesions at baseline (Lymph node only, Non-lymph node only, Lymph node and 
non-lymph node); 
• Non-target lesions at baseline (Yes and No); 
A subject data listing of disease history and characteristics will be provided. 
5.2.5 
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 (WHODDMAR18_HD_B2).  The 
number (percentage) of subjects who took prior and concomitant medications will be 
summarized on the Full Analysis Set by histology group, Anatomical Therapeutic Chemical 
(ATC) class (i.e., anatomical class, pharmacologic class), and WHODD preferred term.   
Prior medications are defined as medications that stopped before the first dose of study drug.  
Concomitant medications are 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 28 days after the subject’s last dose.  A 
medication that cannot be determined as prior/concomitant/post-treatment due to 
missing/incomplete dates will be regarded as a concomitant medication.  
Prior and concomitant medications will be summarized respectively.  All medications will be 
presented in subject data listings. 
Previous anticancer therapies 
Number of regimens, type of regimens, duration of last regimen (months), time from end of 
last regimen to first dose (months) and best response to the last regimen will be summarized 
for prior anticancer medications.   
The number (percentage) of subjects who took prior anticancer medications will be 
summarized on the Full Analysis Set by histology group, Anatomical Therapeutic Chemical 
(ATC) class (i.e., anatomical class, pharmacologic class), and WHODD preferred term.   
Number of radiotherapy, sites of radiotherapy, total dose (cGy) per subject, time from end of 
last radiotherapy to first dose (months) and tumor lesion progressed since most recent 
radiotherapy, will be summarized for prior anticancer radiotherapy.   
Previous anticancer medication and radiotherapy will be summarized/listed separately. 
5.2.6 
Treatment Compliance 
Not applicable. 


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5.3 
Data Analysis General Considerations 
5.3.1 
Pooling of Centers 
This study is a multicenter study.  Subjects from all centers will be pooled for all analyses. 
5.3.2 
Adjustments for Covariates 
Not applicable. 
5.3.3 
Multiple Comparisons/Multiplicity 
Not applicable. 
5.3.4 
Examination of Subgroups 
No subgroup analyses are planned for this study. 
5.3.5 
Handling of Missing Data, Dropouts, and Outliers 
In general, missing data including dates will be treated as missing and no data imputation 
will be applied, unless otherwise specified.  Data that are potentially spurious or erroneous 
will be queried and examined during the review of the study data. 
 
For efficacy data summarized for the FAS, subjects with missing response status (subjects 
whose baseline or post-baseline tumor assessment is missing) will be considered as non-
responders and will be included in the denominator when calculating the response rate. 
5.3.6 
Other Considerations 
Not applicable. 
5.4 
Efficacy Analyses 
Efficacy analyses will be performed on the Full Analysis Set. 
5.4.1 
Primary Efficacy Analyses 
The primary analysis will be based on investigator assessments of tumor response according 
to RECIST 1.1 (Eisenhauer, et al. 2009). 
The primary analysis is to examine the number of responders (CR or PR) within each histology 
subject cohort.  Confirmed response (PR or CR) will be used in this analysis.  All responses 
must be confirmed no less than 28 days following the initial assessment of response.  In order 
for stable disease (SD) to be considered the best overall response, it must occur ≥ 5 weeks 
following the first dose of study drug. 


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Objective response rate (ORR) is defined as the proportion of subjects achieving the best 
overall response (BOR) of CR or PR as per RECIST 1.1.  ORR will be calculated with a 2-
sided, exact 95% confidence interval (CI), using the Clopper-Pearson method. 
5.4.2 
Secondary Efficacy Analyses 
The secondary analyses will be to estimate the PFS, DOR, and OS in all cohorts combined.  
Median PFS, DOR, and OS with the corresponding 95% confidence intervals (CI) will be 
estimated using Kaplan-Meier method (Kaplan; Meier. 1958).  Descriptive statistics will be 
provided.  Duration of response (DOR) will be calculated for subjects with an objective 
response of PR or CR.  
Censoring rules for PFS/DOR are listed in section 8:  definitions and conventions for data 
handling.  For OS, subjects who were alive at the data cutoff date will be censored at the data 
cutoff date, and subjects who were lost to follow-up, withdrew consent, or had survival status 
collected as “Study terminated by Sponsor” will be censored at the date the subject was last 
known to be alive. 
5.4.3 
Other Efficacy Analyses 
No other efficacy analyses are planned for this study. 
5.5 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Analyses 
5.5.1 
Pharmacokinetic Analyses 
Blood samples will be collected for the PK analysis of eribulin as follows: 
1. Immediately post-infusion on Day 1 of each cycle for the first 3 cycles; 
2. Pre-infusion and immediately post-infusion on Day 8 of each cycle for the first 3 cycles. 
Plasma concentrations of eribulin will be tabulated and summarized by histology and time.  
5.5.2 
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Analyses 
Exposure-response Analyses 
Following FDA guidance, PK sampling will be conducted in subjects across the pediatric 
program at regular intervals in order to adequately characterize the PK of eribulin in the 
pediatric population in the various age cohorts to explore exposure-response (ER) relationships 
for efficacy and safety (AE).  The relationship between exposure to eribulin mesylate and AE 
or efficacy will be explored graphically and may be modelled if a relationship is deemed to 
exist. 


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5.6 
Safety Analyses 
All safety analyses will be performed on the Safety Analysis Set.  Safety data, presented by 
histology type, will be summarized on an “as treated” basis using descriptive statistics (e.g., n, 
mean, standard deviation, median, minimum, Q1, Q3 and maximum for continuous variables; 
n [%] for categorical variables).  Safety variables include treatment-emergent adverse events 
(TEAEs), clinical laboratory parameters, vital signs, 12-lead ECG results, and performance 
status.  
 Study Day 1 for all safety analyses is defined as the date of the first dose of study drug.  
5.6.1 
Extent of Exposure 
The number of cycles administered, duration of treatment, number of doses, total dose (mg/m2) 
per subject, actual dose intensity (mg/m2/week) per subject and relative dose intensity per 
subject will be summarized for eribulin mesylate and be presented by n, mean with standard 
deviation, median, minimum, Q1, Q3 and maximum. 
Duration of Treatment (weeks) = (Date of first dose of last cycle + 21 - date of first dose of 
study drug) / 7. 
Actual Dose Intensity (mg/m2/week) = Total dose (mg/m2) / Duration of treatment (weeks). 
Relative Dose Intensity (%) = Actual Dose intensity (mg/m2/week)/ Planned dose intensity * 
100, where Planned dose intensity is 0.933 mg/m2/week = 1.4 mg/m2 * 2 / 3 weeks. 
The number of subjects who had dose changes will be summarized for eribulin mesylate. 
5.6.2 
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 21.1 or higher) lower 
level term (LLT) closest to the verbatim term.  The linked MedDRA preferred term (PT) and 
primary system organ class (SOC) will also be captured in the database. 
A treatment-emergent adverse event (TEAE) is defined as an AE that emerged during 
treatment, having been absent at pretreatment (Baseline) or  
• Reemerged during treatment, having been present at pretreatment (Baseline) but stopped 
before treatment, or  
• Worsened in severity during treatment relative to the pretreatment state, when the AE 
was 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. 


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The TEAEs will be summarized by histology 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 a 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 Common Terminology Criteria for Adverse Events (CTCAE) 
V4.03 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 TEAEs with fatal outcomes will be summarized by 
MedDRA SOC and PT for each histology type.  A subject data listing of all AEs with fatal 
outcomes will be provided. 
The number (percentage) of subjects with treatment-emergent serious adverse events (SAEs) 
will be summarized by MedDRA SOC and PT for each histology type.  A subject data listing 
of all SAEs was provided. 
The number (percentage) of subjects with TEAEs leading to discontinuation from study drug 
will be summarized by MedDRA SOC and PT for each histology type.  A subject data listing 
of all AEs leading to discontinuation from study drug will be provided. 
5.6.3 
Laboratory Values 
Laboratory results will be summarized using Système International (SI) units, as appropriate.  
For all hematology and chemistry parameters listed in the protocol Section 9.5.1.6.3 (Table 8), 
the actual value and the change from baseline to each post-baseline visit will be summarized 
using descriptive statistics (n, mean, standard deviation, median, Q1, Q3, minimum, 
maximum).  
Laboratory test results will be assigned a classification according to CTCAE grade 
(Appendix 1 in the protocol).  Shifts of CTCAE grade from baseline to worst post-baseline 
will be presented.  Percentages will be based on the number of subjects with both non-
missing baseline and at least one post-baseline result for relevant parameters. 
Urinalysis and pregnancy test data will be listed. 
5.6.4 
Vital Signs 
Descriptive statistics for vital signs parameters (i.e., systolic and diastolic blood pressure 
(BP), pulse, temperature, weight, and height) and changes from baseline will be presented by 
visit. 
A listing of all vital sign measurements will be provided. 


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5.6.5 
Electrocardiograms 
ECG assessments will be performed.  QT intervals will be measured from Lead II and will be 
corrected for heart rate (QTc) using Fridericia's (QTcF) and Bazett's (QTcB) correction 
factors.  The primary QTc parameter will be QTcF.  Secondary parameters will be QTcB, 
QT, QRS, and heart rate.  
Shift tables will present shifts from baseline to end of treatment in ECG interpretation 
(categorized as normal; abnormal, not clinically significant; and abnormal, clinically 
significant).  
In addition, the number and percentage of subjects with at least 1 post-baseline abnormal 
ECG result in QTc Fridericia and Bazett's during the treatment period will be summarized.  
Clinically abnormal ECG results in QTc Fridericia and Bazett's will be categorized as 
follows: 
Absolute QTc interval prolongation: 
• QTc interval >450 ms 
• QTc interval >480 ms 
• QTc interval >500 ms 
Change from baseline in QTc interval: 
• QTc interval increase from baseline >30 ms 
• QTc interval increase from baseline >60 ms 
5.6.6 
Other Safety Analyses 
The changes of Karnofsky and Lansky performance status scores from baseline to worst post-
baseline will be presented in shift tables. 
5.7 
Other Analyses 
Not applicable. 
5.8 
Exploratory Analyses 
Exploratory analyses may be conducted as appropriate.  Any exploratory analyses that are 
performed will be appropriately titled and labeled as exploratory and will be clearly 
distinguished from planned analyses when results are reported in the Clinical Study Report. 


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6 
INTERIM ANALYSES 
Data will be monitored on an ongoing basis; depending on evaluation by the investigators and 
sponsor, if sufficient responses (PR or CR) are observed, then this histology type will be 
recommended for inclusion in the subsequent study.  
7 
CHANGES IN THE PLANNED ANALYSES 
Not applicable. 
8 
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING 
Censoring Rules for PFS/DOR 
The PFS censoring rules in this SAP and definition of progression date follow the Food and 
Drug Administration (FDA) “Guidance for Industry Clinical Trial Endpoints for the Approval 
of Cancer Drugs and Biologics (2007)”.   
Table 1 Censoring Rules for Progression-free Survival Endpoint 
Situation 
End Date 
Censored 
Investigator documented PD 
Date of the first assessment of the 
series of radiologic tests that 
determined PD 
No 
Death during the study before first PD 
Date of death 
No 
No baseline or post-baseline tumor 
assessments 
Date of first dose  
Yes 
No progression and no death at the time 
of data cutoff 
Date of last adequate tumor 
assessment* prior to data cutoff 
Yes 
Non-study anticancer treatment initiated 
before progression or death 
Date of last adequate tumor 
assessment* prior to or on date of 
non-study anticancer treatment 
Yes 
Death or progression after more than 
one missed tumor assessments** 
Date of last adequate tumor 
assessment* prior to missed tumor 
assessments 
Yes 
PD = progressive disease. 
* Adequate tumor assessment is radiologic assessment of CR, PR, SD, non-CR/non-PD or 
PD as determined by investigators at regular interval as defined in the protocol.  Any tumor 
assessments after new anticancer treatment starts will be removed in the definition of PFS. 
**More than one missed visit/adequate tumor assessment is defined as having the duration 
between the last adequate tumor assessment and PD or death being longer than the gap limit. 
a)  The gap from baseline to the 1st assessment post-baseline (calculated from C1D1), gap 
limit = 2*6 weeks + 2*3 Days = 90 days.  


Statistical Analysis Plan 
E7389-G000-223 
 
 
Eisai 
FINAL Version 1.0:  08 Apr 2021 
Confidential 
Page 17 of 18 
 
b)  The gap from the 1st assessment post-baseline, or from any later assessment -- call it 
 
"previous assessment", to the next assessment. 
• if Study Day of the previous assessment < (18 weeks - 3 days), then gap limit = 2*6 
weeks + 2*3 days = 90 days;  
• if (18 weeks - 3 days) <= Study Day of the previous assessment < 24 weeks - 3 days,  
then gap limit = 6 weeks + 9 weeks + 2*3 days = 111 days; 
• if Study Day of the previous assessment >= 24 weeks - 3 days, the gap limit = 2*9 weeks 
+ 2*3 days = 132 days.  
 
9 
PROGRAMMING SPECIFICATIONS 
The rules for programming derivations and dataset specifications are provided in separate 
documents. 
10 STATISTICAL SOFTWARE 
All statistical analyses will be performed using SAS v9.4. 
11 MOCK TABLES, LISTINGS, AND GRAPHS 
The study TLG shells will be provided in a separate document, which will show the content 
and format of all tables, listings, and graphs in detail. 
12 REFERENCES 
Kaplan, E. L.; Meier, P. (1958). "Nonparametric estimation from incomplete observations". 
Journal of the American Statistical Association. 53 (282): 457–481. 
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. 
Cancer Therapy Evaluation Program, Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0 [published 28 May 2009 (v4.03: June 14, 2010)].  Available from: 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf. 
13 APPENDICES 
Not applicable. 


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Prot_000.pdf: 
Clinical Study Protocol
incorporating Amendment 2.0
E7389-G000-223
Eisai
FINAL: 20 Dec 2018
Confidential
Page 1 of 90
REVISION HISTORY
Revisions per Amendment 2.0
Date: 20 Dec 2018
Change
Rationale
Affected Protocol Sections
Number of sites increased to 40
Increased to help to achieve 
recruitment targets.

Synopsis - Sites

Section 6
Two exploratory objectives of 
DOR and OS were changed to 
secondary objectives.
Following feedback from the FDA 
and the EMA PDCO. These 
objectives have moved from 
exploratory to secondary 
objectives.

Synopsis - Objectives

Section 8.2, Section 8.3
Number of subjects planned was 
increased to 45 and hence the 
number of subjects in each of the 
histology groups was increased to 
approximately 15. The 
determination of sample size text 
updated accordingly.
Following feedback from the EMA 
PDCO, the sample size was 
increased to be compliant with the 
EMA Pediatric Investigational 
Plan.

Synopsis - Study Design, 
Number of Subjects, 
Efficacy Analysis, Sample 
Size Rationale

Section 9.3, Section 9.7.2
Changed inclusion criteria #5 
“Performance level: Performance 
score ≥50%. Karnofsky (for 
subjects >16 years of age) or 
Lansky (for subjects ≤16 years of 
age).  “Subjects who are unable 
to walk because of paralysis 
and/or previous surgeries, but 
who are in a wheelchair, will be 
considered ambulatory for the 
purpose of assessing 
performance score.”
Clarification of inclusion criteria # 
5.

Synopsis- Inclusion 
Criteria

Section 9.3.1
Changed inclusion criteria #6 
“Monoclonal antibodies: ≥ 3 half-
lives must have elapsed from 
infusion of last dose of antibody 
(including checkpoint inhibitors), 
and toxicity related to prior 
antibody therapy must be 
recovered to Grade ≤1.”
“Hematopoietic growth factors: 
≥14 days after the last dose of a 
long-acting growth factor (eg, 
Neulasta) or 7 days for a short-
acting growth factor.  For agents 
that have known AEs occurring 
beyond 7 days after administration, 
this period must be extended 
beyond the time during which AEs 
Clarification of inclusion criteria 
#6.

Synopsis - Inclusion 
Criteria

Section 9.3.1


Clinical Study Protocol
incorporating Amendment 2.0
E7389-G000-223
Eisai
FINAL: 20 Dec 2018
Confidential
Page 2 of 90
Change
Rationale
Affected Protocol Sections
are known to occur. The duration 
of this interval must be discussed 
with the sponsor.”
Changed inclusion criteria #8 “Or 
creatinine clearance or radioisotope
GFR ≥50 mL/min/1.73 m2 based 
on a 12 or 24 hour urine creatinine 
collection.”
Correction to inclusion criteria #8.

Synopsis - Inclusion 
Criteria

Section 9.3.1
Changed exclusion criteria #1 “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 
commenced/adjusted/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 
condoms plus diaphragm or 
cervical/vault cap with 
spermicide.”
“**Must be on a stable dose of the 
same oral hormonal contraceptive 
product for at least 4 weeks before 
dosing with study drug and for the 
duration of the study and for 6 
months after study drug 
discontinuation. For sites outside 
of the EU, double barrier methods 
of contraception must be used for 
subjects who have 
commenced/switched oral 
contraceptive, or adjusted dose, 
within 4 weeks prior to dosing”
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 or for 
28 days 3 months after study drug 
discontinuation).  No sperm 
donation is allowed during the 
study period or for 28 days
3 months after study drug 
Clarification of exclusion criteria 
#1 and removal of duplicate text.
Updated duration of 
contraception/window before 
sperm donation to 3 months (after 
study drug discontinuation) for 
male subjects following site 
feedback to be more conservative 
and more in line with USPI.

Synopsis - Exclusion 
Criteria

Section 9.3.2


Clinical Study Protocol
incorporating Amendment 2.0
E7389-G000-223
Eisai
FINAL: 20 Dec 2018
Confidential
Page 3 of 90
Change
Rationale
Affected Protocol Sections
discontinuation.
Added text to exclusion criteria #2 
“Concomitant medications:
“• Strong CYP3A4 
inducers/inhibitors (See Section 
9.4.6.1.1, Drug-Drug 
Interactions)”.
Updated in line with eribulin study 
protocols.

Synopsis - Exclusion 
Criteria

Section 9.3.2
Added 18fluordeoxyglucose (FDG)-
PET/CT scans.
Included FDG/PET scans, as per 
standard of practice at many sites

Synopsis - Efficacy 
Assessment

Section 9.5.1.4, Section 
9.5.1.6.7, Section 9.5.2, 
Table 9
The exploratory endpoints of DOR 
and OS were changed to secondary 
endpoints.
Following feedback from the FDA 
and the EMA PDCO. These 
endpoints have moved from 
exploratory to secondary 
endpoints.

Synopsis - Exploratory 
Endpoints

Section 9.7.1.1.2, Section 
9.7.1.1.3, Section 9.7.1.6.2
E7389-G000-223 is a Phase 2, 
multicenter, open-label study to 
conduct a preliminary assessment 
of the safety and activity of 
eribulin mesylate in pediatric 
subjects with relapsed/refractory 
RMS, NRSTS, or EWS.  If there is 
at least 1 response (PR or CR) in at 
least 1 of these histology types, the 
study will proceed to a second 
study, a two-arm, randomized, 
open-label study to assess the 
efficacy and safety of eribulin 
mesylate versus a comparator.
Study design text amended in line 
with the change in sample size.

Synopsis - Study Design

Section 9.1, Section 9.2
Changed text “In Study E7389-
G000-223, up to 30 45 pediatric 
subjects, with up to 10 
approximately 15 subjects each 
with RMS, NRSTS, or EWS, will 
be enrolled to receive eribulin
mesylate as an intravenous (IV) 
infusion at a dose of 1.4 mg/m2
(Recommended Phase 2 Dose 
[RP2D]) on Days 1 and 8 of each 
21-day cycle as determined by the 
dose finding study ADVL1314 
(Eisai Study E7389-A001-113)”.
Removed study design figure.
Study design text amended in line 
with the change in sample size.

Synopsis – Study Design

Section 9.1
Changed text: For each histology 
type, up to 10 approximately 15 
Test amended for clarification and 
in line with change in sample size.

Synopsis-Study Design, 
Efficacy Analyses, Interim 


Clinical Study Protocol
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E7389-G000-223
Eisai
FINAL: 20 Dec 2018
Confidential
Page 4 of 90
Change
Rationale
Affected Protocol Sections
subjects will be treated.  “Data will 
be monitored on an ongoing 
basis; depending on evaluation 
by the investigators and sponsor, 
if sufficient responses If there is at 
least 1 response (PRs or CRs) are
observed, then this histology type 
will be recommended for inclusion 
in the follow-up subsequent
study.”
Analyses

Section 9.1, Section 9.7.3
Extended screening period from 14 
to 28 days.
Following feedback from 
investigators, to allow more time 
for completion of screening 
procedures and to prevent 
unnecessary repeat scans.  The 
screening period was extended 
from 14 to 28 days.

Synopsis – Study Design

Section 9.1, Section 9.5.2, 
Table 9
Text clarified: all subjects will 
have an end of treatment visit 
within 28 days of the last dose of 
study medication. The follow-up 
period will begin immediately after 
the end of treatment visit until
death, the subject withdraws 
consent unless study is terminated 
by sponsor.
Updated for clarification

Synopsis – Study Design

Section 9.1
Added text to clarify the frequency 
of follow up and to increase the 
duration of follow up for long term 
survival.  
Following feedback from the EMA 
PDCO, the duration of follow up 
was clarified and increased.

Synopsis – Duration of 
Treatment

Section 9.1

Section 9.5.2, Table 9
Changed text “The primary 
analysis is to examine the number 
of responders within each 
histology subject cohort.  If there is 
at least 1 response in a subject 
cohort, the corresponding histology 
will be recommended for inclusion 
in a randomized study.  Confirmed 
response (PR or CR) will be used 
in this analysis.  The analysis is 
planned using data from up to 24 
weeks after 150 subjects in each 
cohort have completed response
assessments. In each of the 
histology groups of RMS, 
NRSTS, and EWS, 
approximately 15 subjects will be 
enrolled and treated with 
eribulin mesylate.  Data will be 
Following feedback from the EMA 
PDCO and increased sample size.

Synopsis – Efficacy 
Analysis

Section 9.7.1.6.1


Clinical Study Protocol
incorporating Amendment 2.0
E7389-G000-223
Eisai
FINAL: 20 Dec 2018
Confidential
Page 5 of 90
Change
Rationale
Affected Protocol Sections
monitored on an ongoing basis; 
depending on evaluation by the 
investigators and sponsor, if 
sufficient responses (partial 
response [PR] or complete 
response [CR]) are observed, 
then this histology type will be 
recommended for inclusion in 
the subsequent study.  At the 
latest, the primary analysis will 
be performed when 
approximately 15 subjects have 
completed 24 weeks of response 
assessments.
The secondary analyses were 
updated to include DOR and OS.  
The exploratory analyses of DOR 
and OS were removed.
Following feedback from the FDA 
and the EMA PDCO, exploratory 
endpoints of DOR and OS were 
moved to secondary endpoints.

Synopsis- Secondary 
Efficacy Analyses

Section 9.7.1.6
Schafer, et al 2016 reference 
updated from abstract to full 
publication 2018.
Reference updated with recent 
publication.

Section 7.1.3.2, Section 
7.2, Section 10
Changed text “Additional 
exploratory endpoints efficacy 
assessments on the exposure of 
eribulin will be evaluated and the 
relationship between exposure and 
AEs and efficacy will also be 
explored.on DOR and OS (for up 
to 1 year after last subject in), will 
also be assessed.”
Following feedback from the FDA 
and the EMA PDCO. These 
endpoints have moved from 
exploratory to secondary 
endpoints.

Section 9.5.1.3.3
Magnesium added to the chemistry 
panel for Clinical Laboratory 
Tests.
Updated in line with eribulin study 
protocols.

Section 9.5.1.6.3, Table 8.
Added Appendix 2 Modified 
“Balis” Pediatric Scale of 
Peripheral Neuropathies.
Included as an appendix for easy
reference.

Appendix 2


Clinical Study Protocol
incorporating Amendment 2.0
E7389-G000-223
Eisai
FINAL: 20 Dec 2018
Confidential
Page 6 of 90
Revisions per Amendment 1.1
Date: 29 Sep 2017
Change
Rationale
Affected Protocol Sections
Subjects will be followed for 
survival approximately every 12 
weeks and the follow-up period 
will begin immediately after the 
End of Treatment visit.
During the follow-up period, 
subjects who have gone off study 
without progression should have 
tumor assessments every 6-12 
weeks, at the investigators 
discretion, from the date of last 
tumor assessment until disease 
progression, death, or initiation of 
another anticancer therapy.
The text has been updated for 
clarification purposes. 
In-view of the patient population, 
CNS imaging will only be required 
for subjects with a history of 
protocol eligible brain metastasis 
and as clinically indicated.

Synopsis ( Study Design; 
Follow-up section)

9.1 Overall Study Design 
and Plan, Follow-up 
section
Assessment grade added for 
NRSTS
Updated for clarification.

Synopsis Inclusion 
Criteria

Section 9.3.1
Time of full neurological 
examination and assessment 
criteria used was modified.
Updated for clarity.

Synopsis, Other 
Assessments

Section 9.5.1.2.1

Section 9.5.1.3.2

Section 9.5.1.6

Table 9, Footnote n
Note: CNS imaging is required to 
confirm eligibility for subjects with
a known history of CNS disease.
In-view of the patient population, 
CNS imaging will only be required 
for subjects with a history of 
protocol eligible brain metastasis 
and as clinically indicated.

Synopsis (Exclusion 
criteria)

Section 9.3.2 Exclusion 
Criteria
Antibodies: 3 half-lives must have 
elapsed from infusion of last dose 
of antibody (including checkpoint 
inhibitors), and toxicity related to 
prior antibody therapy must be 
recovered to Grade ≤1
Update in-line with Eribulin study 
protocols

Synopsis (Inclusion 
Criteria)

Section 9.3.1 Inclusion 
Criteria
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 
Clarification that for sites outside 
the EU, double barrier method of 
contraception is acceptable for 
those subjects that are not on a 
stable dose of hormonal 
contraception.

Synopsis (Exclusion 
Criteria)

Section 9.3.2 Exclusion 
Criteria


Clinical Study Protocol
incorporating Amendment 2.0
E7389-G000-223
Eisai
FINAL: 20 Dec 2018
Confidential
Page 7 of 90
Change
Rationale
Affected Protocol Sections
administration, then the subject 
must agree to use a medically 
acceptable method of 
contraception, ie, double barrier 
methods of contraception such as 
condoms plus diaphragm or 
cervical/vault cap with spermicide.
If hematological toxicities do not 
recover following a dose reduction 
to dose level -1 and the use of 
hematopoietic growth factors, the 
dose should be reduced to dose 
level -2. If non-hematological 
toxicities do not recover following 
a dose reduction to dose level -1, a 
second dose reduction to dose level 
-2 should be made. If either 
hematologic or non-hematologic 
toxicities do not recover despite 
two dose reductions, the subject 
should be discontinued from 
treatment.  However, if the subject 
is deemed to have clinical benefit, 
continuation of treatment may be 
discussed with the sponsor.
The text has been updated for 
clarification purposes.

Synopsis (Study 
treatments)

Section 9.4.1.1.1 Eribulin 
Mesylate
Brain scans will not be performed 
at screening, but will be performed
as clinically indicated to assess 
potential CNS disease and/or 
metastases. For subjects with a 
history of protocol-eligible treated 
brain metastases, a brain scan will 
be required at screening and all 
tumor assessment time points (eg, 
every 6 weeks). Brain scans will 
not be performed for subjects with 
a CR outside the brain.
In-view of the patient population, 
CNS imaging will only be required 
for subjects with a history of 
protocol eligible brain metastasis 
and as clinically indicated.

Synopsis (Efficacy 
Assessments)

9.5.1.4 Tumor 
Assessments
Confirmed response (PR or CR) 
will be used in this analysis.
The text has been updated for 
clarification purposes; responses 
confirmed 4 weeks post initial 
assessment of PR/CR per RECIST 
1.1 will be used in the analysis.  
The text has been updated for 
clarification purposes; responses 
confirmed 4 weeks post initial 
assessment of PR/CR per RECIST 
1.1 will be used in the analysis.  

Synopsis (Efficacy 
Analysis)

Section 9.7.1.6.1 Primary 
Efficacy Analysis

Synopsis (Interim 
Analysis)

Section 9.7.3 Interim 
Analysis


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Page 8 of 90
Change
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Affected Protocol Sections
The mainstay of the treatment of 
sarcoma in all age groups is
surgical excision (Table 4).
The text has been amended for 
clarification purposes.

Section 7.1.1 Current 
Therapeutic Options
The prognosis for children with 
metastatic NRSTS at diagnosis 
and, recurrent NRSTS is poor.
Text updated for clarification 
purposes.

Section 7.1.1.2 Treatment 
Strategies for Non-
rhabdomyosarcoma Soft 
Tissue Sarcoma
Standard first-line treatment for
patients with metastatic EWS is 
either a 3 drug regimen of 
vincristine, doxorubicin and 
cyclophosphamide or a 5 drug 
regimen VAC with 
ifosfamide/etoposide.
Confirmatory Phase 2 trials 
demonstrated a response rate of 
only 8% (Balamuth and Womer, 
2010). The development of the 
IGF1R monoclonal antibody, 
Ganitumab, is ongoing (COG study 
AEWS1221).
Text updated for clarification 
purposes.

7.1.1.3 Treatment 
Strategies for Ewing 
Sarcoma
Laboratory assessment of 
cholesterol, globulin, and 
triglycerides was removed
Text updated due to typographical 
error

Table 8 Clinical 
Laboratory Tests
Concomitant radiotherapy for local 
control is allowed from Week 24.
From week 24, the subject may 
receive radiotherapy for local 
control and continue to receive 
drug on study

Section 9.4.6
A CT/MRI scan of the brain will 
not be performed during the 
Screening Phase, but will be 
performed as clinically indicated to 
assess potential CNS disease 
and/or metastases and as clinically 
indicated and at all time points
(including screening) for subjects 
with protocol-eligible treated brain
metastases.
In-view of the patient population, 
CNS imaging will only be required 
for subjects with a history of 
protocol eligible brain metastasis 
and as clinically indicated.
In-view of the patient population, 
CNS imaging will only be required 
for subjects with a history of 
protocol eligible brain metastasis 
and as clinically indicated.

9.5.1.6.7Other Safety
Assessments, Brain Scan

Table 9 Schedule of 
Assessments
Footnote k. was modified to note 
Pre-study phase: Screening CT or 
MRI of the brain should be 
performed between Day -14 and 
Day -1 for subjects with previously 
treated protocol-eligible brain 
metastases only.
In-view of the patient population, 
CNS imaging will only be required 
for subjects with a history of 
protocol eligible brain metastasis 
and as clinically indicated.

Table 9 Schedule of 
Assessments


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Change
Rationale
Affected Protocol Sections
For subjects with previously 
treated protocol-eligible brain 
metastases, a brain scan must be 
performed at all tumor assessment 
time points. The same 
methodology and scan acquisition 
techniques used at screening 
should be used throughout the 
study to ensure comparability.
Global change: removal of 
Appendix 1 Sponsor’s Grading for 
Laboratory Values
For clarification purposes since the 
Sponsor’s grading is aligned with 
CTCAE V4.0

Appendix 1
Revisions per Amendment 1.0
Date: 05 Jul 2017
Change
Rationale
Affected Protocol Sections
Update from Ewing’s sarcoma to 
Ewing sarcoma
Consistency of text

Global change
Previous text:
Or creatinine clearance or 
radioisotope GFR ≥70 
mL/min/1.73 m2 based on a 12 or 
24 hour urine creatinine collection.
Amended text:
Or creatinine clearance or 
radioisotope GFR ≥50
mL/min/1.73 m2 based on a 12 or 
24 hour urine creatinine collection.
Inclusion criteria was carried over 
from pediatric phase 1 study 113 
and therefore has been updated in-
line with the label for Halaven
where impaired renal function is 
defined as creatinine clearance 
<50 mL/min. Additionally, 
considering that renal elimination 
accounts for approximately 10% 
total systemic clearance of 
eribulin,  adjustment for a pediatric 
population is not required.

Synopsis (Inclusion Criteria 8)

Section 9.3.1 Inclusion 
Criteria 8
Previous text:
2. Concomitant medications:

Receiving drugs that 
prolong the QTc.
Amended text:
2. Concomitant medications:

Receiving drugs that 
prolong the QTc.
The inclusion criteria were carried 
over from pediatric phase 1 study 
113. The criteria have been 
updated in-line with the Halaven 
label where concomitant use of 
drugs that prolong the QTc is not 
contraindicated.

Synopsis (Exclusion Criteria 
2)

Section 9.3.2 Exclusion 
Criteria 2
Previous text:
Increase the frequency of ECG and 
electrolyte monitoring in subjects 
who develop Grade 2 QTc 
prolongation or have clinically 
The text has been updated in-line 
with the Halaven label.

Section 9.4.1 1.1 ERIBULIN 
MESYLATE, Instructions for 
QTc Prolongation on 
Electrocardiogram (ECG)


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Change
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relevant electrolyte abnormalities.  
Permanently discontinue eribulin 
mesylate in subjects who develop 
≥Grade 3 QTc prolongation, and 
monitor ECGs and electrolytes 
frequently until the QTc interval 
return to baseline.
Amended text:
Increase the frequency of ECG and 
electrolyte monitoring in subjects 
who: develop Grade 2 QTc 
prolongation, are receiving agents 
that are known to prolong QTc 
interval, or have clinically 
relevant electrolyte abnormalities.  
Permanently discontinue eribulin 
mesylate in subjects who develop 
≥Grade 3 QTc prolongation, and 
monitor ECGs and electrolytes 
frequently until the QTc interval 
returns to baseline.
Previous text:
2. Concomitant medications:
Corticosteroids: Subjects receiving 
corticosteroids who have not been 
on a stable or decreasing dose of
corticosteroid for at least 7 days 
prior to study drug administration 
(except when indicated for Central 
Nervous System (CNS) 
metastases, when the exclusion is 
at least 28 days).
Amended text:
Concomitant medications:
Corticosteroids: Subjects receiving 
corticosteroids who have not been 
on a stable or decreasing dose of 
corticosteroid for at least 7 days 
prior to study drug administration
(except when indicated for Central 
Nervous System (CNS) 
metastases, then subjects must 
not have received corticosteroids 
for when the exclusion is at least 
Text updated to clarify that for 
patients with brain metastases who 
have discontinued corticosteroids,
a 4 week washout period is 
required per exclusion 9, for 
inclusion into the study.

Section 9.3.2 Exclusion 
Criteria 2


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Revisions per Amendment 1.0
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Change
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28 days).
Previous text:
A serum β-hCG or urine test 
(depending on local practice) will 
be performed for females of 
childbearing potential prior to 
starting treatment (within 7 days 
prior to randomization).
f Female subjects of childbearing 
potential require a negative urine 
or serum (depending on local 
practice) pregnancy test prior to 
starting treatment (within 7 days 
prior to Cycle 1 Day 1). 
Amended text:
A serum β-hCG or urine test 
(depending on local practice) will 
be performed for females of 
childbearing potential prior to 
starting treatment (within 7 days
72 hours prior to randomization
the first dose of study drug).
fFemale subjects of childbearing 
potential require a negative urine 
or serum (depending on local 
practice) pregnancy test prior to 
starting treatment (within 7 days
72 hours prior to Cycle 1 Day 1). 
Text amended to clarify that serum 
β-hCG or urine test is required 
within 72 hours of first dose of 
study drug and to align exclusion 
criteria 1, section 9.5.1.6.7 and 
Schedule of Procedures/
Assessments (Table 9).

Section 9.5.1.6.7, OTHER 
SAFETY 
ASSESSMENTS, 
Pregnancy test, Schedule 
of 
Procedures/Assessments 
(Table 9), pregnancy test, f
Footnote k updated to j, footnote l 
and m updated to k, footnote n 
updated to l and footnote o updated 
to m.
Footnote m removed from tumor 
assessment at follow-up
Alignment of Schedule of 
Procedures/Assessments and 
footnotes
Schedule of Procedures/
Assessments (Table 9).


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1
TITLE PAGE
Clinical Study Protocol
Study Protocol 
Number:
E7389-G000-223
Study Protocol 
Title:
A Phase 2, multicenter, open-label study to assess safety and 
preliminary activity of eribulin mesylate in pediatric subjects with 
relapsed/refractory rhabdomyosarcoma (RMS), non-
rhabdomyosarcoma soft tissue sarcoma (NRSTS) and Ewing sarcoma 
(EWS)
Sponsor:
Eisai Inc.
155 Tice Boulevard
Woodcliff Lake, 
New Jersey 07677
US
Eisai Ltd.
European Knowledge 
Centre
Mosquito Way
Hatfield, Hertfordshire 
AL10 9SN UK
Investigational 
Product Name:
E7389/Halaven® (eribulin/eribulin mesylate/eribulin mesylate)
Indication:
Relapsed/refractory Rhabdomyosarcoma, Non rhabdomyosarcoma 
Soft Tissue Sarcoma and Ewing sarcoma in Pediatric Subjects 
Phase:
2
Approval Date(s):
20 Mar 2017 (Original Protocol)
05 Jul 2017 (Amendment 1.0)
29 Sep 2017 (Amendment 1.1)
20 Dec 2018 (Amendment 2.0)
IND Number:
116,292
GCP Statement:
This study is to be performed in full compliance with International 
Council on Harmonisation of Technical Requirements for 
Registration of 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.


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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.


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2
CLINICAL PROTOCOL SYNOPSIS
Compound No.:  E7389
Name of Active Ingredients:  eribulin mesylate
Study Protocol Title
A Phase 2, multicenter, open-label study to assess safety and preliminary activity of eribulin mesylate 
in pediatric subjects with relapsed/refractory rhabdomyosarcoma (RMS), non-rhabdomyosarcoma 
soft tissue sarcoma (NRSTS) and Ewing sarcoma (EWS)
Investigator
Douglas S Hawkins, MD.
Katie Albert, MD.
Sites
Approximately 40 sites in the US. The Study will be conducted by the COG network.
Study Period and Phase of Development
Approximately 24 to 36 months from first subject providing signed informed consent to last subject 
last visit (LSLV).  
Phase 2
Objectives
Primary Objectives

To conduct a preliminary assessment of activity of eribulin mesylate in pediatric subjects 
with relapsed/refractory RMS, NRSTS or EWS to determine whether each cohort warrants 
further investigation.
Secondary Objectives

To evaluate the progression-free survival (PFS), using Response Evaluation Criteria in Solid 
Tumors (RECIST) 1.1, of eribulin mesylate in pediatric subjects with relapsed/refractory 
RMS, NRSTS, or EWS in all cohorts combined.

To evaluate the safety and tolerability of eribulin in the pediatric subjects with 
relapsed/refractory RMS, NRSTS, or EWS in all cohorts combined.

To evaluate the duration of response (DOR) of eribulin mesylate in pediatric subjects with 
relapsed/refractory RMS, NRSTS, or EWS.

To evaluate the overall survival (OS) of pediatric subjects with relapsed/refractory RMS, 
NRSTS and EWS.
Exploratory Objectives

To evaluate the exposure of eribulin mesylate in pediatric subjects with relapsed/refractory 
RMS, NRSTS, or EWS.

To explore the relationship between exposure to eribulin mesylate and adverse events (AE) 
and efficacy.

Study Design


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E7389-G000-223 is a Phase 2, multicenter, open-label study to conduct a preliminary assessment of 
the safety and activity of eribulin mesylate in pediatric subjects with relapsed/refractory RMS, 
NRSTS, or EWS.  
Forty-five pediatric subjects, with approximately 15 subjects each with RMS, NRSTS, or EWS, will 
be enrolled to receive eribulin mesylate as an intravenous (IV) infusion at a dose of 1.4 mg/m2
(Recommended Phase 2 Dose [RP2D]) on Days 1 and 8 of each 21-day cycle, as determined by the 
dose finding study ADVL1314 (Eisai Study E7389-A001-113). 
Outline

Pediatric subjects with relapsed/refractory RMS, NRSTS or EWS will be enrolled to receive 
therapy with eribulin mesylate. 

For each histology type, approximately 15 subjects will be treated.  Data will be monitored 
on an ongoing basis; depending on evaluation by the investigators and sponsor, if sufficient 
responses (partial response [PR] or complete response [CR]) are observed, then this histology 
type will be recommended for inclusion in the subsequent study.

Subjects will continue study therapy until progression of disease (per RECIST 1.1), 
intolerable toxicity or withdrawal of consent.
Pre-study Phase:
Day -28 to -1, computed tomography (CT) / magnetic resonance imaging (MRI) scans must be 
performed within 28 days prior to study drug administration.  All clinical and laboratory test results 
to determine eligibility must be performed within 7 days prior to study drug administration, unless 
otherwise indicated.
Treatment Phase:
The treatment phase will start on Day 1 of Cycle 1.
Follow-up:
The follow-up period will begin immediately after the End of Treatment visit until death or informed 
consent is withdrawn, unless the study is terminated by the sponsor. Subjects will be followed for 
survival approximately every 12 weeks for 1 year and then annually thereafter. As well as follow-up 
for survival, the annual surveillance will also assess any long term effects of the study treatment.
During the follow-up period, subjects who have gone off study treatment without progression should 
have tumor assessments every 6-12 weeks, at the investigators discretion, from the date of last tumor 
assessment until disease progression, death, or initiation of another anticancer therapy, whichever 
occurs first, unless the study is terminated by the sponsor.  Follow-up data will be required unless 
consent is withdrawn.
Number of Subjects
The target enrollment is 45 subjects.
Inclusion Criteria
Subjects must meet all of the following criteria to be included in this study:
1.
Age: ≥12 months to <18 years old at the time of informed consent.
2.
Diagnosis: Histologically confirmed RMS, NRSTS (Grade 2 or 3) or EWS which is relapsed or 
refractory (failed front line therapy).
3.
The presence of measurable disease meeting the following criteria:

At least 1 lesion of ≥1.0 cm in the longest diameter for a non-lymph node or ≥1.5 cm in the 
short-axis diameter for a lymph node that is serially measurable according to RECIST 1.1 


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using computerized tomography/magnetic resonance imaging (CT/MRI).

Lesions that have had radiotherapy must show subsequent radiographic evidence of increase 
in size by at least 20% to be deemed a target lesion.
4.
Therapeutic options: Subject’s current disease state must be one for which there is no known 
curative therapy or therapy proven to prolong survival with an acceptable quality of life.
5.
Performance level: Performance score ≥50%. Karnofsky (for subjects >16 years of age) or 
Lansky (for subjects ≤16 years of age).  Subjects who are unable to walk because of paralysis 
and/or previous surgeries, but who are in a wheelchair, will be considered ambulatory for the 
purpose of assessing performance score. 
6.
Subjects must have fully recovered from the acute toxic effects of all prior anticancer therapy and 
must meet the following minimum duration from prior anticancer directed therapy prior to study 
drug administration.  If, after the required time frame, the numerical eligibility criteria are met, 
eg, blood count criteria, the subject is considered to have recovered adequately:

Cytotoxic chemotherapy or other chemotherapy known to be myelosuppressive: ≥21 days 
after the last dose of cytotoxic or myelosuppressive chemotherapy (42 days if prior 
nitrosourea).

Anticancer agents not known to be myelosuppressive (eg, not associated with reduced 
platelet or Absolute neutrophil count [ANC] counts): ≥7 days after the last dose of agent.

Monoclonal antibodies: ≥3 half-lives must have elapsed from infusion of last dose of 
antibody (including checkpoint inhibitors), and toxicity related to prior antibody therapy must 
be recovered to Grade ≤1.

Hematopoietic growth factors: ≥14 days after the last dose of a long-acting growth factor (eg, 
Neulasta) or 7 days for a short-acting growth factor.  For agents that have known AEs 
occurring beyond 7 days after administration, this period must be extended beyond the time 
during which AEs are known to occur. The duration of this interval must be discussed with 
the sponsor.

Interleukins, interferons, and cytokines (other than hematopoietic growth factors): ≥21 days 
after the completion of interleukins, interferons or cytokines (other than hematopoietic 
growth factors).

Stem cell infusions (with or without total body irradiation [TBI]): ≥84 days.

Allogeneic (non-autologous) bone marrow or stem cell transplant, or any stem cell infusion 
including donor lymphocyte infusion or boost infusion: ≥84 days after infusion and no 
evidence of graft versus host disease (GVHD).

Autologous stem cell infusion including boost infusion: ≥42 days.

Cellular therapy:  ≥42 days after the completion of any type of cellular therapy (eg, modified 
T-cells, natural killer cells, dendritic cells, etc).

Radiation therapy (XRT)/External Beam Irradiation including Protons: ≥14 days after local 
XRT; ≥150 days after TBI, craniospinal XRT or if radiation to ≥50% of the pelvis; ≥42 days 
if other substantial BM radiation.

Radiopharmaceutical therapy (eg, radiolabeled antibody, 131I-Metaiodobenzylguanidine):  
≥42 days after systemically administered radiopharmaceutical therapy. 
7.
Adequate bone marrow function, defined as:

ANC ≥1.0 x 109/L.

Platelet count ≥100 x 109/L (transfusion independent, defined as not receiving platelet 


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transfusions within a 7-day period prior to study drug administration).

Hemoglobin at least 8.0 g/dL at Baseline (blood transfusions are allowed during the 
screening period to correct hemoglobin values less than 8.0 g/dL).
Note: As blood transfusions are permitted to meet the hemoglobin criteria, subjects requiring 
transfusion must not be known to be refractory to red blood cell or platelet transfusions.
8.
Adequate renal function, defined as 

A serum creatinine based on age/gender, derived from the Schwartz formula for estimating 
glomerular filtration rate (GFR) (see table below).
Age
Maximum Serum Creatinine (mg/dL)
Male
Female
6 months to <1 year
0.5
0.5
1 to <2 years
0.6
0.6
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 glomerular filtration rate (GFR) (Schwartz and 
Gauthier. J Pediatr. 1985;106:522–6) utilizing child length and stature data 
published by the Centers for Disease Control and Prevention (CDC).

Or creatinine clearance or GFR ≥50 mL/min/1.73 m2 based on a 12 or 24 hour urine 
creatinine collection. 
9.
Adequate liver function, defined as:

Bilirubin (sum of conjugated + unconjugated) ≤1.5 x upper limit of normal (ULN) for age.

Alanine aminotransferase (ALT) ≤110 U/L. For the purpose of this study, the ULN for ALT
is 45 U/L.

Serum albumin ≥2 g/dL.
10. Informed consent: All subjects and/or their parents or legally authorized representatives must 
sign a written informed consent.  Assent, when appropriate, will be obtained according to 
institutional guidelines.  Subjects must be willing to comply with all aspects of the protocol.
Exclusion Criteria
Subjects who meet any of the following criteria will be excluded from this study:
1.
Pregnancy, breastfeeding, contraception:  Females who are breastfeeding or pregnant at 
Screening or Baseline (as documented by a positive beta-human chorionic [β-hCG] (or human 
chorionic gonadotropin [hCG] test with a minimum sensitivity of 25 IU/L or equivalent units of 
β-hCG [or hCG]).  A separate baseline assessment is required if a negative screening pregnancy 
test was obtained more than 72 hours before the first dose of study drug.
-
Females of childbearing potential* who:


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◦
Do not agree to use a highly effective method of contraception for the entire study period 
and for 6 months after study drug discontinuation, ie:
◦
Total abstinence (if it is their preferred and usual lifestyle).
◦
An intrauterine device (IUD) or intrauterine system (IUS).
◦
A contraceptive implant.
◦
an oral contraceptive**.
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 
commenced/adjusted/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 condoms 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).
**Must be on a stable dose of the same oral hormonal contraceptive product for at least 4 weeks 
before dosing with study drug and for the duration of the study and for 6 months after study drug 
discontinuation. ..
◦
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 or for 3 months 
after study drug discontinuation).  No sperm donation is allowed during the study period 
or for 3 months after study drug discontinuation.
2.
Concomitant medications:

Corticosteroids: Subjects receiving corticosteroids who have not been on a stable or 
decreasing dose of corticosteroid for at least 7 days prior to study drug administration (except 
when indicated for Central Nervous System (CNS) metastases, then subjects must not have 
received corticosteroids for at least 28 days).

Anticancer Agents: Subjects who are currently receiving other anticancer agents.

Anti-GVHD agents post-transplant: Subjects who are receiving cyclosporine, tacrolimus or 
other agents to prevent graft-versus-host disease post bone marrow transplant.

Strong CYP3A4 inducers/inhibitors (See Section 9.4.6.1.1, Drug-Drug Interactions).
3.
Received prior therapy with eribulin mesylate.
4.
Any other malignancy that required treatment (except for non-melanoma skin cancer, or 
histologically confirmed complete excision of carcinoma in situ), within 2 years prior to study 
drug administration.
5.
Has hypersensitivity to eribulin or any of the excipients.


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6.
Has a prior history* of viral hepatitis (B or C) as demonstrated by positive serology (presence of 
antigens) or have an uncontrolled infection requiring treatment (* Subjects with a known prior 
history of hepatitis B or C may be eligible pending agreement with the sponsor).
7.
Has > Grade 1 peripheral sensory neuropathy or > Grade 1 peripheral motor neuropathy graded 
according to the Modified (“Balis”) Pediatric Scale of Peripheral Neuropathies.
8.
Has cardiac pathology: 

Subjects with known congestive heart failure, symptomatic or left ventricular (LV) ejection 
fraction <50% or shortening fraction <27% 

Subjects with congenital long QT syndrome, bradyarrhythmias, or QTc >480 msec on at least 
2 separate ECGs.
9.
Has CNS Disease:  Subjects with brain or subdural metastases are not eligible unless the 
metastases are asymptomatic and do not require treatment or have been adequately treated by 
local therapy (eg, surgery or radiotherapy) and have discontinued the use of corticosteroids for 
this indication for at least 4 weeks prior to study drug administration.  Confirmation of 
radiographic stability must be done by comparing the brain scan (CT or MRI) performed during 
the Screening Period, using the same imaging modality, to a brain scan performed earlier (and 
following local therapy where applicable). Subjects must be clinically stable.  It is not the 
intention of this protocol to treat subjects with active brain metastases.
Note: CNS imaging is required to confirm eligibility for subjects with a known history of CNS 
disease.
10. Have had or are planning to have the following invasive procedures:

Major surgical procedure or significant traumatic injury within 28 days prior to study drug 
administration.

Laparoscopic procedure or open biopsy within 7 days prior to study drug administration.

Central line placement or subcutaneous port placement is not considered major surgery but 
must be placed at least 2 days prior to study drug administration.

Core biopsy, including bone marrow biopsy within 2 days prior to study drug administration.

Fine needle aspirate within 3 days prior to study drug administration.
11. Has any serious concomitant illness that in the opinion of the investigator(s) could affect the 
subject’s safety or interfere with the study assessments.
12. Subjects with known human immunodeficiency virus (HIV); due to lack of available safety data 
for eribulin therapy in HIV infected subjects.
Study Treatment(s)
Administration of eribulin mesylate by 2-5 min IV infusion at 1.4 mg/m2 on Days 1 and 8 of each 
21-day cycle.  Eribulin may be diluted in up to 100 mL 0.9% sodium chloride, and administered as an 
IV infusion over 15 minutes (maximum infusion duration), where clinically appropriate.
Criteria for Dosing Modifications
Dose reduction and interruption for eribulin mesylate related toxicity will be performed according to 
the following instructions.
Treatment will not be administered when any of the following values are recorded (Table 1).
Table 1
Criteria for Administration of Eribulin Mesylate
a): Do not administer Cycle 1 Day 1 treatment where:


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Absolute Neutrophil Count
<1.0 × 109/L  or 1,000/mm3
Platelets
<100 × 109/L or 100,000/mm3
Non-hematological toxicity
Any > Grade 2 except for inadequately treated nausea 
and/or vomiting
b): Do not administer any Day 8 treatment where:
Absolute Neutrophil Count
<0.75 × 109/L or 750/mm3
Platelets
<75 × 109/L or 75,000/mm3
Non-hematological toxicity
Any > Grade 2 except for inadequately treated nausea 
and/or vomiting
c): Do not administer any subsequent Day 1 treatment where:
Absolute Neutrophil Count
<1.0 × 109/L or 1,000/mm3
Platelets
<75 × 109/L or 75,000/mm3
Non-hematological toxicity
Any > Grade 2 except for inadequately treated nausea 
and/or vomiting
If the dose cannot be administered as planned due to treatment-related toxicity, the dose should be 
delayed according to the following instructions.
Day 1 of each cycle: If treatment cannot be administered on Day 1, the dosing should be delayed 
until recovery to above the values in Table 1 or Grade ≤2 as appropriate (for Cycle 1 & subsequent 
cycles). The Day 1 dose will be rescheduled for when the criteria for treatment administration are 
met. The dose level may have to be reduced following a dose delay in accordance to the instructions 
for dose reduction (Table 2 and Table 3).
Day 8 of each cycle: If treatment cannot be administered on Day 8, the dosing should be delayed 
until recovery to above these values (Table 1). The Day 8 dosing will be delayed for a maximum of 
7 days and as follows:

If recovery occurs on or before Day 15, dosing will be resumed at the next lower dose level 
(Table 3) and this will be the new Day 8.  

If hematological or non-hematological toxicity has not resolved to the above values on 
Day 15, the second administration in the cycle will be omitted.  Dosing will be resumed at 
the next lower dose level (Table 3) and as scheduled on Day 1 of the next cycle if recovery 
has occurred to the above values.  
Please note, use of hematopoietic growth factors is not permitted in Cycle 1 and is only permitted in 
subsequent cycles as per institutional guidelines.
The treatment will be permanently reduced to the next lowest dose level (Table 3) after the 
occurrence of any of the following events:
Table 2
Criteria for Reduction of Eribulin Mesylate to the Next Lowest Dose 
Level
Absolute Neutrophil Count
Grade 4 neutropenia >7 days
Grade 3 or 4 febrile neutropenia and/or infection requiring treatment 
with antibiotics and/or growth factors


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Platelets
Grade 4 thrombocytopenia
Grade 3 thrombocytopenia requiring platelet or blood transfusion or 
both
Non-hematological toxicity
Grade 3 or 4 non-hematological toxicities (attributable to study drug); 
except Grade 3 hypophosphatemia, hypokalemia, hypocalcemia or 
hypomagnesemia that respond to supplementation
Table 3
Eribulin Mesylate Dose Modifications
Dose modifications based on adverse events (AEs) for eribulin mesylate (Starting dose determined 
by COG protocol ADVL1314/Eisai Study E7389-A001-113; 1.4 mg/m2).
Dose Level
Eribulin mesylate
(mg/m2)
0*
1.4
-1
1.1
-2
0.8
* Dose level 0 refers to the starting dose.
If hematological toxicities do not recover following a dose reduction to dose level -1 and the use of 
hematopoietic growth factors the dose should be reduced to dose level -2. If non-hematological 
toxicities do not recover following a dose reduction to dose level -1, a second dose reduction to dose 
level -2 should be made. If either hematologic or non-hematologic toxicities do not recover despite 
two dose reductions, the subject should be discontinued from treatment.  However, if the subject is 
deemed to have clinical benefit, continuation of treatment may be discussed with the sponsor.
Do not re-escalate dose after the dose level has been reduced.
Duration of Treatment
Subjects may remain on study treatment as long as they do not meet any of the following criteria:  1) 
experience objective progression of disease (according to RECIST 1.1); 2) exhibit no clinical benefit 
(in the opinion of the investigator); 3) experience unacceptable toxicity leading to withdrawal from 
the study; 4) withdraw or are withdrawn from the study for any reason, or; 5) termination of the study 
program, whichever occurs first. 
As long as the subject is still receiving clinical benefit and has not experienced intolerable toxicity, he 
or she can continue to receive study treatment.  An end of treatment (EOT) visit within 28 days after 
last date of receiving investigational drug will be performed for subjects who discontinue study 
treatment.  After discontinuation of treatment and completion of the EOT visit, subjects will be
followed up for survival approximately every 12 weeks for 1 year, and then annually thereafter, 
unless consent is withdrawn or death.  
Concomitant Drug/Therapy
Supportive care will be allowed as per institutional guidelines.  Growth factors that support platelet or 
white blood cell number or function can only be administered in accordance with dose modification 
guidelines or for culture proven bacteremia or invasive fungal infection. Prophylactic granulocyte 
colony-stimulating factor should NOT be administered during Cycle 1.
Subjects should not receive any other anticancer therapy (including chemotherapy, radiation therapy, 
immunotherapy or biologic therapy) or investigational agents while receiving study drug.  If these 
therapies are administered, the subject will be removed from the study.


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Assessments
Efficacy Assessments
Tumor response and progression will be evaluated according to RECIST 1.1 criteria.  Copies of all 
scans for tumor assessments will be sent to an imaging core laboratory designated by the sponsor for 
quality assessment, archiving and potential independent review. Tumor assessment scans will be 
performed following the guidelines provided by the imaging core laboratory.  Decisions concerning 
treatment discontinuation due to progressive disease will be based on investigator assessment.
Tumor assessments (CT chest, and CT or MRI abdomen, pelvis, and other known or suspected sites 
or disease) will be performed during screening and then every 6 weeks (within the sixth week) on a 
fixed schedule from the date of first study drug administration. Magnetic resonance imaging scans 
may be used instead of CT scans for abdomen and pelvis; however, chest must be assessed using CT.  
Scans that were performed within the screening window, but before informed consent, may be used if 
they were acquired consistent with the guidelines provided by the imaging core laboratory.  The same 
method of assessment must be used at all time-points as used at pre-study.  Partial and complete 
responses will be confirmed at least 4 weeks after initial documentation of PR or CR typically on the 
next consecutive scheduled tumor assessment. After 24 weeks subjects with CR, PR or stable disease 
(SD) may have imaging decreased to every 9 weeks (within the ninth week).  
A bone scan or 18FDG-PET/CT scan will be performed during screening to establish a baseline (a 
historical bone scan performed within 6 weeks before study drug administration is acceptable),
approximately every 24 weeks (in conjunction with a scheduled tumor assessment visit) and as 
clinically indicated. Lesions identified on bone scans should be followed with cross-sectional 
imaging. 
Brain scans will be performed as clinically indicated to assess potential CNS disease and/or 
metastases.  For subjects with a history of protocol-eligible treated brain metastases, a brain scan will 
be required at screening and all tumor assessment time points (eg, every 6 weeks). 
Subjects who discontinue treatment without objective evidence of disease progression will continue 
to have tumor assessments, per the schedule of assessments, until disease progression, death, or 
initiation of another anticancer therapy.  
Pharmacokinetic Assessments
Blood samples will be collected for PK analysis of eribulin as follows:
1.
Immediately post-infusion on Day 1 of each cycle for the first 3 cycles
2.
Pre-infusion and immediately post-infusion on Day 8 of each cycle for the first 3 cycles
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Assessments
Exposure-response Analyses
Following FDA guidance, PK sampling will be conducted in subjects across the pediatric program at 
regular intervals in order to adequately characterize the PK of eribulin in the pediatric population in 
the various age cohorts to explore exposure-response relationships for activity/efficacy and safety.  
The relationship between exposure to eribulin mesylate and AE and efficacy will be explored 
graphically.
Safety Assessments
Safety assessments will consist of monitoring and recording all adverse events (AEs) according to
Common Terminology Criteria for Adverse Events (CTCAE v4.03). This includes listing of all 
grades (for both increasing and decreasing severity) and serious adverse events (SAEs); regular 
laboratory evaluation for hematology, blood chemistry, and urine values; periodic measurement of 


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vital signs, the performance status, and physical examinations.
Other Assessments
ECG monitoring to evaluate RR, PR, QRS, and QT intervals and QTc interval (corrected for heart 
rate [QTc] using Fridericia's [QTcF] and Bazett's [QTcB] correction factors) at pre-study, during 
Cycle 1 (pre- and post-infusion Day1 and Day 8) and as clinically indicated during subsequent cycles 
and during follow-up (28 days after the last dose of drug).
A full neurological examination will be conducted at Screening. On subsequent cycles an assessment 
of neuropathy (neuropathy present/absent and CTC AE Grade) will be assessed as part of the physical 
examination
Bioanalytical Methods
Plasma concentrations of eribulin mesylate will be determined using a validated liquid 
chromatography coupled with tandem mass spectrometry (LC-MS/MS) method.  The lower limit of 
quantification (LLOQ) is 0.2 ng/mL.
Statistical Methods
Study Endpoints
Primary Endpoints

Objective response:  number of subjects achieving a best objective response of partial or 
complete response (PR or CR), by up to 24 weeks after all subjects have completed response 
assessment. Response assessment will be as determined by investigator.
Secondary Endpoints

PFS: defined as the time from the first dose date to the date of disease progression or date of 
death (whichever occurs first).

Safety and tolerability: AEs, SAEs, clinical laboratory values, ECG parameters, vital sign 
measurements, and performance status.

DOR: defined as the time from the first date of documented PR or CR to the date of disease 
progression or date of death (whichever occurs first).

OS: defined as the time from the first dose date to the date of death.
Exploratory Endpoints

Exposure of eribulin mesylate.
Analysis Sets
Full Analysis Set (FAS) will consist of all subjects who receive at least 1 dose of study drug.
Safety Analysis Set (SAS) will consist of all subjects who receive at least 1 dose of study drug. 
Pharmacokinetic Analysis Set (PAS) will include subjects who have at least 1 evaluable plasma 
concentration and sufficient dosing information.
Efficacy Analyses
The primary analysis will be based on investigator assessments of tumor response.
The primary analysis is to examine the number of responders within each histology subject cohort. 
Confirmed response (PR or CR) will be used in this analysis.  In each of the histology groups of 
RMS, NRSTS, and EWS, approximately 15 subjects will be enrolled and treated with eribulin 
mesylate.  Data will be monitored on an ongoing basis; depending on evaluation by the investigators 
and sponsor, if sufficient responses (partial response [PR] or complete response [CR]) are observed, 


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then this histology type will be recommended for inclusion in the subsequent study.  At the latest, the 
primary analysis will be performed when approximately 15 subjects have completed 24 weeks of 
response assessments.
Secondary Efficacy Analyses
The secondary analyses will be to estimate the PFS, DOR, and OS in all cohorts combined.  Median 
PFS, DOR, and OS will be estimated using Kaplan-Meier method. 
Pharmacokinetic Analyses
Observed eribulin concentrations from this study will be overlaid with existing observed 
concentrations and model-predicted 90% prediction intervals at the same dose level from other 
studies to demonstrate comparability in exposure.
Safety Analyses
Safety analyses will be performed on all subjects who receive at least 1 dose of study drug.  It will 
include safety data collected from screening to data cut-off. Safety data include the incidence and 
severity of AEs, clinical laboratory test results, performance status, ECG readings, and vital signs 
measurements.
Vital signs, resting 12-lead ECGs, hematology, clinical chemistry, and urinalysis data will be listed.  
Descriptive summary statistics (mean, standard deviation, median, minimum, and maximum) of 
clinical laboratory test results, vital signs measurements, ECG parameters, and changes from Baseline 
will be presented by cohort and overall.  Treatment-emergent abnormal laboratory test results, vital 
signs, and ECGs will be listed.
All AEs and SAEs will be listed.  Treatment-emergent AEs (TEAEs), treatment-related TEAEs, and 
SAEs will be summarized by cohort, system organ class, preferred term, and CTCAE v. 4.03 grade.  
QT intervals will be measured from Lead II and will be corrected for heart rate (QTc) using QTcF 
and QTcB correction factors.  The primary QTc parameter will be QTcF.  Secondary parameters will 
be QTcB, QT, QRS, and heart rate.
Interim Analyses
Data will be monitored on an ongoing basis; depending on evaluation by the investigators and 
sponsor, if sufficient responses (PR or CR) are observed, then this histology type will be 
recommended for inclusion in the subsequent study.
Sample Size Rationale
A total of 45 subjects will be enrolled. In each of the histology groups of RMS, NRSTS, and EWS, 
approximately 15 subjects will be enrolled and treated with eribulin mesylate.  The sample size is 
considered sufficient based on clinical judgment and is not obtained from statistical calculation. 


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3
TABLE OF CONTENTS
1
TITLE PAGE...................................................................................................................12
2
CLINICAL PROTOCOL SYNOPSIS.............................................................................14
3
TABLE OF CONTENTS.................................................................................................25
4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS..................................30
5
ETHICS............................................................................................................................33
5.1
Institutional Review Boards/Independent Ethics Committees ..............................33
5.2
Ethical Conduct of the Study.................................................................................33
5.3
Subject Information and Informed Consent...........................................................34
6
INVESTIGATORS AND STUDY PERSONNEL..........................................................35
7
INTRODUCTION ...........................................................................................................35
7.1
Childhood Soft Tissue Sarcomas...........................................................................35
7.1.1
Current Therapeutic Options........................................................................35
7.1.1.1
Treatment Strategies for Rhabdomyosarcoma.....................................36
7.1.1.2
Treatment Strategies for Non-rhabdomyosarcoma Soft Tissue 
Sarcoma................................................................................................37
7.1.1.3
Treatment Strategies for Ewing Sarcoma ............................................37
7.1.2
Fulfillment of a Therapeutic Need...............................................................38
7.1.3
E7389 (eribulin mesylate)............................................................................38
7.1.3.1
Mechanism of Action...........................................................................38
7.1.3.1.1
Tumor Biology-Based Mechanisms ..............................................39
7.1.3.2
Clinical Experience With Eribulin.......................................................39
7.1.3.3
Non-Clinical Evidence for Activity of Eribulin in Pediatric 
Sarcomas..............................................................................................41
7.2
Study Rationale......................................................................................................41
8
STUDY OBJECTIVES....................................................................................................42
8.1
Primary Objective..................................................................................................42
8.2
Secondary Objectives.............................................................................................42
8.3
Exploratory Objective(s)........................................................................................42
9
INVESTIGATIONAL PLAN..........................................................................................43
9.1
Overall Study Design and Plan..............................................................................43
9.2
Discussion of Study Design...................................................................................44
9.3
Selection of Study Population................................................................................44
9.3.1
Inclusion Criteria .........................................................................................44
9.3.2
Exclusion Criteria ........................................................................................46
9.3.3
Removal of Subjects From Therapy or Assessment....................................49


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9.4
Treatments..............................................................................................................49
9.4.1
Treatments Administered.............................................................................49
9.4.1.1
Criteria for Dosing Modifications........................................................49
9.4.1.1.1
Eribulin Mesylate...........................................................................49
9.4.2
Identity of Investigational Products.............................................................52
9.4.2.1
Chemical Name, Structural Formula of Eribulin Mesylate .................52
9.4.2.2
Labeling for Study Drug......................................................................52
9.4.2.3
Storage Conditions...............................................................................52
9.4.3
Method of Assigning Subjects to Treatment Groups...................................53
9.4.4
Selection of Doses in the Study...................................................................53
9.4.5
Selection and Timing of Dose for Each Subject..........................................53
9.4.6
Prior and Concomitant Therapy...................................................................53
9.4.6.1
Drug-Drug Interactions........................................................................53
9.4.6.1.1
Eribulin mesylate ...........................................................................53
9.4.6.2
Prohibited Concomitant Therapies and Drugs.....................................54
9.4.7
Treatment Compliance.................................................................................54
9.4.8
Drug Supplies and Accountability...............................................................54
9.5
Study Assessments.................................................................................................56
9.5.1
Assessments.................................................................................................56
9.5.1.1
Demography.........................................................................................56
9.5.1.2
Baseline Assessments ..........................................................................56
9.5.1.2.1
Medical History and Physical Examinations.................................56
9.5.1.3
Efficacy Assessments...........................................................................57
9.5.1.3.1
Primary...........................................................................................57
9.5.1.3.2
Secondary.......................................................................................57
9.5.1.3.3
Exploratory ....................................................................................57
9.5.1.4
Tumor Assessments .............................................................................57
9.5.1.5
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Assessments.............................................................58
9.5.1.5.1
Pharmacokinetic Assessments .......................................................58
9.5.1.5.2
Pharmacodynamic, Pharmacogenomic, and Other Biomarker, 
Assessments...................................................................................58
9.5.1.6
Safety Assessments..............................................................................58
9.5.1.6.1
Adverse Events ..............................................................................59
9.5.1.6.2
Serious Adverse Events and Events Associated with Special 
Situations........................................................................................60
9.5.1.6.3
Laboratory Measurements .............................................................61


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9.5.1.6.4
Vital Signs and Weight Measurements..........................................63
9.5.1.6.5
Physical Examinations...................................................................63
9.5.1.6.6
Electrocardiograms ........................................................................63
9.5.1.6.7
Other Safety Assessments..............................................................63
9.5.2
Schedule of Procedures/Assessments ..........................................................64
9.5.3
Appropriateness of Measurements...............................................................69
9.5.4
Reporting of Serious Adverse Events, Pregnancy, and Events 
Associated with Special Situations..............................................................69
9.5.4.1
Reporting of Serious Adverse Events..................................................69
9.5.4.2
Reporting of Pregnancy and Exposure to Study Drug Through 
Breastfeeding .......................................................................................70
9.5.4.3
Reporting of Events Associated with Special Situations.....................70
9.5.4.3.1
Reporting of Adverse Events Associated With Study Drug 
Overdose, Misuse, Abuse, or Medication Error ............................70
9.5.4.4
Expedited Reporting ............................................................................71
9.5.4.5
Regulatory Reporting of Adverse Events ............................................71
9.5.5
Completion/Discontinuation of Subjects.....................................................71
9.5.6
Abuse or Diversion of Study Drug ..............................................................72
9.6
Data Quality Assurance .........................................................................................72
9.6.1
Data Collection ............................................................................................72
9.6.2
Clinical Data Management ..........................................................................72
9.7
Statistical Methods.................................................................................................72
9.7.1
Statistical and Analytical Plans....................................................................73
9.7.1.1
Study Endpoints...................................................................................73
9.7.1.1.1
Primary Endpoint...........................................................................73
9.7.1.1.2
Secondary Endpoints .....................................................................73
9.7.1.1.3
Exploratory Endpoints ...................................................................73
9.7.1.2
Definitions of Analysis Sets.................................................................73
9.7.1.3
Subject Disposition..............................................................................74
9.7.1.4
Demographic and Other Baseline Characteristics ...............................74
9.7.1.5
Prior and Concomitant Therapy...........................................................74
9.7.1.6
Efficacy Analyses ................................................................................74
9.7.1.6.1
Primary Efficacy Analysis.............................................................74
9.7.1.6.2
Secondary Efficacy Analyses ........................................................74
9.7.1.7
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Analyses...................................................................75
9.7.1.7.1
Pharmacokinetic Analyses.............................................................75


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9.7.1.7.2
Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Analyses.........................................................................................75
9.7.1.8
Safety Analyses....................................................................................75
9.7.1.8.1
Extent of Exposure.........................................................................75
9.7.1.8.2
Adverse Events ..............................................................................75
9.7.1.8.3
Laboratory Values..........................................................................76
9.7.1.8.4
Vital Signs......................................................................................76
9.7.1.8.5
Electrocardiograms ........................................................................77
9.7.1.8.6
Other Safety Analyses....................................................................77
9.7.2
Determination of Sample Size .....................................................................77
9.7.3
Interim Analysis...........................................................................................77
9.7.4
Other Statistical/Analytical Issues ...............................................................78
9.7.5
Procedure for Revising the Statistical Analysis Plan...................................78
10
REFERENCE LIST .........................................................................................................79
11
PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE PROCEDURES).......82
11.1
Changes to the Protocol .........................................................................................82
11.2
Adherence to the Protocol......................................................................................82
11.3
Monitoring Procedures...........................................................................................82
11.4
Recording of Data..................................................................................................83
11.5
Identification of Source Data.................................................................................83
11.6
Retention of Records..............................................................................................83
11.7
Auditing Procedures and Inspection......................................................................84
11.8
Handling of Study Drug.........................................................................................84
11.9
Publication of Results ............................................................................................84
11.10 Disclosure and Confidentiality ..............................................................................85
11.11 Discontinuation of Study .......................................................................................85
11.12 Subject Insurance and Indemnity...........................................................................85
12
APPENDICES .................................................................................................................86
LIST OF IN-TEXT TABLES
Table 1
Criteria for Administration of Eribulin Mesylate ......................................19
Table 2
Criteria for Reduction of Eribulin Mesylate to the Next Lowest Dose 
Level ..........................................................................................................20
Table 3
Eribulin Mesylate Dose Modifications......................................................21
Table 4
Principles of RMS, NRSTS and EWS Treatment......................................36
Table 5
Criteria for Administration of Eribulin Mesylate ......................................49


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Table 6
Criteria for Reduction of Eribulin Mesylate to the Next Lowest Dose 
Level ..........................................................................................................51
Table 7
Eribulin Mesylate Dose Modifications......................................................51
Table 8
Clinical Laboratory Tests...........................................................................62
Table 9
Schedule of Procedures/Assessments in Study E7389-G000-223.............65
LIST OF APPENDICES
Appendix 1
Measurements of Performance Status........................................................87
Appendix 2
Modified “Balis” Pediatric Scale of Peripheral Neuropathies...................88


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4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
ADI
adipocytic soft tissue sarcoma
AE
adverse event
ALL
acute lymphoblastic leukemia
ALT
alanine aminotransferase
ANC
absolute neutrophil count
AST
aspartate aminotransferase
BSA
body surface area
CI
confidence interval
CNS
central nervous system
COG
Children’s Oncology Group
CR
complete response
CRA
clinical research associate
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CV
curriculum vitae
DOR
duration of response
ECG
Electrocardiogram
EFS
event-free survival
EMT
epithelial-mesenchymal transition
EWS
Ewing sarcoma
FDA
Food and Drug Administration
GCP
good clinical practice
GFR
glomerular filtration rate
GVHD
graft versus host disease
hCG
human chorionic gonadotropin
HIV
human immunodeficiency virus
HR
hazard ratio
ICF 
informed consent form
ICH
International Council on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IIR
Independent imaging review
IRB
Institutional Review Board


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Abbreviation
Term
IUD
intrauterine device
IUS
intrauterine system
IV
Intravenous
IxRS
interactive voice / web response system
LLN
lower limit of normal
LMS
Leiomyosarcoma
MCR
maintained complete response
MedDRA
Medical Dictionary for Regulatory Activities
MHRA
Medicines and Healthcare Products Regulatory Agency
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
NCI
National Cancer Institute
NRSTS
non-rhabdomysosarcoma soft tissue sarcoma
ORR
objective response rate
OS
overall survival
PD
progressive disease
PET
positron emission tomography
PFS
progression-free survival
PI
principal investigator
PK
Pharmacokinetic
PPTP
Pediatric Preclinical Testing Program
PR
partial response
PT
preferred term
RECIST
Response Evaluation Criteria in Solid Tumors
RMS
Rhabdomyosarcoma
RP2D
recommended Phase 2 dose
SAE
serious adverse event
SAP
statistical analysis plan
SAS
safety analysis set
SD
stable disease
SOC
system organ class
STS
soft tissue sarcoma
TEAE
treatment-emergent adverse event
TBI
total body irradiation


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Abbreviation
Term
ULN
upper limit of normal
VAC
vinca alkaloid, actinomycin D, and cyclophosphamide
WHO DD
World Health Organization Drug Dictionary
XRT
Radiation therapy


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5
ETHICS
5.1
Institutional Review Boards/Independent Ethics Committees
The protocol, Informed Consent Form (ICF), and appropriate related documents will be
reviewed and approved by an Institutional Review Board (IRB) or Independent Ethics 
Committee (IEC) constituted and functioning in accordance with ICH E6 (Good Clinical 
Practice), Section 3, and any local regulations, ie, 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 CRA[s], change of telephone number[s]).  Documentation of 
IRB/IEC compliance with the ICH E6 and any local regulations regarding constitution and 
review conduct will be provided to the sponsor.
A signed letter of study approval from the IRB/IEC chairman must be sent to the principal 
investigator with a copy to the sponsor before study start and the release of any study drug to 
the site by the sponsor or its designee (ICH E6, Section 4.4).  If the IRB/IEC decides to 
suspend or terminate the study, the investigator will immediately send the notice of study 
suspension or termination by the IRB/IEC to the sponsor.
Study progress is to be reported to IRB/IECs annually (or as required) by the investigator or 
sponsor, depending on local regulatory obligations.  If the investigator is required to report to 
the IRB/IEC, he/she will forward a copy to the sponsor at the time of each periodic report.  
The investigator(s) or the sponsor will submit, depending on local regulations, periodic 
reports and inform the IRB/IEC of any reportable adverse events (AEs) per ICH guidelines 
and local IRB/IEC standards of practice.  Upon completion of the study, the investigator will 
provide the IRB/IEC with a brief report of the outcome of the study, if required.
At the end of the study, the sponsor should notify the IRB/IEC and Competent Authority 
(CA) within 90 days.  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.
The definition for end of the study, as required by certain regulatory agencies, is the time of 
data cut-off for the final analysis or the time of last subject/last visit, whichever occurs later. 
5.2
Ethical Conduct of the Study
This study will be conducted in accordance with standard operating procedures of the 
sponsor (or designee), which are designed to ensure adherence to GCP guidelines as required 
by the following:

Principles of the World Medical Association Declaration of Helsinki 2008.

ICH E6 Guideline for GCP (CPMP/ICH/135/95) of the European Agency for the 
Evaluation of Medicinal Products, Committee for Proprietary Medicinal Products, 


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International Council on 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.

European Good Clinical Practice Directive 2005/28/EC and Clinical Study Directive 
2001/20/EC for studies conducted within any EU country.  All SUSARs will be 
reported, as required, to the Competent Authorities of all involved EU member states.
5.3
Subject Information and Informed Consent
As part of administering the informed consent document, the investigator must explain to 
each subject or guardian/legally authorized representative the nature of the study, its purpose, 
the procedures involved, the expected duration, the potential risks and benefits involved, any 
potential discomfort, potential alternative procedure(s) or course(s) of treatment available to 
the subject, and the extent of maintaining confidentiality of the subject’s records.  Each 
subject 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 authorized representative should 
understand the statement before signing and dating it and will be given a copy of the signed 
document.  If a subject is unable to read or if a legally authorized representative is unable to 
read, an impartial witness should be present during the entire informed consent discussion.  
After the ICF and any other written information to be provided to subjects is read and 
explained to the subject or the subject’s legally authorized representative, and after the 
subject or the subject’s legally authorized representative has orally consented to the subject’s 
participation in the study and, if capable of doing so, has signed and personally dated the 
ICF, the witness should sign and personally date the consent form.  The subject will be asked 
to sign an ICF before any study-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 Federal Regulations, Title 21 CFR 
Part 50.  Each subject 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 or the subject’s legally authorized representative should be informed in a timely 
manner if new information becomes available that may be relevant to the subject’s 
willingness to continue participation in the study.  The communication of this information 
should be documented.


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6
INVESTIGATORS AND STUDY PERSONNEL
This study will be conducted by qualified investigators under the sponsorship of Eisai (the 
sponsor) at approximately 40 sites in the US. 
The name and telephone and fax numbers of the medical monitor and other contact personnel 
at the sponsor are listed in the Investigator Study File provided to each site.
7
INTRODUCTION
7.1
Childhood Soft Tissue Sarcomas
Sarcomas represent about 6% of all malignancies in children and adolescents, and 1% in 
adults, with an annual incidence of 10 in 1 million children under the age of 15 years and 2 to 
3 per 100,000 in adults (German Childhood Cancer Registry, 2010; Storm, 1998). The 
incidence of sarcomas increased by almost 2% per year in children during 1988 to 1997, 
mainly due to an increase in urogenital rhabdomyosarcoma (RMS) (Pastore, et al., 2006).  
Although the incidence of sarcoma increases with age, sarcoma makes up a larger proportion 
of all cancers in children (Gurney, et al., 1999). The most common histological type in 
childhood is rhabdomyosarcoma (RMS), which accounts for approximately 39% of all cases 
of soft tissue sarcoma (STS), followed by fibrohistiocytic tumors (10%), synovial sarcoma 
(9%), Ewing sarcoma (EWS) and (also known as primitive neuroectodermal tumor [PNET]
of soft tissue; 9.2%), fibroblastic and myofibroblastic tumors (6%), nerve sheath tumors 
(5%), liposarcoma (2.3%), extrarenal rhabdoid tumors (2%), leiomyosarcoma (LMS; 2%), 
alveolar soft parts sarcoma (1.4%), and blood vessel tumors (1.4%).  An additional 9.3% of 
tumors are unspecified sarcoma (National Cancer Institute, 2016).
7.1.1
Current Therapeutic Options
The mainstay of the treatment of sarcoma in all age groups is definitive local therapy 
(surgical excision, radiotherapy or both (Table 4).  The consensus is that all patients with 
RMS and EWS should receive chemotherapy as part of their primary treatment (surgery or if 
surgery is not feasible, radiotherapy) (Van Gaal, et al., 2012).  The role of chemotherapy in 
the primary treatment of non-rhabdomyosarcoma (NRSTS) has not been established.


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Table 4
Principles of RMS, NRSTS and EWS Treatment
Treatment
RMS
EWS
NRSTS
Primary
Surgical excision (where 
feasible)
Definitive radiotherapy if 
wide excision not possible
Multi-agent neo/adjuvant 
chemotherapy (all patients)
Surgical excision (where 
feasible)
Definitive radiotherapy if 
wide excision not possible
Multi-agent neo/adjuvant 
chemotherapy (all patients)
Surgical excision (where 
feasible)
Radiotherapy (residual or 
high-risk disease or 
inoperable)
± Adjuvant chemotherapy 
(role not established)
First 
Relapse
Multi-agent chemotherapy 
Multi-agent chemotherapy
Single-agent or combination 
chemotherapy
≥Second 
Relapse
Investigational treatments
Investigational treatments
Investigational treatments
EWS = Ewing sarcoma, NRSTS = non-rhabdomyosarcoma soft tissue sarcoma, RMS = rhabdomyosarcoma.
Source:  National Cancer Institute, 2016. Childhood Soft Tissue Sarcoma Treatment for Health Professionals 
PDQ®.  Retrieved Feb 2016, from http://www.cancer.gov/publications/pdq/information-summaries
Treatments for relapsed/refractory disease are broadly similar across the tumor types (Table
4).  Further information on treatment options for each tumor types is provided below.
7.1.1.1
Treatment Strategies for Rhabdomyosarcoma
Patients with RMS who relapse after initial treatment, or who experience progressive disease 
while on treatment, have a poor prognosis.  The 5-year survival rate for these patients varies 
between 17% and 24%, and is only 5% in patients with alveolar RMS (Pappo, et al., 1999; 
Dantonello, et al., 2009).  Standard treatment for patients following relapse is suboptimal and 
no standard regimen has been identified.  Local therapy (surgery and/or radiotherapy) should 
be considered where feasible.  
Treatment selection for patients with relapsed or progressive RMS depends on the site(s) of 
recurrence, prior chemotherapy, and individual patient factors.  Treatment for local or 
regional recurrence may include wide local excision, surgical removal of tumor, 
metastatectomy for isolated pulmonary metastasis, or radiotherapy.  The standard approach at 
first relapse is active single agent or combination chemotherapy not previously used in the 
treatment of the patient’s sarcoma.  The following are treatment options for relapsed, 
progressive, or recurrent RMS (Saylors, et al., 2001; Mascarenhas, et al., 2010):

Etoposide-containing regimens: ifosfamide and etoposide, or ifosfamide, carboplatin, 
and etoposide.

Cyclophosphamide-containing regimens: cyclophosphamide and topotecan, or 
vinorelbine and cyclophosphamide.

Topoisomerase inhibitor-containing regimens: irinotecan with or without vincristine, 
or topotecan, vincristine, and doxorubicin.


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Several factors can adversely influence the possibility of cure with further treatment after the 
first relapse: presence of metastatic disease, prior use of radiotherapy and chemotherapy 
containing alkylating agents, large size and unfavorable site of the tumor, nodal involvement 
at initial diagnosis, alveolar histology, and short time to relapse (Chisholm, et al., 2011).  The 
presence of metastatic disease is the strongest predictor of clinical outcomes in patients with 
RMS.  Despite aggressive multimodality treatments, these children fare poorly; only 25% are 
expected to be free of disease 3 years after diagnosis (Maurer, et al., 1993; Crist, et al., 2001).
Following the second relapse, there is no evidence-based standard therapy in this setting and 
the goal of treatment is no longer curative intent.  The choice of agent(s) is based upon the 
treatment options available at the institution including access to clinical studies, individual 
patient/tumor factors (eg, extent of disease, comorbidities, intensity of prior treatment, age) 
and patient/parent choice.  
The evaluation of new agents in development is therefore particularly relevant in this setting.  
This approach of studying single agent investigational agents in the relapsed setting has been 
followed for targeted agents (eg, bortezomib and pazopanib) and new chemotherapeutic 
agents (eg, ixabepilone, irinotecan, vinorelbine, and temozolomide).
7.1.1.2
Treatment Strategies for Non-rhabdomyosarcoma Soft Tissue Sarcoma
The prognosis for children with metastatic NRSTS at diagnosis and, recurrent NRSTS is 
poor.  Decisions about treatment options are based on site of recurrence, tumor biologic 
characteristics, prior therapies and individual patient considerations.
Standard treatment options for metastatic childhood STS include multimodality therapy with 
chemotherapy, radiotherapy, and surgical resection of pulmonary metastases.  Only 3 
prospective multi-institutional clinical trials for NRSTS have been conducted, with fewer 
than 200 subjects enrolled.  Thus, the approach to the treatment of NRSTS in children 
depends largely on the experience in adults with STS (Meyer and Spunt, 2004). The 
treatment paradigms in adults tend to include an anthracycline in first-line with or without 
ifosfamide, followed by gemcitabine and docetaxel or trabectedin as second-line therapy.  
Several combination regimens have undergone clinical evaluation in subjects with recurrent, 
unresectable or metastatic disease, but none of these regimens improved the outcome for 
these subjects.
The NRSTS is a broad category that includes many subtypes of sarcoma, any of which may 
be enrolled on this study. It is noted that in the adult sarcoma experience with eribulin 
mesylate, responses have been observed in leimyocsarcoma, liposarcoma, synovial sarcoma, 
undifferentiated sarcoma, and vascular sarcomas.
7.1.1.3
Treatment Strategies for Ewing Sarcoma
Standard first-line treatment for patients with metastatic EWS is either a 3 drug regimen of 
vincristine, doxorubicin and cyclophosphamide or a 5 drug regimen VAC with 
ifosfamide/etoposide.  In patients who relapse after initial therapy the disease is almost 


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universally fatal.  Salvage therapies include ifosfamide and etoposide, cyclophosphamide and 
topotecan, and temozolomide and irinotecan, or investigational therapies.  Although the 
sarcoma can respond to these combinations, all responses are partial and tend to be of short 
duration.
The addition of ifosfamide and etoposide or dose intensification has failed to improve 
outcomes in patients with metastatic disease.  Patients with lung only metastases seem to 
have a better prognosis than patients with bone metastases.  Up to 20% of patients will have 
long term remissions with chemotherapy and local treatment, but those results have not 
improved in the past 20 years.  
Survival after relapse is typically less than 1 year.  There is no standard therapy for third line 
treatment of EWS, and investigational therapies are recommended.  There is no targeted 
therapy approved for EWS.  Several years ago there was enthusiasm for Insulin-like growth 
factor (IGFR) inhibitors after several anecdotal responses were observed in early phase trials.  
Confirmatory Phase 2 trials demonstrated a response rate of only 8% (Balamuth and 
Womer, 2010). The development of the IGF1R monoclonal antibody, Ganitumab, is ongoing 
(COG study AEWS1221).
7.1.2
Fulfillment of a Therapeutic Need
The backbone of the established gold standard treatment for RMS is a vinca alkaloid with 
actinomycin-D and cyclophosphamide (VAC).  The activity of VAC in RMS has not been 
improved by regimens that alter this backbone.  For NRSTS the standard treatment of 
doxorubicin with or without ifosfamide has not been improved upon for 20 years.  For EWS 
the established standard of 5 drug regimen including vincristine, doxorubicin, 
cyclophosphamide, ifosfamide and etoposide has marginally improved the outcomes for 
patients with localized disease but not for those with relapsed or metastatic disease.  As a 
consequence, new alternatives to the available therapies for children who have failed 
standard treatments for advanced RMS, EWS, and NRSTS, are urgently needed.
7.1.3
E7389 (eribulin mesylate)
7.1.3.1
Mechanism of Action
Eribulin is a synthetic analogue of halichondrin B, a product isolated from the marine sponge 
Halichondria okadai.  Eribulin is an inhibitor of microtubule dynamics with a unique 
microtubule binding site and different effects on microtubule dynamics compared with other 
marketed tubulin-targeting agents.  Eribulin binds with high affinity to the plus ends of 
microtubules, where it suppresses the growth phase of microtubule dynamics without 
affecting the corresponding shortening phase (Jordan, et al., 2005; Smith, et al., 2010).  
Vinca alkaloids (eg, vinblastine) also bind to the plus ends of the microtubule and, with 
lower affinity, along the sides of the microtubule, whereas taxanes (eg, paclitaxel and 
docetaxel) and epothilones (eg, ixabepilone) bind to β-tubulin subunits inside the 
microtubule (Jordan and Wilson, 2004).  In addition to directly suppressing microtubule 
growth, eribulin mesylate induces formation of nonproductive tubulin aggregates, lowering 


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concentrations of free tubulin available for polymerization and thus further inhibiting 
microtubule growth.  It is not known whether these differences will offer a potential 
advantage in terms of safety or efficacy in comparison to existing microtubule inhibitors used 
for treating pediatric cancers.  The tubulin-targeting agents paclitaxel and docetaxel have 
shown minimal activity in pediatric clinical trials, whereas the vinca alkaloids have an 
established role in the treatment of childhood RMS and EWS (Ferrari and Casanova, 2005). 
Due to some similarity with vinca alkaloid microtubule binding sites, eribulin may have a 
broader spectrum of antitumor activity in childhood cancers than the taxanes, even in the 
presence of multidrug resistance (Cortes, et al., 2011). 
7.1.3.1.1
TUMOR BIOLOGY-BASED MECHANISMS
Numerous investigations in human breast cancer models have shown that eribulin induces 
therapeutically meaningful changes in tumor biology and tumor-host interactions that go 
beyond its known classical antimitotic actions (sNDA 201532/S-013; Yoshida, et al., 2014; 
Funahashi, et al., 2014).  Evidence for eribulin-induced changes in tumor biology and tumor-
host interactions falls into 3 main areas:  effects on tumor vascular function and remodeling; 
effects on phenotype and the epithelial-mesenchymal transition (EMT), or more specifically 
the reversal of EMT; and effects on tumor cell migration, invasiveness, and metastatic 
capacity.  In summary, eribulin treatment of human breast cancer cells caused changes in 
morphology and gene expression as well as decreased migration and invasiveness in vitro.  In 
human breast cancer xenograft models in immunocompromised mice, eribulin treatment was 
associated with increased vascular perfusion and permeability in the tumor cores, resulting in 
reduced tumor hypoxia, and changes in the expression of genes in tumor specimens 
associated with a change in phenotype (ie, reversal of EMT).
As found in human breast cancer models, recently completed nonclinical investigations of 
effects of eribulin on human adipocytic (ADI) sarcoma and LMS cell lines and tumor 
xenograft models (submitted to IND 067193, sequence 0665) have also shown that eribulin 
exerts effects on tumor biology and phenotype that go well beyond its classical antimitotic 
effects in this tumor type.  Such effects include morphologic changes in SW872 ADI 
sarcoma and SK-UT 1 LMS cell lines consistent with transitioning to a more differentiated 
phenotype (Study Nos. W-20150640, W-20150639), increased perfusion in SK-LMS-1 
human LMS xenografts (Study No. M15014), and upregulation of adipocyte and smooth 
muscle differentiation markers in SW872 ADI sarcoma and SK-UT-1 LMS cells, 
respectively (Study Nos. W-20150640, W-20150639).  These results, analogous to the 
reported findings associated with reversal of the EMT in human breast cancer models (sNDA 
201532/S-013; Yoshida, et al., 2014; Funahashi, et al., 2014), suggest that eribulin can cause 
phenotypic changes in human ADI sarcomas and LMS that result in more differentiated, less 
aggressive residual tumors.  
7.1.3.2
Clinical Experience With Eribulin
A Phase 1 study (Eisai Study E7389-A001-113, Study 113) of eribulin mesylate in pediatric 
patients with recurrent or refractory solid tumors (excluding CNS), including lymphomas has 
been conducted. Eribulin mesylate was administered intravenously, once per day on Days 1 


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and 8 of a 21-day cycle. This study aimed to determine the MTD and/or the RP2D of this
regimen in Part A1 (patients ≥12 months and <18 years). Additionally, this study aimed to 
describe the toxicities and the pharmacokinetics of eribulin mesylate when administered to 
children. In a preliminary manner, the antitumor effect of eribulin mesylate was also
described.  The MTD was determined to be 1.4 mg/m2, which is the same dose as in the adult 
population.  No major differences were observed in the safety profile between adults and 
pediatric subjects (Schafer, et al., 2018).
A Phase 2 proof of concept study (Eisai Study E7389-E044-207, Study 207), a 
non-randomized, multicenter Phase 2 study in adults with intermediate or high grade 
advanced STS (Schӧffski, et al., 2011), was conducted with a primary endpoint of 
progression-free rate at Week 12 (PFR12weeks).  This study reached statistical significance in 
the ADI (46.9%, 95% 2-sided confidence interval [CI]; 29.1, 65.3) and LMS (31.6%, 95% 
2-sided CI; 17.6, 48.7) strata.  The study concluded that eribulin has activity in pretreated 
subjects with ADI sarcoma and LMS; however, outcomes in pretreated subjects with 
synovial sarcoma and other types of STS did not meet the pre-specified primary efficacy 
criteria for activity.  The study yielded objective responses in 2 subjects with ADI sarcoma 
(n=32), with 1 subject experiencing a complete response (CR) and the other a partial 
response (PR).  
Following the result of this proof of concept study (Study 207), a pivotal Phase 3 study (Eisai 
Study E7389-G000-309, Study 309) in adult ADI and LMS subtypes ‘A randomized trial of 
eribulin versus dacarbazine in advanced leiomyosarcoma and liposarcoma’ was conducted. 
The primary endpoint was to evaluate the efficacy of eribulin compared with dacarbazine in 
terms of overall survival (OS).  This study demonstrated that eribulin had an OS benefit over 
dacarbazine, Hazard Ratio (HR) 0.768, P=0.02 with an OS of 13.5 months for subjects on the
eribulin arm compared with 11.5 months for subjects on the dacarbazine arm.  There was no 
significant difference in progression-free survival (PFS) between the treatment arms in the 
overall population (Schöffski et al., 2016). 
Pre-planned, exploratory subgroup analyses of OS and PFS by histology showed that eribulin 
significantly favored subjects with the ADI subtype.  For OS, this yielded a HR of 0.51 
(95% CI 0.35, 0.75), P=0.0006, with a median OS of 15.6 months for subjects on the eribulin 
arm compared with 8.4 months for subjects on the dacarbazine arm.  The difference in PFS 
was also highly significant in subjects with the ADI subtype in favor of eribulin, with a HR 
of 0.52 (95% CI 0.35, 0.78), P=0.0015 and a median PFS of 2.9 months for subjects on the 
eribulin arm compared with 1.7 months for subjects on the dacarbazine arm.  No significant 
difference between the treatment arms was observed for OS or PFS in subjects with LMS 
histology (Halaven USPI, 2016).
This is the first time any agent has demonstrated improved OS in late line adult liposarcoma.  
Following the results of this study, regulatory applications were submitted globally and on 
28 Jan 2016 eribulin was approved by the Food and Drug Administration (FDA) for the 


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treatment of patients with unresectable or metastatic liposarcoma who have received a prior 
anthracycline-containing regimen. 
In addition to the pivotal study (Study 309) and following the results of Study 207, a Phase 2 
study was also conducted in Japan (Eisai Study E7389-J081-217, NDA 201532/Seq 0102).  
This study evaluated the safety and efficacy of eribulin in previously treated Japanese 
subjects with advanced STS.  The primary efficacy endpoint was PFR12weeks .  The results of 
this study demonstrated significant activity in the ADI and LMS subtypes.  The PFR12weeks 
was 60.0% (95% CI: 42.1, 76.1) in the ADI or LMS stratum, 31.3% (95% CI: 11.0, 58.7) in 
the OTH stratum, and 51.0% (95% CI: 36.6, 65.2) in total (Study E7389-J088-217 Clinical 
Study Report). 
7.1.3.3
Non-Clinical Evidence for Activity of Eribulin in Pediatric Sarcomas
The potential antitumor activity of eribulin in human pediatric tumor models was evaluated 
in the NCI’s Pediatric Preclinical Testing Program (PPTP; Study Nos. PPC-2-12-02N 
submitted to IND 067193, sequence 0636 and PPC-2013-01N submitted to IND 067193, 
sequence 0652).  In the 24 cell line in vitro screening panel, eribulin demonstrated potent 
cytotoxic activity with a median relative half maximal inhibitory concentration value of 
0.27 nM (range: <0.10 to 14.8 nM).  The panel included 4 RMS (RD, Rh18, Rh30, and 
Rh41) and 4 EWS cell lines.  The in vitro pattern of activity for eribulin was similar to that 
previously described by the PPTP for vincristine (Kolb, et al., 2013).  
In the PPTP’s in vivo panel of 43 human pediatric tumor xenografts, eribulin induced 
significant differences in event-free survival (EFS) distribution compared with control in 
26 of 30 (83%) of the evaluable solid tumor xenografts and in 8 of 8 (100%) of the evaluable 
acute lymphoblastic leukemia (ALL) xenografts.  An objective response was observed in 
18 of 35 (51%) solid tumor xenografts.  Complete responses (CRs) or maintained CRs 
(MCRs) were observed in 6 of 7 RMS xenograft models (Rh28, Rh30, Rh30R, and Rh41 
cells).  CRs or MCRs were also observed in 1 of 2 Wilms’ tumor, 4 of 5 EWS, 2 of 4 
glioblastoma, and 3 of 6 osteosarcoma xenografts.  For the ALL panel, all 8 xenografts 
achieved CR or MCR (Kolb, et al., 2013).
The PPTP concluded that the high level of activity observed for eribulin against the PPTP 
preclinical models made eribulin an interesting agent to consider for pediatric evaluation.  
The activity pattern observed for eribulin in the solid tumor panels is comparable or superior 
to that observed previously for vincristine.  Eribulin showed high activity against RMS, 
EWS, osteosarcoma, and ALL xenografts (Kolb, et al., 2013).
7.2
Study Rationale
The unique survival advantage seen in Study 309, and the activity of eribulin seen in both 
Studies 207 and 217, suggests that it is desirable to pursue development in pediatric 
sarcomas.  However, the potential differences in the sensitivity of specific tumor subtypes to 
microtubule inhibition make it difficult to justify development of eribulin in pediatric 


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populations based on the clinical antitumor activity in adults alone.  Strong supportive 
evidence from nonclinical studies is provided in Section 7.1.3.3.
In addition to the encouraging results seen in the PPTP, and the unique survival advantage 
observed in adult liposarcoma subtype, the aim of eribulin development in childhood 
sarcoma is also based upon and the unmet medical need in advanced RMS, EWS, and 
NRSTS.  Eribulin may offer a potential new alternative to the available therapies for children 
who have failed standard treatments for advanced RMS, EWS, and NRSTS.  
A Phase 1 study (Eisai Study E7389-A001-113, Study 113) of eribulin mesylate in pediatric 
patients with recurrent or refractory solid tumors (excluding CNS), including lymphomas has 
been conducted.  The MTD was determined to be 1.4 mg/m2, which is the same dose as in 
the adult population.  No major differences were observed in the safety profile between 
adults and pediatric subjects (Schafer, et al., 2018).
8
STUDY OBJECTIVES
8.1
Primary Objective
The primary objectives of the study are:

To conduct a preliminary assessment of activity of eribulin mesylate in pediatric 
subjects with relapsed/refractory RMS, NRSTS or EWS to determine whether each 
cohort warrants further investigation.
8.2
Secondary Objectives
The secondary objectives of the study are:

To evaluate the PFS, using Response Evaluation Criteria in Solid Tumors 
(RECIST) 1.1, of eribulin mesylate in pediatric subjects with relapsed/refractory 
RMS, NRSTS, or EWS in all cohorts combined.

To evaluate the safety and tolerability of eribulin in the pediatric subjects with 
relapsed/refractory RMS, NRSTS, or EWS in all cohorts combined.

To evaluate the duration of response (DOR) of eribulin mesylate in pediatric subjects 
with relapsed/refractory RMS, NRSTS, or EWS.

To evaluate the overall survival (OS) of pediatric subjects with relapsed/refractory 
RMS, NRSTS and EWS.
8.3
Exploratory Objective(s)

To evaluate the exposure of eribulin mesylate in pediatric subjects with 
relapsed/refractory RMS, NRSTS, or EWS.

To explore the relationship between exposure to eribulin mesylate and AEs and 
efficacy.


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9
INVESTIGATIONAL PLAN
9.1
Overall Study Design and Plan
E7389-G000-223 is a Phase 2, multicenter, open-label study to conduct a preliminary 
assessment of the safety and activity of eribulin mesylate in pediatric subjects with 
relapsed/refractory RMS, NRSTS, or EWS.  
Forty-five pediatric subjects, with approximately 15 subjects each with RMS, NRSTS, or 
EWS, will be enrolled to receive eribulin mesylate as an intravenous (IV) infusion at a dose 
of 1.4 mg/m2 (Recommended Phase 2 Dose [RP2D]) on Days 1 and 8 of each 21-day cycle
as determined by the dose finding study ADVL1314 (Eisai Study E7389-A001-113). 
Outline

Pediatric subjects with relapsed/refractory RMS, NRSTS or EWS will be enrolled to 
receive therapy with eribulin mesylate. 

For each histology type, approximately 15 subjects will be treated.  Data will be 
monitored on an ongoing basis; depending on evaluation by the investigators and 
sponsor, if sufficient responses (PRs or CRs) are observed, then this histology type 
will be recommended for inclusion in the subsequent study.

Subjects will continue study therapy until progression of disease (per RECIST 1.1), 
intolerable toxicity or withdrawal of consent.
Pre-study Phase:
Day -28 to -1, computed tomography (CT) / magnetic resonance imaging (MRI) scans must 
be performed within 28 days prior to study drug administration.  All clinical and laboratory 
test results to determine eligibility must be performed within 7 days prior to study drug 
administration, unless otherwise indicated.
Treatment Phase:
The treatment phase will start on Day 1 of Cycle 1.
Follow-up:
The follow-up period will begin immediately after the End of Treatment visit until death or 
informed consent is withdrawn, unless the study is terminated by the sponsor. Subjects will 
be followed for survival approximately every 12 weeks for 1 year and then annually 
thereafter. As well as follow-up for survival, the annual surveillance will also assess any 
long term effects of the study treatment.
During the follow-up period, subjects who have gone off study treatment without progression 
should have tumor assessments every 6 - 12 weeks, at the investigator’s discretion, from the 
date of last tumor assessment until disease progression is documented, death, or initiation of


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another anticancer therapy, whichever occurs first, unless the study is terminated by the 
sponsor.  Follow-up data will be required unless consent is withdrawn.
9.2
Discussion of Study Design
This is an open-label study to conduct a preliminary assessment of safety and activity of 
eribulin mesylate in pediatric subjects with relapsed/refractory RMS, NRSTS, or EWS. The 
secondary objective of PFS is an appropriate surrogate endpoint for studies in STS as there 
are significant correlations between PFS and OS (R=0.61) and between objective response 
rate (ORR) and OS (R=0.51) (Zer, at al., 2016).  
9.3
Selection of Study Population
The subject population for this study comprises pediatric subjects aged ≥12 months to 
<18 years at the time of informed consent, with a histologically confirmed diagnosis of RMS, 
NRSTS, or EWS, that is considered to be relapsed or refractory (ie, subjects have failed 
front-line therapy).
Approximately 45 subjects will be enrolled. Subjects who do not meet all of the inclusion 
criteria or who meet any of the exclusion criteria will not be eligible to receive study drug.
9.3.1
Inclusion Criteria
Subjects must meet all of the following criteria to be included in this study:
1.
Age: ≥12 months to <18 years old at the time of informed consent.
2.
Diagnosis: Histologically confirmed RMS, NRSTS (Grade 2 or 3) or EWS which is 
relapsed or refractory (failed front line therapy).
3.
The presence of measurable disease meeting the following criteria:

At least 1 lesion of ≥1.0 cm in the longest diameter for a non-lymph node or ≥1.5 cm 
in the short-axis diameter for a lymph node that is serially measurable according to 
RECIST 1.1 using CT/MRI.

Lesions that have had radiotherapy must show subsequent radiographic evidence of 
increase in size by at least 20% to be deemed a target lesion.
4.
Therapeutic options: Subject’s current disease state must be one for which there is no 
known curative therapy or therapy proven to prolong survival with an acceptable quality 
of life.
5.
Performance level: Performance score ≥50%. Karnofsky (for subjects >16 years of age) 
or Lansky (for subjects ≤16 years of age). Subjects who are unable to walk because of 
paralysis and/or previous surgeries, but who are in a wheelchair, will be considered 
ambulatory for the purpose of assessing performance score.
6.
Subjects must have fully recovered from the acute toxic effects of all prior anticancer 
therapy and must meet the following minimum duration from prior anticancer directed 


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therapy prior to study drug administration.  If, after the required time frame, the 
numerical eligibility criteria are met, eg, blood count criteria, the subject is considered to 
have recovered adequately:

Cytotoxic chemotherapy or other chemotherapy known to be myelosuppressive: 
≥21 days after the last dose of cytotoxic or myelosuppressive chemotherapy (42 days 
if prior nitrosourea).

Anticancer agents not known to be myelosuppressive (eg, not associated with reduced 
platelet or absolute neutrophil count [ANC] counts): ≥7 days after the last dose of 
agent.

Monoclonal antibodies: 3 half-lives must have elapsed from infusion of last dose of 
antibody (including checkpoint inhibitors), and toxicity related to prior antibody 
therapy must be recovered to Grade ≤1.

Hematopoietic growth factors: ≥14 days after the last dose of a long-acting growth
factor (eg, Neulasta) or 7 days for a short-acting growth factor.  For agents that have 
known AEs occurring beyond 7 days after administration, this period must be 
extended beyond the time during which AEs are known to occur. The duration of this 
interval must be discussed with the sponsor.

Interleukins, interferons, and cytokines (other than hematopoietic growth factors): 
≥21 days after the completion of interleukins, interferons or cytokines (other than 
hematopoietic growth factors).

Stem cell infusions (with or without total body irradiation [TBI]): ≥84 days.

Allogeneic (non-autologous) bone marrow or stem cell transplant, or any stem cell 
infusion including donor lymphocyte infusion or boost infusion: ≥84 days after 
infusion and no evidence of graft versus host disease (GVHD).

Autologous stem cell infusion including boost infusion: ≥42 days.

Cellular therapy: ≥42 days after the completion of any type of cellular therapy (eg, 
modified T-cells, natural killer cells, dendritic cells, etc).

Radiation therapy (XRT)/External Beam Irradiation including Protons: ≥14 days after 
local XRT, ≥150 days after TBI, craniospinal XRT or if radiation to ≥50% of the 
pelvis, ≥42 days if other substantial BM radiation.

Radiopharmaceutical therapy (eg, radiolabeled antibody, 
131I-metaiodobenzylguanidine):  ≥42 days after systemically administered 
radiopharmaceutical therapy. 
7.
Adequate bone marrow function, defined as:

ANC ≥1.0 × 109/L 

Platelet count ≥100 × 109/L (transfusion independent, defined as not receiving platelet 
transfusions within a 7-day period prior to study drug administration)

Hemoglobin at least 8.0 g/dL at Baseline (blood transfusions are allowed during the 
screening period to correct hemoglobin values less than 8.0 g/dL)


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Note: As blood transfusions are permitted to meet the hemoglobin criteria, subjects 
requiring transfusion must not be known to be refractory to red blood cell or platelet 
transfusions.
8. Adequate renal function, defined as:

A serum creatinine based on age/gender as follows, derived from the Schwartz 
formula for estimating glomerular filtration rate (GFR) (see table below)
Age
Maximum Serum
Creatinine (mg/dL)
Male
Female
6 months to <1 year
0.5
0.5
1 to <2 years
0.6
0.6
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 
glomerular filtration rate (GFR) (Schwartz and Gauthier. J Pediatr. 1985;106:522–6) utilizing child 
length and stature data published by the Centers for Disease Control and Prevention (CDC).

Or creatinine clearance or GFR ≥50 mL/min/1.73 m2 based on a 12 or 24 hour urine 
creatinine collection. 
9.
Adequate liver function, defined as:
a.
Bilirubin (sum of conjugated + unconjugated) ≤1.5 × upper limit of normal (ULN) for 
age
b. ALT ≤110 U/L. For the purpose of this study, the ULN for ALT is 45 U/L.
c.
Serum albumin ≥2 g/dL
10. Informed consent:  All subjects and/or their parents or legally authorized representatives 
must sign a written informed consent.  Assent, when appropriate, will be obtained 
according to institutional guidelines.  Subjects must be willing to comply with all aspects 
of the protocol.
9.3.2
Exclusion Criteria
Subjects who meet any of the following criteria will be excluded from this study:
1.
Pregnancy, breastfeeding, contraception:  Females who are breastfeeding or pregnant at 
Screening or Baseline (as documented by a positive beta-human chorionic [β-hCG] (or 
human chorionic gonadotropin [hCG] test with a minimum sensitivity of 25 IU/L or 
equivalent units of β-hCG [or hCG]).  A separate baseline assessment is required if a 
negative screening pregnancy test was obtained more than 72 hours before the first dose 
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-
Females of childbearing potential* who:
◦
Do not agree to use a highly effective method of contraception for the entire study 
period and for 6 months after study drug discontinuation, ie:
◦
Total abstinence (if it is their preferred and usual lifestyle)
◦
An intrauterine device (IUD) or intrauterine system (IUS)
◦
A contraceptive implant
◦
An oral contraceptive**
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 
commenced/adjusted/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 condoms 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).
**Must be on a stable dose of the same oral hormonal contraceptive product for at least 
4 weeks before dosing with study drug and for the duration of the study and for 6 months 
after study drug discontinuation.
◦
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 or for 3 months after study drug discontinuation).  No sperm 
donation is allowed during the study period or for 3 months after study drug 
discontinuation.
2.
Concomitant medications:

Corticosteroids: Subjects receiving corticosteroids who have not been on a stable or 
decreasing dose of corticosteroid for at least 7 days prior to study drug administration
(except when indicated for Central Nervous System (CNS) metastases, then subjects 
must not have received corticosteroids for at least 28 days)

Anticancer Agents: Subjects who are currently receiving other anticancer agents 

Anti-GVHD agents posttransplant: 
-
Subjects who are receiving cyclosporine, tacrolimus or other agents to prevent 
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
Strong CYP3A4 inducers/inhibitors (See Section 9.4.6.1.1, Drug-Drug Interactions).
3.
Received prior therapy with eribulin mesylate (when confirmed) 
4.
Any other malignancy that required treatment (except for non-melanoma skin cancer, or 
histologically confirmed complete excision of carcinoma in situ), within 2 years prior to 
study drug administration.
5.
Has hypersensitivity to eribulin or any of the excipients.
6.
Has a prior history* of viral hepatitis (B or C) as demonstrated by positive serology 
(presence of antigens) or have an uncontrolled infection requiring treatment (* Subjects 
with a known prior history of hepatitis B or C may be eligible pending agreement with 
the sponsor.
7.
Has >Grade 1 peripheral sensory neuropathy or >Grade 1 peripheral motor neuropathy 
graded according to the Modified (“Balis”) Pediatric Scale of Peripheral Neuropathies
8.
Has cardiac pathology: Subjects with known congestive heart failure, symptomatic or left 
ventricular (LV) ejection fraction <50% or shortening fraction <27% and subjects with 
congenital long QT syndrome, bradyarrhythmias, or QTc >480 msec on at least 2 
separate ECGs
9.
Has CNS Disease:  Subjects with brain or subdural metastases are not eligible unless the 
metastases are asymptomatic and do not require treatment or have been adequately 
treated by local therapy (eg, surgery or radiotherapy) and have discontinued the use of 
corticosteroids for this indication for at least 4 weeks prior to study drug administration.  
Confirmation of radiographic stability must be done by comparing the brain scan (CT or 
MRI) performed during the Screening Period, using the same imaging modality, to a 
brain scan performed earlier (and following local therapy where applicable). Subjects 
must be clinically stable.  It is not the intention of this protocol to treat subjects with 
active brain metastases.
Note:  CNS imaging is required to confirm eligibility for subjects with a known history 
of CNS disease 
10. Have had or are planning to have the following invasive procedures:

Major surgical procedure or significant traumatic injury within 28 days prior to study 
drug administration

Laparoscopic procedure or open biopsy within 7 days prior to study drug 
administration.

Central line placement or subcutaneous port placement is not considered major 
surgery but must be placed at least 2 days prior to study drug administration.

Core biopsy, including bone marrow biopsy within 2 days prior study drug 
administration

Fine needle aspirate within 3 days prior to study drug administration.
11. Has any serious concomitant illness that in the opinion of the investigator(s) could affect 
the subject’s safety or interfere with the study assessments
12. Subjects with known human immunodeficiency virus (HIV); due to lack of available 
safety data for eribulin therapy in HIV infected subjects.


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9.3.3
Removal of Subjects From Therapy or Assessment
The investigator may discontinue treating a subject with study treatment or withdraw the 
subject from the study at any time for safety or administrative reasons.  The subject may 
decide to discontinue study treatment or withdraw from the study at any time for any reason.  
The reason for discontinuation will be documented.  If a subject discontinues study 
treatment, the subject will enter the 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.  A subject removed from the study for any 
reason other than toxicity or progression may be replaced.  
During the Follow-Up Period, subjects who have discontinued study treatment without 
progression should have disease assessments as per the Schedule of Assessments from the 
date of the last assessment until disease progression as per RECIST 1.1 is documented, death
or another anticancer therapy is initiated.
All subjects will be followed for survival until death, except where a subject withdraws 
consent or the sponsor chooses to halt survival follow-up after completion of the primary 
study analysis.
9.4
Treatments
9.4.1
Treatments Administered
Eribulin mesylate will be administered by IV infusion over 2-5 minutes on Days 1 and 8 of 
each 21-day cycle.  Eribulin may be diluted in up to 100 mL 0.9% sodium chloride, and 
administered as an IV infusion over 15 minutes (maximum infusion duration), where 
clinically appropriate.
9.4.1.1
Criteria for Dosing Modifications
Dose reduction and interruption will be performed according to the instructions in
Section 9.4.1.1.1.
9.4.1.1.1
ERIBULIN MESYLATE
Treatment will not be administered when any of the following values are recorded (Table 5).
Table 5
Criteria for Administration of Eribulin Mesylate
a): Do not administer Cycle 1 Day 1 treatment where:
Absolute Neutrophil Count
<1.0× 109/L or 1,000/mm3


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Platelets
<100 × 109/L or 100,000/mm3
Non-hematological toxicity
Any > Grade 2 except for inadequately treated nausea 
and/or vomiting
b): Do not administer any Day 8 treatment where:
Absolute Neutrophil Count
<0.75 × 109/L or 750/mm3
Platelets
<75 × 109/L or 75,000/mm3
Non-hematological toxicity
Any > Grade 2 except for inadequately treated nausea 
and/or vomiting
c): Do not administer any subsequent Day 1 treatment where:
Absolute Neutrophil Count
<1.0 × 109/L or 1,000/mm3
Platelets
<75 × 109/L or 75,000/mm3
Non-hematological toxicity
Any > Grade 2 except for inadequately treated nausea 
and/or vomiting
If the dose cannot be administered as planned due to treatment-related toxicity, the dose 
should be delayed according to the following instructions.
Day 1 of each cycle: If treatment cannot be administered on Day 1, the dosing should be 
delayed until recovery to above these values in Table 5 or Grade ≤2 as appropriate (for Cycle 
1 & subsequent cycles). The Day 1 dose will be rescheduled for when the criteria for 
treatment administration are met. The dose level may have to be reduced following a dose 
delay in accordance to the instructions for dose reduction (Table 6 and Table 7).
Day 8 of each cycle: If treatment cannot be administered on Day 8, the dosing should be 
delayed until recovery to above these values (Table 5). The Day 8 dosing will be delayed 
for a maximum of 7 days and as follows:

If recovery occurs on or before Day 15, dosing will be resumed at the next lower dose 
level (Table 7) and this will be the new Day 8.

If hematological or non-hematological toxicity has not resolved to the above values 
on Day 15, the second administration in the cycle will be omitted.  Dosing will be 
resumed at the next lower dose level (Table 7) and as scheduled on Day 1 of the next 
cycle if recovery has occurred to the above values.  
Please note, use of hematopoietic growth factors is not permitted in Cycle 1 and is only 
permitted in subsequent cycles as per institutional guidelines.
The treatment will be permanently reduced to the next lowest dose level (Table 6) after the 
occurrence of the following events:


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Table 6
Criteria for Reduction of Eribulin Mesylate to the Next Lowest 
Dose Level
Absolute Neutrophil Count
Grade 4 neutropenia > 7 days
Grade 3 or 4 febrile neutropenia and/or infection requiring treatment 
with antibiotics and/or growth factors
Platelets
Grade 4 thrombocytopenia
Grade 3 thrombocytopenia requiring platelet or blood transfusion or both
Non-hematological toxicity
Grade 3 or 4 non-hematological toxicities (attributable to study drug); 
except Grade 3 hypophosphatemia, hypokalemia, hypocalcemia or 
hypomagnesemia that respond to supplementation
If hematological  toxicities do not recover following a dose reduction to dose level -1 and the 
use of hematopoietic growth factors,  the dose should be reduced to dose level -2. If non-
hematological toxicities do not recover following a dose reduction to dose level -1, a second 
dose reduction to dose level -2 should be made. If either hematologic or non-hematologic 
toxicities do not recover despite two dose reductions, the subject should be discontinued from
treatment. However, if the subject is deemed to have clinical benefit, continuation of 
treatment may be discussed with the sponsor.
Dose modifications are based on AEs for eribulin mesylate (starting dose determined by 
COG protocol ADVL1314/Eisai Study E7389-A001-113; 1.4 mg/m2; Table 7).
Table 7
Eribulin Mesylate Dose Modifications
Dose level
Eribulin mesylate (mg/m2)
0*
1.4
-1
1.1
-2
0.8
* Dose level 0 refers to the starting dose.
Do not re-escalate dose level after the dose level has been reduced.
Instructions for QTc Prolongation on Electrocardiogram (ECG):
Increase the frequency of ECG and electrolyte monitoring in subjects who: develop Grade 2 
QTc prolongation, are receiving agents that are known to prolong QTc interval, or have 
clinically relevant electrolyte abnormalities.  Permanently discontinue eribulin mesylate in 
subjects who develop ≥Grade 3 QTc prolongation, and monitor ECGs and electrolytes 
frequently until the QTc interval returns to baseline.


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9.4.2
Identity of Investigational Products
Eribulin mesylate will be supplied by the sponsor in labeled containers.
9.4.2.1
Chemical Name, Structural Formula of Eribulin Mesylate

Test drug code:  E7389

Generic name:  Eribulin Mesylate

Chemical name (IUPAC):  11,15:18,21:24,28-Triepoxy-7,9-ethano-12,15-methano-
9H,15H-furo[3,2-i] furo[2',3':5,6]pyrano[4,3-b][1,4]dioxacyclopentacosin-5(4H)-one, 
2-[(2S)-3-amino-2-hydroxypropyl]hexacosahydro-3-methoxy-26-methyl-20,27-
bis(methylene)-,(2R,3R,3aS,7R,8aS,9S,10aR,11S, 
12R,13aR,13bS,15S,18S,21S,24S,26R,28R,29aS)-, methanesulfonate (salt)

Molecular formula:  C41H63NO14S (C40H59NO11・CH4O3S)

Molecular weight:  826.0

Structural formula:  
9.4.2.2
Labeling for Study Drug
Eribulin mesylate will be labeled in accordance with text that is in full regulatory compliance 
with each participating country and is translated into the required language(s) for each of 
those countries.
9.4.2.3
Storage Conditions
Study drug will be stored in accordance with the labeled storage conditions.  Temperature 
monitoring is required at the storage location to ensure that the study drug is maintained 
within an established temperature range.  The investigator or designee (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 


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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
The subjects will receive eribulin mesylate only.
9.4.4
Selection of Doses in the Study
Eribulin mesylate will be administered at the RP2D (1.4 mg/m2; Eisai Study 
E7389-A001-113).  Further information on dose modification is provided in Section 9.4.1.
9.4.5
Selection and Timing of Dose for Each Subject
Eribulin mesylate should be administered by IV infusion over 2-5 minutes on Days 1 and 8 
of a 21-day cycle. Eribulin may be diluted in up to 100 mL 0.9% sodium chloride, and 
administered as an IV infusion over 15 minutes (maximum infusion duration), where 
clinically appropriate.
9.4.6
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 28 days after the final
dose of study drug will be recorded.  Additionally, all diagnostic, therapeutic, or surgical 
procedures relating to malignancy should be recorded.  Any medication that is considered 
necessary for the subject’s health and that is not expected to interfere with the evaluation of 
or interact with eribulin may be continued during the study.
Supportive care will be allowed as per institutional guidelines.  Growth factors that support 
platelet or white blood cell number or function can only be administered in accordance with 
dose modification guidelines or for culture proven bacteremia or invasive fungal infection. 
Prophylatic granulocyte colony-stimulating factor should NOT be administered in Cycle 1.
Subjects should not receive any other anticancer therapy (including chemotherapy, radiation 
therapy, immunotherapy or biologic therapy) or investigational agents while receiving study 
drug.  If these therapies are administered, the subject will be removed from the study. From 
week 24, the subject may receive radiotherapy for local control and continue to receive drug 
on study.  
9.4.6.1
Drug-Drug Interactions
9.4.6.1.1
ERIBULIN MESYLATE
In adults, no drug-drug interactions are expected with CYP3A4 inhibitors, CYP3A4 inducers 
or P-glycoprotein (P-gp) inhibitors. Clinically meaningful differences in exposure (AUC) 


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were not observed in patients with advanced solid tumors when Halaven was administered 
with or without ketoconazole (a strong inhibitor of CYP3A4 and a P-gp inhibitor) and when 
Halaven was administered with or without rifampin (a CYP3A4 inducer).  Eribulin does not 
inhibit CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A4 enzymes or induce 
CYP1A2, CYP2C9, CYP2C19 or CYP3A4 enzymes at relevant clinical concentrations. 
Eribulin is not expected to alter the plasma concentrations of drugs that are substrates of 
these enzymes (Halaven USPI, 2016).
Currently, drug-drug interactions of eribulin mesylate have not been studied in children, 
therefore pediatric subjects taking medications that are strong CYP3A4 inducers (eg, 
phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, St. John’s Wort) or 
inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, 
saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) or taking nutritional 
supplements known to inhibit CYP3A4, will be excluded from the study.
Please refer to http://medicine.iupui.edu/flockhart/table.htm for the most current information.
9.4.6.2
Prohibited Concomitant Therapies and Drugs
Subjects should not receive other antitumor therapies while on study.  If subjects receive 
additional antitumor therapies, such as chemotherapy, hormone therapy, palliative 
radiotherapy (up to week 24), or immunotherapy, this will be judged to represent evidence of 
disease progression, and study medication will be discontinued.  These subjects should 
complete all off-treatment assessments and continue to be followed for survival in the 
Follow-Up Period.
Details of other prohibited concomitant therapies and drugs are provided in Section 9.3.2
(Exclusion criterion #2).
9.4.7
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.
9.4.8
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.


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
A copy of the IRB/IEC-approved ICF and any other documentation provided to the 
subjects to be used in this study.

The IRB/IEC membership list and statutes or Health and Human Services Assurance 
number.

A copy of the certification and a table of the normal laboratory ranges for the 
reference laboratory conducting the clinical laboratory tests required by this protocol.

An investigator-signed and dated FDA Form FDA 1572, where applicable.

Financial Disclosure form(s) for the principal investigator (PI) and all 
subinvestigators listed on Form FDA 1572, where applicable.

A signed and dated curriculum vitae (CV) of the PI including a copy of the PI’s 
current medical license or medical registration number on the CV.

A signed and dated clinical studies agreement.
The investigator and the study staff will be responsible for the accountability of all study 
drugs (dispensing, inventory, and record keeping) following the sponsor’s instructions and 
adherence to Good Clinical Practice (GCP) guidelines as well as local or regional 
requirements.
Under no circumstances will the investigator allow the study drugs to be used other than as 
directed by this protocol.  Study drugs will not be dispensed to any individual who is not 
enrolled in the study.  
The site must maintain an accurate and timely record of the following:  receipt of all study 
drugs, dispensing of study drugs to the subject, collection and reconciliation of unused study 
drugs that are either returned by the subjects or shipped to site but not dispensed to subjects, 
and return of reconciled study drugs to the sponsor or (where applicable) destruction of 
reconciled study drugs at the site.  This includes, but may not be limited to: (a) 
documentation of receipt of study drugs, (b) study drugs dispensing/return reconciliation log, 
(c) study drugs accountability log, (d) all shipping service receipts, (e) documentation of 
returns to the sponsor, and (f) certificates of destruction for any destruction of study 
drugs/study supplies that occurs at the site.  All forms will be provided by the sponsor.  Any 
comparable forms that the site wishes to use must be approved by the sponsor.
The study drugs and inventory records must be made available, upon request, for inspection 
by a designated representative of the sponsor or a representative of a health authority (eg, 
FDA, 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 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 


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accountability and reconciliation procedures by the site’s personnel and documentation 
procedures by the sponsor’s personnel, study drugs that are to be returned to the sponsor’s 
designated central or local depot(s) must be boxed, sealed, and shipped back to the central or 
local depot(s) following all local regulatory requirements.  In some regions, study drugs may 
be removed from the site and hand delivered to the central or local depot by sponsor 
representatives.  Where study drugs are approved for destruction at the site, destruction will 
occur following the site’s standard procedures and certificates of destruction will be provided 
to the sponsor.
Drug accountability will be reviewed during site visits and at the completion of the study.
9.5
Study Assessments
9.5.1
Assessments
9.5.1.1
Demography
Subject demography information will be collected at the Screening Visit.  Demography 
information includes date of birth (or age), sex, race/ethnicity.
9.5.1.2
Baseline Assessments
Baseline characteristics and assessments will be collected at the Screening Visit.  End-of-
Treatment assessments will be collected within 28 days of the last dose of study drug.  
Screening and Baseline characteristics and End-of-Treatment assessments are listed in the 
Schedule of Procedures/Assessments (Table 9).
9.5.1.2.1
MEDICAL HISTORY AND PHYSICAL EXAMINATIONS
Medical and surgical history and current medical conditions will be recorded at the Screening 
Visit.  All medical and surgical history relating to anticancer treatment 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 Procedures/Assessments (Table 9).  A comprehensive physical 
examination will include evaluations of the head, eyes, ears, nose, throat, neck, chest 
(including heart and lungs), abdomen, limbs, skin, and at baseline, a complete neurological 
examination.  On subsequent evaluations an assessment of neuropathy (neuropathy 
present/absent and CTC AE Grade) will be made as part of the physical 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.


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9.5.1.3
Efficacy Assessments
9.5.1.3.1
PRIMARY
Efficacy will be evaluated by objective tumor responses provided as determined by the 
investigator according to RECIST v1.1. For analysis purposes, ORR is defined as the 
proportion of subjects who achieve a CR plus those who achieve a PR. 
9.5.1.3.2
SECONDARY
Efficacy will also be evaluated according to a secondary endpoint (PFS; defined as the time 
from the date of the first dose of study treatment until the date of first documentation of 
progressive disease (PD) or date of death [whichever occurs first]).  Assessments for these 
endpoints are to be performed every 6 weeks by use of consistent imaging methodology (ie, 
CT scan/MRI or bone scan) and consistent use or nonuse of contrast media) until Week 24, 
then every 9 weeks.  In addition, OS status (disposition) and DOR will be assessed 
throughout the study.  For subjects receiving radiotherapy and/or surgery for local control 
post week 24, progression will be assessed as the date of radiotherapy/surgical procedure.
9.5.1.3.3
EXPLORATORY
Additional exploratory endpoints on the exposure of eribulin will be evaluated and the 
relationship between exposure and AEs and efficacy will also be explored.
9.5.1.4
Tumor Assessments
Tumor response and progression will be evaluated according to RECIST 1.1 criteria.  Copies 
of all scans for tumor assessments will be sent to an imaging core laboratory designated by 
the sponsor.  Tumor assessments will be carried out following the guidelines provided by the 
imaging core laboratory. Decisions concerning treatment discontinuation for PD will be 
based on investigator assessment.
Tumor assessments (CT chest, and CT or MRI abdomen, pelvis, and other known or 
suspected sites or disease) will be performed during screening and then every 6 weeks 
(within the sixth week) on a fixed schedule from the date of first study drug administration.
Magnetic resonance imaging (MRI) scans may be used instead of CT scans for abdomen and 
pelvis; however, chest must be assessed using CT.  The same method of assessment must be 
used at all time-points as used at pre-study.  Partial and complete responses will be confirmed 
at least 4 weeks after initial documentation of PR or CR, typically on the next consecutive 
scheduled tumor assessment.  After 24 weeks subjects with CR, PR or stable disease (SD) 
may have imagining decreased to every 9 weeks (within the ninth week).  A bone scan using 
whole body bone MRI, 99m-technetium based bone scans, 18fluordeoxyglucose (FDG)-
PET/CT scans or 18F-sodium fluoride positron emission tomography [NaF PET] will be 
performed during screening to establish a baseline (a historical bone scan performed within 6 
weeks before study drug administration is acceptable), approximately every 24 weeks (in 


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conjunction with a scheduled tumor assessment visit), and as clinically indicated. Lesions 
identified on bone scans should be followed with cross-sectional imaging. 
Brain scans will be performed as clinically indicated to assess potential CNS disease and/or 
metastases.  For subjects with a history of protocol-eligible treated brain metastases, a brain 
scan will be required at screening and all tumor assessment time points (eg, every 6 weeks). 
Subjects who discontinue treatment without objective evidence of disease progression will 
continue to have tumor assessments performed, per the schedule of assessments, until disease 
progression, death, or initiation of another anticancer therapy.  
9.5.1.5
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker
Assessments
9.5.1.5.1
PHARMACOKINETIC ASSESSMENTS
Samples for PK analysis of eribulin will be collected immediately post-infusion on Day 1 
each cycle for 3 cycles, and pre-infusion and immediately post-infusion on Day 8 each cycle 
for 3 cycles (Table 9).  Plasma concentrations of eribulin will be tabulated and summarized 
by dose level and time.
9.5.1.5.2
PHARMACODYNAMIC, PHARMACOGENOMIC, AND OTHER BIOMARKER, ASSESSMENTS
Not applicable.
9.5.1.6
Safety Assessments
Safety assessments will consist of monitoring and recording all AEs, according to Common 
Terminology Criteria for Adverse Events (CTCAE) v 4.03.  This includes listing of all grades 
(for both increasing and decreasing severity), and SAEs; regular monitoring of hematology, 
blood chemistry, and urine values; periodic measurement of vital signs; performance status, 
and physical examinations as detailed in Table 9.
Other Assessments
ECG monitoring to evaluate RR, PR, QRS, and QT intervals and QTc interval (corrected for 
heart rate [QTc] using Fridericia's [QTcF] and Bazett's [QTcB] correction factors) at pre-
study, during Cycle 1 (pre- and post-infusion Day1 and Day 8) and as clinically indicated 
during subsequent cycles and during follow-up (28 days after the last dose of drug).
A full neurologic examination will be conducted at Screening. On subsequent cycles an 
assessment of neuropathy (neuropathy present/absent and CTC AE Grade) will be made as 
part of the physical examination.


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9.5.1.6.1
ADVERSE EVENTS
An adverse event (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
eribulin mesylate.
The criteria for identifying AEs in this study are:

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of an investigational product, 
whether or not considered related to the investigational product (Note:  Every sign or 
symptom should not be listed as a separate AE if the applicable disease [diagnosis] is 
being reported as an AE).

Any new disease or exacerbation of an existing disease. However, worsening of the 
primary disease should be captured under efficacy assessments as disease progression 
rather than as an AE.

Any deterioration in nonprotocol-required measurements of a laboratory value or 
other clinical test (eg, ECG or x-ray) that results in symptoms, a change in treatment, 
or discontinuation of study drug.

Recurrence of an intermittent medical condition (eg, headache) not present 
pretreatment (Baseline).

An abnormal laboratory test result should be considered an AE if the identified 
laboratory abnormality leads to any type of intervention, withdrawal of study drug, or
withholding of study drug, whether prescribed in the protocol or not.
All AEs and SAEs, regardless of relationship to study drug or procedure, should be recorded
beginning from the time the subject and/or their parents or legally authorized representatives 
signs the study ICF through the last visit.  
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 (QTc) results, if not otherwise considered part of a clinical symptom that is 
being reported as an AE, should be considered an AE if the QTc interval is more than 450 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 28 days after the subject’s last dose, or until resolution, 
whichever comes first. SAEs will be collected for 28 days posttreatment and followed until 
resolution or, if resolution is unlikely, until the event or sequelae stabilize.


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Progression of malignant disease should not be recorded as an adverse event in studies where 
it is included as an endpoint for underlying disease. However, the symptoms experienced as 
part of progression of disease should be recorded as the adverse event. If the progression 
leads to an untoward medical occurrence (increased pain, pleural effusion, etc), then this 
medical occurrence should also be recorded as the adverse event.
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 v4 (National Institutes 
of Health Cancer Therapy Evaluation Program, 2010).  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.
9.5.1.6.2
SERIOUS ADVERSE EVENTS AND EVENTS ASSOCIATED WITH SPECIAL SITUATIONS
A serious adverse event (SAE) is any untoward medical occurrence that at any dose:

Results in death


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
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. 
Every effort must be made to identify the cause of death if it occurs within 28 days of 
last dose. The cause of death must be recorded on the Adverse Event page.
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.
If possible, a blood sample for the measurement of study drug plasma concentration should 
be drawn at the first report of an SAE or a severe unexpected AE and at its resolution.
9.5.1.6.3
LABORATORY MEASUREMENTS
Clinical laboratory tests to be performed, including hematology, chemistry, and urinalysis, 
are summarized in Table 8.  Subjects should be in a seated or supine position during blood 


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collection.  The Schedule of Procedures/Assessments (Table 9) shows the visits and time 
points at which blood for clinical laboratory tests and urine for urinalysis will be collected in 
the study.
Efforts should be made to conduct study visits on the day scheduled.  If holidays or other 
reasons make the day impossible, then sample collection may be up to 2 days sooner or later. 
Clinical laboratory assessments may be conducted based on Table 9.
Table 8
Clinical Laboratory Tests
Category
Parameters
Hematology
Hematocrit, hemoglobin, platelets, RBC count, and WBC count 
with differential (bands, basophils, eosinophils, lymphocytes, 
monocytes, neutrophils)
Chemistry
Electrolytes
Chloride, potassium, sodium, magnesium
Liver function tests
Alanine aminotransferase, alkaline phosphatase, aspartate 
aminotransferase, total bilirubin
Renal function tests
Blood urea/blood urea nitrogen, creatinine
Other
* Albumin, calcium (total + ionized),  glucose, lactate 
dehydrogenase, phosphorus, total protein, uric acid
Urinalysis
Bacteria, casts, crystals, epithelial cells, glucose, ketones, occult 
blood, pH, protein, RBCs, specific gravity, WBCs
RBC = red blood cell, WBC = white blood cell.
*
All to be assessed at baseline.  Uric acid is not required at 
subsequent chemistry measurement time points.
Clinical laboratory tests during the Treatment Phase will be performed by designated local
laboratories.  All blood and urine samples will be collected and sent to the local laboratory on 
the day of collection unless otherwise instructed 
Local laboratories will perform tests to qualify subjects for entry into the study.  Laboratory 
certification as available will be included in the final clinical study report for this study.
All hematology, blood chemistry (including pregnancy test, as applicable), and urinalysis 
samples are to be obtained prior to study drug administration and results reviewed prior to 
administration/dispensing of study drug at the beginning of each treatment cycle. Refer to 
Section 9.4.1.1 for the management of clinically significant laboratory abnormalities.
A laboratory abnormality may meet the criteria to qualify as an AE as described in this 
protocol (see Section 9.5.1.6.1 and the CRF Completion Guidelines).  In these instances, the 
AE corresponding to the laboratory abnormality will be recorded on the Adverse Event CRF.


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9.5.1.6.4
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]), and weight (kg) 
will be obtained at the visits designated in the Schedule of Procedures/Assessments (Table 9) 
by a validated method.  
9.5.1.6.5
PHYSICAL EXAMINATIONS
Physical examinations will be performed as designated in the Schedule of 
Procedures/Assessments (Table 9).  Documentation of the physical examination will be 
included in the source documentation at the site.  Only changes from screening physical 
examination findings that meet the definition of an AE will be recorded on the Adverse 
Events CRF.
9.5.1.6.6
ELECTROCARDIOGRAMS
Electrocardiograms will be obtained as designated in the Schedule of 
Procedures/Assessments (Table 9).  Complete, standardized, 12-lead ECG recordings that 
permit all 12 leads to be displayed on a single page with an accompanying lead II rhythm 
strip below the customary 3 × 4 lead format are to be used.  In addition to a rhythm strip, a 
minimum of 3 full complexes should be recorded from each lead simultaneously.  Subjects 
must be in the recumbent position for a period of 5 minutes prior to the ECG.
An ECG abnormality may meet the criteria of an AE as described in this protocol (see
Section 9.5.1.6.1) and the CRF Completion Guidelines.  In these instances, the AE 
corresponding to the ECG abnormality will be recorded on the Adverse Events CRF.
9.5.1.6.7
OTHER SAFETY ASSESSMENTS
Brain Scan
A CT/MRI scan of the brain will be performed as clinically indicated and at all time points 
(including screening) for subjects with protocol-eligible treated brain metastases.
Bone Scan
Bone scans may be performed every 24 weeks during the Treatment Phase, and as clinically 
indicated, using 99Tc bone scans, NaF (PET) bone scans, 18FDG-PET/CT scans or whole 
body bone MRI.  The same methodology used at screening should be performed at all 
subsequent bone assessments.
Pregnancy Test
A serum β-hCG or urine test (depending on local practice) will be performed for females of 
childbearing potential prior to starting treatment (within 72 hours prior to the first dose of 
study drug).


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Karnofsky and Lansky Performance Status
Karnofsky (for subjects >16 years of age) or Lansky (for subjects ≤16 years of age)
performance status will be assessed at Screening, Days 1 and 8 during Cycle 1, Day 1 of each 
subsequent treatment cycle, and at the End-of-Treatment Visit.  
9.5.2
Schedule of Procedures/Assessments
Table 9 presents the schedule of procedures/assessments for the study.


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Table 9
Schedule of Procedures/Assessments in Study E7389-G000-223
Phase
Pretreatme
nt
Treatment
Follow-up
until 1-
year
Annual 
Follow-up
Period
Screeninga
Cycle 1
Cycle 2b
Cycle 3b
Additional 
Cyclesb
EOT
Visit
1
2
3
4
5
6
7
8
9
10
11+
11+
Day
–28 to –1
1
8
15
1
8
15
1
8
15
1
8
15
Within 28
days after 
last dose of 
drug
Procedures/Assessmen
ts
Informed consent
X
Medical history
X
Inclusion/exclusion
X
Vital signsc
X
X
X
X
X
X
X
X
X
X
Heightd
X
X
X
X
Weight, BSA
X
X
X
X
X
X
X
Physical examination
X
X
X
X
X
X
X
Performance statuse
X
X
X
X
X
X
X
Pregnancy testf
X
X
Hematologyg
X
Weekly
Weekly
Weekly
Weekly
X
Chemistry
X
Weekly
X
X
X
X
Eribulin mesylate 
administration (21-Day 
X
X
X
X
X
X
X
X


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Table 9
Schedule of Procedures/Assessments in Study E7389-G000-223
Phase
Pretreatme
nt
Treatment
Follow-up
until 1-
year
Annual 
Follow-up
Period
Screeninga
Cycle 1
Cycle 2b
Cycle 3b
Additional 
Cyclesb
EOT
Visit
1
2
3
4
5
6
7
8
9
10
11+
11+
Day
–28 to –1
1
8
15
1
8
15
1
8
15
1
8
15
Within 28
days after 
last dose of 
drug
Procedures/Assessmen
ts
cycle
Neurologic 
examinationn
X
X
X
X
Pharmacokinetic 
samplingh
X
X
X
X
X
X
ECGi
X
X
X
Clinically indicated
X
Urinalysis
X
X
Clinically indicated
X
Tumor assessmentj
X
Every 6 weeks (counting from 
date of Cycle 1 Day 1) until 
Week 24, then every 9 weeks
X
Brain CT/MRIk
X
As clinically indicated and at all time points for subjects with protocol-eligible treated 
brain metastases at screening
Bone scanl
X
Every 24 weeks and as clinically indicated
Prior/concomitant 
medications
Throughout


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Table 9
Schedule of Procedures/Assessments in Study E7389-G000-223
Phase
Pretreatme
nt
Treatment
Follow-up
until 1-
year
Annual 
Follow-up
Period
Screeninga
Cycle 1
Cycle 2b
Cycle 3b
Additional 
Cyclesb
EOT
Visit
1
2
3
4
5
6
7
8
9
10
11+
11+
Day
–28 to –1
1
8
15
1
8
15
1
8
15
1
8
15
Within 28
days after 
last dose of 
drug
Procedures/Assessmen
ts
Adverse events
Throughout
X
Survival status
Xm
Xo
BSA = body surface area, CT = computed tomography, ECG = electrocardiogram, EOT = end of treatment, MRI = magnetic resonance imaging.
a.
The Screening Period extends from Day -28to Day -1. Day -28 to -1, computed tomography (CT) / magnetic resonance imaging (MRI) scans must be
performed within 28 days prior to study drug administration.  For logistical purposes, informed consent may be obtained from Day -29.  All clinical and 
laboratory studies to determine eligibility must be performed within 7 days prior to study drug administration unless otherwise indicated.  Laboratory 
values used to assess eligibility must be no older than 7 days at the start of therapy.
b.
Assessments/procedures may be obtained within 72 hours prior to the start of the subsequent cycle. 
c.
Vital signs should be performed Day 1, Day 8, and at the End of Treatment (EOT) for subjects receiving eribulin mesylate. 
d.
Height should be measured every other cycle from Cycle 3. 
e.
Performance status will be measured using Karnofsky or Lansky scales.
f.
Female subjects of childbearing potential require a negative urine or serum (depending on local practice) pregnancy test prior to starting treatment (within 72 
hours prior to Cycle 1 Day 1). 
g.
Subjects will need to have hematology samples obtained weekly; an outside complete blood count can be performed when at the physician’s discretion.
h.
PK sample collection schedule: 
1. Immediately post- eribulin infusion on Day1 of each cycle for the first 3 cycles
2. Pre- eribulin infusion and immediately post-infusion on Day 8 of each cycle for the first 3 cycles. 
i.
On Days 1 and 8 of Cycle 1, two 12-lead ECGs will be obtained: one 15-30 minutes before infusion and a second one immediately after the infusion. The 
post-infusion ECG should precede the collection of the post-infusion PK sample on Days 1 and 8 of Cycle 1.


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j.
Pre-study phase:  Screening tumor assessments using CT of the chest/abdomen and pelvis and other areas of known disease or newly suspected disease 
should be performed between Day -28 and Day -1.  Detailed image acquisition guidelines will be provided by the imaging core laboratory. Scans that were 
performed within this window but before informed consent may be used if they were acquired consistent with the guidelines provided by the imaging core 
laboratory.  Scans of the abdomen, pelvis, and other areas of the body may be done with MRI instead of CT, but evaluation of the chest must be done with 
CT.
Treatment phase:  Tumor assessments of the chest, abdomen, and pelvis and other areas of known disease that were scanned at screening, or newly suspected 
disease, must be performed every 6 weeks (within Week 6) during Treatment Cycles, counting from the date of first dose (or sooner if there is evidence of 
progressive disease) until Week 24 and then every 9 weeks (or sooner if clinically indicated) thereafter and should utilize the same methodology (CT/MRI) 
and scan acquisition techniques (including use or nonuse of IV contrast) as were used for the screening assessments.  A chest x-ray or skeletal x-ray that 
clearly demonstrates a new metastatic lesion may be used to document progression in lieu of the CT/MRI scans.  
Follow-Up Period: Subjects who have gone off study without progression should have tumor assessments every 6 weeks from the date of last tumor 
assessment until disease progression or initiation of another anti-cancer therapy.  At week 24 and thereafter, these scans may be conducted every 9 weeks.
k.
Pre-study phase:  Screening CT or MRI of the brain should be performed between Day -28 and Day -1 for subjects with previously treated protocol-eligible 
brain metastases only.
For subjects with previously treated protocol-eligible brain metastases, a brain scan must be performed at all tumor assessment time points.  The same 
methodology and scan acquisition techniques used at screening should be used throughout the study to ensure comparability.
l.
Bone scans may be performed, where indicated, using 99Tc based bone scans, NaF (PET) bone scans, 18FDG-PET/CT scans or whole body bone MRI.  The 
same methodology used at screening should be performed at all subsequent bone assessments.
m.
Subjects will be followed for survival approximately every 12 weeks from the end of treatment for 1 year, unless consent is withdrawn or death
n.
A full neurological examination will be conducted at Screening.  During Cycle 2 (Day 1), Cycle 3 (Day 1), and Day 1 of any additional cycle, neurological
status (as a minimum, neuropathy present/absent and NCI CTC Grade) will be assessed as part of the physical examination.
o.
Subjects will be followed up annually after the 1 year follow up is complete (See footnote ‘m’), for survival and assessment of any latent effects of the study 
treatment, unless consent is withdrawn or death


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9.5.3
Appropriateness of Measurements
All clinical assessments are standard measurements commonly used in studies of soft tissue 
sarcomas.
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.
9.5.4
Reporting of Serious Adverse Events, Pregnancy, and Events Associated 
with Special Situations
9.5.4.1
Reporting of Serious Adverse Events
All SAEs, regardless of their relationship to study treatment, must be reported on a 
completed SAE form by email or fax as soon as possible but no later than 1 business 
day from the date the investigator becomes aware of the event.
Serious adverse events, regardless of causality assessment, must be collected through the last 
visit in the Treatment Phase, and for 28 days after the subject’s last dose.  All SAEs must be 
followed to resolution or, if resolution is unlikely, to stabilization.  Any SAEs judged by the 
investigator to be related to the study treatment or any protocol-required procedure should be 
reported to the sponsor regardless of the length of time that has passed since study 
completion.
The detailed contact information for reporting of SAEs is provided in the Investigator Study 
File.
For urgent safety issues, please ensure all appropriate medical care is administered to the 
subject and contact the appropriate study team member listed in the Investigator Study File.
It is very important that the SAE report form be filled out as completely as possible at the
time of the initial report.  This includes the investigator’s assessment of causality.
Any follow-up information received on SAEs should be forwarded within 1 business day of 
its receipt.  If the follow-up information changes the investigator’s assessment of causality, 
this should also be noted on the follow-up SAE form.
Preliminary SAE reports should be followed as soon as possible by detailed descriptions 
including copies of hospital case reports, autopsy reports, and other documents requested by 
the sponsor.
The investigator must notify his/her IRB/IEC of the occurrence of the SAE in writing, if 
required by their institution.  A copy of this communication must be forwarded to the sponsor 
to be filed in the sponsor’s Trial Master File.


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


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All AEs associated with overdose, misuse, abuse, or medication error should be captured on 
the Adverse Event CRF and also reported using the procedures detailed in Reporting of 
Serious Adverse Events (Section 9.5.4.1) even if the AEs do not meet serious criteria.  Abuse 
is always to be captured as an AE.  If the AE associated with an overdose, misuse, abuse, or 
medication error does not meet serious criteria, it must still be reported using the SAE form 
and in an expedited manner but should be noted as non-serious on the SAE form and the 
Adverse Event CRF.
9.5.4.4
Expedited Reporting
The sponsor must inform investigators and regulatory authorities of reportable events, in 
compliance with applicable regulatory requirements, on an expedited basis (ie, within 
specific time frames).  For this reason, it is imperative that sites provide complete SAE 
information in the manner described above.
9.5.4.5
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.
9.5.5
Completion/Discontinuation of Subjects
A subject may elect to discontinue the study at any time for any reason.  All subjects who 
discontinue the study are to complete the study’s discontinuation procedures indicated in the 
Schedule of Procedures/Assessments (Table 9).
The investigator will promptly explain to the subject involved that the study will be 
discontinued for that subject and provide appropriate medical treatment and other necessary 
measures for the subject.  A subject who has ceased to return for visits will be followed up by 
mail, phone, or other means to gather information such as the reason for failure to return, the 
status of treatment compliance, the presence or absence of AEs, and clinical courses of signs 
and symptoms.  
Subjects who discontinue from the study will be discontinued for 1 of these primary reasons: 
AE(s), lost to follow-up, subject choice, inadequate therapeutic effect, progression of disease, 
withdrawal of consent, pregnancy, study terminated by sponsor, or 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.
A subject removed from the study for any reason other than toxicity or progression may be 
replaced.


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9.5.6
Abuse or Diversion of Study Drug
During the study, the investigator will report any concern about abuse or diversion of study 
drugs by completing the Abuse or Diversion of Study Drug CRF.
Adverse events associated with abuse or diversion will be appropriately reported as AEs and 
monitored per Section 9.5.1.6.1.  Abuse is always to be captured as an AE.
During the study, the investigator should be aware of the possibility of abuse or diversion of 
study drugs and should report any concern about mishandling, abuse, loss, theft, or diversion 
of study drugs by completing the Potential Abuse-related Medication Handling Event CRF.
9.6
Data Quality Assurance
This study will be organized, performed, and reported in compliance with the protocol, 
SOPs, working practice documents, and applicable regulations and guidelines.  Site audits 
will be made periodically by the sponsor’s or the CRO’s qualified compliance auditing team, 
which is an independent function from the study team responsible for conduct of the study.  
9.6.1
Data Collection
Data required by the protocol will be collected on the CRFs and entered into a validated data 
management system that is compliant with all regulatory requirements.  As defined by ICH 
guidelines, the CRF is a printed, optical, or electronic document designed to record all of the 
protocol-required information to be reported to the sponsor on each study subject.
Data collection on the CRF must follow the instructions described in the CRF Completion 
Guidelines.  The investigator has ultimate responsibility for the collection and reporting of all 
clinical data entered on the CRF.  The investigator or designee as identified on Form 
FDA 1572 must sign the completed CRF to attest to its accuracy, authenticity, and 
completeness.
Completed, original CRFs are the sole property of Eisai and should not be made available in 
any form to third parties without written permission from Eisai, except for authorized 
representatives of Eisai or appropriate regulatory authorities.
9.6.2
Clinical Data Management
All software applications used in the collection of data will be properly validated following 
standard computer system validation that is compliant with all regulatory requirements.  All 
data, both CRF and external data (eg, laboratory data), will be entered into a clinical system.
9.7
Statistical Methods
All statistical analyses will be performed by the sponsor or designee after the study is 
completed and the database is locked.  Statistical analyses will be performed using SAS 


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software or other validated statistical software as required.  Details of the statistical analyses 
will be included in a separate statistical analysis plan (SAP).
9.7.1
Statistical and Analytical Plans
The statistical analyses of study data are described in this section.  Further details of the 
analytical plan will be provided in the SAP, which will be finalized before database lock.
9.7.1.1
Study Endpoints
9.7.1.1.1
PRIMARY ENDPOINT
The primary endpoint is:

Objective response: number of subjects achieving a best objective response of partial 
or complete response (PR or CR), by up to 24 weeks after all subjects have completed 
response assessment. Response assessment will be as determined by investigator.
9.7.1.1.2
SECONDARY ENDPOINTS
The secondary endpoints are:

PFS: defined as the time from the first dose date to the date of disease progression or 
date of death (whichever occurs first).

Safety and tolerability: AEs, SAEs, clinical laboratory values, ECG parameters, vital 
sign measurements, and performance status.

DOR: defined as the time from the first date of documented PR or CR to the date of 
disease progression or date of death (whichever occurs first).

OS: defined as the time from the first dose date to the date of death.
9.7.1.1.3
EXPLORATORY ENDPOINTS
The exploratory endpoints are:

Exposure of eribulin mesylate.
9.7.1.2
Definitions of Analysis Sets
The Full Analysis Set (FAS) will consist of all subjects who receive at least 1 dose of study 
drug.
The Safety Analysis Set (SAS) will consist of all subjects who receive at least 1 dose of 
study drug. 
The Pharmacokinetic Analysis Set (PAS) will include subjects who have at least 1 
evaluable plasma concentration and sufficient dosing information.


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9.7.1.3
Subject Disposition
The number and percentage of subjects who discontinue the study treatment as well as the 
reason for discontinuation will be summarized.
9.7.1.4
Demographic and Other Baseline Characteristics
Demographic and other baseline characteristics will be summarized using descriptive 
statistics.  Continuous demographic and baseline variables include age, weight, and vital 
signs; categorical variables include sex, age group, and race.
9.7.1.5
Prior and Concomitant Therapy
All investigator terms for medications recorded in the CRF will be coded to an 11-digit code 
using the World Health Organization Drug Dictionary (WHO DD) (2017 or current).  The 
number (percentage) of subjects who took prior and concomitant medications will be 
summarized on the Full Analysis Set by treatment, Anatomical Therapeutic Chemical (ATC) 
class (ie, anatomical class, therapeutic class), and WHO DD preferred term.  Prior 
medications will be defined as medications that stopped before the first dose of study drug.  
Concomitant medications will be defined as medications that (1) started before the first dose 
of study drug and were continuing at the time of the first dose of study drug, or (2) started on 
or after the date of the first dose of study drug (or, started at the time of or after the first dose 
of study drug) up to 28 days after the subject’s last dose.  All medications will be presented 
in subject data listings.
9.7.1.6
Efficacy Analyses
Efficacy analyses will be performed on the FAS. 
9.7.1.6.1
PRIMARY EFFICACY ANALYSIS
The primary analysis will be based on investigator assessments of tumor response.
The primary analysis is to examine the number of responders within each histology subject 
cohort. Confirmed response (PR or CR) will be used in this analysis.  In each of the 
histology groups of RMS, NRSTS, and EWS, approximately 15 subjects will be enrolled and 
treated with eribulin mesylate.  Data will be monitored on an ongoing basis; depending on 
evaluation by the investigators and sponsor, if sufficient responses (PRs or CRs) are
observed, then this histology type will be recommended for inclusion in the subsequent 
study. At the latest, the primary analysis will be performed when approximately 15 subjects 
have completed 24 weeks of response assessments.
9.7.1.6.2
SECONDARY EFFICACY ANALYSES
The secondary analyses will be to estimate the PFS, DOR, and OS in all cohorts combined.  
Median PFS, DOR, and OS will be estimated using Kaplan-Meier method. Descriptive 


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statistics will be provided. Duration of response (DOR) will be calculated for subjects with 
an objective response of PR or CR.
9.7.1.7
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker
Analyses
9.7.1.7.1
PHARMACOKINETIC ANALYSES
Blood samples will be collected for the PK analysis of eribulin as follows:
1.
Immediately post-infusion on Day 1 of each cycle for the first 3 cycles
2. Pre-infusion and immediately post-infusion on Day 8 of each cycle for the first 3 cycles
9.7.1.7.2
PHARMACODYNAMIC, PHARMACOGENOMIC, AND OTHER BIOMARKER ANALYSES
Exposure-response Analyses
Following FDA guidance, PK sampling will be conducted in subjects across the pediatric 
program at regular intervals in order to adequately characterize the PK of eribulin in the 
pediatric population in the various age cohorts to explore exposure-response relationships for 
activity/efficacy and safety.  The relationship between exposure to eribulin mesylate and AE 
and efficacy will be explored graphically.
9.7.1.8
Safety Analyses
All safety analyses will be performed on the Safety Analysis Set.  Safety data, presented by 
treatment arm, 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).  Safety variables include adverse events, clinical laboratory 
parameters, vital signs, 12-lead ECG results, and performance status. 
9.7.1.8.1
EXTENT OF EXPOSURE
The number of cycles administered, duration of treatment, and the number of subjects who 
had dose reduction and dose delay will be summarized for eribulin mesylate.
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 20.0 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 treatment-emergent adverse event (TEAE) is defined as an AE that emerges during 
treatment, having been absent at pretreatment (Baseline) or 


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
Reemerges during treatment, having been present at pretreatment (Baseline) but 
stopped before treatment, or 

Worsens in severity during treatment relative to the pretreatment state, when the AE 
is continuous.
Only those AEs that are treatment-emergent will be included in summary tables.  All AEs, 
treatment-emergent or otherwise, will be presented in subject data listings.
The incidence of TEAEs will be summarized with the number and 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 and percentage of subjects with TEAEs will also be summarized by highest CTCAE 
grade (CTCAE v4.03).
The number and percentage of subjects with treatment-related TEAEs will also be 
summarized by MedDRA SOC and PT.  
The number and percentage of subjects with treatment-emergent SAEs will be summarized 
by MedDRA SOC and PT. A subject data listing of all SAEs will be provided.
The number and percentage of subjects with TEAEs with fatal outcome will be summarized 
by MedDRA SOC and PT.  A subject data listing of all AEs with fatal outcome will be 
provided.
The number and percentage of subjects with TEAEs leading to study drug discontinuation 
will be summarized by MedDRA SOC and PT. A subject data listing of all AEs leading to 
study drug discontinuation 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 9.5.1.6.3, the actual value and the change 
from baseline and to the end of treatment (defined as the last on-treatment value) will be 
summarized using descriptive statistics.  Qualitative parameters listed in Section 9.5.1.6.3
will be summarized using frequencies (number and percentage of subjects). Shift tables will 
be provided presenting post-baseline against the baseline with number and percentage of
subjects.  Percentages will be based on the number of subjects with both baseline and the 
corresponding post-baseline measurements.
Laboratory test results will be assigned a classification according to CTCAE grade. 
Summaries of CTCAE grade and shifts from baseline will be presented.
9.7.1.8.4
VITAL SIGNS
Descriptive statistics for vital signs parameters (systolic and diastolic BP, pulse, temperature,
weight, and height) and changes from baseline will be presented by visit.


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9.7.1.8.5
ELECTROCARDIOGRAMS
ECG assessments will be performed. QT intervals will be measured from Lead II and will be 
corrected for heart rate (QTc) using Fridericia's (QTcF) and Bazett's (QTcB) correction 
factors. The primary QTc parameter will be QTcF. Secondary parameters will be QTcB, 
QT, QRS, and heart rate.
Shift tables will present shifts from baseline to end of treatment in ECG interpretation 
(categorized as normal; abnormal, not clinically significant; and abnormal, clinically 
significant). 
In addition, the number and percentage of subjects with at least 1 post-baseline abnormal 
ECG result in QTc Fridericia during the treatment period will be summarized.  Clinically 
abnormal ECG results in QTc Fridericia will be categorized as follows:
Absolute QTc interval prolongation:

QTc interval >450 ms

QTc interval >480 ms

QTc interval >500 ms
Change from baseline in QTc interval:

QTc interval increase from baseline >30 ms

QTc interval increase from baseline >60 ms
9.7.1.8.6
OTHER SAFETY ANALYSES
Performance Status
Karnofsky and Lansky performance status scores and their changes from baseline will be 
summarized using descriptive statistics.
9.7.2
Determination of Sample Size
A total of 45 subjects will be enrolled. In each of the histology groups of RMS, NRSTS, and 
EWS, approximately 15 subjects will be enrolled and treated with eribulin mesylate.  The 
sample size is considered sufficient based on clinical judgment and is not obtained from 
statistical calculation.
9.7.3
Interim Analysis
Data will be monitored on an ongoing basis; depending on evaluation by the investigators 
and sponsor, if sufficient responses (PR or CR) are observed, then this histology type will be 
recommended for inclusion in the subsequent study.


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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 its initial finalization, the sponsor will determine how the 
revision impacts the study and how the revision should be implemented.  The details of the 
revision will be documented and described in the clinical study report.


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11 PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE 
PROCEDURES)
11.1
Changes to the Protocol
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 should be kept informed of such changes as required by local 
regulations.  In these cases, the sponsor may be required to send a letter to the IRB/IEC and 
the Competent Authorities detailing such changes.
11.2
Adherence to the Protocol
The investigator will conduct the study in strict accordance with the protocol (refer to 
ICH E6, Section 4.5).
11.3
Monitoring Procedures
The sponsor’s CRA will maintain contact with the investigator and designated staff by 
telephone, letter, or email between study visits.  Monitoring visits to each site will be 
conducted by the assigned CRA as described in the monitoring plan.  The investigator will 
allow the CRA to inspect the clinical, laboratory, and pharmacy facilities to assure 
compliance with GCP and local regulatory requirements.  The CRFs and subject’s 
corresponding original medical records (source documents) are to be fully available for 
review by the sponsor’s representatives at regular intervals.  These reviews verify adherence 
to study protocol and data accuracy in accordance with local regulations.  All records at the 
site are subject to inspection by the local auditing agency and to IRB/IEC review.
In accordance with ICH E6, Section 1.52, source documents include, but are not limited to,
the following:

Clinic, office, or hospital charts


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
Copies or transcribed health care provider notes that have been certified for accuracy 
after production

Recorded data from automated instruments such as IxRS, x-rays, and other imaging 
reports (eg, sonograms, CT scans, magnetic resonance images, radioactive images, 
ECGs, rhythm strips, EEGs, polysomnographs, pulmonary function tests) regardless 
of how these images are stored, including microfiche and photographic negatives

Pain, quality of life, or medical history questionnaires completed by subjects

Records of telephone contacts

Diaries or evaluation checklists

Drug distribution and accountability logs maintained in pharmacies or by research 
personnel

Laboratory results and other laboratory test outputs (eg, urine pregnancy test result 
documentation and urine dip-sticks)

Correspondence regarding a study subject’s treatment between physicians or 
memoranda sent to the IRBs/IECs

CRF components (eg, questionnaires) that are completed directly by subjects and 
serve as their own source
11.4
Recording of Data
A CRF is required and must be completed for each subject by qualified and authorized 
personnel.  All data on the CRF must reflect the corresponding source document, except 
when a section of the CRF itself is used as the source document.  Any correction to entries 
made on the CRF must be documented in a valid audit trail 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 is responsible for retaining all study documents, including but not limited to the 
protocol, copies of CRFs, the Investigator's Brochure, and regulatory agency registration 
documents (eg, Form FDA 1572, ICFs, and IRB/IEC correspondence).  In addition, the 
sponsor will send a list of treatment codes by study subject to the investigator after the 
clinical database for this study has been locked.  The site should plan to retain study 


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documents, as directed by the sponsor, for at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or at least 3 years have elapsed since the formal 
discontinuation of clinical development of the investigational product.
It is requested that at the completion of the required retention period, or should the 
investigator retire or relocate, the investigator contact the sponsor, allowing the sponsor the 
option of permanently retaining the study records.
11.7
Auditing Procedures and Inspection
In addition to routine monitoring procedures, the sponsor’s Clinical Quality Assurance 
department conducts audits of clinical research activities in accordance with the sponsor’s 
SOPs to evaluate compliance with the principles of ICH GCP and all applicable local 
regulations.  If a government regulatory authority requests an inspection during the study or 
after its completion, the investigator must inform the sponsor immediately.
11.8
Handling of Study Drug
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, 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.


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


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12 APPENDICES


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Appendix 1
Measurements of Performance Status
Karnofsky Performance Status and Lansky Play-Performance Scale for Pediatric 
Patients
Rating/Score
Description
Lansky
Karnofsky
100
Fully active, normal
Normal, no complaints
90
Minor restrictions with strenuous 
physical activity
Able to carry on normal activities. 
Minor signs or symptoms of disease
80
Active, but gets tired more quickly
Normal activity with effort
70
Both greater restriction of, and less 
time spent in, active play
Care for self. Unable to carry on 
normal activity or do active work
60
Up and around, but minimal active 
play; keeps busy with quieter 
activities
Requiring occasional assistance, but 
able to care for most needs
50
Lying around much of the day, but 
gets dressed; no active play; 
participates in all quiet play and 
activities
Requires considerable assistance and 
frequent medical care
40
Mostly in bed; participates in quiet 
activities
Disabled, requires special care and 
assistance
30
Stuck in bed; needs help even for 
quiet play
Severely disabled, Hospitalization 
indicated though death nonimminent
20
Often sleeping; play is entirely 
limited to very passive activities
Very sick. Hospitalization necessary. 
Active supportive treatment 
necessary
10
Does not play nor get out of bed
Moribund
0
Unresponsive
Dead


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Appendix 2
Modified “Balis” Pediatric Scale of Peripheral 
Neuropathies
Peripheral Motor Neuropathy:
Grade 1: Subjective weakness, but no deficits detected on neurological exam, other than 
abnormal deep tendon reflexes.
Grade 2: Weakness that alters fine motor skills (buttoning shirt, coloring, writing or 
drawing, using eating utensils) or gait without abrogating ability to perform these tasks.
Grade 3: Unable to perform fine motor tasks (buttoning shirt, coloring, writing or drawing, 
using eating utensils) or unable to ambulate without assistance.
Grade 4: Paralysis.
Peripheral Sensory Neuropathy:
Grade 1: Paresthesias, pain, or numbness that do not require treatment or interfere with 
extremity function.
Grade 2: Paresthesias, pain, or numbness that are controlled by non-narcotic medications 
(without causing loss of function), or alteration of fine motor skills (buttoning shirt, writing 
or drawing, using eating utensils) or gait, without abrogating ability to perform these tasks.
Grade 3: Paresthesias or pain that are controlled by narcotics, or interfere with extremity 
function (gait, fine motor skills as outlined above), or quality of life (loss of sleep, ability to 
perform normal activities severely impaired).
Grade 4: Complete loss of sensation, or pain that is not controlled by narcotics.


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PROTOCOL SIGNATURE PAGE
Study Protocol Number:
E7389-G000-223
Study Protocol Title:
A Phase 2, multicenter, open-label study to assess safety and 
preliminary activity of eribulin mesylate in pediatric subjects 
with relapsed/refractory rhabdomyosarcoma (RMS), non-
rhabdomyosarcoma soft tissue sarcoma (NRSTS) and Ewing 
sarcoma (EWS)
Investigational Product 
Name:
E7389 (eribulin mesylate)
IND Number:
116,292
SIGNATURES
Authors:
Oncology Business Group, Eisai Ltd.
Date
Date
nc.
Date
Associate Director, Biostatistics
Oncology Business Group, Eisai Inc.
Date
PPD
PPD
PPD
PPD


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INVESTIGATOR SIGNATURE PAGE
Study Protocol Number:
E7389-G000-223
Study Protocol Title:
A Phase 2, multicenter, open-label study to assess safety and 
preliminary activity of eribulin mesylate in pediatric subjects 
with relapsed/refractory rhabdomyosarcoma (RMS), non-
rhabdomyosarcoma soft tissue sarcoma (NRSTS) and Ewing 
sarcoma (EWS)
Investigational Product 
Name:
E7389 (eribulin mesylate)
IND Number:
116,292
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 on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH) and all applicable 
local Good Clinical Practice (GCP) guidelines, including the Declaration of Helsinki.
Medical Institution
Investigator
Signature
Date