Conditions: Refractory or Recurrent Solid Tumors Rhabdomyosarcoma Non-Rhabdomyosarcoma Soft Tissue Sarcoma Ewing Sarcoma
Keywords: eribulin mesilate irinotecan combination therapy children
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 40
Healthy volunteers: no

Brief summary:
The Phase 1 part of the study is conducted to determine the maximum tolerated dose (MTD) and Recommended Phase 2 Dose (RP2D) of eribulin mesilate in combination with irinotecan hydrochloride in pediatric participants with relapsed/refractory solid tumors (excluding central nervous system \[CNS\] tumors).

The Phase 2 part of the study is conducted to assess the objective response rate (ORR) and duration of response (DOR) of eribulin mesilate in combination with irinotecan hydrochloride in pediatric participants with relapsed/refractory rhabdomyosarcoma (RMS), non-rhabdomyosarcoma soft tissue sarcoma (NRSTS) and ewing sarcoma (EWS).

Detailed description:

Arms:
arm 1: In Schedules A and B, eribulin mesilate at the dose of 1.4 milligrams per meters squared (mg/m\^2) will be administered as an intravenous (IV) infusion on Days 1 and 8 of each 21-day cycle. In Schedule A, irinotecan hydrochloride at the doses of 20 mg/m\^2 or 40 mg/m\^2 will be administered as an IV infusion on Days 1 to 5 of a 21-day cycle. In Schedule B, irinotecan hydrochloride at the doses of 100 mg/m\^2 or 125 mg/m\^2 will be administered as an IV infusion on Days 1 and 8 of a 21-day cycle.

Interventions: intervention 1: Eribulin mesilate intervention 2: Irinotecan hydrochloride
Intervention descriptions: intervention 1: IV infusion intervention 2: IV infusion

Protocol document:
Prot_000.pdf: 
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1
TITLE PAGE
Clinical Study Protocol
Study Protocol 
Number:
E7389-G000-213
Study Protocol 
Title:
A Phase 1/2 single-arm study evaluating the safety and efficacy of 
eribulin mesilate in combination with irinotecan in children with 
refractory or recurrent solid tumors
Sponsor
Eisai Inc.
155 Tice Boulevard
Woodcliff Lake, 
New Jersey 07677
USA
Eisai Ltd. 
European Knowledge Centre
Mosquito Way
Hatfield, Hertfordshire 
AL10 9SN UK
Investigational 
Product Name:
E7389/HALAVEN (eribulin mesilate)
Indication:
Refractory or recurrent solid tumors in children
Phase:
1/2
Approval Date(s):
28 Sep 2016 
(Original Protocol)
10 May 2018 
(Protocol Amendment 01)
02 Aug 2018
(Protocol Amendment 02)
12 Oct 2018 
(Protocol Amendment 03)
10 Jul 2019
(Protocol Amendment 04)
14 Jul 2020
(Protocol Amendment 05)
29 Mar 2021
(Protocol Amendment 06)
IND Number:
116292
EudraCT Number:
2016-003352-67
GCP Statement:
This study is to be performed in full compliance with International 
Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) and all applicable local 
Good Clinical Practice (GCP) and regulations.  All required study 
documentation will be archived as required by regulatory 
authorities.


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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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REVISION HISTORY
Amendment 06
Date: 29 Mar 2021
Change
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Sections
To clarify subjects aged >6 months 
and <12 months will be enrolled to 
Schedule A with a modified dose of 
eribulin Dose Level -2 (0.8 mg/m2
Day 1 and Day 8) with the 
irinotecan dose maintained Dose 
Level 1 (40 mg/m2 Day 1 – Day 5) 
of a 21-day cycle.
Subjects >6 months and <12 months of 
age are included per request from 
European Medicines Agency's 
Paediatric Committee (EMA PDCO). 
For eribulin, the dose selected (0.8 
mg/m2) is aligned with guidance on 
pediatric dosing Children’s Cancer and 
Leukaemia Group (CCLG)-
Chemotherapy Standardization Group 
2008) which recommends that the dose 
in patients aged <12 months should be 
approximately 75% of calculated dose 
by body surface area.  As eribulin has 
not been tested previously in this infant 
age group and is being used in 
combination with irinotecan in this 
study, the dose selected is the same as 
the lowest dose level in this study 
(Dose Level -2). This approach also 
takes into account that while eribulin is 
predominantly excreted unchanged in 
urine (5-7%) and feces (82%), it is 
partially (< 15%) metabolized by the 
cytochrome P450 (CYP) 3A4 liver 
enzyme and liver maturation of 
CYP3A4 has not occurred fully in these 
younger subjects.
For irinotecan, the starting dose 
remains the same as the ≥12 months 
age group (40 mg/m2 ), which is 
consistent with standard practice with 
irinotecan in this population and with 
previous studies with irinotecan used in 
combination, where the identified full 
dose of irinotecan is maintained for the 
infant age group (Hawkins, et al.,
2018).
Synopsis (Study Design 
[Phase 2], Inclusion 
criteria), 9.1 (Phase 2), 9.2,
9.3.1b 9.4.1, Table 11, 
9.4.4 (Phase 2).
Amended Inclusion Criterion 1b to 
include subjects >6 months and <12 
months of age in Phase 2.
As requested by the EMA PDCO.
Synopsis, 9.3.1, 9.4.1
For subjects >6 months and <12 
months of age in Phase 2, further 
dose reductions have been included 
Additional dose reductions for eribulin 
in infants have been included in case of 
toxicities requiring a dose reduction.  
Synopsis, Table 5, 9.4.1, 
Table 11, 9.4.4 


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Sections
for this age group for eribulin in 
case of toxicities requiring a dose 
reduction. 
Specified if toxicities do not recover 
after 2 dose reductions, treatment 
with that agent must be 
discontinued.
Pharmacokinetic (PK): Specified 
that subjects who weigh under 6 kg 
will not have samples for PK 
analysis taken.
To align with the Spanish Agency of 
Medicines and Medical Devices 
(AEMPS) requirements from 
Amendment 02.
Synopsis, 9.5.1.3.2 (Phase 
2 (Cycle 1)
Vital signs, physical examination,
and chemistry assessments during 
Phase 2 for the >6 months and <12 
months age group will be weekly.
Additional assessments for safety 
monitoring in the infant subjects.
9.5.1.5, Table 14
Urinalysis assessments during Phase 
2 for the >6 months and <12 months 
age group will be as clinically 
indicated after Cycle 1.
Additional assessments for safety 
monitoring in the infant subjects.
9.5.1.5, Table 14
Hematology assessments during 
Phase 2 will be twice weekly for the
>6 months and <12 months age 
group (every 3 to 4 days).
Additional assessments for safety 
monitoring in the infant subjects.
9.5.1.5, Table 14
Subjects in the age groups > 6 
months to < 12 months and ≥18 to 
≤25 years old are included for 
descriptive purposes only and will 
not contribute to the full sample size 
analyses.
Subjects in the age group > 6 
months to <12 months will receive 
approximately 75% of the RP2D of 
eribulin (rationale for lower dose is 
provided in Section 9.4.4) and 
therefore should not been included 
in the full sample size analyses.
The EMA PDCO requested that 
subjects in the age group ≥18 to ≤25 
years old should not be included in 
the full sample size analyses.
To clarify how data from these age 
groups will be reported.
Synopsis, 9.7.2
References were added to the 
reference list.
10
Minor editorial, grammatical, and 
formatting changes 
For consistency/clarification.
Throughout 


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Amendment 05
Date: 14 Jul 2020  
Change
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Extended study duration from 36 
to 42 months.
Due to slower than anticipated 
enrollment in Phase 1.
Synopsis, 5.1
As per protocol amendment #5, 
the recommended Phase 2 dose 
(RP2D) was selected to be 
Schedule A Dose Level 1 –
eribulin (1.4 mg/m2) Day 1 and 
Day 8 and irinotecan (40 mg/m2)  
Days 1-5.  
Included the RP2D following 
completion of the Phase 1 portion of 
the study, as per requests from health 
authorities for additional countries 
participating in the Phase 2 portion of 
the study.
Synopsis, 9.1, 9.1.2, 9.2, 
9.4.1, 9.4.4, 9.5.1.5 (Table 14
[footnote l])   
Updated Inclusion Criterion 1a

≥12 months to ≤25 years at the 
time of consent (no more than 
25% of subjects between the 
ages of 18 and 25 years will be 
enrolled in this study).
Increasing the upper age limit to 
enroll a low number (≤25%) of 
patients 18 to 25 given the similarity 
in the pathophysiology and treatment 
paradigms of sarcoma for children 
and young adults.
Synopsis, 9.3.1
Updated Exclusion Criterion 10.
Have had or are planning to have 
the following invasive procedures: 

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.
Removed “but must be placed at least 
2 days prior to study drug 
administration,” as this 2-day window 
was not deemed necessary for non-
major procedures and moved as a sub-
bullet.
Synopsis, 9.3.2  
Criteria for administration of 
study drug; Day 8 Bowel function 
deteriorated since pre-
treatment/baseline and requires 
antidiarrheal medications for 
within 24 hours before the next
administration of irinotecan 
hydrochloride.
Clarified that this criteria is specific 
for irinotecan hydrochloride 
administration rather than for eribulin 
administration.
Synopsis (Table 1), 9.4.1
(Table 7)
Included dose levels specifically 
for the Phase 2 portion of the 
study 
Included to allow more flexibility on 
dose reductions for either study drug 
depending upon which agent is 
causing the toxicity.
Synopsis, 9.4.1  
Included, “If, in the opinion of the 
Investigator, a dose reduction as 
per the criteria noted in Table 2 is 
not necessary, due to adequate 
supportive care and use of 
prophylaxis (eg, growth factor 
support) to prevent recurrences, 
each individual case should be 
Included following feedback from 
Investigators to allow some flexibility 
on dosing and dose reductions where 
the subject is receiving clinical benefit 
and where this is considered to be 
safe.
Synopsis, 9.4.1  


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discussed with and agreed by the 
Sponsor.”
For Schedule A, irinotecan doses 
Days 2-5 can be delayed up to 
cycle Day 10 (of a 21 day cycle), 
at the discretion of the investigator 
and as long as the subject meets 
the criteria for administration of 
study medication for Day 8.    
Added that CT scans will be with 
oral and intravenous (IV) contrast 
unless clinically contraindicated.
Clarified, following feedback from 
investigators, that in some instances 
use of oral/IV contrast is not possible 
in a pediatric population.
Synopsis, 9.5.1.3.1   
Clarified that if only chest CT is 
performed then oral CT contrast is 
not required.
This exception for not using oral 
contrast is clarified.
Synopsis, 9.5.1.3.1    
Included ‘irrespective of dose 
delays’
Clarified that the schedule of tumor 
assessments should be maintained as 
per protocol and not changed due to 
dose delays.
Synopsis, 9.5.1.3.1    
For bone scans, added:  
approximately every 24 weeks (in 
conjunction with a scheduled 
tumor assessment visit), and as 
clinically indicated.  Bone lesions 
must be followed with anatomic 
imaging.  
To be consistent with section 9.5.1.3.1 
of the protocol.
Synopsis, 9.5.1.3.1, 9.5.1.5
(Table 13 [footnote r] and 
Table 14 [footnote r])
Specified that eribulin, irinotecan 
and its active metabolite, SN-38 
will be analyzed using validated 
liquid chromatography with 
tandem mass spectrometry (LC-
MS/MS) methods. 
Added test methods details for clarity. 
Synopsis, 9.5.1.3.4  
Removed: “In Phase 1 (Dose-
Escalation), pharmacokinetics of 
irinotecan and SN-38 will be 
assessed with (Cycle 1, Day 1) 
and without eribulin 
coadministration (Cycle 1, Day 
12) for Schedule A.  
Pharmacokinetics of eribulin will 
be assessed in Cycle 1.”
There is no PK blood sampling on 
Cycle 1 Day 12 to evaluate PK.
Synopsis, 9.7.1.7.1
Updated reference for consortium 
study ADVL1314 (Schafer, et al., 
2018).  
Full paper now published and 
therefore included as a reference. 
7.1.3.3.2, 10


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In instances where a subject 
becomes pregnant, the following 
language has been included “The 
Investigator should confirm 
whether they agree to follow-up
assessments (including survival 
follow-up) or whether the subject 
wishes to withdraw consent. If a 
subject withdraws consent, the 
date should be documented in the 
source documents”
To clarify if subjects become pregnant 
that the investigator should confirm 
whether, despite stopping study 
treatment they would agree to follow-
up or if consent will be withdrawn.
9.5.3.2
Minor editorial, grammatical, and 
formatting changes
For consistency/clarification.
Throughout
The table below describes revisions in Amendment 04 per the protocol template (Nov 2016). 
Revisions per Amendment 04
Date: 10 Jul 2019  
Change
Rationale
Affected Protocol Sections
Updated description of sample 
size for Phase 2 to ‘approximately 
75’ or ‘approximately 25 per 
histology’ and updated trial 
schema.
To allow for more flexibility.
Synopsis, 9.1, 9.2, 9.3, 9.7.1.6.1, 
9.7.2
Updated inclusion criterion #8 to 
remove the use of radioisotope for 
the measurement of the 
glomerular filtration rate (GFR). 
Correction to inclusion criterion 
#8.
Synopsis, 9.3.1
Amended exclusion criterion #3 to 
allow subjects who received prior 
therapy with irinotecan 
hydrochloride in Phase 2 if there 
was no tumor progression during 
prior irinotecan therapy.
Following feedback from 
investigators subjects who 
received prior irinotecan 
hydrochloride should be eligible 
as long there was no tumor 
progression during irinotecan 
therapy.
Synopsis, 9.3.2
Clarification of exclusion criterion 
#4.
To clarify that the exclusion is for 
any other malignancy than that 
being studied, other than stated 
exceptions.
Synopsis, 9.3.2
Updated exclusion criterion #9.
To clarify that patients that do not 
have a history of CNS metastasis 
are not required to undergo a brain 
scan. 
Synopsis, 9.3.2
Included language ‘subjects 
known to have reduced UGT1A1 
Added language regarding 
hematological safety monitoring 
Synopsis, 9.4.1


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activity will be monitored 
carefully for hematological 
toxicity’.
for subjects with reduced 
UGT1A1 activity in line with the 
irinotecan SmPC. 
Added FDG-PET scans.
Scan included as standard practice 
in many sites.
Synopsis, 9.5.1.3.1, 9.5.1.5 (Table 
11 [footnote r], Table 12 [footnote 
r])
Updated details of MIBG scans 
for neuroblastoma patients. 
To provided clarification that 
MIBG scans are optional for 
neuroblastoma patients.
Synopsis, 9.5.1.3.1, 9.5.1.5 (Table 
11 [footnote u])
Updated description of secondary 
efficacy analyses.  Progression-
free survival (PFS) will be 
analyzed by Kaplan-Meier 
methodology and median PFS 
with corresponding confidence 
interval will be presented.
Clinical benefit rate (CBR) 
definition updated in places to 
remove ‘at week 12’ in the 
heading as the duration is defined 
within the definition. 
Updated description of PFS and 
CBR (no change to analyses).
Synopsis, 9.7.1.1.2, 9.7.1.6.2
Updated the description of safety 
data analysis in statistical methods 
section.
To appropriately reflect Eisai 
oncology standard safety analysis.
Synopsis, 9.7.1.8, 9.7.1.8.3, 
9.7.1.8.5, 9.7.1.8.6
Updated List of Abbreviations and 
Definitions of Terms. 
To add to or correct the current 
list to agree with Protocol.
4
Updated estimated study LSLV 
date (to Mar 2021).
Correction of study end date.
5.1
Updated formal name of the 
International Council for 
Harmonisation of Technical 
Requirements for Pharmaceuticals 
for Human Use (ICH).
The ICH updated its formal title in 
2018. 
5.2 
Updated description of laboratory 
analysis values, ECG and other 
safety analyses.
For clarification.
9.7.1.8.3, 9.7.1.8.5, 9.7.1.8.6
Minor administrative changes.
For consistency/clarification.
Throughout


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The table below describes revisions in Amendment 03 per the new protocol template (Nov 
2016). 
Revisions per Amendment 03
Date: 12 Oct 2018  
Change
Rationale
Affected Protocol Sections
Updated the exploratory objective 
‘To explore the relationship 
between model-derived exposure 
to eribulin and the active
metabolite for irinotecan (SN 38) 
in terms of area under the curve 
and AEs and efficacy endpoints 
using a model-based approach’. 
Updated for clarification. 
Synopsis, 8.3
Clarification that the duration of 
treatment up to 1 year is from the 
‘start of study treatment’.
Added for clarification.
Synopsis, 9.1.2, 9.3.3, 9.4.1
Updated exclusion criterion #12 to 
include that subjects with active or 
severe chronic inflammatory 
bowel disease or bowel 
obstruction are excluded from the 
study.
Updated per ANSM and Greece 
EOF request.
Synopsis, 9.3.2
ECG and electrolyte monitoring 
will occur ‘more frequently in 
consultation with cardiologist 
advice and in line with local 
practice’.
Updated per ANSM request. 
Synopsis, 9.4.1
For neuroblastoma subjects (Phase 
1 only), included MIBG
assessments and when to perform 
them.
Added following request from 
Investigator.
Synopsis, 9.5.1.3.1, 9.5.1.5 (Table 
11 [footnote u])
Clarification that toxicity during 
Phase 2 will be monitored on an 
ongoing basis using the same rule 
as Phase 1.  ‘If the number of AEs 
that would have qualified as DLTs 
on the Phase 1 portion exceeds 
1/3, a meeting with the 
investigators will be convened to 
determine if the dose should be 
lowered.  Likewise if ongoing 
moderate toxicities develop into 
“intolerable Grade 2” events, the 
recommended Phase 2 dose may 
also be re-evaluated in 
Added following responses to 
ANSM.
Synopsis, 9.7.1.8


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consultation with the protocol 
investigators’.
All other evaluation of safety 
other than the Phase 1 primary 
objective in DLT evaluation will 
be performed on the Safety 
Analysis Set. 
Updated interim analyses to 
include an assessment of 
tolerability.  Removed ‘safety 
summaries may be provided 
periodically’ due to this update.
More detail provided following 
ANSM request.
Synopsis, 9.7.3
Added ‘No attenuated live 
vaccines must be administered for 
the duration of the study and 6 
months following discontinuation 
of irinotecan’.
Added per ANSM request.
9.4.6.2
Included monthly pregnancy tests 
are required for all sexually active 
subjects. 
Added per ANSM request.
9.5.1.4.3, 9.5.1.4.7, 9.5.1.5 (Table 
11 [footnote i], Table 12 [footnote 
i])
Added magnesium as part of the 
clinical laboratory testing panel. 
Added per ANSM request.
9.5.1.4.3 (Table 10), 9.5.1.5 
(Table 11 [footnote k], Table 12 
[footnote k]), Appendix 1
Removed assessment for globulin.
Assessment not required.
9.5.1.4.3 (Table 10), 9.5.1.5 
(Table 11 [footnote k], Table 12 
[footnote k]) 
Updated sponsor’s grading for 
CTCAE laboratory values. 
New laboratory values for 
CTCAE v5.0.  
Appendix 1
The table below describes revisions in Amendment 02 per the new protocol template (Nov 
2016). 
Revisions per Amendment 02
Date: 02 Aug 2018  
Change
Rationale
Affected Protocol Sections
Added restriction to concomitant 
use with St. John's Wort in 
exclusion criterion #2. 
Added to be compliant with 
irinotecan SmPC.
Synopsis, 9.3.2, 9.4.6.1


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Added criteria for study drug 
discontinuation.
Added new Tables (Tables 3 and 
8) which list the criteria for study 
drug discontinuation.
Added for additional subject 
safety following request from 
MHRA. 
Synopsis, 9.4.1
Amended PK sampling schedule 
to reduce the frequency of PK 
blood draws in relation to the 
subjects weight/blood volume.  
Subjects under 6 kg will not have 
samples for PK analysis taken.
Added following request from 
AEMPS.
Synopsis, 9.5.1.3.2, 9.5.1.5 (Table 
11 [footnote m])
Updated Tables 11 and 12 
(previously Tables 9 and 10) to 
indicate that Screening is from -28 
to -1 days (rather than -14 to -1).
Reflects the change made in the 
previous amendment.    
9.5.1.5 (Table 11, Table 12)
The table below describes revisions in Amendment 01 per the new protocol template (Nov 
2016). 
Revisions per Amendment 01
Date: 10 May 2018  
Change
Rationale
Affected Protocol Sections
Up to approximately 50 study 
sites.  
Plan to increase the number of 
investigational sites as more sites 
are necessary to complete the 
study. 
Synopsis, 6
Added Ewing sarcoma (EWS) as a 
treatment group.
Ewing sarcoma (EWS) patients 
were included in this study 
following review from the FDA, 
preclinical (PPTP) data 
(eribulin/irinotecan) and noting a 
partial response in Ewing patients 
in Study E7389-A001-113. 
Synopsis, 7.1.1 (Table 4), 7.2, 
8.1, 9.1 , 9.2, 9.3, 9.3.1, 9.4.3, 
9.7.2, 9.7.3, 10 
Included duration of response 
(DOR) as part of the primary 
objective for Phase 2. 
Included duration of response as 
part of the primary objective for 
Phase 2 following review by the 
FDA.
Synopsis, 8.1, 9.2, 9.7.1.6.1, 
9.7.1.6.2
Replaced ‘extra-cranial solid 
tumors’ with ‘solid tumors 
(excluding CNS)’. 
Amend for clarity that Phase 1 of 
this protocol is not intended to 
treat patients with CNS tumors.
Synopsis, 8.1, 9.1, 9.2, 9.3.1, 
9.7.1.1.1
Expanded maximum number of 
subjects for Phase 2 of study from 
Each histology group has a 
maximum of 25 subjects for 
Phase 2.  RMS, NRSTS and the 
newly added EWS groups, bring 
Synopsis, 9.1, 9.2, 9.3, 9.7.2


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50 to 75, consistent with addition 
of an EWS treatment group.  
the maximum number of subjects 
to 75.   
Subjects <12 months are included 
for descriptive purposes only and 
will not contribute to the 
determination of the MTD/RP2D 
for this study, or to the sample 
size.
Included to clarify how data from 
<12 month age group will be 
managed.
Synopsis, 9.1, 9.2, 9.3, 9.3.1, 
9.4.1, 9.7.1.1.1, 9.7.2
Amended inclusion criterion #1 to 
include subjects aged >6 months 
to <12 months for Phase 1 and 
Schedule A only.  
The infant subject group was 
included as per request from 
BFARM and EMA Pediatric 
Investigational Plan (PIP). 
For added safety, infant subjects 
are to be enrolled 1 dose level 
below the ≥12 months to <18 
years group. 
Synopsis, 9.1, 9.3.1, 9.4.1
Extended the window in which 
computerized tomography (CT) / 
magnetic resonance imaging 
(MRI) scans can be performed 
from previous 14 days to up to 28 
days before study drug 
administration.
Following feedback from the 
investigators.  An extended 
screening window (28 days before 
first dose) for pre-screening scans 
was included.
Synopsis, 9.1.1, 9.1.1.1,
9.5.1.5 (Table 9 [footnotes b, p, 
q], Table 10 [footnotes b, p, q])
Included clarification on duration 
of treatment. ‘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 for up to 1 year, after 
which any continued treatment 
would need to be discussed with 
the Sponsor’.
In order to be compliant with the 
EMA PIP, the duration of 
treatment may be for up to 1 year. 
Synopsis, 9.1.2, 9.3.3, 9.4.1
Included clarification on Follow-
Up ‘After discontinuation from 
study treatment and completing 
the off-treatment visit, subjects 
will be followed up at least 4 
weeks later (ie, greater than or 
equal to 28 days after last dose) 
unless they withdraw consent’.  
In order to be compliant with the 
PIP, the follow-up period must be 
at least 28 days after last dose of 
study drug. 
Synopsis, 9.1.3, 9.3.3, 9.5.1.5 
(Table 9 [footnote t], Table 10 
[footnote t]) 
Included clarification on 
performance level Karnofsky or 
Lansky score: 
Patients who are unable to walk 
because of paralysis and/or 
previous surgeries, but who are in 
Clarification of inclusion criterion 
#5.  
Synopsis, 9.3.1


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a wheelchair, will be considered 
ambulatory for the purpose of 
assessing the performance score.
Increased the required time for 
males to be on highly effective 
contraception from 28 days to 3 
months (exclusion criterion #1). 
Increased the restriction on sperm 
donation from 28 days to 3 
months after study drug 
discontinuation. 
EU SmPC for irinotecan 
recommends that “men have to 
use effective contraception during 
and up to 3 months after 
treatment”. 
Synopsis, 9.3.2
Removed ‘irinotecan 
hydrochloride’ from Phase 1 
exclusion criterion #3.
Fixed numbering: exclusion 
criteria #3 and #4 were intended to 
be 2 bullet points within exclusion 
criterion #3.
Following feedback from the 
Investigators, amendment to allow 
prior treatment with irinotecan 
hydrochloride in Phase 1 as this is 
commonly used as first-line 
treatment in this setting.  
  
Synopsis, 9.3.2 
Added new exclusion #13 “Has 
received a live-virus vaccination 
within 30 days of planned start of 
study therapy.  Seasonal flu 
vaccines that do not contain live 
virus are permitted.” 
Included in line with the 
Irinotecan SmPC.
Synopsis, 9.3.2
Change in protocol on drug-drug 
interactions to include the 
following:
Avoid co-administration of 
irinotecan with strong CYP3A4 
inhibitors and inducers, and 
UGT1A1 inhibitors. For subjects 
requiring anti-epileptic therapy, 
switch to a non-enzyme inducing 
anti-epileptic agent.
Included in line with the 
Irinotecan SmPC.
9.3.2 (exclusion criterion #2 and 
Synopsis, CYP3A4 only), 
9.4.6.1.2
Inclusion of an option to remain 
on treatment in the event of an 
adverse event which leads to 
treatment interruption or delay of 
either study drug.  The subject 
may continue treatment with the 
other study drug as long as there is 
a clinical benefit for up to 1 year, 
after which any continued 
treatment would need to be 
discussed with the Sponsor.
To allow subjects to continue on 
either study drug in the event of an 
AE which leads to discontinuation 
of the other study drug. 
Synopsis, 9.3.3, 9.4.1


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Hematological toxicity:
Subjects who have Grade 4 
neutropenia or platelets 
<75,000/mm3 on Day 8 will have 
their dose withheld.  If the toxicity 
resolves to ANC ≥750/mm3 and 
platelets ≥75,000/mm3
(transfusion independent) by Day 
11, the dose may be given.  If the 
toxicity does not resolve to ANC 
≥750/mm3 and platelets 
≥75,000/mm3 by Day 11, the dose 
will be omitted and this will be 
considered a DLT.  Subjects 
should receive subsequent cycles 
of drug but at the next lower dose 
level.  Subjects who require that 
their Day 8 dose be omitted for 
Grade 4 neutropenia or platelets 
<75,000 mm3 after two dose 
reductions must be removed from 
protocol therapy.
Subjects who meet hematological 
DLT criteria on Day 8 will have 
their Day 8 dose omitted.  
Subjects should receive 
subsequent cycles of drug but at 
the next lower dose level.  
Subjects who require that their 
Day 8 dose be omitted for 
hematologic DLT after two dose 
reductions must be removed from 
protocol therapy.
Non-hematological toxicity:
Subjects who have Grade 3 or 
Grade 4 non-hematological 
toxicity attributable to the study 
drug prior to the Day 8 dose (with 
the exception of the DLT 
exclusions) will be considered to 
have had a DLT.  If the toxicity 
resolves to meet eligibility or 
≤Grade 2 (if not part of eligibility 
criteria) by Day 8, the dose may 
be given but at the next lower dose 
level. 
Subjects who have Grade 3 or 
Grade 4 non-hematological 
toxicity attributable to the study 
drug on Day 8 prior to dosing 
Updated dose-modification 
criteria in line with protocol 
E7389-G000-213. 
Synopsis, 9.4.1


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(with the exception of the DLT 
exclusions) will have their dose 
withheld and this will be 
considered a DLT.  If the toxicity 
resolves to meet eligibility or 
≤Grade 2 (if not part of eligibility 
criteria) by Day 11, the dose may 
be given but at the next lower dose 
level.  If the toxicity does not 
resolve by Day 11, the dose will 
be omitted. Subjects should 
receive subsequent cycles of drug 
but with dose modifications.
For subjects <12 months any 
≥Grade 2 non-hematological 
toxicity attributable to study drug 
prior to the Day 8 dose will have 
their dose omitted.  Subjects 
should receive subsequent cycles 
of drug at the next lower dose 
level.
Subjects who have a dose-limiting 
hematological or non-
hematological toxicity that does 
not resolve to meet eligibility or 
baseline parameters within 21 
days after the planned start of the 
next treatment cycle must be 
removed from protocol therapy.
Any drug-related non-
hematological toxicity ≥Grade 2 in 
infant subject population (<12 
months) will be considered a 
DLT.
Additional DLT criteria included 
for the infant subjects.
Synopsis, 9.4.1
For subjects <12 months, if 
following de-escalation from dose 
level -1 (to dose level -2 in 
Schedule A), 2 DLTs are 
observed, that dose and schedule 
will be declared too toxic for 
further evaluation.  
Additional dose modification 
criteria included for the infant 
subjects.
Synopsis, 9.4.1
Eribulin dose defined for dose 
level -2 for subjects <12 months in 
Schedule A.  
Added safety for infant subjects. 
Synopsis, 9.4.1 
Myelosuppression that causes a 
delay of >14 days between 
treatment cycles is added as a
hematological DLT.
Included as a DLT following team 
review and review of the previous 
pediatric eribulin protocol.
Synopsis, 9.4.1


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Updated CTCAE from v4.03 to 
v5.0. 
v5.0 CTCAE is the current 
version.
Synopsis, 9.4.1, 9.5.1.4, 9.5.1.4.1, 
9.7.1.8.2, 10 , 12 (Appendix 1)
After data cutoff for the primary 
analysis, tumor assessments may 
be performed as clinically 
indicated using the investigator’s 
discretion, following the 
prevailing local standard of care.
Clarification on tumor 
assessments after data cutoff. 
Synopsis, 9.5.1.3.1
Removed: “To confirm responses, 
tumor assessments should be 
obtained on the next consecutive 
cycle after initial documentation 
of either a PR or CR.  If the 
institutional investigator 
determines that the subject has 
progressed based on clinical 
evidence, he/she may opt not to 
confirm this finding 
radiographically.”
A statement that all responses 
must be confirmed no less than 28 
days following the initial 
assessment of response, was 
included so this was contradictory 
and required removal.
A subject can always discontinue 
for clinical progression but it is 
censored for progression-free 
survival.
Synopsis, 9.5.1.3.1
Changed schedule for tumor 
assessments: rather than 
performing tumor assessments 
every 6 weeks on a fixed schedule,
they will instead be performed 
every 6 weeks until Week 12 and 
every 9 weeks thereafter on a 
fixed schedule Therefore the 
assessments would be; Week 6, 
12, 21, 30 etc.
Following feedback from the 
investigators, the schedule of 
tumor assessments was felt to be 
too burdensome therefore the 
frequency after 12 Weeks was 
reduced.  
Schedule of assessments needed to 
be updated to reflect the change in 
the fixed schedule of tumor 
assessments. 
Synopsis, 9.5.1.3.1, 9.5.1.5
Lesions identified on bone scans 
should be followed with anatomic 
imaging, rather than cross-
sectional imaging. 
Clarification. 
Synopsis, 9.5.1.3.1
Following feedback from the 
Principal Investigator, included:
“An exception to the requirement 
for following chest disease by CT 
will be allowed where subjects 
have either non-parenchymal 
tumors, mediastinal and/or chest 
wall lesions.  These may be 
assessed (at Screening and post-
baseline) using contrast-enhanced 
MRI. However, a chest CT is 
required at Screening for all 
subjects, and lung parenchymal 
This is more in line with clinical 
practice and will improve 
compliance with the tumor 
assessment schedule. 
Synopsis, 9.5.1.3.1


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lesions should be followed using 
CT (as per standard practice).  If 
there is either an equivocal new 
lung lesion based on MRI or 
symptoms suggesting a new 
lesion, these should also be 
confirmed with chest x-ray or 
CT”.  Confirmation by chest x-ray 
may be used in lieu of CT.
A brain scan CT or MRI will be 
performed as clinically indicated 
to assess potential for 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 at all tumor assessment time 
points.
In view of the patient population, 
CNS imaging will only be 
required as clinically indicated for 
subjects with a history of protocol-
eligible treated brain metastasis.
Synopsis, 9.5.1.3.1,
9.5.1.5 (Table 9 [footnote q]), 
Table 10 [footnote q])
  
Include PK sampling schedule for 
subjects <12 months.
Subjects <12 months of age:

Cycle 1, Day 1: Before the 
irinotecan and eribulin 
infusion and then immediately 
after the end of the eribulin 
infusion (ie, 10 ± 5 minutes 
from the start of the eribulin 
infusion).

Cycle 1, Day 4 or 5: During 
the collection of the first twice 
weekly CBC sample.

Cycle 1, Day 8: Before the 
eribulin infusion and then 
immediately after the end of 
the eribulin infusion (ie, 10 ± 5 
minutes from the start of the 
eribulin infusion).
Included PK sampling schedule 
suitable for subjects <12 months.
Synopsis, 9.5.1.3.2, 9.5.1.5 (Table 
9 [footnote m])
Updated Principles of the World 
Medical Association Declaration 
of Helsinki from 2008 to 2013. 
2013 is the current version. 
5.2
Added background on EWS.
Introduction was changed to 
include background on EWS 
because EWS was added as a 
treatment group.
7.1.1.3, 7.1.2


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Updated section with MTD/RP2D 
data from a recently published 
Eisai clinical study. 
Including results from the 
completed Phase 1 Study E7389-
A001-113.
7.1.3.3.2
Removed ‘non-hematological 
toxicities’ from right column of 
Tables. 
Wording was redundant. 
9.4.1 (Table 5, Table 6)
Included storage and labeling 
information for irinotecan 
hydrochloride as an 
Investigational Product.
Labeling and storage 
specifications provided. 
9.4.2, 9.4.2.3, 9.4.2.4.1, 9.4.2.4.3
Added clarification regarding the 
pregnancy test: ‘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’. 
Clarification of information 
contained in exclusion criterion 
#1. 
9.5.1.4.7, 
9.5.1.5 (Table 9 [footnote i], 
Table 10 [footnote i]) 
Removed tumor assessment from 
schedule of assessments on Cycle 
2 Day 15.
This box was checked in error in 
the original protocol.  Tumor 
assessments start at 6 weeks from 
C1D1 on a fixed schedule. 
9.5.1.5 (Table 9, Table 10)
For 12-lead ECG, added ‘(after 
irinotecan administration and prior 
to eribulin infusion on the days 
when administered together)’.
Clarification on when to perform 
the pre-eribulin infusion ECG 
assessments.  
9.5.1.5 (Table 9 [footnote n], 
Table 10 [footnote n])
Vital signs, Physical exam and 
Chemistry assessments during 
Phase 1 for <12 months subject 
group will be weekly.
Additional assessments for the 
infant subjects.
9.5.1.5 (Table 9)
Urinalysis assessments during 
Phase 1 for <12 months subject 
group will be as clinically 
indicated after Cycle 1.
Additional assessments for the 
infant subjects.
9.5.1.5 (Table 9)
Hematology assessments during 
Phase 1 will be twice weekly for 
subjects <12 months (every 3 to 4 
days).
Additional assessments for the 
infant subjects.
9.5.1.5 (Table 9)
Added the Balis peripheral 
neuropathy scale as Appendix 3.
Original protocol referred to the 
Balis peripheral neuropathy scale 
in exclusion criterion #7, but did 
not provide the scale.     
12 (Appendix 3)


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2
CLINICAL PROTOCOL SYNOPSIS
Compound No.:  E7389
Name of Active Ingredient:  eribulin mesilate and irinotecan hydrochloride
Study Protocol Title
A Phase 1/2 single-arm study evaluating the safety and efficacy of eribulin mesilate in combination 
with irinotecan in children with refractory or recurrent solid tumors
Investigator
Sites
Up to approximately 50 sites
Study Period and Phase of Development
Approximately 42 months from first subject signed informed consent to last subject last visit (LSLV).  
Phase 1/2, open-label, non-randomized.
Objectives
Primary Objectives

Phase 1: To determine the maximum tolerated dose (MTD) and Recommended Phase 2 Dose 
(RP2D) of eribulin mesilate in combination with weekly and daily irinotecan hydrochloride in 
pediatric subjects with relapsed/refractory solid tumors (excluding CNS)

Phase 2: To assess the objective response rate (ORR) and duration of response (DOR) of eribulin 
mesilate in combination with irinotecan hydrochloride in pediatric subjects with relapsed/refractory 
rhabdomyosarcoma (RMS), non-rhabdomyosarcoma soft tissue sarcoma (NRSTS) and Ewing 
sarcoma (EWS)
Secondary Objectives
Phase 1:

To assess the safety and tolerability of eribulin mesilate in combination with irinotecan 
hydrochloride in pediatric subjects

To determine the optimal schedule of irinotecan hydrochloride when administered with standard 
schedule (Days 1 and 8) of eribulin mesilate in pediatric subjects
Phase 2:

To assess Progression Free Survival (PFS) of eribulin mesilate in combination with irinotecan 
hydrochloride in pediatric subjects

To assess the Clinical Benefit Rate (CBR) at 12 weeks of eribulin mesilate in combination with 
irinotecan hydrochloride in pediatric subjects 
Phase 1 and 2:

To evaluate the pharmacokinetic (PK) profile of eribulin, irinotecan and its active metabolite and 
compare to appropriate historical data
PPD


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Exploratory Objectives
Phase 1 and 2:

To explore the relationship between model-derived exposure to eribulin and the active metabolite 
for irinotecan (SN 38) in terms of area under the curve and AEs and efficacy endpoints using a 
model-based approach
Study Design
E7389-G000-213 is a Phase 1/2, multicenter, open-label study to assess the safety and efficacy of 
eribulin mesilate in combination with irinotecan hydrochloride in pediatric subjects.
This study is divided into 2 phases:
Phase 1: Will determine the MTD/RP2D of eribulin mesilate in combination with irinotecan 
hydrochloride in pediatric subjects with relapsed/refractory solid tumors (excluding CNS). 
Eribulin mesilate will be administered as an intravenous (IV) infusion on Days 1 and 8 of each 21 day 
cycle, at the RP2D determined in the single-agent dose finding study E7389-A001-113 (1.4 mg/m2), 
starting dose.
Irinotecan hydrochloride will be administered as an IV infusion using 2 different dose schedules:
1.
Days 1-5 of a 21 day cycle at the following doses; 20 mg/m2 and 40 mg/m2
And 
2.
Days 1 and 8 of a 21 day cycle at the following doses; 100 mg/m2 and 125 mg/m2
These doses of irinotecan are derived from studies looking at MTD of single agent irinotecan or
irinotecan combinations administered at the various corresponding schedules (Blaney, et al, 2001; 
Vassal, et al, 2003; Casey, et al, 2009).
Dosing schedules to be evaluated are described below:
Schedule A
Eribulin mesilate on Day 1 and Day 8 of a 21 day cycle (Starting dose determined by COG protocol 
ADVL1314/Eisai Study E7389-A001-113).
Irinotecan hydrochloride on Days 1-5 of a 21 day cycle.
Dose Level
Eribulin mesilate 
(mg/m2)
Irinotecan 
hydrochloride
(mg/m2)
-2
0.8
20
-1
1.1
20
0*
1.4
20
1
1.4
40
*Dose level 0 refers to the starting dose.


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Dose level -2 is a further dose reduction in Schedule A for subjects <12 months only.
Schedule B
Eribulin mesilate and irinotecan hydrochloride on Day 1 and Day 8 of a 21-day cycle.
Dose Level
Eribulin mesilate 
(mg/m2)
Irinotecan 
hydrochloride
(mg/m2)
-1
1.1
100
0*
1.4
100
1
1.4
125
*Dose level 0 refers to the starting dose.
Subjects will be enrolled alternately on Schedule A or Schedule B (ie, every other subject will be 
enrolled on to Schedule A), as allocated by the Sponsor.  If enrollment is halted or discontinued for any 
schedule, subjects will be enrolled on to the other schedule provided it is open for accrual.
Subjects <12 months will be enrolled on to Schedule A only and at one dose level behind ≥12 months 
subjects in order to maximize safety for infant subjects.  
Dose Escalation 
The traditional 3+3 design will be used for the conduct of Phase 1 of this study.
For both schedules A and B, 3 subjects will be entered into each dose level. The first subject at each 
dose level, within a schedule, must complete the Day 8 assessments before further subjects can be 
entered at the same dose level.  All 3 subjects in the cohort will be followed for a full cycle before the 
next dose level opens. If 1 subject experiences a DLT, the cohort will need to be expanded to 6 
subjects on the same dose level. 
If no DLT is observed in a dose cohort, then the dose can be escalated and 3 subjects can be enrolled 
onto the next dose level. The MTD is defined as the highest dose level at which fewer than 1/3 of 
subjects experience a DLT during Cycle 1 of therapy. 
If, at dose level 0, there are 2 or more subjects with a DLT out of 3 subjects (or 2 DLTs out of 6 
subjects after expansion) in Cycle 1, the MTD will have been exceeded and the dose will be 
de-escalated to dose level -1, and the next 3 subjects will be enrolled onto this lower dose level.
The MTD will be determined based on the incidence of DLTs in Cycle 1 of each dose level.  Subjects 
who do not complete Cycle 1 for any reason other than toxicity, ie, DLT, will be replaced in that cohort 
in order to complete the number necessary (up to 6) to assess the safety of the dose level cohort. 
Toxicities subsequent to Cycle 1 will also be reviewed but will not count towards determination of 
dose escalation and MTD/RP2D.  If protocol-defined DLTs are observed in a subject after the first 
cycle at any dose level, the dose will be reduced to the next lower dose level for subsequent cycles.
DLTs are defined as any of the following using the National Cancer Institute Common Terminology 
Criteria for Adverse Events (CTCAE Version -5.0) during Cycle 1:


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Hematological:
1.
Neutropenia Grade 4 that lasts >7 days
2.
Thrombocytopenia Grade 4 on 2 separate days, or requiring a platelet transfusion on 2 separate 
days, within a 7-day period 
3.
Thrombocytopenia Grade 3 complicated by bleeding or requiring platelet or blood transfusion 
4.
Neutropenia Grade 3 or 4 complicated by fever and/or infection (ANC <1.0 × 109/L, fever 
≥38.0°C) 
5.
Myelosuppression that causes a delay of >14 days between treatment cycles
6.
Grade 4 neutropenia or platelets < 75,000/mm3 on Day 8 that does not resolve to ANC ≥ 750/mm3
and platelets ≥ 75,000/mm3 (transfusion independent) by Day 11 will be considered dose-limiting.
Non-hematological:
1.
Grade 3 or 4 non-hematological toxicities related to study drug except for:
-
inadequately treated nausea and/or vomiting,
-
Grade 3 liver enzyme elevation (including ALT/AST), 
-
Grade 3 fever or Grade 3 infection, 
-
Grade 3 hypophosphatemia, hypokalemia, hypocalcemia or hypomagnesemia responsive to oral 
supplementation  
2.
Grade 3 or above diarrhea despite adequate treatment 
3.
Non-hematological toxicity that causes a delay of ≥14 days between treatment cycles 
4.
Day 8 dose omission or interruption for more than 2 weeks due to non-recovery of any toxicity 
related to the study drug 
5.
For subjects <12 months (at the time of DLT), any ≥Grade 2 drug-related non-hematological 
toxicity 
6.
DLT exception: Allergic reactions that lead to discontinuation of study drug during Cycle 1
Accrual will be suspended when a cohort of 3 or 6 has enrolled with pending toxicity data or when the 
MTD/RP2D for the combination has been met.  If, following de-escalation from dose level 0 (to dose 
level-1), 2 DLTs are observed, that dose and schedule will be declared too toxic for further evaluation.  
For subjects <12 months, if following de-escalation from dose level -1 (to dose level -2 in Schedule A), 
2 DLTs are observed, that dose and schedule will be declared too toxic for further evaluation. Up to 36 
pediatric subjects (18 subjects per schedule) who meet all the inclusion criteria and none of the 
exclusion criteria, will be enrolled in Phase 1. The sample size does not include subjects <12 months. 
MTDs will be obtained for both Schedule A and Schedule B and the most appropriate schedule will be 
taken forward to Phase 2 and will represent the RP2D (See Section 9.4.1 for details on schedule 
selection).
Phase 2: Will evaluate the safety and efficacy of eribulin mesilate in combination with irinotecan 
hydrochloride in pediatric subjects with relapsed/refractory RMS, NRSTS and EWS, using the 
combination dose and schedule determined in Phase 1. As per protocol amendment #5, following 
review of the data from the Phase 1 portion of the study, Schedule A Dose Level 1 - eribulin (dose 1.4 
mg/m2) Day 1 and Day 8 and irinotecan (dose 40 mg/m2) Days 1-5, was selected as the dose and 
schedule to take forward into Phase 2 (RP2D). As per Amendment 6, subjects aged >6 months and 


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<12 months will be enrolled to Schedule A with a modified dose of eribulin Dose Level -2 (0.8 mg/m2
Day 1 and Day 8) with the irinotecan dose maintained Dose Level 1 (40 mg/m2 Day 1 – Day 5) of a 
21-day cycle in order to maximize safety for infant subjects.
Approximately 75 pediatric subjects (approximately 25 subjects per histology type, RMS, NRSTS and 
EWS) who meet all the inclusion criteria and none of the exclusion criteria, will be enrolled in Phase 2, 
using a Simon two-stage design.
Trial schema Phase 2
Outline

Subjects will be enrolled on to either the RMS, NRSTS or EWS histology type, the proportion of 
the responders (ORR) will be estimated. 

Subjects will continue with their treatment until progression of disease, intolerable toxicity or 
withdrawal of consent.

Each tumor histology type will have a futility analysis after 9 subjects are treated.  Recruitment will 
be suspended for up to 24 weeks after 9 subjects have been enrolled to complete ORR assessment.  
If more than 2 responses (partial responses [PR] or complete responses [CR]) are observed and 
documented in that histology type, then recruitment will continue, and that histology type will 
expand to approximately 25 subjects.  If 2 or fewer responses (PR or CR) are observed, recruitment
to that histology type will close.  An assessment of tolerability will be also be conducted at this 
time.

The study will enroll a minimum of 27 (ie, 9 for each negative histology type), and approximately
75 (ie, approximately 25 for each positive histology type) subjects.


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Pre-study Phase:
Day -28 to -1, computerized 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 (D1) of Cycle 1 (C1).  Subjects will receive eribulin mesilate 
by IV infusion on Days 1 and 8 of a 21-day cycle together with IV irinotecan hydrochloride 
administered on either:

Days 1-5 
or 

Days 1 and 8 of a 21-day cycle (See Study Design of Phase 1).
The most appropriate schedule will be taken forward to Phase 2 and will represent the RP2D (See 
Study Design of Phase 2).
Subjects in both Phase 1 and Phase 2 can remain on treatment for up to 1 year if they are receiving 
clinical benefit, as outlined in the Duration of Treatment.
Follow-up
All subjects will have an off-treatment visit within 28 days after the last dose of study medication.  
After discontinuation from study treatment and completing the off-treatment visit, subjects will be 
followed up at least 4 weeks later (ie, greater than or equal to 28 days after last dose, but no more than 
1 year) unless they withdraw consent.
Subjects who discontinue without objective evidence of disease progression will continue to have 
tumor assessments performed as per the Schedule of Assessments until disease progression, death, or 
another anticancer therapy is initiated, whichever occurs first, unless study is terminated.  Follow-up 
data will be required unless consent is withdrawn.
Number of Subjects
The maximum number of subjects is approximately 111 (not including subjects of age <12 months).
Up to 36 subjects in Phase 1 and a total of approximately 75 subjects in Phase 2. 
For Phase 2, Simon’s two-stage design will be used.  Nine subjects will be enrolled on to each 
histology type (RMS, NRSTS and EWS) in the first stage, at which point a futility analysis will be 
performed.  Enrollment will be terminated if 2 or fewer responses are observed in these 9 subjects.  If 
more than 2 responses are observed, then enrollment will continue to approximately 25 subjects in each 
histology type.
Inclusion Criteria
Subjects must meet all of the following criteria to be included in this study:
1.
Age: 


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a.
≥12 months to ≤25 years at the time of consent (no more than 25% of subjects between the 
ages of 18 and 25 years will be enrolled in this study).
b.
In Phase 1, >6 months and <12 months at the time of consent (Schedule A only) subjects will 
be enrolled one dose level behind the ≥12 months subjects in order to maximize safety for 
infant subjects.  In Phase 2, subjects aged >6 months and <12 months at the time of consent 
will be enrolled to Schedule A with a modified dose of eribulin, Dose Level -2 (0.8 mg/m2 Day
1 and Day 8) with the irinotecan dose maintained (40 mg/m2 Day 1 – Day 5) of a 21-day cycle
in order to maximize safety for infant subjects.
2.
Diagnosis: 
Phase 1: Histologically confirmed solid tumor, excluding CNS tumors, which is relapsed or 
refractory, and for which there are no currently available therapies.
Phase 2: Histologically confirmed RMS, NRSTS and EWS which is relapsed or refractory having 
received at least 1 prior systemic therapy, including primary treatment.
3. Disease status:
Phase 1: Subjects must have either measurable or evaluable disease as per RECIST 1.1.
Phase 2: Subjects must have measurable disease as per RECIST 1.1.
Measurable disease is defined as meeting the following criteria:
a.
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 computerized tomography/magnetic resonance imaging (CT/MRI). 
b.
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.
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 the performance score.
6.
Subjects must have fully recovered from the acute toxic effects of all prior anticancer treatments 
prior to study drug administration:

Myelosuppressive chemotherapy:  Must not have received within 21 days prior to study drug 
administration (42 days if prior nitrosourea).

Hematopoietic growth factors:  Must not have received a long-acting growth factor (eg, 
Neulasta) within 14 days, or a short-acting growth factor within 7 days.  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.

Targeted therapy (antineoplastic agent, eg, tyrosine kinase inhibitor):  Must not have received 
an antineoplastic targeted therapy within 14 days.  For agents that have known AEs occurring 
beyond 14 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.

Immunotherapy:  Must not have received immunotherapy, eg, tumor vaccines, within 42 days.

Monoclonal antibodies:  Must not have received within at least 3 half-lives of the antibody 
after the last dose of a monoclonal antibody.


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
Radiotherapy (XRT):  Must not have received within 14 days prior to study drug 
administration (small field) or 42 days for craniospinal XRT, or if ≥50% radiation of pelvis.

Autologous Stem cell infusion:  At least 84 days must have elapsed after stem cell infusion
prior to study drug administration

Allogeneic bone marrow transplant, including mini-transplant:  No evidence of active Graft vs. 
Host disease and at least 100 days must have elapsed after transplant or stem cell infusion prior 
to study drug administration
7.
Adequate bone marrow function, defined as:

Peripheral absolute neutrophil count (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 (Hb) at least 8.0 g/dL at baseline (blood transfusions are allowed during the 
screening period to correct Hb values less than 8.0 g/dL).
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 
GFR (Schwartz and Gauthier, 1985), See table below. 

Or serum creatinine clearance or GFR ≥50ml/min/1.73m2, based on a 12 or 24h urine 
creatinine collection. 
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 
GFR (Schwartz et al. J. Peds, 106:522, 1985) utilizing child length and stature data published by the 
CDC.
9.
Adequate liver function, defined as:

Bilirubin (sum of conjugated + unconjugated) ≤1.5 times the ULN for age.

Alkaline phosphatase, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) 
≤3 × ULN (in the case of liver metastases ≤5 × ULN), unless there are bone metastases, in 
which case liver-specific alkaline phosphatase must be separated from the total and used to 
assess the liver function instead of the total alkaline phosphatase.  

Serum albumin ≥2 g/dL.
10. Informed consent:  All subjects and/or their parents or guardians 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.   


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Exclusion Criteria
Subjects who meet any of the following criteria will be excluded from this study:
1.
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:
◦
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, 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 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 dose for at 
least 7 days prior to study drug administration. 

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 including traditional herbal medicinal products (eg, St. 
John’s Wort). See Section 9.4.6.1, Drug-Drug Interactions.  
3.
Prior Therapies:


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
Phase 1: Received prior therapy with eribulin mesilate within 6 months prior to study drug 
administration. 

Phase 2: Received prior therapies with eribulin mesilate or irinotecan hydrochloride (for prior 
irinotecan hydrochloride, subjects can be included if there was no tumor progression during 
irinotecan therapy).   
4.
Any other malignancy that required treatment (except 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 either study drug or any of the excipients. 
6.
Has a known 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, defined as: 

Subjects with known congestive heart failure, symptomatic or 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 28 days prior to study drug administration.  Subjects must be clinically stable.  It is not the 
intention of this protocol to treat subjects with active brain metastases.
Note: Screening CNS imaging for subjects with a known history of CNS disease is required.
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. 
o
Central line placement or subcutaneous port placement is not considered major surgery.

Laparoscopic procedure or open biopsy within 7 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. Subjects with known human immunodeficiency virus (HIV); due to lack of available safety data 
for eribulin therapy in HIV infected patients.
12. 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 (including active or severe chronic 
inflammatory bowel disease or bowel obstruction).
13. Has received a live-virus vaccination within 30 days of planned start of study therapy.  Seasonal 
flu vaccines that do not contain live virus are permitted.
Study Treatments
Administration of eribulin mesilate by IV infusion on Days 1 and 8 of a 21-day cycle in combination 
with irinotecan hydrochloride administered by IV infusion on either Days 1-5 of a 21-day cycle 
(Schedule A), or Days 1 and 8 of a 21-day cycle (Schedule B).


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Irinotecan will be administered first (on days where both treatments are due to be administered), as a 
30 minute infusion, followed by eribulin as a 2-5 minute bolus infusion.  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.
In the event of an adverse event which leads to treatment interruption or delay of either study drug, the
subject may continue treatment with the other study drug, as long as there is a clinical benefit, for up to 
1 year, from start of study treatment, after which any continued treatment would need to be discussed 
with the Sponsor.  
Phase 1
The dosing schedules being evaluated for Phase 1 are summarized in the Study Design section of the 
synopsis.
Subjects will be allocated in an alternate fashion to either Schedule A or Schedule B, ie, every other 
subject will be allocated to Schedule A, until an MTD is reached.  Subjects are allocated to respective 
treatment schedules by the Sponsor. If enrollment is halted or discontinued for any schedule, subjects 
will be enrolled on the other schedule provided it is open for accrual.
Subjects <12 months will be allocated to Schedule A only and will be enrolled at one dose-level behind 
≥12 months subjects. These subjects are included for descriptive purposes only and will not contribute 
to the determination of the MTD/RP2D for this study. 
Phase 2
The dose and schedule that is deemed the most appropriate from Phase 1 will be used in Phase 2, 
following sponsor review together with the investigators. If there is no difference in the safety and 
efficacy between Schedules A and B, following review with the investigators, Schedule B will be taken 
forward to Phase 2 on the basis of convenience.
If a large number of dose modifications are observed after completion of Cycle 1 (eg, intolerable Grade 
2 toxicities), the sponsor will discuss with investigators whether a lower dose level than the MTD 
should be carried forward as the RP2D for this study.
As per protocol amendment #5, the data from the Phase 1 portion of this study showed that there was a 
tolerable safety profile in both schedules, with similar PK profiles; however, 2 PRs were noted in 
Schedule A, one of which was confirmed. Following discussions with the investigators and 
independent experts, based upon the similar toxicity and PK profiles and taking into account the 2 PRs 
noted in Schedule A, Schedule A Dose Level 1 (eribulin 1.4 mg/m2D1 and D8 with irinotecan 40 
mg/m2 D1 – D5 of a 21- day cycle) was selected as the RP2D for the Phase 2 portion of this study. 
As per Amendment 6, subjects aged >6 months and <12 months will be enrolled to Schedule A with a 
modified dose of eribulin Dose Level -2 (0.8 mg/m2 D1 and D8) with the irinotecan dose maintained 
Dose Level 1 (40 mg/m2 D1 – D5) of a 21- day cycle.
Criteria for Dosing Modifications


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Dose reduction and interruption for eribulin mesilate and irinotecan hydrochloride-related toxicity will 
be performed according to the following instructions:
Treatment will not be administered if any of the following values are recorded (Table 1).
Table 1
Criteria for Administration of Study Medication
a): Do not administer Cycle 1 Day 1 treatment where:
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.
Gastrointestinal toxicity
Bowel function deteriorated since pre-
treatment/baseline and requires antidiarrheal 
medications for within 24 hours before the next 
chemotherapy administration.
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.
Gastrointestinal toxicity
Bowel function deteriorated since pre-
treatment/baseline and requires antidiarrheal 
medications for within 24 hours before the next
administration of irinotecan hydrochloride.
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.
Gastrointestinal toxicity
Bowel function deteriorated since pre-
treatment/baseline and requires antidiarrheal 
medications for within 24 hours before the next 
chemotherapy administration.
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 (Tables 1a Cycle 1 & 1c subsequent cycles). The Day 1 dose will be 


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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).
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) as follows:
Hematological toxicity:

Subjects who have Grade 4 neutropenia or platelets <75,000/mm3 on Day 8 will have their 
dose withheld. If the toxicity resolves to ANC ≥750/mm3 and platelets ≥75,000/mm3
(transfusion independent) by Day 11, the dose may be given. If the toxicity does not resolve to 
ANC ≥750/mm3 and platelets ≥75,000/mm3 by Day 11, the dose will be omitted and this will 
be considered a DLT. Subjects should receive subsequent cycles of drug but at the next lower 
dose level (Table 4). Subjects who require that their Day 8 dose be omitted for Grade 4 
neutropenia or platelets <75,000 mm3 after two dose reductions must be removed from 
protocol therapy.

Subjects who meet hematological DLT criteria on Day 8 will have their Day 8 dose omitted.  
Subjects should receive subsequent cycles of drug but at the next lower dose level.  Subjects
who require that their Day 8 dose be omitted for hematologic DLT after two dose reductions
must be removed from protocol therapy.
Non-hematological toxicity:

Subjects who have Grade 3 or Grade 4 non-hematological toxicity attributable to the study 
drug prior to the Day 8 dose (with the exception of the DLT exclusions) will be considered to 
have had a DLT. If the toxicity resolves to meet eligibility or ≤Grade 2 (if not part of 
eligibility criteria) by Day 8, the dose may be given but at the next lower dose level. 

Subjects who have Grade 3 or Grade 4 non-hematological toxicity attributable to the study 
drug on Day 8 prior to dosing (with the exception of the DLT exclusions) will have their dose 
withheld and this will be considered a DLT. If the toxicity resolves to meet eligibility or 
≤Grade 2 (if not part of eligibility criteria) by Day 11, the dose may be given but at the next 
lower dose level. If the toxicity does not resolve by Day 11, the dose will be omitted. Subjects 
should receive subsequent cycles of drug but with dose modifications (Table 4).

For subjects <12 months any ≥Grade 2 non-hematological toxicity attributable to study drug 
prior to the Day 8 dose will have their dose omitted. Subjects should receive subsequent 
cycles of drug at the next lower dose level (Table 4).

Subjects who have a dose-limiting hematological or non-hematological toxicity that does not 
resolve to meet eligibility or baseline parameters within 21 days after the planned start of the 
next treatment cycle must be removed from protocol therapy.
For Schedule A, irinotecan doses Days 2-5 can be delayed up to cycle Day 10 (of a 21 day cycle), at 
the discretion of the investigator and as long as the subject meets the criteria for administration of 
study medication for Day 8 as detailed in Table 1. If the subject does not meet the Day 8 criteria for 
administration by cycle Day 10 then dosing should not occur until the next cycle and as long as the 
subject meets the subsequent Day 1 dosing criteria for administration (Table 1).


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Please note, use of hematopoietic growth factor support is not permitted in Cycle 1 and is only 
permitted in subsequent cycles as per institutional guidelines. Subjects known to have reduced 
UGT1A1 activity will be monitored carefully for hematological toxicity.  
The treatment will be permanently reduced to the next lowest dose level (Table 4) after the occurrence 
of the following events.  
Table 2
Criteria for Reduction of Study Medication 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.
For subjects <12 months (at the time of DLT), any ≥Grade 2 
non-hematological toxicity attributable to study drug prior to the 
Day 8 dose will have their dose omitted and this will be 
considered a DLT.  Subjects should receive subsequent cycles of 
drug but with dose modifications as per Table 10.
Gastrointestinal toxicity
≥Grade 3 or intolerable Grade 2 diarrhea. 
For subjects on dose levels 0 and -1 dose reductions of 20% of 
the current irinotecan dose should be made.  If there are 2 or 
more diarrhea DLTs on these dose levels, the irinotecan dose 
levels will be re-evaluated by the Sponsor, and an appropriate 
lower dose level will be agreed with the investigator.  If the 
diarrhea toxicity does not recover following a dose reduction of 
20% (of dose level 0 or -1), treatment should be discontinued.  
If hematological or non-hematological toxicities do not recover following a dose reduction to dose 
level -1 (dose-level -2 for subjects <12 months ) and the use of hematopoietic growth factors, for 
hematological toxicities, the subject will discontinue treatment (except for cases of irinotecan related 
diarrhea, see Table 2).  
However, if the subject is deemed to have clinical benefit, continuation of treatment may be discussed 
with the sponsor.  


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If, in the opinion of the investigator, a dose reduction as per the criteria noted in Table 2 is not 
necessary, due to adequate supportive care and use of prophylaxis (eg, growth factor support) to 
prevent recurrences, each individual case should be discussed with and agreed by the Sponsor.
To ensure safety for subjects, the study drug must be discontinued in the cases outlined in the table 
below:
Table 3
Criteria for Discontinuation of Study Medication
ALT >3 × ULN and total bilirubin >2 × ULN
ALT >8 × ULN at any time, regardless of total bilirubin or accompanying symptoms
ALT >5 × ULN for 2 or more weeks, regardless of total bilirubin or accompanying symptoms
ALT >3 × ULN, accompanied by symptoms consistent with hepatic injury (fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, or rash). Clinical judgement should be 
used based on the combination of the laboratory LFT results and clinical symptoms. Additionally, 
in subjects with liver metastases with pre-existing ALT>3 x ULN at study baseline, any additional 
increase in ALT values from baseline and clinical symptoms consistent with a syndrome of hepatic 
injury as described above should be considered for further assessment and drug discontinuation.
Clinical symptoms alone consistent with deterioration of liver function should lead to additional 
laboratory assessments and evaluation of potential study drug related liver toxicity.
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 study treatment in subjects who develop ≥ Grade 3 QTc prolongation, and 
monitor ECGs and electrolytes more frequently in consultation with cardiologist advice and in line 
with local practice until the QTc interval returns to baseline.
Table 4
Study Medication Dose Levels by Schedule for Phase 1
Dose Level
Eribulin mesilate (mg/m2)
Irinotecan hydrochloride (mg/m2)
Schedule A
-2
0.8
20
-1
1.1
20
0
1.4
20
1
1.4
40
Schedule B
-1
1.1
100
0
1.4
100
1
1.4
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Dose level -2 is a further dose reduction in Schedule A for subjects <12 months only.
Do not re-escalate dose level after the dose level has been reduced.
Phase 2
Following protocol amendment #5, Schedule A Dose Level 1 (eribulin 1.4 mg/m2 D1 and D8 with 
irinotecan 40 mg/m2 D1 – D5 of a 21- day cycle) was selected as the RP2D for the Phase 2 portion of 
this study for subjects ≥ 12 months of age. 
As per Amendment 6, subjects > 6 months and < 12 months of age should receive Schedule A with a 
modified dose of eribulin Dose Level -2 (0.8 mg/m2 D1 and D8) with the irinotecan dose maintained 
(Dose Level 1, 40 mg/m2 D1 – D5) of a 21-day cycle.
The dose levels as per Table 5 should be used in the Phase 2 portion of the study when following the 
criteria for dose reductions (Table 2), the agent most likely to be the cause of toxicity (eg, irinotecan 
for diarrhea, eribulin for neuropathy or neutropenia) should be reduced by one dose level if these 
criteria are met. If in the investigator’s opinion both agents should be reduced this may be permitted 
after discussion with the Sponsor.
Table 5
Schedule A Dose Levels for Phase 2 
Dose Level
Eribulin mesilate (mg/m2)
Eribulin – Days 1 & 8
-4
0.4
-3
0.6
-2**
0.8
-1
1.1
1*
1.4
Irinotecan hydrochloride (mg/m2) – Days 1-5
-2
20
-1
30
1*
40
For subjects ≥12 months to < 25 years of age:
*Dose level 1 eribulin (1.4 mg/m2 Days 1 and 8) and irinotecan (40 mg/m2 Days 1 – 5). 
For subjects >6 to <12 months of age:
**Dose level -2 for eribulin (0.8 mg/m2 Days 1 and 8) and Dose level 1(40 mg/m2 Days 1 – 5) for irinotecan is 
maintained.
Do not re-escalate dose level after the dose level has been reduced.  If toxicities do not recover after 
two dose reductions, treatment with that agent must be discontinued.
Duration of Treatment
Subjects benefiting from study treatment in the opinion of the investigator will continue to receive 
treatment, until disease progression (according to RECIST 1.1), intolerable toxicity, subject 


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noncompliance with safety or efficacy assessments, initiation of another anticancer therapy, voluntary
discontinuation by the subject at any time, or study termination by the sponsor, whichever occurs first.
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 for up to 1 year, from start of study treatment after 
which any continued treatment would need to be discussed with the Sponsor.  
An Off-Treatment Visit will be performed within 28 days from last date of receiving study drug for 
subjects who discontinue study treatment. After discontinuation from study treatment and completing
the off-treatment visit, subjects will be followed up at least 4 weeks later (ie, greater than or equal to 28 
days after last dose but no more than 1 year) unless they withdraw consent.
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 (prophylactic granulocyte colony-stimulating factor should NOT be administered during 
Cycle 1) or for culture proven bacteremia or invasive fungal infection. 
Use of prophylactic antidiarrheal medication prior to dosing to ameliorate irinotecan hydrochloride-
associated diarrhea is allowed as per institutional guidelines (Benson, et al., 2004).
Subjects should not receive any other anticancer therapy (including chemotherapy, radiation therapy, 
cancer immunotherapy or targeted therapy) or investigational agents while receiving study drug.  If 
these therapies are administered, the subject will be discontinued from the study.
Assessments
Efficacy Assessments
Tumor response and progression will be evaluated according to RECIST 1.1 criteria.  Tumor 
assessments will be performed every 6 weeks until Week 12 and every 9 weeks thereafter on a fixed 
schedule.  For Phase 2, copies of scans for tumor assessments will be sent to an imaging core 
laboratory designated by the sponsor for quality assessment and archival and potential independent 
review. Computed tomography (CT) scans (with oral and intravenous contrast, unless clinically 
contraindicated) of chest, abdomen, and pelvis and other known sites of disease will be obtained at pre-
study (within 28 days prior to Cycle 1 Day 1), and every 6 weeks thereafter (counting from C1D1), 
irrespective of dose delays.  Magnetic resonance imaging (MRI) scans may be used instead of CT 
scans for abdomen and pelvis; however, chest must be assessed using CT.  If only chest CT is 
performed, then oral CT contrast is not required. The same method of assessment must be used at all 
time-points as used at pre-study. However, a chest x-ray may be used to identify new lesions in lieu of 
chest CT where appropriate (and after initial chest CT at screening). 
An exception to the requirement for following chest disease by CT will be allowed where subjects have
either non-parenchymal tumors, mediastinal and/or chest wall lesions. These may be assessed (at 
Screening and post-baseline) using contrast-enhanced MRI. However, a chest CT is required at 
Screening for all subjects, and lung parenchymal lesions should be followed using CT (as per standard 
practice). If there is either an equivocal new lung lesion based on MRI or symptoms suggesting a new 
lesion, these should also be confirmed with chest x-ray or CT.
After 12 weeks, subjects with CR, PR or stable disease (SD) may have imaging frequency decreased to 
every 9 weeks.  


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A bone scan (technetium-99m [Tc]-based scintigraphy, whole body bone MRI.
18F-sodium fluoride 
positron emission tomography [NaF PET]), or 18FDG-PET will be performed at screening, 
approximately every 24 weeks (in conjunction with a scheduled tumor assessment visit), and as 
clinically indicated.  Bone lesions must be followed with anatomic imaging.
Subjects with neuroblastoma (which can be included in phase 1 only) may have meta-
iodobenzulguanidine (MIBG) scintigraphy and bilateral bone marrow biopsies assessments performed 
at sites where this is standard practice, at the discretion of the treating physician. This is an optional 
assessment for neuroblastoma subjects. Subjects that have positive lesions by MIBG scan at screening 
(within 28 days prior to administration of study drug) are not required to undergo PET or technetium-
99m bone scans. After identifying positive lesions at screening, repeat measurements may be 
performed within 4 weeks after confirmation of a PR or CR or as clinically indicated. Subjects with 
positive urinary catecholamines at baseline, should be assessed in cases of CR (catecholamines should 
be negative to confirm CR). Subjects with MIBG positive lesions at screening will be evaluable for 
MIBG response using the revised version of the International Neuroblastoma Response Criteria 
(INRC) scoring (Brodeur GM, et al., 1993).
A brain scan (CT with contrast or MRI [pre- and post-gadolinium]) will be performed as clinically 
indicated to assess potential for 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 at all tumor 
assessment time points. For all subjects, a follow-up brain scan must be performed to confirm CR 
within 1 week following response confirmation, or if clinically indicated.  
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.
All subjects will have an Off-Treatment Visit within 28 days after the last dose of study medication.
Subjects that discontinue treatment without objective evidence of disease progression will continue to 
have tumor assessments performed as per the Schedule of Assessments until disease progression, 
death, or another anticancer therapy is initiated, whichever occurs first, unless the study is terminated.  
Follow-up data will be required unless consent is withdrawn.   
After data cut-off for the primary analysis, tumor assessments may be performed as clinically indicated 
using the investigator’s discretion, following the prevailing local standard of care.
Pharmacokinetic Assessments
Blood samples (2 mL per sample) will be collected for PK analysis of both irinotecan and its 
metabolite (SN-38), and eribulin as follows:
Phase 1 (Cycle 1):
Subjects ≥12 months of age and >10 kg:

Cycle 1, Day 1 at the end of the irinotecan infusion (irinotecan is administered first), and at the 
end of the eribulin infusion, then at 1, 2, 4, 6 and 24 hours post-eribulin infusion. Both 
irinotecan (and its metabolite, SN-38) and eribulin will be assayed.

At 72 and 120 hours post eribulin infusion, eribulin only will be assayed. 


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Please note that eribulin will be administered immediately after the end of the irinotecan infusion and 
PK blood sample draw.
Subjects <12 months of age as well as those ≥12 months of age and ≤10 kg (subjects under 6 kg will 
not have PK samples taken):

Cycle 1, Day 1: At the end of the irinotecan infusion (irinotecan is administered first), and then 
immediately after the end of the eribulin infusion (ie, 10 ± 5 minutes from the start of the 
eribulin infusion).

Cycle 1, Day 4 or 5: During the collection of the first twice weekly CBC sample.

Cycle 1, Day 8: Before the eribulin infusion and then immediately after the end of the eribulin 
infusion (ie, 10 ± 5 minutes from the start of the eribulin infusion).
Please note that eribulin will be administered immediately after the end of the irinotecan infusion and 
PK blood sample draw.
Phase 2 (Cycle 1):
Eribulin assay only: Cycle 1, Day 1 (at the end of the infusion, 0.5 to 6 hours and 24 to 120 hours after 
eribulin infusion) and on Cycle 1, Day 8 (pre dose of eribulin and at the end of the infusion). Subjects
who weigh under 6 kg will not have PK samples taken.
Safety Assessments
Safety assessments will consist of monitoring and recording all AEs (as per CTCAE v5.0 for both 
increasing and decreasing severity) and serious adverse events (SAEs); regular laboratory evaluation 
for hematology, blood chemistry, and urine values; periodic measurement of vital signs and the 
performance of physical examinations. 
Other Assessments
ECG monitoring to evaluate RR, PR, QRS, and QT intervals (QTc B or F) and QTc interval at pre 
study, during Cycle 1 (pre- and post-infusion Day 1 and Day 8) and as clinically indicated during 
subsequent cycles and during Off Treatment Visit (28 days after the last dose of drug).
Pharmacodynamic, Pharmacogenomic, and other Biomarker Assessments
Not applicable.
Bioanalytical Methods
Eribulin, irinotecan and its active metabolite, SN-38 will be analyzed using validated liquid 
chromatography with tandem mass spectrometry (LC-MS/MS) methods.
Statistical Methods
Primary Endpoints

Phase 1: The MTD/RP2D of eribulin mesilate in combination with irinotecan hydrochloride in 
pediatric subjects with relapsed/refractory solid tumors, excluding CNS tumors 

Phase 2: Objective response rate (ORR):  defined as the proportion of subjects achieving a best 
overall response of confirmed partial or complete response, as determined by investigator review.


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Secondary Endpoints 
Phase 1 & 2:

Safety and tolerability: adverse events (AEs), serious adverse events, clinical laboratory values, 
ECG parameters, vital sign measurements and physical examinations

The pharmacokinetic profile of eribulin, irinotecan and its active metabolite 
Phase 2:

Progression-free survival (PFS): defined as the time from the first dose date to the date of disease 
progression as determined by investigator review, or death

The Clinical Benefit Rate (CBR): defined as the proportion of subjects with best overall response 
(BOR) of CR, PR or durable SD based on RECIST 1.1 (durable SD >11 weeks)
Subjects aged >6 to <12 months and subjects ≥18 to ≤25 years will be included for descriptive 
purposes only and will not contribute to the full sample size analyses for this study. As subjects in the 
age group > 6 months to <12 months will receive approximately 75% of the RP2D of eribulin 
(rationale for lower dose is provided in Section 9.4.4 of the protocol) and the EMA PDCO requested 
that subjects in the age group ≥18 to ≤25 years old should not be included in the full sample size 
analyses.
Analysis Sets
Full Analysis Set (FAS) will consist of subjects who receive at least 1 dose of either study drug. 
Safety Analysis Set will consist of subjects who receive at least 1 dose of either study drug. 
Pharmacokinetic Analysis Set (PAS) will include subjects who documented dosing history and at 
least one post-dosing quantifiable drug concentration.
Dose Evaluable Set (DES) for Phase 1 will consist of all subjects who completed Cycle 1 treatment 
and were evaluated for DLT, and those who discontinued during Cycle 1 due to DLT. The DES will 
be used for evaluation of each dose level for dose-escalation.
Dose escalation (Phase 1)
The number of subjects with DLTs will be summarized for each dose level in each schedule being 
evaluated.  The incidence of adverse events will also be summarized for each dose level, by preferred 
term and body system.  Laboratory data and other safety assessments, such as vital signs, ECG, will be 
summarized for each dose level.
Primary Efficacy Analysis (Phase 2)
Efficacy analyses will be performed on the FAS.  Antitumor activity of eribulin mesilate in 
combination with irinotecan hydrochloride will be assessed by ORR, defined as the proportion of 
subjects with best response designation of CR or PR as per RECIST 1.1, during treatment, divided by 
the number of subjects in the FAS.
ORR will be estimated and summarized for each histology type.  A Simon two-stage design will be 
used within each histology type.  The following hypothesis will be tested at a one-sided 5% 
significance level:  


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Ho: p ≤ 30%         Vs            Ha: p ≥ 55%.
The first stage will enroll 9 subjects.  A futility analysis will be performed when the data for the 9 
subjects is available (investigator assessed responses).  If there are 2 or less responders among the 9 
subjects, the enrollment in this histology type will be stopped.  If there are 3 or more responders (CR or 
PR), the enrollment will continue to the second stage up to approximately 25 subjects.  If there are 12 
or more responders out of 25 subjects, the null hypothesis will be rejected.  Collect and hold of tumor 
scans will enable a possibility to confirm responses in case independent review is required.
In addition, ORR along with respective confidence interval will also be provided by histology.
Duration of response (DOR) will be calculated for responders and summarized descriptively.  DOR is
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).
Secondary Efficacy Analyses
PFS will be analyzed by Kaplan-Meier methodology and median PFS with 90% confidence interval 
will be presented.
Clinical benefit rate, defined as the proportion of subjects with best overall response (BOR) of CR, PR 
or durable SD based on RECIST 1.1, will be summarized descriptively. Durable SD is defined as SD 
with duration of more than 11 weeks.
Pharmacokinetic Analyses
Plasma concentrations of eribulin, irinotecan and its active metabolite SN-38 will be tabulated and 
summarized by dose level, day and time.  In Phase 1, PK parameters for eribulin, irinotecan and SN-38 
will be derived from plasma concentrations by noncompartmental analysis using actual times.  
Minimally, the following PK parameters will be calculated: maximum observed plasma concentration 
(Cmax), time of maximum observed concentration following drug administration (tmax), area under the 
concentration-time curve (AUC).  The Phase 2 PK data will be assessed using a PopPK approach, with 
the addition of Phase 1 data.
In Phase 1 the PK of both drugs (eribulin and irinotecan) will be assessed on C1D1 and in Phase 2 
eribulin will be assessed on C1D1 and C1D8.
Pharmacokinetic and Pharmacodynamic Analyses
Exploratory/graphical analysis will be conducted for PK/ pharmacodynamic (PD) evaluations, ie, dose 
and/or exposure effect relationships will be explored for the effects of eribulin mesilate on tumor 
responses as determined by RECIST 1.1 (CR, PR and SD), PFS and ORR, as well as AEs/dose 
reductions, and may be followed by model-based analysis. In addition the effects of eribulin mesylate 
administration on absolute neutrophil count (ANC) may be evaluated using a semi-physiological model 
for hematological toxicity. Further details will be documented separately in a population analysis plan 
(PAP).
Safety Analyses
The primary endpoint for Phase 1, ie, the incidence of DLTs during Cycle 1 will be summarized by 
dose cohort for the DES using frequency and percentage. 
Additionally, toxicity in Phase 2 for the Safety Analysis Set will be monitored on an ongoing basis. If
the number of AEs that would have qualified as DLTs on the Phase 1 portion exceeds 1/3, a meeting 


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with the investigators will be convened to determine if the dose should be lowered. The rule of one-
third (1/3) will be applied to the number of subjects in an increment of 3 subjects at the same dose level 
(eg, 3, 6, 9 subjects).  Likewise, if ongoing moderate toxicities develop into “intolerable Grade 2” 
events, the recommended Phase 2 dose may also be re-evaluated in consultation with the protocol 
investigators.
All evaluation of safety other than the Phase 1 primary objective in DLT evaluation will be performed 
on the Safety Analysis Set.  Safety data that will be evaluated include adverse events, clinical 
laboratory results, physical examination results, ECG, and vital signs.
Safety analyses will be performed on all subjects who received at least 1 dose of study drug. It will 
include safety data collected from screening to data cutoff and the incidence and severity of AEs, 
clinical laboratory test results, physical examination findings, 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.  
All AEs and SAEs will be listed.  Treatment-emergent AEs, treatment-related TEAEs, and SAEs will 
be summarized by cohort, system organ class, and preferred term and CTCAE v5.0 grade.  QT 
intervals will be measured from Lead II and will be corrected for heart rate (QTc) using Fridericia's 
(QTcF) correction factor.  The primary QTc parameter will be QTcF.  Secondary parameters will be 
QTcB, QT, QRS, and heart rate.
Interim Analyses
There will be an interim analysis to define MTD and RP2D prior to initiating Phase 2 of the study.  In 
Phase 2, for each histology (RMS, NRSTS and EWS), there will be 1 futility analysis of efficacy: this 
is planned after data from the first 9 subjects is available.  At the futility analysis, if there are 2 or 
fewer responses then enrollment to that histology will be discontinued.  Enrollment to that histology 
will be suspended during the futility analysis (eg, from when the 9th subject is enrolled up until 24 
weeks, or until 3 responses have been achieved).  An assessment of tolerability will also be conducted 
at this time.  
Sample Size Rationale
Phase 1: Up to 6 subjects can be enrolled in up to 3 dose levels, there are 2 schedules being evaluated 
(Schedule A and Schedule B).  Therefore, a maximum of 36 subjects are anticipated to be enrolled on 
this phase (not including subjects <12 months).
Phase 2: Approximately 75 subjects (approximately 25 in each histology group) will be enrolled.  A 
Simon two-stage design will be used for each histology group.  The following hypothesis will be tested 
at a one-sided 5% significance level:  
Ho: p ≤30%         Vs            Ha: p ≥ 55%.
In the first stage, 9 subjects will be accrued.  If there are 2 or fewer responses in these 9 subjects, the 
enrollment to this histology type (RMS, NRSTS, and EWS) will be stopped.  Otherwise, approximately 
16 additional subjects will be enrolled in the second stage for a total of approximately 25 subjects. The 
null hypothesis will be rejected if 12 or more responses are observed in 25 subjects.  This design yields 
a type I error rate of 0.05 (one-sided) and power of 80% when the true response rate is 55%. Note:


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Subjects aged >6 to <12 months and subjects ≥18 to ≤25 years will be included for descriptive 
purposes only and will not contribute to the full sample size analyses for this study.


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3
TABLE OF CONTENTS
1
TITLE PAGE ................................................................................................................1
2
CLINICAL PROTOCOL SYNOPSIS..........................................................................19
3
TABLE OF CONTENTS.............................................................................................42
4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................47
5
ETHICS.......................................................................................................................49
5.1
Institutional Review Boards/Independent Ethics Committees.............................49
5.2
Ethical Conduct of the Study..............................................................................49
5.3
Subject Information and Informed Consent ........................................................50
6
INVESTIGATORS AND STUDY PERSONNEL .......................................................51
7
INTRODUCTION.......................................................................................................51
7.1
Childhood Soft Tissue Sarcoma .........................................................................51
7.1.1
Current Therapeutic Options.....................................................................51
7.1.1.1
Treatment for Rhabdomyosarcoma ...................................................52
7.1.1.2
Treatment Strategies for Non-Rhabdomyosarcoma Soft Tissue 
Sarcoma............................................................................................53
7.1.1.3
Treatment Strategies for Ewing Sarcoma ..........................................53
7.1.2
Fulfillment of a Therapeutic Need ............................................................54
7.1.3
E7389 (eribulin mesilate) .........................................................................54
7.1.3.1
Mechanism of Action........................................................................54
7.1.3.2
Regulatory Status..............................................................................55
7.1.3.3
Clinical Experience with Eribulin .....................................................55
7.1.3.3.1
Adult Population.........................................................................55
7.1.3.3.2
Pediatric Population....................................................................56
7.1.3.4
Non-Clinical Evidence for Activity of Eribulin in Pediatric 
Sarcomas ..........................................................................................56
7.1.4
Irinotecan Hydrochloride..........................................................................57
7.2
Study Rationale..................................................................................................57
8
STUDY OBJECTIVES................................................................................................58
8.1
Primary Objectives.............................................................................................58
8.2
Secondary Objectives.........................................................................................58
8.3
Exploratory Objectives.......................................................................................58
9
INVESTIGATIONAL PLAN ......................................................................................59
9.1
Overall Study Design and Plan...........................................................................59
9.1.1
Pretreatment Phase ...................................................................................60
9.1.1.1
Screening Period...............................................................................61
9.1.2
Treatment Phase.......................................................................................61


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9.1.3
Follow-Up Period.....................................................................................61
9.2
Discussion of Study Design................................................................................62
9.3
Selection of Study Population ............................................................................63
9.3.1
Inclusion Criteria......................................................................................63
9.3.2
Exclusion Criteria.....................................................................................66
9.3.3
Removal of Subjects From Therapy or Assessment ..................................68
9.4
Treatments.........................................................................................................69
9.4.1
Treatments Administered..........................................................................69
9.4.2
Identity of Investigational Products ..........................................................78
9.4.2.1
Chemical Name, Structural Formula of Eribulin Mesilate .................78
9.4.2.2
Irinotecan Hydrochloride ..................................................................78
9.4.2.3
Labeling for Investigational Products................................................79
9.4.2.4
Storage Conditions ...........................................................................79
9.4.2.4.1
General .......................................................................................79
9.4.2.4.2
Eribulin Mesilate.........................................................................79
9.4.2.4.3
Irinotecan Hydrochloride ............................................................79
9.4.3
Method of Assigning Subjects to Treatment Groups.................................80
9.4.4
Selection of Doses in the Study ................................................................80
9.4.5
Selection and Timing of Dose for Each Subject........................................81
9.4.6
Prior and Concomitant Therapy................................................................81
9.4.6.1
Drug-Drug Interactions.....................................................................82
9.4.6.1.1
Eribulin Mesilate.........................................................................82
9.4.6.1.2
Irinotecan Hydrochloride ............................................................82
9.4.6.2
Prohibited Concomitant Therapies and Drugs ...................................83
9.4.7
Treatment Compliance .............................................................................83
9.4.8
Drug Supplies and Accountability ............................................................83
9.5
Study Assessments.............................................................................................84
9.5.1
Assessments .............................................................................................84
9.5.1.1
Demography.....................................................................................84
9.5.1.2
Baseline Assessments .......................................................................85
9.5.1.2.1
Medical History and Physical Examinations................................85
9.5.1.3
Efficacy Assessments .......................................................................85
9.5.1.3.1
Tumor Response Assessments.....................................................85
9.5.1.3.2
Pharmacokinetic Assessments.....................................................87
9.5.1.3.3
Pharmacodynamic, Pharmacogenomic, and Other Biomarker, 
Assessments................................................................................88
9.5.1.3.4
Bioanalytical Methods ................................................................88
9.5.1.4
Safety Assessments...........................................................................88


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9.5.1.4.1
Adverse Events and Events Associated with Special Situations...88
9.5.1.4.2
Serious Adverse Events and Events Associated with Special 
Situations....................................................................................90
9.5.1.4.3
Laboratory Measurements...........................................................91
9.5.1.4.4
Vital Signs and Weight Measurements........................................92
9.5.1.4.5
Physical Examinations ................................................................92
9.5.1.4.6
Electrocardiograms .....................................................................92
9.5.1.4.7
Other Safety Assessments ...........................................................93
9.5.1.5
Schedule of Procedures/Assessments................................................93
9.5.2
Appropriateness of Measurements..........................................................104
9.5.3
Reporting of Serious Adverse Events, Pregnancy, and Events 
Associated with Special Situations .........................................................104
9.5.3.1
Reporting of Serious Adverse Events..............................................104
9.5.3.2
Reporting of Pregnancy and Exposure to Study Drug Through 
Breastfeeding..................................................................................105
9.5.3.3
Reporting of Events Associated with Special Situations..................105
9.5.3.3.1
Reporting of Adverse Events Associated With Study Drug 
Overdose, Misuse, Abuse, or Medication Error.........................105
9.5.3.4
Expedited Reporting .......................................................................106
9.5.3.5
Regulatory Reporting of Adverse Events ........................................106
9.5.4
Completion/Discontinuation of Subjects.................................................106
9.5.5
Abuse or Diversion of Study Drug..........................................................107
9.6
Data Quality Assurance....................................................................................107
9.6.1
Data Collection.......................................................................................107
9.6.2
Clinical Data Management .....................................................................107
9.7
Statistical Methods...........................................................................................107
9.7.1
Statistical and Analytical Plans...............................................................108
9.7.1.1
Study Endpoints..............................................................................108
9.7.1.1.1
Primary Endpoints ....................................................................108
9.7.1.1.2
Secondary Endpoints.................................................................108
9.7.1.2
Definitions of Analysis Sets............................................................108
9.7.1.3
Subject Disposition.........................................................................109
9.7.1.4
Demographic and Other Baseline Characteristics............................109
9.7.1.5
Prior and Concomitant Therapy ......................................................109
9.7.1.6
Efficacy Analyses...........................................................................109
9.7.1.6.1
Primary Efficacy Analysis.........................................................109
9.7.1.6.2
Secondary Efficacy Analyses....................................................110


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9.7.1.7
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Analyses..............................................................110
9.7.1.7.1
Pharmacokinetic Analyses ........................................................110
9.7.1.7.2
Pharmacokinetic and Pharmacodynamic Analyses ....................110
9.7.1.8
Safety Analyses ..............................................................................111
9.7.1.8.1
Extent of Exposure....................................................................111
9.7.1.8.2
Adverse Events.........................................................................111
9.7.1.8.3
Laboratory Values.....................................................................112
9.7.1.8.4
Vital Signs ................................................................................112
9.7.1.8.5
Electrocardiograms ...................................................................112
9.7.1.8.6
Other Safety Analyses...............................................................113
9.7.2
Determination of Sample Size ................................................................113
9.7.3
Interim Analysis.....................................................................................114
9.7.4
Other Statistical/Analytical Issues ..........................................................114
9.7.5
Procedure for Revising the Statistical Analysis Plan...............................114
10
REFERENCE LIST...................................................................................................115
11
PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE PROCEDURES).....120
11.1
Changes to the Protocol....................................................................................120
11.2
Adherence to the Protocol................................................................................120
11.3
Monitoring Procedures.....................................................................................120
11.4
Recording of Data............................................................................................121
11.5
Identification of Source Data............................................................................121
11.6
Retention of Records........................................................................................121
11.7
Auditing Procedures and Inspection .................................................................122
11.8
Handling of Study Drug ...................................................................................122
11.9
Publication of Results ......................................................................................122
11.10 Disclosure and Confidentiality .........................................................................123
11.11 Discontinuation of Study..................................................................................123
11.12 Subject Insurance and Indemnity......................................................................123
12
APPENDICES...........................................................................................................124
LIST OF IN-TEXT TABLES
Table 1
Criteria for Administration of Study Medication.....................................30
Table 2
Criteria for Reduction of Study Medication to the Next Lowest Dose 
Level......................................................................................................32
Table 3
Criteria for Discontinuation of Study Medication....................................33
Table 4
Study Medication Dose Levels by Schedule for Phase 1 .........................33


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Table 5
Schedule A Dose Levels for Phase 2.......................................................34
Table 6
Principles of RMS, NRSTS and EWS Treatment....................................52
Table 7
Criteria for Administration of Study Medication.....................................72
Table 8
Criteria for Reduction of Study Medication to the Next Lowest Dose 
Level......................................................................................................74
Table 9
Criteria for Discontinuation of Study Medication....................................75
Table 10
Study Medication Dose Levels by Schedule for Phase 1 .........................76
Table 11
Schedule A Dose Levels for Phase 2.......................................................77
Table 12
Clinical Laboratory Tests........................................................................91
Table 13
Schedule of Procedures/Assessments in Study E7389-G000-213:  
Phase 1...................................................................................................94
Table 14
Schedule of Procedures/Assessments in Study E7389-G000-213:  
Phase 2...................................................................................................99
LIST OF IN-TEXT FIGURES
Figure 1
Study E7389-G000-213 Design: Phase 2 ................................................60
LIST OF APPENDICES
Appendix 1
Sponsor’s Grading for Laboratory Values.............................................125
Appendix 2
Measurements of Performance Status ...................................................128
Appendix 3
Modified “Balis” Pediatric Scale of Peripheral Neuropathies................129


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4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
AE
adverse event
ALT
alanine aminotransferase
ANC
absolute neutrophil count
AST
aspartate aminotransferase
AUC
area under the concentration-time curve
BOR
best overall response
CBR
clinical benefit rate
CNS
central nervous system
COG
Children’s Oncology Group
CR
complete response
CRA
clinical research associate
CT
computerized tomography
CTCAE
Common Terminology Criteria for Adverse Events
CYP3A4
cytochrome P450 3A4
DES
Dose Evaluable Set
DLT
dose limiting toxicity
DOR
duration of response
ECG
electrocardiogram
EWS
Ewing sarcoma
FAS
Full Analysis Set
FDG
fluorodeoxyglucose
GCP
Good Clinical Practice
GFR
glomerular filtration rate
GVHD
graft versus host disease
Hb
hemoglobin
HR
hazard ratio
ICF
informed consent form
ICH
International Council on Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IRB
Institutional Review Board
IV
intravenous
LC-MS/MS
liquid chromatography with tandem mass spectrometry


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Abbreviation
Term
LSLV
last subject last visit
MIBG
meta-iodobenzulguanidine
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
NRSTS
non-rhabdomyosarcoma soft tissue sarcoma
ORR
objective response rate
PAS
Pharmacokinetic Analysis Set
PD
pharmacodynamic
PET
positron emission tomography
PFR
progression-free rate
PFS
progression-free survival
PK
pharmacokinetic
PPTP
Pediatric Preclinical Testing Program
PR
partial response
RMS
rhabdomyosarcoma
RP2D
recommended Phase 2 dose
SAE
serious adverse event
SAP
statistical analysis plan
SD
stable disease
SmPC
Summary of Product Characteristics
STS
soft tissue sarcoma
TEAE
treatment-emergent adverse event
ULN
upper limit of normal
VAC
vinca alkaloid with actinomycin-D and cyclophosphamide
XRT
radiotherapy


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5
ETHICS
5.1
Institutional Review Boards/Independent Ethics Committees
The protocol, informed consent form (ICF), and appropriate related documents must be 
reviewed and approved by an Institutional Review Board (IRB) or Independent Ethics 
Committee (IEC) constituted and functioning in accordance with ICH E6 (Good Clinical 
Practice), Section 3, and any local regulations (eg, 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 
last subject/last visit.  It is estimated that the study duration will be 42 months and will end in 
Sept 2021.  
5.2
Ethical Conduct of the Study
This study will be conducted in accordance with standard operating procedures of the 
sponsor (or designee), which are designed to ensure adherence to GCP guidelines as required 
by the following:

Principles of the World Medical Association Declaration of Helsinki 2013

ICH E6 Guideline for GCP (CPMP/ICH/135/95) of the European Agency for the 
Evaluation of Medicinal Products, Committee for Proprietary Medicinal Products, 


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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 Trial 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 and/or the subject’s parents or guardian 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.  Assent, 
when appropriate, will be obtained according to institutional guidelines.  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 and/or the subject’s parents or guardian 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 and/or the subject’s parents or if a legally acceptable
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 and/or the subject’s parents or guardian, and 
after the subject and/or the subject’s parents or guardian 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 and/or the subject’s parents or guardian 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 up to 50 investigational sites.
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 Sarcoma
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 rhabodomyosarcoma (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 STS.
Non-rhabdomyosarcoma soft tissue sarcoma (NRSTS) is a heterogeneous group of tumors 
derived from mesenchymal tissue.  NRSTS is discussed as a unique group due to the rarity of 
each histopathological subtype, and accounts for about 3% to 5% of all childhood 
malignancies. Although NRSTS can occur at any age group, the disease more commonly 
occurs in children above the age of 5 years.  Certain subtypes, such as synovial sarcoma and 
alveolar soft part sarcoma, straddle both age groups (Ferrari, et al., 2011). Fibrosarcoma, 
malignant peripheral nerve sheath tumor, and other fibromatous neoplasms account for 10% 
to 20% of childhood STS.  
“Other specified” STS is a heterogeneous subgroup accounting for approximately 25% of 
cases with the most frequently reported histological types including synovial sarcoma and 
leiomyosarcoma (LMS), whereas the ‘unspecified’ STSs account for approximately 10% of 
the total number of STS cases (Stiller, et al., 2001).
7.1.1
Current Therapeutic Options
The aim of treatment of sarcoma in all age groups is broadly similar, with the goal of primary 
treatment being complete surgical excision (Table 6).  If surgery is not feasible, then 
radiotherapy should be considered.  In RMS, multi-agent chemotherapy should be 
administered as part of primary treatment, either in the adjuvant or neoadjuvant setting 
(Van Gaal, et al., 2012).  However, the role of adjuvant or neoadjuvant chemotherapy in the 
primary treatment of NRSTS has not been established by randomized trials.
Treatments for relapsed/refractory disease are broadly similar across the tumor types (Table 
6).  Further information on treatment options for each tumor types is provided below.


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Table 6
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
7.1.1.1
Treatment 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 gold standard first-
line chemotherapy treatment for RMS is a vinca alkaloid with actinomycin-D and 
cyclophosphamide (VAC).  The standard approach at first relapse is 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 vincristine, or 
temozolomide, 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 adverse clinical outcome 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 usually no longer of curative intent.  The choice of agent(s) is based 
upon the treatment options available at the institution including access to clinical trials, 
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.  
The 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 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 
unresectable or metastatic disease, but none of these regimens improved the outcome for 
these subjects.
7.1.1.3
Treatment Strategies for Ewing Sarcoma
Standard first-line treatment for patients with metastatic EWS is induction VIDE 
(Vincristine, ifosfamide, Doxorubicin, Etoposide) followed either by maintenance VAC or 
VAI.  In patients who relapse after initial therapy the disease is almost 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.  


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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.
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 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 mesilate)
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 mesilate induces formation of nonproductive tubulin aggregates, lowering 
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 


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broader spectrum of antitumor activity in childhood cancers than the taxanes, even in the 
presence of multidrug resistance (Cortes, et al., 2011).
7.1.3.2
Regulatory Status
Eribulin mesilate (E7389); HALAVEN is indicated in the EU for the treatment of adult 
patients with locally advanced or metastatic breast cancer who have progressed after at least 
one chemotherapeutic regimen for advanced disease and for adult patients with unresectable 
liposarcoma who have received prior anthracycline containing therapy (unless unsuitable) for 
advanced or metastatic disease (Halaven Summary of Product Characteristics, 2016).
Eribulin has recently been approved by the FDA (28 Jan 2016) and the EMA (02 May 2016) 
for the treatment of unresectable/metastatic liposarcoma following the results of ‘A 
randomized trial of eribulin versus dacarbazine in advanced leiomyosarcoma and 
liposarcoma’.  Eribulin demonstrated an overall survival (OS) benefit over dacarbazine, 
hazard ratio (HR) 0.77 P=0.0169, with an OS of 13.5 months for subjects on the eribulin arm 
compared with 11.5 months for subjects on the dacarbazine arm (Schöffski, et al., 2016; Eisai 
Study, E7389-G000-309).  In liposarcoma subjects specifically, eribulin demonstrated an OS 
benefit over dacarbazine, HR 0.51, with an OS of 15.6 months for subjects on the eribulin 
arm compared with 8.4 months for subjects on the dacarbazine arm.  
7.1.3.3
Clinical Experience with Eribulin
7.1.3.3.1
ADULT POPULATION
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 adipocytic (ADI) (46.9%, 95% two-sided confidence interval [CI]; 29.1, 65.3) and LMS 
(31.6%, 95% two-sided CI; 17.6, 48.7) strata.  The study concluded that eribulin has activity 
in pretreated subjects with ADI sarcoma and leiomyosarcoma (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). 


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Exploratory subgroup analyses of OS and PFS by histology showed that eribulin significantly
favored subjects with the ADI (adipocytic, also known as liposarcoma) 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.  The OS (HR 0.90, 95% CI 0.69, 1.18) and PFS (1.05, 95% CI 0.81, 1.35) 
differences between the treatment arms in subjects with LMS histology did not reach 
statistical significance (HALAVEN USPI, 2015).  This is the first time any agent has 
demonstrated improved OS in late line adult liposarcoma.  
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).  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 PFR12wks 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 other 
(OTH) stratum, and 51.0% (95% CI: 36.6, 65.2) in total (Study E7389-J088-217 Clinical 
Study Report). 
7.1.3.3.2
PEDIATRIC POPULATION
A Phase 1 study (Study E7389-A001-113) has been conducted by Eisai.  This was an open 
label, multi-center, dose escalation study of eribulin mesilate in pediatric subjects with 
recurrent or refractory solid tumors (excluding CNS), including lymphomas.  This study 
found that eribulin mesilate was well tolerated in this pediatric population and that the 
MTD/RP2D of eribulin mesilate in pediatric subjects was 1.4 mg/m2 on Day 1 and Day 8 of a 
21-Day cycle(same as the adult dose). The primary DLT was neutropenia. (Schafer, et al., 
2018).  
7.1.3.4
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: < 0.1 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 somewhat 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 
29 of 35 (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 


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(MCRs) were observed in 6 of 7 RMS xenograft models, 1 of 2 Wilms’ tumors, 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).  
7.1.4
Irinotecan Hydrochloride
The activity of irinotecan in pediatric solid tumors has been investigated since shortly after 
its approval for colon cancer in 1996.  Responses have been noted in RMS and Ewing’s 
sarcoma.  Although early trials showed single agent response rates as high as 38% 
(Bisogno, et al., 2006), larger trials have shown lower response rates, under 10% 
(Bomgaars, et al., 2007).  Preclinical as well as clinical studies have demonstrated substantial 
improvement in activity when irinotecan is combined with other agents, such as the 
microtubule inhibitor vincristine, with one study (Pappo, et al., 2007) reporting a 70% 
response rate in RMS for the combination.  This led to a Phase 3 trial comparing the 
outcomes of untreated RMS patients with vincristine, Actinomycin D and cyclophosphamide 
(VAC, the current standard of care) with VAC alternating with vincristine and irinotecan 
(VAC/VI). Results from this study showed that VAC/VI did not significantly improve OS or 
EFS compared with VAC (2-year EFS 64% in each group; 2-year OS 86% and 84% in 
VAC/VI and VAC groups, respectively; Hawkins, et al., 2014).
Various schedules of irinotecan have been investigated in pediatric patients, with every 
3 week dosing and daily times 5 every 3 weeks, or daily times 5 for 2 weeks in a row, with a 
one week break.  Anti-tumor activity is similar with different schedules, but toxicity profiles 
can be markedly different (Mascarenhas, et al., 2010); Less frequent dosing results in more 
hematologic toxicity and alopecia, whereas more frequent dosing results in more 
gastrointestinal toxicity, including diarrhea and less neutropenia.  After up to a year of 
induction cytotoxic chemotherapy, pediatric patients tend to tolerate the daily dosing 
regimens better, and they have become standard salvage regimens for several pediatric 
tumors (Wagner, 2015). 
7.2
Study Rationale
Anti-microtubule agents have shown moderate single agent activity against RMS both in the 
clinic and in the laboratory.  This activity is significantly enhanced in combination regimens 
with alkylating agents (cyclophosphamide, ifosfamide) or camptothecins (irinotecan, 
topotecan).  The hypothesis behind this trial is that substituting the antimicrotubule agent, 
eribulin, which is more potent in preclinical models, for vincristine as a combination partner 
with irinotecan will result in substantial efficacy against RMS, NRSTS and EWS. It should 
be possible to use a regimen of eribulin and irinotecan (ie, replace vincristine) considering 
that the primary toxicity profiles of each individual agent do not overlap the synergy 


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observed when irinotecan is combined with a microtubule inhibitor, and the activity observed 
for eribulin in the solid tumor panels of the PPTP (described above) is comparable or 
superior to that observed previously for vincristine.
8
STUDY OBJECTIVES
8.1
Primary Objectives

Phase 1: To determine the maximum tolerated dose (MTD) and Recommended Phase 2 
Dose (RP2D) of eribulin mesilate in combination with weekly and daily irinotecan 
hydrochloride in pediatric subjects with relapsed/refractory solid tumors, excluding CNS

Phase 2: To assess the objective response rate (ORR) and duration of response (DOR) of 
eribulin mesilate in combination with irinotecan hydrochloride in pediatric subjects with 
RMS, NRSTS, and EWS
8.2
Secondary Objectives
Phase 1:

To assess the safety and tolerability of eribulin mesilate in combination with irinotecan 
hydrochloride in pediatric subjects

To determine the optimal schedule of irinotecan hydrochloride when administered with 
standard schedule (Day 1 and 8) of eribulin mesilate in pediatric subjects
Phase 2:

To assess the Progression Free Survival (PFS) of eribulin mesilate in combination with 
irinotecan hydrochloride in pediatric subjects 

To assess the Clinical Benefit Rate (CBR) at 12 weeks of eribulin mesilate in combination 
with irinotecan hydrochloride in pediatric subjects 
Phases 1 & 2:

To evaluate the pharmacokinetic profile of eribulin, irinotecan and its active metabolite 
and compare to appropriate historical data
8.3
Exploratory Objectives
Phases 1 & 2:

To explore the relationship between model-derived exposure to eribulin and the active 
metabolite for irinotecan (SN 38) in terms of area under the curve and AEs and efficacy 
endpoints using a model-based approach


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9
INVESTIGATIONAL PLAN
9.1
Overall Study Design and Plan
E7389-G000-213 is a Phase 1/2, multicenter, open-label study to assess the safety and 
efficacy of eribulin mesilate in combination with irinotecan hydrochloride in pediatric 
subjects.
The study is divided into 2 Phases:

Phase 1: Will determine the MTD/RP2D and optimal schedule of eribulin mesilate in 
combination with irinotecan hydrochloride in pediatric subjects with relapsed/refractory 
solid tumors, excluding CNS.

Phase 2: Will evaluate the safety and efficacy of eribulin mesilate in combination with 
irinotecan hydrochloride in pediatric subjects with relapsed/refractory RMS, NRSTS and 
EWS, using the combination dose and schedule determined in Phase 1.
Phase 1
Eribulin mesilate will be administered as an intravenous (IV) infusion on Days 1 and 8 of 
each 21 day cycle, at the RP2D determined in the single-agent dose finding study 
E7389-A001-113 (1.4 mg/m2) in pediatric subjects with relapsed/refractory solid tumors, 
excluding CNS.
Irinotecan hydrochloride will be administered as an IV infusion using 2 different dose 
schedules:

Days 1-5 of a 21 day cycle at the following doses; 20 mg/m2 and 40 mg/m2 (Schedule A).
And 

Days 1 and 8 of a 21 day cycle at the following doses; 100 mg/m2 and 125 mg/m2
(Schedule B).
Subjects will be allocated in an alternate fashion to either Schedule A or Schedule B by the 
Sponsor, ie every other subject will be allocated to Schedule A until an MTD is reached. 
Subjects <12 months will be allocated to Schedule A only and at one dose-level behind 
subjects ≥12 months.  These subjects are included for descriptive purposes only and will not 
contribute to the determination of the MTD/RP2D for this study.  
Phase 2
Pediatric subjects with relapsed/refractory RMS, NRSTS or EWS will be enrolled on to 
either the RMS, NRSTS or EWS histology cohort, and the proportion of the responders ORR 
will be estimated at the RP2D determined in the Phase 1 portion of the study. As per 
protocol amendment #5, this is Schedule A Dose Level 1 eribulin (1.4 mg/m2) Day 1 and 
Day 8 and irinotecan (40 mg/m2) Days 1-5.  Subjects will continue with their treatment until 


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progression of disease, intolerable toxicity or withdrawal of consent.  As per Amendment 6, 
subjects aged >6 months and <12 months will be enrolled to Schedule A with a modified 
dose of eribulin Dose Level -2 (0.8 mg/m2 Day 1 and Day 8) with the irinotecan dose 
maintained Dose Level 1 (40 mg/m2 Day 1 – Day 5) of a 21-day cycle.
Each tumor histology type will have a futility analysis after 9 subjects are treated.  
Enrollment will be suspended for up to 24 weeks after 9 subjects have been enrolled to 
complete ORR assessment.  If more than 2 responses (partial responses [PR] or complete 
responses [CR]) are observed and documented in that histology type, then recruitment will 
continue, and that histology type will expand to approximately 25 subjects in total.  If ≤2 
responses are observed, enrollment to that histology type will close.  
The study will enroll a minimum of 27 (ie, 9 for each negative histology type), and a total of
approximately 75 (ie, approximately 25 for each positive histology type) subjects.
The end of the study will be the time of the last subject/last visit.  However, subjects will 
continue to receive study treatment as long as they demonstrate clinical benefit.
An overview of the study design (Phase 2) is presented in Figure 1.
Figure 1
Study E7389-G000-213 Design: Phase 2
EWS = Ewing sarcoma, NRSTS = non-rhabdomyosarcoma soft tissue sarcoma, RMS = rhabdomyosarcoma
9.1.1
Pretreatment Phase
The Pretreatment Phase will last for up to 28 days and will include a Screening Period and a 
Baseline Period.  Day -28 to -1, computed tomography (CT) / magnetic resonance imaging 


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(MRI) scans must be performed within 28 days prior to administration of study drug.  All 
clinical and laboratory test results to determine eligibility must be performed within 7 days 
prior to administration of study drug, unless otherwise indicated.
9.1.1.1
Screening Period
Screening will occur between Day -28 and Day -1.  The purpose of the Screening Period is to 
obtain informed consent and to establish protocol eligibility.  Informed consent can be 
obtained from Day -29 after the study has been fully explained to each subject and/or the 
subject’s parents or guardian, and before the conduct of any screening procedures or 
assessments.  Assent, when appropriate, will be obtained according to institutional 
guidelines.  Subjects must be willing to comply with all aspects of the protocol.  Procedures 
to be followed when obtaining informed consent are detailed in Section 5.3.
The Screening Disposition case report form (CRF) page must be completed to indicate 
whether the subject is eligible to participate in the study and to provide reasons for screen 
failure, if applicable.
9.1.2
Treatment Phase
The Treatment Phase will commence from Day 1 (D1) of Cycle 1 (C1).  In Phase 1 subjects 
will receive eribulin mesilate by IV infusion on Days 1 and 8 of a 21-day cycle together with 
IV irinotecan hydrochloride administered on either:

Days 1-5 
or 

Days 1 and 8 of a 21 day cycle.
In Phase 2, the RP2D determined from Phase 1 (eribulin 1.4 mg/m2 D1 and D8 with 
irinotecan 40 mg/m2 D1 – D5 of a 21- day cycle) should be used.  
The Schedule of Assessments should be followed for the subjects’ visits and efforts should 
be made to conduct study visits on the scheduled day (+/- 3 days).
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 for up to 1 year, from start of study 
treatment, after which any continued treatment would need to be discussed with the Sponsor.  
9.1.3
Follow-Up Period
All subjects will have an off-treatment visit within 28 days after the last dose of study 
medication. After discontinuation from study treatment and completing the off-treatment 
visit, subjects will be followed up at least 4 weeks later (ie, greater than or equal to 28 days 
after last dose but no more than 1 year) unless they withdraw consent.  Subjects that 
discontinue treatment without objective evidence of disease progression will continue to have 
tumor assessments performed as per the Schedule of Assessments until disease progression, 


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death, or another anticancer therapy is initiated, whichever occurs first, unless the study is 
terminated.  This follow-up data will be required unless consent is withdrawn.
9.2
Discussion of Study Design
Study E7389-G000-213 is to be conducted as a multicenter, single arm study evaluating the 
safety and efficacy of eribulin mesilate in combination with irinotecan in children with 
refractory or recurrent solid tumors.
This study will follow on from Study E7389-A001-113, which has the primary aim of 
establishing the Maximum Tolerated Dose (MTD)/Recommended Phase 2 dose (RP2D) of 
eribulin mesilate in pediatric subjects with relapsed/refractory solid tumors, excluding CNS.  
The aim of study E7389-G000-213 is two-fold:
Phase 1: To determine the MTD/Recommended Phase 2 Dose (RP2D) and optimal schedule 
of eribulin mesilate in combination with weekly or daily irinotecan hydrochloride in pediatric 
subjects with relapsed/refractory solid tumors, excluding, CNS.
Phase 2: To assess the objective response rate (ORR) and duration of response (DOR) of 
eribulin mesilate in combination with irinotecan hydrochloride in pediatric subjects with 
relapsed/refractory RMS, NRSTS and EWS.
The maximum number of subjects is approximately111:  Up to 36 subjects in Phase 1 and 
approximately 75 subjects in Phase 2. The sample size does not include subjects <12 
months.
In Phase 1, eribulin mesilate will be administered as an intravenous (IV) infusion on Days 1 
and 8 of each 21-day cycle at the dose determined by COG study ADVL1314 (Eisai Study 
E7389-A001-113), 1.4 mg/m2, together with IV irinotecan hydrochloride administered in two 
different dose schedules:
Schedule A

Irinotecan hydrochloride 20 mg/m2 Days 1-5 of a 21-day cycle 

Irinotecan hydrochloride 40 mg/m2 Days 1-5 of a 21-day cycle
Schedule B

Irinotecan hydrochloride 100 mg/m2 Day 1 and Day 8 of a 21-day cycle

Irinotecan hydrochloride 125 mg/m2 Day 1 and Day 8 of a 21-day cycle
These doses of irinotecan are derived from studies looking at the MTD of single agent 
irinotecan or irinotecan combinations administered at the various corresponding schedules 
(Blaney, et al., 2001; Vassal, et al., 2003; Casey, et al., 2009).


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The rationale for the two different dose schedules of irinotecan is that the dose-limiting 
toxicity (DLT) of irinotecan is schedule–dependent. When given on a weekly or every 2 
week or 3 week schedule, the DLT is typically neutropenia.  When given on a more frequent 
schedule i.e. daily, the DLT tends to be gastrointestinal toxicity such as diarrhea.  After 
induction therapy, which can last for up to 1 year, pediatric patients may have more 
sensitivity to agents with a hematologic toxicity, and alternate schedules of irinotecan have 
been developed in children with relapsed or refractory sarcoma.  When combined with 
temozolomide, daily irinotecan (either 10 days every 3 weeks or 5 days every 3 weeks) has 
equivalent activity to single agent irinotecan but superior hematologic tolerance 
(Wagner, et al., 2004; Casey, et al., 2009).  
The Phase 1 portion of this study will evaluate two schedules of irinotecan; weekly dosing 
(Schedule B), or daily dosing (Schedule A), in parallel to assess if there are major toxicity or 
efficacy differences between the two schedules of irinotecan when combined with standard 
weekly dosing of eribulin.  Following Sponsor review of the safety and efficacy data from 
Phase 1 in conjunction with the study investigators, the dose and schedule that is the most 
appropriate will be used in Phase 2, to evaluate the efficacy of eribulin in combination with 
irinotecan in subjects with RMS, NRSTS and EWS.  
As per protocol amendment #5, the data from the Phase 1 portion of this study showed that 
there was a tolerable safety profile in both schedules, with similar PK profiles; however, 2 
PRs were noted in Schedule A, one of which was confirmed.  Following discussions with the 
investigators and independent experts, based upon the similar toxicity and PK profiles and 
taking into account the 2 PRs noted in Schedule A, Schedule A Dose Level 1 (eribulin 1.4 
mg/m2 D1 and D8 with irinotecan 40 mg/m2 D1 – D5 of a 21- day cycle) was selected as the 
RP2D for the Phase 2 portion of this study. 
As per Amendment 6, subjects aged >6 months and <12 months will be enrolled to Schedule 
A with a modified dose of eribulin Dose Level -2 (0.8 mg/m2 Day 1 and Day 8) with the 
irinotecan dose maintained Dose Level 1 (40 mg/m2 Day 1 – Day 5) of a 21-day cycle.
9.3
Selection of Study Population
Up to 111 pediatric subjects (36 subjects in Phase 1 [the sample size does not include
subjects of age <12 months] and approximately 75 subjects in Phase 2) will be enrolled into 
the study.  Subjects who do not meet all of the inclusion criteria or who meet any of the 
exclusion criteria will not be eligible to participate in the study.
9.3.1
Inclusion Criteria
Subjects must meet all of the following criteria to be included in this study:
1.
Age: 
a. ≥12 months to ≤25 years old at the time of consent (no more than 25% of subjects 
between the ages of 18 and 25 years will be enrolled in this study).
b. In Phase 1, >6 months and <12 months at the time of consent (Schedule A only)
subjects will be enrolled one dose level behind the ≥12 months subjects in order to 


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maximize safety for infant subjects. In Phase 2, subjects aged >6 months and <12 
months at the time of consent will be enrolled to Schedule A with a modified dose of 
eribulin Dose Level -2  (0.8 mg/m2 D1 and D8) with the irinotecan dose maintained 
(Dose Level 1, 40 mg/m2 D1 – D5) of a 21-day cycle in order to maximize safety for 
infant subjects.  
2. Diagnosis: 
Phase 1: Histologically confirmed solid tumors, excluding CNS tumor, which is relapsed 
or refractory, and for which there are no currently available therapies. 
Phase 2: Histologically confirmed RMS, NRSTS or EWS which is relapsed or refractory 
having received at least 1 prior therapy, including primary treatment.
3. Disease status:
Phase 1: Subjects must have either measurable or evaluable disease as per RECIST 1.1.
Phase 2: Subjects must have measurable disease as per RECIST 1.1.
Measurable disease is defined as meeting the following criteria:
a.
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 computed tomography/magnetic resonance imaging (CT/MRI). 
b. 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.
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 the performance score. 
6. Subjects must have fully recovered from the acute toxic effects of all prior anticancer 
treatments prior to study drug administration:

Myelosuppressive chemotherapy:  Must not have received within 21 days prior to 
study drug administration (42 days if prior nitrosourea).

Hematopoietic growth factors:  Must not have received a long-acting growth factor 
(eg, Neulasta) within 14 days or a short-acting growth factor within 7 days.  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.

Targeted therapy (antineoplastic agent, eg, tyrosine kinase inhibitor):  Must not have 
received an antineoplastic targeted therapy within 14 days.  For agents that have 
known AEs occurring beyond 14 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.

Immunotherapy:  Must not have received immunotherapy, eg, tumor vaccines, within 
42 days.


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
Monoclonal antibodies:  Must not have received within at least 3 half-lives of the 
antibody after the last dose of a monoclonal antibody.

Radiotherapy (XRT):  Must not have received within 14 days prior to study drug 
administration (small field) or 42 days for craniospinal XRT, or if ≥50% radiation of 
pelvis.

Autologous Stem cell infusion: At least 84 days must have elapsed after stem cell 
infusion prior to study drug administration.

Allogeneic bone marrow transplant, including mini-transplant:  No evidence of active 
Graft vs. Host disease and at least 100 days must have elapsed after transplant or stem 
cell infusion prior to study drug administration.
7. Adequate bone marrow function, defined as:

Peripheral absolute neutrophil count (ANC) ≥1 × 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 (Hb) at least 8.0 g/dL at baseline (blood transfusions are allowed during 
the screening period to correct Hb values less than 8.0 g/dL).
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 GFR (Schwartz and Gauthier, 1985), See table below. 

Or serum creatinine clearance or GFR ≥50ml/min/1.73m2, based on a 12 or 24h urine 
creatinine collection. 
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 
GFR (Schwartz, et al. J. Peds, 106:522,1985) utilizing child length and stature data published by the 
CDC.
9. Adequate liver function, defined as:

Bilirubin (sum of conjugated + unconjugated) ≤1.5 times the ULN for age.


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
Alkaline phosphatase, alanine aminotransferase (ALT) and aspartate aminotransferase 
(AST) ≤3 × ULN (in the case of liver metastases ≤5 × ULN), unless there are bone 
metastases, in which case liver-specific alkaline phosphatase must be separated from 
the total and used to assess the liver function instead of the total alkaline phosphatase.  

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 [ß-hCG] (or 
human chorionic gonadotropin [hCG] test with a minimum sensitivity of 25 IU/L or 
equivalent units of ß -hCG [or hCG]).  A separate baseline assessment is required if a 
negative screening pregnancy test was obtained more than 72 hours before the first dose 
of study drug.
-
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, 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.


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Males who have not had a successful vasectomy (confirmed azoospermia) or they and 
their female partners do not meet the criteria above (ie, not of childbearing potential or 
practicing highly effective contraception throughout the study period 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 
dose for at least 7 days prior to study drug administration. 

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 including traditional herbal medicinal products 
(eg, St. John’s Wort). See Section 9.4.6.1, Drug-Drug Interactions.
3. Prior Therapies:

Phase 1: Received prior therapy with eribulin mesilate within 6 months prior to study 
drug administration.

Phase 2: Received prior therapies with eribulin mesilate or irinotecan hydrochloride
(for prior irinotecan hydrochloride, subjects can be included if there was no tumor 
progression during irinotecan therapy).
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 either study drug or any of the excipients. 
6. Has a known 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, defined as: 

Subjects with known congestive heart failure, symptomatic or 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 28 days prior to study drug administration.  
Subjects must be clinically stable.  It is not the intention of this protocol to treat subjects 
with active brain metastases.


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Note: Screening CNS imaging for subjects with a known history of CNS disease is 
required.
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. 
o
Central line placement or subcutaneous port placement is not considered major 
surgery

Laparoscopic procedure or open biopsy within 7 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. Subjects with known human immunodeficiency virus (HIV); due to lack of available 
safety data for eribulin therapy in HIV infected patients.
12. 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 (including active or severe 
chronic inflammatory bowel disease or bowel obstruction).
13. Has received a live-virus vaccination within 30 days of planned start of study therapy.  
Seasonal flu vaccines that do not contain live virus are permitted.  
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.  After discontinuation from study 
treatment and completing off-treatment visit, subjects will be followed up at least 4 weeks 
later (ie, greater than or equal to 28 days after last dose but no more than 1 year) unless they 
withdraw consent.  The investigator should confirm whether a subject will withdraw from 
study treatment but agree to continue protocol-specified, off-treatment study visits,
procedures or whether the subject will withdraw consent.  If a subject withdraws consent, the 
date will be documented in the source documents.  The Discontinuation From Treatment 
CRF page will be completed indicating the primary reason(s) for discontinuation.  In 
addition, the date of last dose of study drug(s) will be recorded on the Study Drug Dosing 
CRF page. Before a subject is withdrawn from study medication due to AE, the possibility 
of continuing on a single agent should be considered. In the event of an adverse event which 
leads to treatment interruption or delay of either study drug.  The subject may continue 
treatment with the other study drug as long as there is a clinical benefit for up to 1 year, from 
start of study treatment, after which any continued treatment would need to be discussed with 
the Sponsor.
During the Follow-Up Period, subjects who have discontinued study treatment without 
objective disease progression should have tumor assessments performed according to the 


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Schedule of Assessments from the date of the last assessment until disease progression is 
documented or another anticancer therapy is initiated, whichever occurs first, unless the 
study is terminated or the subject withdraws consent for follow-up.
9.4
Treatments
9.4.1
Treatments Administered
Administration of eribulin mesilate by IV infusion on Days 1 and 8 of a 21-day cycle in 
combination with irinotecan hydrochloride administered by IV infusion on either Days 1-5 of 
a 21-day cycle (Schedule A), or Days 1 and 8 of a 21-day cycle (Schedule B).
Irinotecan will be administered first (on days where both treatments are due to be 
administered), as a 30-minute infusion, followed by eribulin as a 2-5 minute bolus infusion.  
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.
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 for up to 1 year, from start of study 
treatment, after which any continued treatment would need to be discussed with the Sponsor.  
In the event of an adverse event which leads to treatment interruption or delay of either study 
drug, the subject may continue treatment with the other study drug, as long as there is a 
clinical benefit for up to 1 year, from start of study treatment after which any continued 
treatment would need to be discussed with the Sponsor.  
Phase 1
The dosing schedules being evaluated for Phase 1 will be as follows:
Schedule A
Eribulin mesilate on Day 1 and Day 8 of a 21 day cycle (Starting dose determined by COG 
protocol ADVL1314/Eisai Study E7389-A001-113).
Irinotecan hydrochloride on Days 1-5 of a 21-Day cycle.
Dose Level
Eribulin mesilate 
(mg/m2)
Irinotecan 
hydrochloride
(mg/m2)
-2
0.8
20
-1
1.1
20
0*
1.4
20
1
1.4
40
*Dose level 0 refers to the starting dose.


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Dose level -2 is a further dose reduction in Schedule A for subjects <12 months only.
Schedule B
Eribulin mesilate and irinotecan hydrochloride on Day 1 and Day 8 of a 21-day cycle.
Dose Level
Eribulin mesilate 
(mg/m2)
Irinotecan 
hydrochloride
(mg/m2)
-1
1.1
100
0*
1.4
100
1
1.4
125
*Dose level 0 refers to the starting dose.
Subjects will be allocated in an alternate fashion to either Schedule A or Schedule B, ie, 
every other subject will be allocated to Schedule A, by the Sponsor until an MTD is reached.  
If 1 schedule halts or pauses enrollment subjects will be enrolled on the other schedule 
provided it is open for accrual.  
Subjects <12 months will be enrolled on to Schedule A only and at 1 dose level behind ≥12 
months subjects in order to maximize safety for infant subjects. These subjects are included 
for descriptive purposes only and will not contribute to the determination of the MTD/RP2D 
for this study, or to the sample size. 
Dose Escalation 
The traditional 3+3 design will be used for the conduct of Phase 1 of this study.
For both schedules A and B, 3 subjects will be entered into each dose level. The first subject 
at each dose level must complete the Day 8 assessments before further subjects can be 
entered at the same dose level.  All 3 subjects in the cohort will be followed for a full cycle 
before the next dose level opens. If 1 subject experiences a DLT, the cohort will need to be 
expanded to 6 subjects on the same dose level. 
If no DLT is observed in a dose cohort, then the dose can be escalated and 3 subjects can be 
enrolled onto the next dose level.  The MTD is defined as the highest dose level at which 
fewer than 1/3 of subjects experience a DLT during Cycle 1 of therapy. 
If, at dose level 0, there are 2 or more subjects with a DLT out of 3 subjects (or 2 DLTs out 
of 6 subjects after expansion) in Cycle 1, the MTD will have been exceeded and the dose will 
be deescalated to dose level -1, and the next 3 subjects will be enrolled onto this lower dose 
level.
The MTD will be determined based on the incidence of DLTs in Cycle 1 of each dose level.  
Subjects who do not complete Cycle 1 for any reason other than toxicity, ie, DLT, will be 


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replaced in that cohort in order to complete the number necessary (up to 6) to assess the 
safety of the dose level cohort. 
Toxicities subsequent to Cycle 1 will also be reviewed, but will not count towards 
determination of dose escalation and MTD/RP2D.  If protocol-defined DLTs are observed in 
a subject after the first cycle at any dose level, the dose will be reduced to the next lower 
dose level for subsequent cycles. 
DLTs are defined as any of the following using the National Cancer Institute Common 
Terminology Criteria for Adverse Events (CTCAE Version 5.0) during Cycle 1:
Hematological:
1.
Neutropenia Grade 4 that lasts >7 days
2.
Thrombocytopenia Grade 4 on 2 separate days, or requiring a platelet transfusion on 2 
separate days, within a 7-day period 
3.
Thrombocytopenia Grade 3 complicated by bleeding or requiring platelet or blood 
transfusion 
4.
Neutropenia Grade 3 or 4 complicated by fever and/or infection (ANC <1.0 × 109/L, 
fever ≥38.0°C) 
5.
Myelosuppression that causes a delay of >14 days between treatment cycles 
Grade 4 neutropenia or platelets <75,000/mm3 on Day 8 that does not resolve to ANC 
≥750/mm3 and platelets ≥75,000/mm3 (transfusion independent) by Day 11 will be 
considered dose-limiting
Non-hematological:
1.
Grade 3 or 4 non-hematological toxicities related to study drug except for:
-
inadequately treated nausea and/or vomiting,  
-
Grade 3 liver enzyme elevation (including ALT/AST), 
-
Grade 3 fever or Grade 3 infection, 
-
Grade 3 hypophosphatemia, hypokalemia, hypocalcemia or hypomagnesemia responsive 
to oral supplementation 
2.
Grade 3 or above diarrhea despite adequate treatment 
3.
Non-hematological toxicity that causes a delay of ≥14 days between treatment cycles 
4.
Day 8 dose omission or interruption for more than 2 weeks due to non-recovery of any 
toxicity related to the study drug 
5.
For subjects <12 months (at the time of DLT), any ≥Grade 2 drug-related non-
hematological toxicity
6.
DLT exception:  Allergic reactions that lead to discontinuation of study drug during 
Cycle 1
Accrual will be suspended when a cohort of 3 has enrolled with pending toxicity data or 
when the MTD/RP2D for the combination has been met.  If, following de-escalation from 


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dose level 0 (to dose level-1), 2 DLTs are observed, that dose and schedule will be declared 
too toxic for further evaluation.  For subjects <12 months, if following de-escalation from 
dose level -1 (to dose level -2 on Schedule A), 2 DLTs are observed, that dose and schedule 
will be declared too toxic for further evaluation.  Subjects <12 months are included for 
descriptive purposes only and will not contribute to the determination of the MTD/RP2D for 
this study.  Up to 36 pediatric subjects (18 subjects per schedule) who meet all the inclusion 
criteria and none of the exclusion criteria, will be enrolled in Phase 1. 
MTDs will be obtained for both Schedule A and Schedule B and the most appropriate 
schedule will be taken forward to Phase 2 and will represent the RP2D (See Section 9.4.4 for 
details on schedule selection).
If a large number of dose modifications are observed after completion of cycle 1 (eg, 
intolerable Grade 2 toxicities), the sponsor will discuss with investigators whether a lower 
dose level than the MTD should be carried forward as the RP2D for this study.
Criteria for Dosing Modifications
Dose reduction and interruption for eribulin mesilate and irinotecan hydrochloride-related 
toxicity will be performed according to the following instructions:
Treatment will not be administered if any of the following values are recorded (Table 7).
Table 7
Criteria for Administration of Study Medication
a): Do not administer Cycle 1 Day 1 treatment where:
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.
Gastrointestinal toxicity
Bowel function deteriorated since pre-
treatment/baseline and requires antidiarrheal 
medications for within 24 hours before the next 
chemotherapy administration.
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.
Gastrointestinal toxicity
Bowel function deteriorated since pre-
treatment/baseline and requires antidiarrheal 


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medications for within 24 hours before the next 
administration of irinotecan hydrochloride.
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.
Gastrointestinal toxicity
Bowel function deteriorated since pre-
treatment/baseline and requires antidiarrheal 
medications for within 24 hours before the next 
chemotherapy administration.
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 (Table 7a Cycle 1 & c 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 8).
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 7b) as follows:
Hematological toxicity:
Subjects who have Grade 4 neutropenia or platelets <75,000/mm3 on Day 8 will have 
their dose withheld.  If the toxicity resolves to ANC ≥750/mm3 and platelets 
≥75,000/mm3 (transfusion independent) by Day 11, the dose may be given. If the 
toxicity does not resolve to ANC ≥750/mm3 and platelets ≥75,000/mm3 by Day 11, 
the dose will be omitted and this will be considered a DLT. Subjects should receive 
subsequent cycles of drug but at the next lower dose level (Table 10).  Subjects who 
require that their Day 8 dose be omitted for Grade 4 neutropenia or platelets <75,000 
mm3 after two dose reductions must be removed from protocol therapy.
Subjects who meet hematological DLT criteria on Day 8 will have their Day 8 dose 
omitted.  Subjects should receive subsequent cycles of drug but at the next lower dose 
level.  Subjects who require that their Day 8 dose be omitted for hematologic DLT 
after two dose reductions must be removed from protocol therapy.
Non-hematological toxicity:
Subjects who have Grade 3 or Grade 4 non-hematological toxicity attributable to the 
study drug prior to the Day 8 dose (with the exception of the DLT exclusions) will be 


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considered to have had a DLT. If the toxicity resolves to meet eligibility or ≤Grade 2 
(if not part of eligibility criteria) by Day 8, the dose may be given but at the next 
lower dose level. 
Subjects who have Grade 3 or Grade 4 non-hematological toxicity attributable to the 
study drug on Day 8 prior to dosing (with the exception of the DLT exclusions) will 
have their dose withheld and this will be considered a DLT. If the toxicity resolves to 
meet eligibility or ≤Grade 2 (if not part of eligibility criteria) by Day 11, the dose 
may be given but at the next lower dose level. If the toxicity does not resolve by Day 
11, the dose will be omitted. Subjects should receive subsequent cycles of drug but 
with dose modifications (Table 10).

For subjects <12 months any ≥Grade 2 non-hematological toxicity attributable to 
study drug prior to the Day 8 dose will have their dose omitted.  Subjects should 
receive subsequent cycles of drug at the next lower dose level (Table 10).

Subjects who have a dose-limiting hematological or non-hematological toxicity that 
does not resolve to meet eligibility or baseline parameters within 21 days after the 
planned start of the next treatment cycle must be removed from protocol therapy.
For Schedule A, irinotecan doses days 2-5 can be delayed up to cycle Day 10 (of a 21 day 
cycle), at the discretion of the Investigator and as long as the subject meets the criteria for 
administration of study medication for Day 8 as detailed in Table 7. If the subject does not 
meet the Day 8 criteria for administration by cycle Day 10 then dosing should not occur until 
the next cycle and as long as the subject meets the subsequent Day 1 dosing criteria for 
administration (Table 8).  
Please note, use of hematopoietic growth factor support is not permitted in Cycle 1 and is 
only permitted in subsequent cycles as per institutional guidelines. Subjects known to have 
reduced UGT1A1 activity will be monitored carefully for hematological toxicity.
The treatment will be permanently reduced to the next lowest dose level (Table 10) after the 
occurrence of the following events  
Table 8
Criteria for Reduction of Study Medication 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 toxicities (attributable to study drug); except 
Grade 3 hypophosphatemia, hypokalemia, hypocalcemia or 
hypomagnesemia that respond to supplementation
For subjects <12 months any ≥ Grade 2 non-hematological 
toxicity attributable to study drug prior to the Day 8 dose 
will have their dose omitted and this will be considered a 
DLT.  Subjects should receive subsequent cycles of drug 
but with dose modifications as per Table 10
Gastrointestinal toxicity
≥Grade 3 or intolerable Grade 2 diarrhea 
For subjects on dose levels 0 and -1 dose reductions of 
20% of the current irinotecan dose should be made.  If 
there are 2 or more diarrhea DLTs on these dose levels, the 
irinotecan dose levels will be re-evaluated by the Sponsor, 
and an appropriate lower dose level will be agreed with the 
investigator.  If the diarrhea toxicity does not recover 
following a dose reduction of 20% (of dose level 0 or -1), 
treatment should be discontinued  
If hematological or non-hematological toxicities do not recover following a dose reduction to 
dose level -1 (dose-level -2 for subjects <12 months) and the use of hematopoietic growth 
factors, for hematological toxicities, the subject will discontinue treatment (except for cases 
of irinotecan related diarrhea, see below).  However, if the subject is deemed to have clinical 
benefit, continuation of treatment may be discussed with the sponsor.
To ensure safety for subjects, the study drug must be discontinued in the cases outlined in
Table 9.
If, in the opinion of the Investigator, a dose reduction as per the criteria noted in Table 8 is 
not necessary, due to adequate supportive care and use of prophylaxis (eg, growth factor 
support) to prevent recurrences, each individual case should be discussed with and agreed by 
the Sponsor.
Table 9
Criteria for Discontinuation of Study Medication
ALT >3 × ULN and total bilirubin >2 × ULN


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ALT >8 × ULN at any time, regardless of total bilirubin or accompanying symptoms
ALT >5 × ULN for 2 or more weeks, regardless of total bilirubin or accompanying symptoms
ALT >3 × ULN, accompanied by symptoms consistent with hepatic injury (fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, or rash). Clinical judgement should be used based on the 
combination of the laboratory LFT results and clinical symptoms. Additionally, in subjects with liver 
metastases with pre-existing ALT >3 x ULN at study baseline, any additional increase in ALT values from 
baseline and clinical symptoms consistent with a syndrome of hepatic injury as described above should be 
considered for further assessment and drug discontinuation. Clinical symptoms alone consistent with 
deterioration of liver function should lead to additional laboratory assessments and evaluation of potential 
study drug related liver toxicity.
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 study treatment in 
subjects who develop ≥ Grade 3 QTc prolongation, and monitor ECGs and electrolytes more 
frequently in consultation with cardiologist advice and in line with local practice until the 
QTc interval returns to baseline.  
Table 10
Study Medication Dose Levels by Schedule for Phase 1
Dose Level
Eribulin mesilate (mg/m2)
Irinotecan hydrochloride (mg/m2)
Schedule A
-2
0.8
20
-1
1.1
20
0
1.4
20
1
1.4
40
Schedule B
-1
1.1
100
0
1.4
100
1
1.4
125
Dose level -2 is a further dose reduction in Schedule A for subjects <12 months only.
Do not re-escalate dose level after the dose level has been reduced.
Phase 2
As per protocol amendment #5, the data from the Phase 1 portion of this study showed that 
there was a tolerable safety profile in both schedules, with similar PK profiles; however, 2 
PRs were noted in Schedule A, one of which was confirmed.  Following discussions with the 
investigators and independent experts, based upon the similar toxicity and PK profiles and 
taking into account the 2 PRs noted in Schedule A, Schedule A Dose Level 1 (eribulin 1.4 


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mg/m2 D1 and D8 with irinotecan 40 mg/m2 D1 – D5 of a 21- day cycle) from Phase 1 was 
selected as the RP2D for the Phase 2 portion of this study for subjects ≥ 12 months of age. 
As per Amendment 6, subjects aged >6 months and <12 months will be enrolled to Schedule 
A with a modified dose of eribulin Dose Level -2 (0.8 mg/m2 D1 and D8) with the irinotecan
dose maintained Dose Level 1 (40 mg/m2 D1 – D5) of a 21-day cycle.
A modified dose of eribulin with the irinotecan dose maintained is being used for subjects 
<12 months in order to maximize safety for infant subjects.  The modified dose of eribulin is 
aligned with the Children’s Cancer and Leukaemia Group (CCLG) (Chemotherapy 
Standardization Group 2008) guidance on pediatric dosing where a dose has not been 
established.   
The dose levels as per Table 11 should be used in the Phase 2 portion of the study when 
following the criteria for dose reductions (Table 8), the agent most likely to be the cause of 
toxicity (eg, irinotecan for diarrhea, eribulin for neuropathy or neutropenia) should be 
reduced by one dose level if these criteria are met. If in the investigator’s opinion both 
agents should be reduced this may be permitted after discussion with the Sponsor.
Table 11
Schedule A Dose Levels for Phase 2
Dose Level
Eribulin mesilate (mg/m2)
Eribulin – Days 1 & 8
-4
0.4
-3
0.6
-2**
0.8
-1
1.1
1*
1.4
Irinotecan hydrochloride (mg/m2) – Days 1-5
-2
20
-1
30
1*
40
For subjects ≥12 month to ≤ 25 years of age:
* Dose level 1 eribulin (1.4 mg/m2 Days 1 and 8) and irinotecan (40 mg/m2 Days 1 – 5).
For subjects >6 months and <12 months of age:
**Dose level -2 for eribulin (0.8 mg/m2 Days 1 and 8) and Dose level 1 for irinotecan (40 mg/m2 Days 1 – 5) is 
maintained.
Do not re-escalate dose level after the dose level has been reduced. If toxicities do not recover after 2
dose reductions, treatment with that agent must be discontinued.


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9.4.2
Identity of Investigational Products
Eribulin mesilate will be supplied by the sponsor in labeled vials.  Irinotecan hydrochloride 
will either be supplied by sponsor or sourced locally by the investigator site, depending on 
local requirements.
9.4.2.1
Chemical Name, Structural Formula of Eribulin Mesilate

Test drug code:  E7389

Generic name:  Eribulin Mesilate

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
Irinotecan Hydrochloride

Generic name:  irinotecan hydrochloride

Chemical name (IUPAC):  (S)-4,11-diethyl-39 3,4,12,14-tetrahydro-4-hydroxy-3,14-
dioxo-1H-pyrano[3',4':6,7]-indolizino[1,2-b]quinolin-9-4-yl-[1,4'-bipiperidine]-1'-
carboxylate, monohydrochloride, trihydrate

Molecular formula:  C33H38N4O6•HCl•3H2O

Molecular weight:  677.19

Structural formula:  


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9.4.2.3
Labeling for Investigational Products 
Both Eribulin mesilate and irinotecan hydrochloride will be labeled in accordance with each 
country specific labeling requirements, and will be translated into the required language(s) 
for each applicable country.
9.4.2.4
Storage Conditions
9.4.2.4.1
GENERAL
Investigational Products will be stored in accordance with the labeled storage conditions.  
Temperature monitoring is required at the storage location to ensure that the study drug is 
maintained within an established temperature range.  The investigator or designee (or if
regionally required, the head of the medical institution) is responsible for ensuring that the 
temperature is monitored throughout the total duration of the study and that records are 
maintained; the temperature should be monitored continuously by using either an in-house 
validated data acquisition system, a mechanical recording device, such as a calibrated chart 
recorder, or by manual means, such that minimum and maximum thermometric values over a 
specific time period can be recorded and retrieved as required.
9.4.2.4.2
ERIBULIN MESILATE
Eribulin mesilate is provided as a single use vial, the contents of which can either be 
administered undiluted or diluted in up to 100 mL of 0.9% sodium chloride injection, PhEur.  
Undiluted or diluted solutions of eribulin mesilate can be stored for up to 4h at room 
temperature or up to 24h under refrigeration (2 -8°C). Further information on storage and 
handling is provided in the Summary of Product Characteristics (SmPC) provided by the 
manufacturer.
9.4.2.4.3
IRINOTECAN HYDROCHLORIDE
Irinotecan hydrochloride will be sourced, labeled for investigational use and stored in 
accordance with the storage conditions detailed in Irinotecan hydrochloride SmPC.


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9.4.3
Method of Assigning Subjects to Treatment Groups
This is an open-label, single-arm study.  All subjects who provide signed informed consent to 
participate in this study and satisfy all eligibility requirements (see Section 9.3) will be 
assigned to receive eribulin mesilate in combination with irinotecan hydrochloride.  
There is no randomization in this study. In Phase 1 subjects will be enrolled in alternate 
fashion to Schedule A or Schedule B (ie, every other subject will be enrolled onto Schedule 
A). If enrollment is halted or discontinued for any schedule, subjects will be enrolled on to 
the other schedule provided it is open for accrual.
In Phase 2 subjects will be enrolled according to histology type (RMS, NRSTS or EWS).
9.4.4
Selection of Doses in the Study
Eribulin mesilate will be administered at RP2D and irinotecan hydrochloride will be 
administered at the different dosing schedules (Schedules A & B) for Phase 1.
Phase 1
The doses of irinotecan to be used in the Phase 1 dosing schedules are derived from studies 
looking at MTD of single agent irinotecan or irinotecan combinations administered at the 
various corresponding schedules (Blaney, et al., 2001; Vassal, et al., 2003; Casey, et al., 
2009).
Schedule A: Eribulin mesilate will be administered on Day 1 and Day 8 of a 21 day cycle 
(Starting dose determined by COG protocol ADVL1314/Eisai Study E7389-A001-113).  
Irinotecan hydrochloride will be administered on Days 1-5 of a 21-Day cycle. 
Schedule B:  Eribulin mesilate and irinotecan hydrochloride will be administered on Day 1 
and Day 8 of a 21-Day cycle.
Phase 2
The dose and schedule that is deemed the most appropriate from Phase 1 will be used in 
Phase 2, following sponsor review together with the investigators.  If there is no difference in 
the safety and efficacy between schedules A and B, following review with the investigators, 
Schedule B will be taken forward to Phase 2 on the basis of convenience. As per protocol 
amendment #5, the data from the Phase 1 portion of this study showed that there was a 
tolerable safety profile in both schedules, with similar PK profiles; however, 2 PRs were 
noted in Schedule A, one of which was confirmed.  Following discussions with the 
investigators and independent experts, based upon the similar toxicity and PK profiles and 
taking into account the 2 PRs noted in Schedule A, Schedule A Dose Level 1 (eribulin 1.4 
mg/m2 D1 and D8 with irinotecan 40 mg/m2 D1 – D5 of a 21- day cycle) was selected as the 
RP2D for the Phase 2 portion of this study. Further information on dose modification for 
each agent is provided in Section 9.4.1.


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As per Amendment 6, subjects aged >6 months and <12 months will be enrolled to Schedule 
A with a modified dose of eribulin Dose Level -2 (0.8 mg/m2 Day 1 and Day 8) with the 
irinotecan dose maintained Dose Level 1 (40 mg/m2 Day 1 – Day 5) of a 21- day cycle.
For eribulin, the dose selected (0.8 mg/m2) is aligned with guidance on pediatric dosing 
(CCLG-Chemotherapy Standardization Group 2008) which recommends the dose for 
patients aged <12 months should be approximately 75% of calculated dose for by body 
surface area.  As eribulin has not been tested previously in this infant age group and is being 
used in combination with irinotecan in this study, the dose selected is the same as the lowest
dose level provided in this study (Dose-Level -2).  This approach also takes into account that 
while eribulin is predominantly excreted unchanged in urine (5-7%) and feces (82%), it is 
partially (< 15%) metabolized by the cytochrome P450 CYP3A4 liver enzyme and liver 
maturation of CYP3A4 has not occurred fully in these younger subjects (Salem, et al., 2014). 
For irinotecan, the dose remains the same as the ≥12 months age group (40 mg/m2 Day 1 –
Day 5), which is consistent with standard practice with irinotecan in this population and with 
previous studies with irinotecan used in combination, where the identified full dose of 
irinotecan is maintained for the infant age group (Hawkins, et al., 2018).
9.4.5
Selection and Timing of Dose for Each Subject
Administration of eribulin mesilate by IV infusion on Days 1 and 8 of a 21-day cycle in 
combination with irinotecan hydrochloride administered by IV infusion on either Days 1-5 of 
a 21-day cycle (Schedule A), or Days 1 and 8 of a 21-day cycle (Schedule B).
Irinotecan will be administered first (on days where both treatments are due to be 
administered), as a 30 minute infusion, followed by eribulin as a 2-5 minute bolus infusion.  
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 30 days after the final 
dose of study drug will be recorded.  Additionally, all diagnostic, therapeutic, or surgical 
procedures relating to malignancy should be recorded.  Any medication that is considered 
necessary for the subject’s health and that is not expected to interfere with the evaluation of 
or interact with eribulin mesilate or irinotecan hydrochloride 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 criteria (prophylactic granulocyte colony-stimulating factor should NOT 
be administered during Cycle 1) or for culture proven bacteremia or invasive fungal 
infection. 


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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 study treatment.
9.4.6.1
Drug-Drug Interactions
9.4.6.1.1
ERIBULIN MESILATE
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) 
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.
Currently, drug-drug interactions of eribulin mesilate have not been studied in children, 
therefore pediatric subjects taking medications that are strong CYP3A4 inducers (eg, St. 
John’s Wort, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital,) or 
inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, 
saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) or taking nutritional 
supplements known to inhibit/induce CYP3A4, will be excluded from the study. Check 
prescribing information of all concomitant medications for all subjects.
Please refer to http://medicine.iupui.edu/flockhart/table.htm for the most current information.
9.4.6.1.2
IRINOTECAN HYDROCHLORIDE
There is no information on drug-drug interactions of irinotecan hydrochloride in the pediatric 
population.  In adult patients with colorectal cancer, the administration of 5-fluorouracil 
(5-FU) and leucovorin (LV) did not substantially alter the disposition of irinotecan 
hydrochloride when the drugs were coadministered, however formal in vivo or in vitro drug 
interaction studies to evaluate the influence of irinotecan hydrochloride on the disposition of 
5-FU and LV have not been conducted. The possible pharmacokinetic interactions of 
irinotecan hydrochloride with other concomitantly administered medications have not been 
formally investigated.
Avoid co-administration of irinotecan with strong CYP3A4 inhibitors and inducers (listed 
above in Section 9.4.6.1.1), and UGT1A1 inhibitors (eg, ketoconazole, atazanavir, 
gemfibrozil, indinavir).  For subjects requiring anti-epileptic therapy, switch to a non-enzyme 
inducing anti-epileptic agent.  Check prescribing information of all concomitant medications 
for all subjects. 


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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, or cancer 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. In addition, no attenuated live vaccines must be administered for 
the duration of the study and 6 months following discontinuation of irinotecan.
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

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 Food and Drug Administration (FDA) Form FDA 1572, 
where applicable

Financial Disclosure form(s) for the principal investigator (PI) and all subinvestigators 
listed on Form FDA 1572, where applicable

A signed and dated curriculum vitae (CV) of the PI including a copy of the PI’s current 
medical license or medical registration number on the CV

A signed and dated clinical studies agreement
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.


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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, 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 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.


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9.5.1.2
Baseline Assessments
Baseline characteristics and assessments will be collected at the Screening Visit.  
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 13 and Table 14).  A comprehensive 
physical examination will include evaluations of the head, eyes, ears, nose, throat, neck, 
chest (including heart and lungs), abdomen, limbs, skin, and a complete neurological 
examination.  A urogenital examination will only be required in the presence of clinical 
symptoms related to this region.  Documentation of the physical examination will be 
included in the source documentation at the site.  Significant findings at the Screening Visit 
will be recorded on the Medical History and Current Medical Conditions CRF.  Changes 
from screening physical examination findings that meet the definition of an AE will be 
recorded on the Adverse Events CRF.
9.5.1.3
Efficacy Assessments
9.5.1.3.1
TUMOR RESPONSE ASSESSMENTS
Tumor assessment will be performed based on RECIST 1.1.  Investigator-determined 
response assessments at each assessment time point will be entered onto the appropriate 
CRF. Tumor assessments will be performed every 6 weeks until Week 12 and every 9 weeks
thereafter on a fixed schedule.  For Phase 1, neuroblastoma subjects can also be evaluated by
meta-iodobenzulguanidine (MIBG) scintigraphy.  For Phase 2, copies of scans for tumor 
assessments will be sent to an imaging core laboratory designated by the sponsor for quality 
assessment, archival, and potential independent review.
Computed tomography (CT) scans (with oral and intravenous contrast, unless clinically 
contraindicated) of chest, abdomen, and pelvis and other known sites of disease will be 
obtained at pre-study (within 28 days prior to Cycle 1 Day 1), and every 6 weeks thereafter 
(counting from C1D1), irrespective of dose delays.  Magnetic resonance imaging (MRI) 
scans may be used instead of CT scans for abdomen and pelvis; however, chest must be 
assessed using CT.  If only chest CT is performed then oral CT contrast is not required. The 
same method of assessment must be used at all time-points as used at pre-study.  However, a 
chest x-ray may be used to identify new lesions in lieu of chest CT where appropriate (and 
after initial chest CT at screening).  Post-screening scans may be performed without contrast 
if a medical contraindication develops while on study treatment.  If iodinated IV contrast is 
contraindicated, chest CT should be done without IV contrast.  MRI should be performed for 
all other body regions (with gadolinium unless contraindicated (eg, severe renal dysfunction).  
An exception to the requirement for following chest disease by CT will be allowed where 
subjects have either non-parenchymal tumors, mediastinal and/or chest wall lesions.  These 


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may be assessed (at Screening and post-baseline) using contrast-enhanced MRI.  However, a 
chest CT is required at Screening for all subjects, and lung parenchymal lesions should be 
followed using CT (as per standard practice).  If there is either an equivocal new lung lesion 
based on MRI or symptoms suggesting a new lesion, these should also be confirmed with 
chest x-ray or CT.  
After 12 weeks, subjects with CR, PR or stable disease (SD) may have imaging frequency 
decreased to every 9 weeks.  A bone scan using whole body bone MRI, technetium-99m 
based bone scans, 18F-sodium fluoride positron emission tomography [NaF PET], or 18FDG-
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 conjunction with a scheduled tumor assessment visit), and as clinically 
indicated.  Lesions identified on bone scans should be followed with anatomic imaging.  
A brain scan (CT with contrast or MRI [pre- and post-gadolinium]) will be performed as 
clinically indicated to assess potential for 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 at all tumor assessment time points. For all subjects, a follow-up brain scan 
must be performed to confirm CR within 1 week following response confirmation, or if 
clinically indicated.   
Low-dose non-contrast CT transmission scans from a positron emission tomography-CT 
(PET-CT) combination scanner are not acceptable, however, they may be used if they are of 
diagnostic quality and are obtained with contrast as indicated above.  Ultrasound should not 
be used for radiographic tumor assessment.  
If subcutaneous masses or nodes are palpable (eg, bulky) and are assessable by both clinical 
and radiographic techniques, the radiographic (CT/MRI) technique should be used for the 
assessment of target and non-target lesions.
Subjects with neuroblastoma (which can be included in phase 1 only) may have meta-
iodobenzulguanidine (MIBG) scintigraphy and bilateral bone marrow biopsies assessments 
performed at sites where this is standard practice, at the discretion of the treating 
physician. This is an optional assessment for neuroblastoma subjects. Subjects that have 
positive lesions by MIBG scan at screening (within 28 days prior to administration of study 
drug) are not required to undergo PET or technetium-99m bone scans. After identifying 
positive lesions at screening, repeat measurements may be performed within 4 weeks after 
confirmation of a PR or CR or as clinically indicated.  Subjects with positive urinary 
catecholamines at baseline, should be assessed in cases of CR (catecholamines should be 
negative to confirm CR). Subjects with MIBG positive lesions at screening will be evaluable 
for MIBG response using the revised version of the International Neuroblastoma Response 
Criteria (INRC) scoring (Brodeur GM, et al., 1993).
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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All subjects will have an Off-Treatment Visit within 28 days after the last dose of study 
medication.  Subjects that discontinue treatment without objective evidence of disease 
progression will continue to have tumor assessments performed as per the Schedule of 
Assessments until disease progression, death, or another anticancer therapy is initiated, 
whichever occurs first, unless the study is terminated.  This follow-up data will be required 
unless consent is withdrawn.  
After data cutoff for the primary analysis, tumor assessments may be performed as clinically 
indicated using the investigator’s discretion, following the prevailing local standard of care.
9.5.1.3.2
PHARMACOKINETIC ASSESSMENTS
Blood samples (2 mL) will be collected for PK analysis of both irinotecan and its metabolite 
(SN-38), and eribulin as follows:
Phase 1 (Cycle 1):
For subjects ≥12 months of age and >10 kg:

Cycle 1, Day 1: At the end of the irinotecan infusion (irinotecan is administered 
first), and at the end of the eribulin infusion, then at 1, 2, 4, 6 and 24 hours post-
eribulin infusion. Both irinotecan (and its metabolite, SN-38) and eribulin will be 
assayed.

At 72 and 120 hours post-eribulin infusion, eribulin only will be assayed. 
Please note that eribulin will be administered immediately after the end of irinotecan infusion 
and PK blood sample draw.
Subjects <12 months of age as well as those ≥12 months of age and ≤10 kg (subjects under 
6 kg will not have PK samples taken):

Cycle 1, Day 1: At the end of the irinotecan infusion (irinotecan is administered first) 
and then immediately after the end of the eribulin infusion (ie, 10 ± 5 minutes from 
the start of the eribulin infusion).

Cycle 1, Day 4 or 5: During the collection of the first twice weekly CBC sample.

Cycle 1, Day 8: Before the eribulin infusion and then immediately after the end of 
the eribulin infusion (ie 10 ± 5 minutes from the start of the eribulin infusion).
Please note that eribulin will be administered immediately after the end of irinotecan infusion 
and PK blood sample draw.
Phase 2 (Cycle 1):
Eribulin assay only:


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Cycle 1, Day 1 (at the end of the infusion, 0.5 to 6 hours and 24 to 120 hours after eribulin 
infusion) and on Cycle 1, Day 8 (predose of eribulin and at the end of the infusion).  
Subjects who weigh under 6 kg will not have PK samples taken.
9.5.1.3.3
PHARMACODYNAMIC, PHARMACOGENOMIC, AND OTHER BIOMARKER, ASSESSMENTS
Not applicable.  
9.5.1.3.4
BIOANALYTICAL METHODS
Eribulin, irinotecan and its active metabolite, SN-38, will be analyzed using validated liquid 
chromatography with tandem mass spectrometry (LC-MS/MS) methods.    
9.5.1.4
Safety Assessments
Safety assessments will consist of monitoring and recording all AEs, including all Common 
Terminology Criteria for Adverse Events (CTCAE) v5.0 grades (for both increasing and 
decreasing severity), and SAEs; regular monitoring of hematology, blood chemistry, and 
urine values; periodic measurement of vital signs and ECGs; performance status, and 
performance of physical examinations as detailed in Table 13 and Table 14.
9.5.1.4.1
ADVERSE EVENTS AND EVENTS ASSOCIATED WITH SPECIAL SITUATIONS
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 drugs are 
eribulin mesilate and irinotecan hydrochloride.
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


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All AEs observed during the study will be reported on the CRF.  All AEs, regardless of 
relationship to study drug or procedure, should be collected beginning from the time the 
subject and/or their parents or legally authorized representatives signs the study ICF through 
the last visit.  Subjects who fail screening primarily due to AE(s) must have the AE(s) 
leading to screen failure reported on the Screening Disposition CRF.  SAEs will be collected 
for 28 days after the last dose.
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 until resolution or for 28 days after the subject's last dose of study 
medication, whichever comes first.  Serious AEs will be collected for 28 days post treatment 
and followed until resolution or, if resolution is unlikely, until the event or sequelae stabilize.  
Progression of malignant disease (PD) 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 a 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 Common Terminology Criteria 
for Adverse Event (CTCAE v5.0 [National Institutes of Health Cancer Therapy Evaluation 
Program, 2017]).  Investigators will report CTCAE grades for all AEs (for both increasing 
and decreasing severity).
Assessing Relationship to Study Treatment
Items to be considered when assessing the relationship of an AE to the study treatment are:

Temporal relationship of the onset of the event to the initiation of the study treatment

The course of the event, especially the effect of discontinuation of study treatment or 
reintroduction of study treatment, as applicable


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
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.
9.5.1.4.2
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

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 


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the above criteria.  All AEs associated with special situations are to be reported on the CRF 
whether or not they meet the criteria for SAEs.  
All SAEs must be followed to resolution or, if resolution is unlikely, to stabilization.
The following hospitalizations are not considered to be SAEs because there is no “adverse 
event” (ie, there is no untoward medical occurrence) associated with the hospitalization:

Hospitalizations for respite care 

Planned hospitalizations required by the protocol

Hospitalization planned before informed consent (where the condition requiring the 
hospitalization has not changed after study drug administration)

Hospitalization for administration of study drug or insertion of access for administration 
of study drug

Hospitalization for routine maintenance of a device (eg, battery replacement) that was in 
place before study entry
9.5.1.4.3
LABORATORY MEASUREMENTS
Clinical laboratory tests to be performed, including hematology, chemistry, and urinalysis, 
are summarized in Table 12.  The Schedule of Procedures/Assessments (Table 13 and 
Table 14) shows the visits and time points at which blood for clinical laboratory tests and 
urine for urinalysis will be collected in the study.
Table 12
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, glucose, magnesium, calcium, 
phosphorus
Liver function tests
Alanine aminotransferase, alkaline phosphatase, aspartate 
aminotransferase, total bilirubin
Renal function tests
Blood urea/blood urea nitrogen, creatinine
Other
*Albumin, cholesterol, lactate dehydrogenase, total protein, 
triglycerides, 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.  Cholesterol, triglycerides and uric acid not required for assessment at 
subsequent chemistry measurement time points.


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Clinical laboratory tests during the Treatment Phase will be performed by local laboratories.  
Laboratory certification as available will be included in the final clinical study report for this 
study.
All hematology, blood chemistry 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.  Please note, following screening, monthly pregnancy 
tests are required for all sexually active subjects. Refer to Table 8 and Table 9 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 9.5.1.4.1 and the CRF Completion Guidelines.  In these instances, the 
AE corresponding to the laboratory abnormality will be recorded on the Adverse Event CRF.
9.5.1.4.4
VITAL SIGNS AND WEIGHT MEASUREMENTS
Vital sign measurements (ie, systolic and diastolic blood pressure [BP] [mmHg], heart rate
[beats per minute], body temperature [in centigrade]), and height, and weight/BSA will be 
obtained at the visits designated in the Schedule of Procedures/Assessments (Table 13 and 
Table 14) by a validated method, such as the Mosteller formula for children:
 (	) =  ℎ () ×  ℎℎ ()
√3600
9.5.1.4.5
PHYSICAL EXAMINATIONS
Physical examinations will be performed as designated in the Schedule of 
Procedures/Assessments (Table 13 and Table 14).  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.
9.5.1.4.6
ELECTROCARDIOGRAMS
Electrocardiograms will be obtained as designated in the Schedule of 
Procedures/Assessments (Table 13 and Table 14).  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 9.5.1.4.1) and the CRF Completion Guidelines.  In these instances, the AE 
corresponding to the ECG abnormality will be recorded on the Adverse Events CRF.


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9.5.1.4.7
OTHER SAFETY 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 7 days of administration of study 
drug) (Table 13).  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.  
Thereafter, monthly pregnancy tests are required for all sexually active subjects.
9.5.1.5
Schedule of Procedures/Assessments
Table 13 and Table 14 present the schedule of procedures/assessments for the study.


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Table 13
Schedule of Procedures/Assessments in Study E7389-G000-213: Phase 1
Phase
Pre-study
Treatmenta
Off Treatment 
Visit
Follow-Upt
Period
Screeningb
Cycle 1
Cycle 2c
Cycle 3c
Additional Cyclesc
Visit
1
2
3
4
5
6
7
8
9
10
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
≥28 days after 
last dose of 
drug
Procedures/Assessments
Informed consentd
X
Medical history
X
Inclusion/exclusion
X
Vital signse
X
X
X
X
X
X
X
X
X
X
Weekly for subjects 
<12 months
Weekly for 
subjects <12 
months
Weekly for subjects 
<12 months
Weekly for subjects 
<12 months
Heightf
X
X
X
X
Weight, BSAg
X
Weekly
X
X
X
X
Physical exam
X
Weekly
X
X
X
X
Weekly for 
subjects <12 
months
Weekly for subjects 
<12 months
Weekly for subjects 
<12 months
Neurologic exam
X
X
X
X
X
Performance statush
X
Weekly
X
X
X
X
Pregnancy testi
X
X


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Table 13
Schedule of Procedures/Assessments in Study E7389-G000-213: Phase 1
Phase
Pre-study
Treatmenta
Off Treatment 
Visit
Follow-Upt
Period
Screeningb
Cycle 1
Cycle 2c
Cycle 3c
Additional Cyclesc
Visit
1
2
3
4
5
6
7
8
9
10
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
≥28 days after 
last dose of 
drug
Procedures/Assessments
Hematologyj
X
Weekly 
Weekly
Weekly
Weekly
X
Twice weekly for 
subjects <12 months 
(every 3 to 4 days)
Twice weekly 
for subjects <12 
months (every 3 
to 4 days)
Twice weekly for 
subjects <12 
months (every 3 to 
4 days)
Twice weekly for 
subjects <12 
months (every 3 to 
4 days)
Chemistryk
X
Weekly
X
X
X
X
Weekly for 
subjects <12 
months
Weekly for subjects 
<12 months
Weekly for subjects 
<12 months
Eribulin mesilate 
administration
X
X
X
X
X
X
X
X
Irinotecan hydrochloride 
administration (Schedule 
A)
X
(D1-5)
X
(D1-5)
X
(D1-5)
X
(D1-5)
Irinotecan hydrochloride 
administration (Schedule 
B)
X
X
X
X
X
X
X
X
Pharmacokinetic 
samplingm
X
X


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Table 13
Schedule of Procedures/Assessments in Study E7389-G000-213: Phase 1
Phase
Pre-study
Treatmenta
Off Treatment 
Visit
Follow-Upt
Period
Screeningb
Cycle 1
Cycle 2c
Cycle 3c
Additional Cyclesc
Visit
1
2
3
4
5
6
7
8
9
10
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
≥28 days after 
last dose of 
drug
Procedures/Assessments
12-lead ECGn
X
X
X
As clinically indicated
X
Urinalysiso
X
X
As clinically indicated
X
As clinically indicated for subjects <12 months
Tumor assessmentp
X
Every 6 weeks (counting from date of 
first dose) until Wk 12, then every 9 
weekse
X
Brain CT/MRIq
X
Clinically indicated and all timepoints for subjects with protocol-eligible treated brain mets at 
screening
Bone Scanr
X
Approximately every 24 weeks (in conjunction with scheduled tumor assessment) and as clinically 
indicated
MIBG Scintigraphy 
(neuroblastoma only)u
X
Clinically indicated
Prior / concomitant 
medicationss
Throughout
Adverse events/SAEs
Throughout
Subsequent anti-cancer 
treatments and survival
X
a.
Efforts should be made to conduct study visits on the scheduled day (+/- 3 days).


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b.
The Screening Period extends from Day -28 to Day -1.  Computed tomography (CT) / magnetic resonance imaging (MRI) scans must be performed within 28 days prior to 
administration of study drug.  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.  
c.
Assessments/procedures may be obtained within 72 hours prior to the start of the subsequent cycle.
d.
For logistical purposes, informed consent may be obtained from Day -29.  
e.
Vital signs will be performed on Day 1 and Day 8 of each cycle for ≥12 months subjects and weekly for subjects <12 months.
f.
Height will be measured at Screening and on Day 1 of every other cycle starting from cycle 3.
g.
BSA is based on a calculation at recruitment that is accepted and customarily used by the site, such as the Mosteller formula for children, adjustments to dosing to be made if 
10% change in body weight.
h.
Performance status will be measured using Karnofsky or Lansky scales (Appendix 2).
i.
Women of childbearing potential require a negative urine or serum (depending on local practice) pregnancy test prior to starting treatment (within 7 days prior to recruitment). 
Sexually active subjects must use an acceptable method of birth control.  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. Thereafter, monthly pregnancy tests are required for sexually active subjects.
j.
Hematology lab tests will be performed weekly for ≥12 month subjects and twice weekly for subjects <12 months; a complete blood count can be performed at an external 
laboratory when the subject is not attending the investigator site for dosing or other study visits.
k.
Albumin, calcium, magnesium, cholesterol, lactate dehydrogenase, phosphorus, total protein, triglycerides, and uric acid are all to be assessed at baseline.  Cholesterol, 
triglycerides and uric acid are not required for assessment at subsequent chemistry measurement time points.
l.
Eribulin will be administered on Day 1 and Day 8 of a 21-day cycle together with irinotecan either on Schedule A (Days 1-5) or Schedule B (Day 1 and Day 8) of a 21-day 
cycle.
m.
PK sample collection schedule: 
For subjects ≥12 months of age and >10 kg: 
Phase 1 (Cycle 1):
-
Cycle 1, Day 1: At the end of the irinotecan infusion (irinotecan is administered first), and at the end of the eribulin infusion, then at 1, 2, 4, 6 and 24, hours post-
eribulin infusion. Both irinotecan (and its metabolite SN-38) and eribulin will be assayed.
-
At 72 and 120 h post-eribulin infusion, eribulin only will be assayed. 
Subjects <12 months of age as well as those ≥12 months of age and ≤10 kg (subjects <6 kg will not have PK samples taken):
-
Cycle 1, Day 1: At the end of the irinotecan infusion (irinotecan is administered first) and then immediately after the end of the eribulin infusion (ie 10 ± 5 minutes 
from the start of the eribulin infusion).
-
Cycle 1, Day 4 or 5: During the collection of the first twice weekly CBC sample.
-
Cycle 1, Day 8: Before the eribulin infusion and then immediately after the end of the eribulin infusion (ie, 10 ± 5 minutes from the start of the eribulin infusion).
n.
12-lead ECG will be obtained pre-infusion (after irinotecan administration and prior to eribulin infusion on the days when administered together) and post-infusion on Day 1 
and Day 8 of Cycle 1 and as clinically indicated during subsequent cycles and during follow-up (28 days after the last dose of drug).
o.
If urine protein is ≥2+ on urinalysis, a 24 hour urine test should be performed.
p.
Pre-study phase:  Screening tumor assessments using CT of the chest/abdomen/pelvis and other areas of known disease or newly suspected disease should be performed 
between Day -28 and Day -1.  Scans of the abdomen, pelvis, and other areas of the body may be done with MRI instead of CT, but evaluation of the chest must be done with 
CT.  Treatment phase:  Tumor assessments of the chest/abdomen/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 (or sooner if there is evidence of progressive disease) until Week 12 and then the frequency may 
decrease to every 9 weeks (or sooner if clinically indicated) thereafter for subjects that have CR, PR or SD 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 (see section 9.5.1.3.1 for exception on chest CT and more details).  


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During the Follow-Up Period, subjects who discontinued study treatment without progression should have tumor assessments as per schedule of assessments until death,
disease progression is documented, or another anticancer therapy is initiated. After Week 12, these scans may be conducted every 9 weeks.
q.
Brain: 
Pre-study phase:  Screening CT or MRI of the brain should be performed to assess potential for CNS disease and/or metastases between Day -28 and Day -1 for subjects with 
previously treated protocol-eligible brain metastases only.
Treatment phase:  For subjects with previously treated protocol-eligible brain metastases, a brain scan must be performed at all tumor assessment time points.  For all 
subjects, CT/MRI of the brain should be performed if clinically indicated.  In subjects with body scans indicating a confirmed CR (according to RECIST 1.1), a CT/MRI of 
the brain will also be required within 1 week after the confirmation assessment to confirm the absence of brain metastases.  The same methodology and scan acquisition 
techniques used at screening should be used throughout the study to ensure comparability.
r.
A bone scan whole body bone MRI, 18 F-NaF PET or 18FDG-PET to assess bone metastases will be performed at screening (within 6 weeks prior to first dose (historical scans 
acceptable) to establish a baseline, and then approximately every 24 weeks (in conjunction with scheduled tumor assessment) and as clinically indicated thereafter.  The same 
methodology used at screening should be performed at all subsequent bone assessments.
s.
Information on anticancer treatment will be collected while subjects are in follow-up for disease progression.
t.
During the Follow-Up stage, data will be collected on all subjects for subsequent anti-cancer treatments and survival (at least 4 weeks after last dose and up to 1 year).  This 
Follow-Up may be conducted as a phone call if the subject is unable to attend the hospital. 
u.
Subjects with neuroblastoma may have MIBG scintigraphy and bilateral bone marrow biopsies at sites where this is standard practice (this is an optional assessment).  
Subjects with MIBG positive lesions at screening (within 28 days of the administration of study drug) are not required to undergo PET or technetium99 bone scans. After 
identifying positive lesions at screening, repeat measurements may be performed within 4 weeks after confirmation of PR or CR, or as clinically indicated; urinary 
catecholamines may be assessed at Baseline and in case of CR for subjects with elevated catecholamines at Baseline.  Subjects with positive lesions at screening will be 
evaluable for MIBG response using the revised version of the International Neuroblastoma Response Criteria (INRC) scoring (Brodeur GM, et al., 1993).    


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Table 14
Schedule of Procedures/Assessments in Study E7389-G000-213: Phase 2
Phase
Pre-study
Treatmenta
Off Treatment 
Visit
Follow-Upt
Period
Screeningb
Cycle 1
Cycle 2c
Cycle 3c
Additional Cyclesc
Visit
1
2
3
4
5
6
7
8
9
10
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
≥28 days 
after last 
dose of drug
Procedures/Assessments
Informed consentd
X
Medical history
X
Inclusion/exclusion
X
Vital signse
X
X
X
X
X
X
X
X
X
X
Weekly for subjects 
<12 months
Weekly for 
subjects <12 
months
Weekly for 
subjects <12 
months
Weekly for subjects 
<12 months
Heightf
X
X
X
X
Weight, BSAg
X
Weekly
X
X
X
X
Physical exam
X
Weekly
X
X
X
X
Weekly for 
subjects <12 
months
Weekly for 
subjects <12 
months
Weekly for subjects 
<12 months
Neurologic exam
X
X
X
X
X
Performance statush
X
Weekly
X
X
X
X
Pregnancy testi
X
X


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Table 14
Schedule of Procedures/Assessments in Study E7389-G000-213: Phase 2
Phase
Pre-study
Treatmenta
Off Treatment 
Visit
Follow-Upt
Period
Screeningb
Cycle 1
Cycle 2c
Cycle 3c
Additional Cyclesc
Visit
1
2
3
4
5
6
7
8
9
10
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
≥28 days 
after last 
dose of drug
Procedures/Assessments
Hematologyj
X
Weekly 
Weekly
Weekly
Weekly
X
Twice weekly for 
subjects <12 months 
(every3 to 4 days)
Twice weekly 
for subjects <12 
months (every 3 
to 4 days)
Twice weekly for 
subjects <12 
months (every 3 to 
4 days)
Twice weekly for 
subjects <12 
months (every 3 to 
4 days)
Chemistryk
X
Weekly
X
X
X
X
Weekly for 
subjects <12 
months
Weekly for 
subjects <12 
months
Weekly for subjects 
<12 months
Eribulin mesilate 
administrationl
X
X
X
X
X
X
X
X
Irinotecan hydrochloride 
administration (Schedule 
A)
X
(D1-5)
X
(D1-5)
X
(D1-5)
X
(D1-5)
Irinotecan hydrochloride 
administration (Schedule 
B)
X
X
X
X
X
X
X
X
Pharmacokinetic 
samplingm
X
X


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Table 14
Schedule of Procedures/Assessments in Study E7389-G000-213: Phase 2
Phase
Pre-study
Treatmenta
Off Treatment 
Visit
Follow-Upt
Period
Screeningb
Cycle 1
Cycle 2c
Cycle 3c
Additional Cyclesc
Visit
1
2
3
4
5
6
7
8
9
10
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
≥28 days 
after last 
dose of drug
Procedures/Assessments
12-lead ECGn
X
X
X
As clinically indicated
X
Urinalysiso
X
X
As clinically indicated
X
As clinically indicated for <12 months
Tumor assessmentp
X
Every 6 weeks (counting from date of 
first dose) until Wk 12, then every 9 
weekse
X
Brain CT/MRIq
X
Clinically indicated and all timepoints for subjects with protocol-eligible treated brain mets at 
screening
Bone Scanr
X
Approximately every 24 weeks (in conjunction with scheduled tumor assessment) and as clinically 
indicated
Prior / concomitant 
medicationss
Throughout
Adverse events/SAEs
Throughout
Subsequent anti-cancer 
treatments and survival
X
a.
Efforts should be made to conduct study visits on the scheduled day (+/- 3 days)
b.
The Screening Period extends from Day -28 to Day -1.  Computed tomography (CT) / magnetic resonance imaging (MRI) scans must be performed within 28 days prior to 
study drug administration.  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.  


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c.
Assessments/procedures may be obtained within 72 hours prior to the start of the subsequent cycle.
d.
For logistical purposes, informed consent may be obtained from Day -29.  
e.
Vital signs will be performed on Day 1 and Day 8 of each cycle for subjects aged ≥12 months and weekly for < 12 months.
f.
Height will be measured at Screening and on Day 1 of every other cycle starting from cycle 3.
g.
BSA based on a calculation at enrollment that is accepted and customarily used by the site, such as the Mosteller formula for children, adjustments to dosing to be made if 
10% change in body weight.  
h.
Performance status will be measured using Karnofsky or Lansky scales (Appendix 2).   
i.
Women of childbearing potential require a negative urine or serum (depending on local practice) pregnancy test prior to starting treatment (within 7 days prior to study drug
administration). Sexually active subjects must use an acceptable method of birth control.  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. Thereafter, monthly pregnancy tests are required for sexually active subjects. 
j.
Hematology lab tests will be performed weekly for subjects aged ≥12 months and twice weekly for subjects <12 months; a complete blood count can be performed at a local 
laboratory when the subject is not attending the investigator site for dosing or other study visits.
k.
Albumin, calcium, magnesium, cholesterol, lactate dehydrogenase, phosphorus, total protein, triglycerides, and uric acid are all to be assessed at baseline.  Cholesterol, 
triglycerides and uric acid are not required for assessment at subsequent chemistry measurement time points.
l.
Eribulin will be administered on Day 1 and Day 8 of a 21-day cycle together with irinotecan either on Schedule A (Days 1-5) or Schedule B (Day 1 and Day 8) of a 21-day 
cycle, depending on which schedule is found to be most appropriate for Phase 2. As per protocol amendment #5, Schedule A Dose Level 1 was selected as the RP2D for the 
Phase 2 portion of this study.
m.
PK sample collection schedule: 
Phase 2 (Cycle 1): Eribulin assay only:
Cycle 1, Day 1 (at the end of the infusion, 0.5 to 6 hours and 24 to 120 hours after eribulin infusion) and on Cycle 1, Day 8 (pre-dose of eribulin and at the end of the 
infusion), Subjects who weigh < 6 kg will not have PK samples taken.
n.
12-lead ECG will be obtained pre-infusion (after irinotecan administration and prior to eribulin infusion on the days when administered together) and post-infusion on Day 1 
and Day 8 of Cycle 1 and as clinically indicated during subsequent cycles and during follow-up (28 days after the last dose of drug).
o.
If urine protein is ≥2+ on urinalysis, a 24 hour urine test should be performed.
p.
Pre-study phase:  Screening tumor assessments using CT of the chest/abdomen/pelvis and other areas of known disease or newly suspected disease should be performed 
between Day -28 and Day -1.  
Treatment phase:  Tumor assessments of the chest/abdomen/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 (or sooner if there is evidence of progressive disease) until Week 12 and then the frequency may decrease 
to every 9 weeks (or sooner if clinically indicated) thereafter for subjects that have CR, PR or SD 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 (see section 9.5.1.3.1 for exception on chest CT and more details).  During the 
Follow-Up Period, subjects who discontinued study treatment without progression should have tumor assessments as per schedule of assessments until death, disease 
progression is documented or another anticancer therapy is initiated. After Week 12, these scans may be conducted every 9 weeks. 
q.
Brain: 
Pre-study phase:  Screening CT or MRI of the brain should be performed to assess potential for CNS disease and/or metastases between Day -28 and Day -1 for subjects 
with previously treated protocol-eligible brain metastases only.
Treatment phase:  For subjects with previously treated protocol-eligible brain metastases, a brain scan must be performed at all tumor assessment time points.  For all 
subjects, CT/MRI of the brain should be performed if clinically indicated.  In subjects with body scans indicating a confirmed CR (according to RECIST 1.1), a CT/MRI of 
the brain will also be required within 1 week after the confirmation assessment to confirm the absence of brain metastases.  The same methodology and scan acquisition 
techniques used at screening should be used throughout the study to ensure comparability.
r.
A bone scan (whole body bone MRI, 18F-NaF PET, or 18FDG-PET to assess bone metastases will be performed at screening (within 6 weeks prior to first dose (historical 
scans acceptable) to establish a baseline, and then approximately every 24 weeks (in conjunction with scheduled tumor assessment) and as clinically indicated thereafter.  The 
same methodology used at screening should be performed at all subsequent bone assessments.


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s.
Information on anticancer treatment will be collected while subjects are in follow-up for disease progression.
t.
During the Follow-Up stage, data will be collected on all subjects for subsequent anti-cancer treatments and survival (at least 4 weeks after last dose and up to 1 year).  This 
Follow-Up may be conducted as a phone call if the subject is unable to attend the hospital.


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9.5.2
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.
9.5.3
Reporting of Serious Adverse Events, Pregnancy, and Events Associated 
with Special Situations
9.5.3.1
Reporting of Serious Adverse Events
All SERIOUS ADVERSE EVENTS, regardless of their relationship to study treatment, 
must be reported on a completed SAE form by email or fax as soon as possible but no 
later than 24 hours from when the investigator becomes aware of the event.  Deaths and 
life-threatening events should be reported immediately by telephone.  The immediate 
report should be followed up within 24 hours by emailing or faxing the completed SAE 
form.
Serious adverse events, regardless of causality assessment, must be collected through the last 
visit 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 SAE judged by the 
investigator to be related to the study treatment or any protocol-required procedure should be 
reported to the sponsor regardless of the length of time that has passed since study 
completion.
The detailed contact information for reporting of SAEs is provided in the Investigator Study 
File.
For urgent safety issues, please ensure all appropriate medical care is administered to the 
subject and contact the appropriate study team member listed in the Investigator Study 
File.
It is very important that the SAE report form be filled out as completely as possible at the 
time of the initial report.  This includes the investigator’s assessment of causality.
Any follow-up information received on SAEs should be forwarded within 24 hours of its 
receipt.  If the follow-up information changes the investigator’s assessment of causality, this 
should also be noted on the follow-up SAE form.
Preliminary SAE reports should be followed as soon as possible by detailed descriptions 
including copies of hospital case reports, autopsy reports, and other documents requested by 
the sponsor.


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The investigator must notify his/her IRB/IEC of the occurrence of the SAE in writing, if 
required by their institution.  A copy of this communication must be forwarded to the sponsor 
to be filed in the sponsor’s Trial Master File.
9.5.3.2
Reporting of Pregnancy and Exposure to Study Drug Through Breastfeeding
Any pregnancy in which the estimated date of conception is either before the last visit or 
within 28 days of last study treatment, or any exposure to study drug through breastfeeding 
during study treatment or within 28 days of last study treatment, must be reported.
If an adverse outcome of a pregnancy is suspected to be related to study drug exposure, this 
should be reported regardless of the length of time that has passed since the exposure to study 
treatment.
A congenital anomaly, death during perinatal period, an induced abortion, or a spontaneous 
abortion are considered to be an SAE and should be reported in the same time frame and in 
the same format as all other SAEs (see Reporting of Serious Adverse Events 
[Section 9.5.3.1]).
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. The investigator should 
confirm whether they agree to follow-up assessments (including survival follow-up) or 
whether the subject wishes to withdraw consent.  If a subject withdraws consent, the date 
should be documented in the source documents. 
9.5.3.3
Reporting of Events Associated with Special Situations
9.5.3.3.1
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.


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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.
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 9.5.3.1) even if the AEs do not meet serious criteria.  Abuse 
is always to be captured as an AE.  If the AE associated with an overdose, misuse, abuse, or 
medication error does not meet serious criteria, it must still be reported using the SAE form 
and in an expedited manner but should be noted as nonserious on the SAE form and the 
Adverse Event CRF.
9.5.3.4
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.
9.5.3.5
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.
All studies that are conducted within any European country will comply with European Good 
Clinical Practice Directive 2005/28/EC and Clinical Trial Directive 2001/20/EC.  All 
suspected unexpected serious adverse reactions (SUSARs) will be reported, as required, to 
the competent authorities of all involved European member states.
9.5.4
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 13 and Table 14).
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.  


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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.  Study disposition 
information will be collected on the Subject Disposition CRF.
A subject removed from the study for any reason may be replaced.
9.5.5
Abuse or Diversion of Study Drug
Not applicable.
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 (CCGs).  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 
software or other validated statistical software as required.  Details of the statistical analyses 
will be included in a separate statistical analysis plan (SAP).


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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 ENDPOINTS
The primary endpoints of the study are:

Phase 1: The MTD/RP2D of eribulin mesilate in combination with irinotecan 
hydrochloride in pediatric subjects with relapsed/refractory solid tumors, excluding CNS
tumors. Note: Subjects <12 months will not contribute to the determination of
MTD/RP2D and data is for descriptive purposes only.
Phase 2: Objective response rate (ORR):  defined as the proportion of subjects achieving 
a best overall response of confirmed partial or complete response, as determined by 
investigator assessment. 
9.7.1.1.2
SECONDARY ENDPOINTS
The secondary endpoints of the study are:
Phase 1 & 2:

Safety and tolerability: adverse events (AEs), serious adverse events, clinical laboratory 
values, ECG parameters, vital sign measurements and physical examinations.

The pharmacokinetic profile of eribulin, irinotecan and its active metabolite.
Phase 2:

Progression-free survival (PFS): defined as the time from the first dose date to the date of 
disease progression as determined by investigator assessment or death.

The Clinical Benefit Rate (CBR): defined as the proportion of subjects with best overall 
response (BOR) of CR, PR or durable SD based on RECIST 1.1 (durable SD is defined 
as SD with duration of >11 weeks).
9.7.1.2
Definitions of Analysis Sets
Full Analysis Set (FAS) will consist of subjects who receive at least 1 dose of either study 
drug. 
Safety Analysis Set will consist of subjects who receive at least 1 dose of either study drug. 
Pharmacokinetic Analysis Set (PAS) will include subjects who have documented dosing 
history and at least one post-dosing quantifiable drug concentration.


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Dose Evaluable Set (DES) for Phase 1 will consist of all subjects who completed Cycle 1 
treatment and were evaluated for DLT, and those who discontinued during Cycle 1 due to 
DLT. DES will be used for evaluation of each dose level for dose-escalation and for 
determination of MTD.
9.7.1.3
Subject Disposition
The number and percentage of subjects who discontinue the study treatment will be 
tabulated, along with the primary reasons for discontinuation.
9.7.1.4
Demographic and Other Baseline Characteristics
Demographic and other baseline characteristics data will be summarized descriptively.  Data 
to be tabulated will include data such as sex, age, and race as well as weight and disease-
specific status and medical history.
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 by dose level, 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 up to 30 days after the subject’s last dose.  All medications will be 
presented in subject data listings.
9.7.1.6
Efficacy Analyses
The primary efficacy analyses will be performed at the time of data cutoff, ie, when all 
subjects have discontinued the treatment or completed at least 6 months of treatment. 
ORR, PFS, and CBR will be summarized descriptively on the FAS. Endpoints related to tumor 
assessments will be based on investigator assessments. Collect and hold of tumor scans will 
enable a possibility to confirm responses in case independent review is required.
9.7.1.6.1
PRIMARY EFFICACY ANALYSIS
ORR will be estimated and summarized for each histology type.  A Simon two-stage design 
will be used within each histology type. The following hypothesis will be tested at a one-
sided 5% significance level:  
Ho: p ≤30%         Vs            Ha: p ≥ 55%.


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The first stage will enroll 9 subjects.  A futility analysis will be performed when the data for 
the 9 subjects is available.  If there are 2 or less responders (CR or PR) among the 9 subjects, 
the enrollment in this histology type will be stopped.  If there are 3 or more responders, the 
enrollment will continue to the second stage to approximately 25 subjects.  If there are 12 or 
more responders out of 25 subjects, the null hypothesis will be rejected.  For final review, 
collect and hold of tumor scans will enable the final report to confirm responses by potential
independent radiologic review.
In addition, ORR along with respective confidence interval will be provided by histology.  
Duration of response (DOR) will be calculated for responders and summarized descriptively.  
DOR is 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).
9.7.1.6.2
SECONDARY EFFICACY ANALYSES
PFS will be analyzed by Kaplan-Meier methodology and median PFS with 90% confidence 
interval will be presented. Clinical benefit rate (CBR) defined as the proportion of subjects with 
best overall response (BOR) of CR, PR or durable SD based on RECIST 1.1, will be summarized 
by descriptive statistics for the FAS. Durable SD is defined as SD with duration of more than 11 
weeks.  
9.7.1.7
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker
Analyses
9.7.1.7.1
PHARMACOKINETIC ANALYSES
Plasma concentrations of eribulin, irinotecan and its active metabolite SN-38 will be 
tabulated and summarized by dose level, day and time.  For Phase 1, PK parameters for 
eribulin, irinotecan and SN-38 will be derived from plasma concentrations by 
noncompartmental analysis using actual times.  Minimally, the following PK parameters will 
be calculated: maximum observed plasma concentration (Cmax), time of maximum observed 
concentration following drug administration (tmax), area under the concentration-time curve 
(AUC).  
In Phase 1 the PK of both drugs (eribulin and irinotecan) will be assessed on C1D1 and in 
Phase 2 eribulin will be assessed on C1D1 and C1D8. The Phase 2 PK data will be assessed 
using a PopPK approach, pooled with Phase 1 data.  A population PK model for eribulin will 
be developed using non-linear mixed effect modelling.  The model will be parameterized in 
terms of clearance and volume of distribution parameters. 
9.7.1.7.2
PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES
Exploratory/graphical analysis will be conducted for PK/PD evaluations, ie, dose and/or 
exposure effect relationships will be explored for the effects of eribulin mesilate on tumor 
responses as determined by RECIST 1.1 (CR, PR and SD), PFS and ORR, as well as AEs/dose 
reductions, and may be followed by model-based analysis.  In addition, the effects of eribulin 


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mesylate administration on absolute neutrophil count (ANC) may be evaluated using a semi-
physiological model for hematological toxicity.  
Further details will be documented separately in a population analysis plan (PAP). 
9.7.1.8
Safety Analyses
The primary endpoint for Phase 1, i.e., the incidence of DLTs will be summarized by dose 
level for the DES using frequency and percentage.  
Additionally, toxicity in Phase 2 for the Safety Analysis Set will be monitored on an ongoing 
basis. If the number of AEs that would have qualified as DLTs on the Phase 1 portion 
exceeds 1/3, a meeting with the investigators will be convened to determine if the dose 
should be lowered. The rule of one-third (1/3) will be applied to the number of subjects in an 
increment of 3 subjects at the same dose level (eg, 3, 6, 9 subjects).  Likewise, if ongoing 
moderate toxicities develop into “intolerable Grade 2” events, the recommended Phase 2 
dose may also be re-evaluated in consultation with the protocol investigators.
All evaluation of safety other than the Phase 1 primary objective in DLT evaluation will be 
performed on the Safety Analysis Set.  Safety data that will be evaluated include adverse 
events, clinical laboratory results, ECG, and vital signs.
Descriptive summary statistics (mean, standard deviation, median, minimum, maximum) of 
clinical laboratory test results, vital signs measurements, ECG parameters, and changes from 
baseline will be presented.  
9.7.1.8.1
EXTENT OF EXPOSURE
The number of cycles administered, duration of treatment, and the number of subjects 
requiring dose reductions, treatment interruption, treatment delay, and treatment 
discontinuation due to adverse events will be summarized.
9.7.1.8.2
ADVERSE EVENTS
The AE verbatim descriptions (investigator terms from the CRF) will be classified into 
standardized medical terminology using the Medical Dictionary for Regulatory Activities 
(MedDRA).  Adverse events will be coded to the MedDRA (Version 20.0 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 or 

Reemerges during treatment, having been present at pretreatment (Baseline) but stopped 
before treatment, or 

Worsens in severity during treatment relative to the pretreatment state, when the AE is 
continuous.


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Only those AEs that are treatment-emergent will be included in summary tables.  All AEs, 
treatment-emergent or otherwise, will be presented in subject data listings.
The incidence of TEAEs will be reported as the number (percentage) of subjects with TEAEs 
by SOC and PT.  A subject will be counted only once within an SOC and PT, even if the 
subject experienced more than 1 TEAE within a specific SOC and PT.  The number 
(percentage) of subjects with TEAEs will also be summarized by highest CTCAE grade
(CTCAE v5.0).
The number (percentage) of subjects with TEAEs will also be summarized by relationship to 
study drug (Yes [related] and No [not related]).
The number (percentage) of subjects with treatment-emergent serious adverse events (SAEs)
will be summarized by MedDRA SOC and PT. A subject data listing of all SAEs will be 
provided.
The number (percentage) of subjects with TEAEs leading to death will be summarized by
MedDRA SOC and PT. A subject data listing of all AEs leading to death will be provided.
The number (percentage) of subjects with TEAEs leading to discontinuation from study drug 
will be summarized by MedDRA SOC and PT. A subject data listing of all AEs leading to 
discontinuation from study drug will be provided.
9.7.1.8.3
LABORATORY VALUES
Laboratory results will be summarized using Système International (SI) units, as appropriate.  
Hematology and chemistry values and their changes from baseline will be summarized using 
descriptive statistics (mean, standard deviation, median, minimum, maximum).  Shift from 
baseline to post-baseline CTCAE grade for hematology and chemistry tests will be presented. 
Laboratory test results will be assigned a classification according to CTCAE grade 
(Appendix 1). Urinalysis data will be listed.   
9.7.1.8.4
VITAL SIGNS
Descriptive statistics for vital signs parameters (ie, systolic and diastolic BP, pulse, 
temperature, weight, and height) and changes from baseline will be presented by visit.
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.


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A shift table will be provided for baseline to post-baseline shift in ECG interpretation 
(categorized as normal; abnormal, not clinically significant; and abnormal, clinically 
significant). 
In addition, the number (percentage) of subjects with at least 1 post-baseline abnormal ECG 
result in QTcF will be summarized.  Clinically abnormal ECG results in QTcF 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 increases from baseline >30 ms

QTC interval increases from baseline >60 ms
9.7.1.8.6
OTHER SAFETY ANALYSES
Karnofsky and Lansky performance status scores will be summarized descriptively.
9.7.2
Determination of Sample Size
For the first line therapy in pediatric patients with NRSTS, RMS, or EWS, the literature 
indicated that the ORR (complete or partial response) ranged from 33.3% to 63% (Pappo, et 
al., 1997; Sandler, et al., 2001).  In children or patients with refractory solid tumor or 
rhabdomyosarcoma, the ORR of a treatment ranged from 0 to 50% (Jacobs, et al., 2010; 
Mascarenhas, et al., 2010).  At the time of the design of this study, there was limited data 
available for eribulin and irinotecan as a treatment in the target populations. 
Phase 1: Up to 6 subjects can be enrolled into each dose level, there are 2 schedules being 
evaluated (Schedule A and Schedule B).  Therefore, a maximum of 36 subjects (not 
including subjects <12 months) are anticipated to be enrolled on this phase. Note: Subjects 
<12 months will not contribute to the determination of MTD/RP2D and data is for 
descriptive purposes only.
Phase 2: A total of approximately 75 subjects (approximately 25 in each histology group) 
will be enrolled.  A Simon two-stage design will be used for each histology group.  The 
following hypothesis will be tested at a one-sided 5% significance level:  
Ho: p ≤30%         Vs            Ha: p ≥ 55%.
In the first stage, 9 subjects will be accrued.  If there are 2 or fewer responses in these 9 
subjects, the enrollment to this histology type (RMS, NRSTS and EWS) will be stopped.  
Otherwise, approximately 16 additional subjects will be enrolled in the second stage for a 
total of approximately 25 subjects per histology. The null hypothesis will be rejected if 12 or 


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more responses are observed in 25 subjects.  This design yields a type I error rate of 0.05 
(one-sided) and power of 80% when the true response rate is 55%.
Note: Subjects aged >6 to <12 months and subjects ≥18 to ≤25 years will be included for 
descriptive purposes only and will not contribute to the full sample size analyses for this study.
As subjects in the age group >6 months to <12 months will receive approximately 75% of the 
RP2D of eribulin (rationale for lower dose is provided in Section 9.4.4 of the protocol) and the 
EMA PDCO requested that subjects in the age group ≥18 to ≤25 years old should not be 
included in the full sample size analyses.
9.7.3
Interim Analysis
There will be an interim analysis to define MTD and RP2D prior to initiating Phase 2 of the 
study.  It is anticipated that selection of the RP2D will be based on an integrated evaluation 
of safety, efficacy, and PK data. In Phase 2, for each histology (RMS, NRSTS and EWS), 
there will be 1 futility analysis of efficacy: this is planned after data from the first 9 subjects 
is available.  At the futility analysis, if there are 2 or fewer responses, then enrollment to that 
histology will be discontinued. Enrollment to that histology will be suspended for up to 24 
weeks after 9 subjects have been enrolled to complete ORR assessment.  An assessment of 
tolerability will also be conducted at this time.
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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RECIST Reference
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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

Copies or transcribed health care provider notes that have been certified for accuracy after 
production


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
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 
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.


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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.
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.


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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
Sponsor’s Grading for Laboratory Values
Sponsor’s Grading for Laboratory Values
Grade 1
Grade 2
Grade 3
Grade 4
BLOOD/BONE MARROW
Anaemia (Hemoglobin)  
<LLN – 10.0 g/dL
<LLN – 100 g/L
<LLN – 6.2 mmol/L
<10.0 – 8.0 g/dL
<100 – 80 g/L
<6.2 – 4.9 mmol/L 
<8.0 g/dL
<80 g/L
<4.9 mmol/L;
transfusion indicated
life-threatening 
consequences; urgent 
intervention indicated
White blood cell (Leukocytes) 
decreased 
<LLN – 3.0109/L
<LLN – 3000/mm3
<3.0 – 2.0109/L
<3000 – 2000/mm3
<2.0 – 1.0109/L
<2000 – 1000/mm3
<1.0109/L
<1000/mm3
Lymphocyte count decreased 
<LLN – 800/mm3
<LLN – 0.8109/L
<800 – 500/mm3
<0.8 – 0.5109/L
<500 – 200/mm3
<0.5 – 0.2109/L
<200/mm3
<0.2109/L
Neutrophil count decreased 
<LLN – 1.5109/L
<LLN – 1500/mm3
<1.5 – 1.0109/L
<1500 – 1000/mm3
<1.0 – 0.5109/L
<1000 – 500/mm3
<0.5109/L
<500/mm3
Platelet count decreased 
<LLN – 75.0109/L
<LLN – 75,000/mm3
<75.0 – 50.0109/L
<75,000 – 50,000/mm3
<50.0 – 25.0109/L
<50,000 – 25,000/mm3
<25.0109/L
<25,000/mm3
METABOLIC/LABORATORY
Albumin, serum- low 
(hypoalbuminemia) 
<LLN – 3 g/dL
<LLN – 30 g/L
<3 – 2 g/dL
<30 – 20 g/L
<2 g/dL
<20 g/L
life-threatening 
consequences; urgent 
intervention indicated
Alkaline phosphatase increased
>ULN - 2.5 x ULN if 
baseline was normal; 
2.0 - 2.5 x baseline if 
baseline was abnormal 
>2.5 - 5.0 x ULN if 
baseline was normal;
>2.5 - 5.0 x baseline if 
baseline was abnormal 
>5.0 – 20.0ULN if 
baseline was normal; 
>5.0 - 20.0 x baseline if 
baseline was abnormal 
>20.0ULN if 
baseline was normal;
>20.0 x baseline if 
baseline was 
abnormal 
ALT
>ULN - 3.0 x ULN if 
baseline was normal; 
1.5 - 3.0 x baseline if 
baseline was abnormal 
>3.0 - 5.0 x ULN if 
baseline was normal; 
>3.0 - 5.0 x baseline if 
baseline was abnormal 
>5.0 - 20.0 x ULN if 
baseline was normal; 
>5.0 - 20.0 x baseline if 
baseline was abnormal 
>20.0 x ULN if 
baseline was normal; 
>20.0 x baseline if 
baseline was 
abnormal 
AST
>ULN - 3.0 x ULN if 
baseline was normal; 
1.5 - 3.0 x baseline if 
baseline was abnormal 
>3.0 - 5.0 x ULN if 
baseline was normal; 
>3.0 - 5.0 x baseline if 
baseline was abnormal 
>5.0 - 20.0 x ULN if 
baseline was normal; 
>5.0 - 20.0 x baseline if 
baseline was abnormal 
>20.0 x ULN if 
baseline was normal; 
>20.0 x baseline if 
baseline was 
abnormal 
Bilirubin (hyperbilirubinemia)
>ULN - 1.5 x ULN if 
baseline was normal; 
> 1.0 - 1.5 x baseline if 
baseline was abnormal 
>1.5 - 3.0 x ULN if 
baseline was normal; 
>1.5 - 3.0 x baseline if 
baseline was abnormal 
>3.0 - 10.0 x ULN if 
baseline was normal; 
>3.0 - 10.0 x baseline if 
baseline was abnormal 
>10.0 x ULN if 
baseline was normal; 
>10.0 x baseline if 
baseline was 
abnormal 
Calcium, serum-low (hypocalcemia) 
<LLN – 8.0 mg/dL
<LLN – 2.0 mmol/L
<8.0 – 7.0 mg/dL
<2.0 – 1.75 mmol/L
<7.0 – 6.0 mg/dL
<1.75 – 1.5 mmol/L
<6.0 mg/dL
<1.5 mmol/L
Calcium, serum-high (hypercalcemia)
>ULN – 11.5 mg/dL
>ULN – 2.9 mmol/L
>11.5 – 12.5 mg/dL
>2.9 – 3.1 mmol/L
>12.5 – 13.5 mg/dL
>3.1 – 3.4 mmol/L
>13.5 mg/dL
>3.4 mmol/L
Cholesterol, serum-high 
(hypercholesterolemia)
>ULN – 300 mg/dL
>ULN – 7.75 mmol/L 
>300 – 400 mg/dL
>7.75 – 10.34 mmol/L 
>400 – 500 mg/dL
>10.34 – 12.92 mmol/L 
>500 mg/dL
>12.92 mmol/L 


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Sponsor’s Grading for Laboratory Values
Grade 1
Grade 2
Grade 3
Grade 4
Creatinine
>ULN – 1.5ULN
>1.5 – 3.0ULN
>3.0 – 6.0ULN
>6.0ULN
GGT (γ-glutamyl transpeptidase) 
>ULN – 3.0ULN
>3.0 – 5.0ULN
>5.0 – 20.0ULN
>20.0ULN
Glucose, serum-high (hyperglycemia)
Abnormal glucose 
above baseline with no 
medical intervention 
Change in daily 
management from 
baseline for a diabetic; 
oral antiglycemic agent 
initiated; workup for 
diabetes 
Insulin therapy initiated; 
hospitalization indicated 
Life-threatening 
consequences; urgent 
intervention indicated 
Glucose, serum-low (hypoglycemia)
<LLN – 55 mg/dL
<LLN – 3.0 mmol/L
<55 – 40 mg/dL
<3.0 – 2.2 mmol/L
<40 – 30 mg/dL
<2.2 – 1.7 mmol/L
<30 mg/dL
<1.7 mmol/L
life-threatening 
consequences; 
seizures
Magnesium, serum-high
(hypermagnesemia)
>ULN - 3.0 mg/dL; 
>ULN - 1.23 mmol/L
N/A
>3.0 - 8.0 mg/dL; 
>1.23 - 3.30 mmol/L
>8.0 mg/dL; 
>3.30 mmol/L; 
life-threatening 
consequences
Magnesium, serum-low 
(hypomagnesemia)
<LLN - 1.2 mg/dL; 
<LLN - 0.5 mmol/L
<1.2 - 0.9 mg/dL; 
<0.5 - 0.4 mmol/L
<0.9 - 0.7 mg/dL; 
<0.4 - 0.3 mmol/L
<0.7 mg/dL; 
<0.3 mmol/L; 
life-threatening 
consequences
Phosphate, serum-low 
(hypophosphatemia) 
Laboratory finding only 
and intervention not 
indicated 
Oral replacement 
therapy indicated 
Severe or medically 
significant but not 
immediately life-
threatening; 
hospitalization or 
prolongation of existing 
hospitalization indicated 
life-threatening 
consequences
Potassium, serum-high (hyperkalemia)
>ULN – 5.5 mmol/L 
>5.5 – 6.0 mmol/L;
intervention initiated 
>6.0 – 7.0 mmol/L
hospitalization indicated
>7.0 mmol/L
life-threatening 
consequences
Potassium, serum-low (hypokalemia) 
<LLN – 3.0 mmol/L
<LLN – 3.0 
mmol/Lsymptomatic; 
intervention indicated
<3.0 – 2.5 mmol/L
hospitalization indicated
<2.5 mmol/L
life-threatening 
consequences
Sodium, serum-high (hypernatremia)
>ULN – 150 mmol/L
>150 – 155 mmol/L
intervention initiated
>155 – 160 mmol/L
hospitalization indicated
>160 mmol/L
life-threatening 
consequences
Sodium, serum-low (hyponatremia)
<LLN – 130 mmol/L
125-129 mmol/L and 
asymptomatic
125-129 mmol/L 
symptomatic; 120-124 
mmol/L regardless of 
symptoms
<120 mmol/L
life-threatening 
consequences
Triglyceride, serum-high 
(hypertriglyceridemia) 
150 – 300 mg/dL
1.71 – 3.42 mmol/L
>300 – 500 mg/dL
>3.42 – 5.7 mmol/L 
>500 – 1000 mg/dL
>5.7 – 11.4 mmol/L
>1000 mg/dL
>11.4 mmol/L
life-threatening 
consequences 
Uric acid, serum-high (hyperuricemia)
>ULN without 
physiologic 
consequences 
N/A
>ULN with physiologic 
consequences 
life-threatening 
consequences


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Sponsor’s Grading for Laboratory Values
Grade 1
Grade 2
Grade 3
Grade 4
ALT = alanine aminotransferase (serum glutamic pyruvic transaminase), AST = aspartate aminotransferase (serum glutamic oxaloacetic 
transaminase), GGT = γ-glutamyl transpeptidase, N/A = not applicable, LLN = lower limit of normal, ULN = upper limit of normal, WBC = 
white blood cell.
Based on Common Terminology Criteria for Adverse events (CTCAE) Version 5.0.  Published: Nov 27, 2017.


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Appendix 2
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 3
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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PPD
PPD
PPD
PPD
PPD


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INVESTIGATOR SIGNATURE PAGE
Study Protocol Number:
E7389-G000-213
Study Protocol Title:
A Phase 1/2 single-arm study evaluating the safety and efficacy 
of eribulin mesilate in combination with irinotecan in children 
with refractory or recurrent solid tumors.
Investigational Product 
Name:
E7389 (eribulin mesilate)
IND Number:
116292
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 Pharmaceuticals for Human Use (ICH) and all applicable local Good 
Clinical Practice (GCP) guidelines, including the Declaration of Helsinki.
Medical Institution
Investigator
Signature
Date

SAP_001.pdf: 
Statistical Analysis Plan
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STATISTICAL ANALYSIS PLAN
Study Protocol 
Number:
E7389-G000-213
Study Protocol 
Title:
A Phase 1/2 single-arm study evaluating the safety and efficacy of 
eribulin mesilate in combination with irinotecan in children with 
refractory or recurrent solid tumors.
Date:
25 Jun 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(s) ..................................................................................6
3.1.2
Secondary Objective(s)...............................................................................6
3.1.3
Exploratory Objective(s) ............................................................................7
3.2
Overall Study Design and Plan.............................................................................7
3.2.1
Phase 1.......................................................................................................7
3.2.2
Phase 2.......................................................................................................9
4
DETERMINATION OF SAMPLE SIZE.....................................................................11
5
STATISTICAL METHODS........................................................................................12
5.1
Study Endpoints.................................................................................................12
5.1.1
Primary Endpoint(s) .................................................................................12
5.1.2
Secondary Endpoint(s) .............................................................................12
5.2
Study Subjects ...................................................................................................13
5.2.1
Definitions of Analysis Sets......................................................................13
5.2.2
Subject Disposition...................................................................................13
5.2.3
Protocol Deviations ..................................................................................13
5.2.4
Demographic and Other Baseline Characteristics......................................13
5.2.5
Prior and Concomitant Therapy................................................................14
5.2.6
Treatment Compliance .............................................................................14
5.3
Data Analysis General Considerations................................................................14
5.3.1
Pooling of Centers....................................................................................14
5.3.2
Adjustments for Covariates ......................................................................14
5.3.3
Multiple Comparisons/Multiplicity...........................................................14
5.3.4
Examination of Subgroups........................................................................15
5.3.5
Handling of Missing Data, Dropouts, and Outliers....................................15
5.3.6
Other Considerations................................................................................15
5.4
Efficacy Analyses ..............................................................................................15
5.4.1
Primary Efficacy Analyses .......................................................................15
5.4.2
Secondary Efficacy Analyses ...................................................................16
5.4.3
Other Efficacy Analyses...........................................................................17
5.5
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other 
Biomarker Analyses...........................................................................................17
5.5.1
Pharmacokinetic Analyses........................................................................17


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5.5.2
Pharmacokinetic Analyses and Pharmacodynamic Analyses.....................18
5.5.3
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Analyses....18
5.6
Safety Analyses..................................................................................................18
5.6.1
Extent of Exposure...................................................................................19
5.6.2
Dose Limiting Toxicities ..........................................................................19
5.6.3
Adverse Events.........................................................................................19
5.6.4
Laboratory Values ....................................................................................20
5.6.5
Vital Signs................................................................................................20
5.6.6
Electrocardiograms...................................................................................21
5.6.7
Other Safety Analyses ..............................................................................21
5.7
Other Analyses...................................................................................................22
5.8
Exploratory Analyses.........................................................................................22
6
INTERIM ANALYSES...............................................................................................22
7
CHANGES IN THE PLANNED ANALYSES ............................................................22
8
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING .............................22
9
PROGRAMMING SPECIFICATIONS .......................................................................22
10
STATISTICAL SOFTWARE......................................................................................23
11
MOCK TABLES, LISTINGS, AND GRAPHS............................................................23
12
REFERENCES............................................................................................................23
13
APPENDICES.............................................................................................................24
13.1
Sponsor’s Grading for Determining Markedly Abnormal Laboratory Results.....24
13.2
Measurements of Performance Status.................................................................27
SIGNATURE PAGE...........................................................................................................28


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2
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
AE
adverse event
ALT
alanine aminotransferase 
AST
aspartate aminotransferase 
ATC
anatomical therapeutic class
AUC
area under the concentration-time curve
BOR
best overall response 
BP
blood pressure 
BSA
body surface area 
CBR
clinical benefit rate
CI
confidence interval
Cmax
maximum observed plasma concentration 
CNS
central nervous system
CR
complete response 
CRF
case report form
CSR
clinical study report
CT
computed tomography
CTCAE
Common Toxicity Criteria for Adverse Events 
DES
dose evaluable set
DLT
dose limiting toxicity
DOR
duration of response
EWS
Ewing sarcoma
FAS
full analysis set
HR
heart rate
MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging 
MTD
maximum tolerated dose
NRSTS
non-rhabdomyosarcoma soft tissue sarcoma


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ORR
objective response rate
PAS
pharmacokinetic analysis set
PD
progressive disease
PFS
progression-free survival
PK
pharmacokinetic
PR
partial response
PT
preferred term
Q1
25th percentile
Q3
75th percentile
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
QTcF
QT interval corrected for heart rate using Fridericia's formula
RECIST
response evaluation criteria in solid tumors 
RMS
rhabdomyosarcoma
RP2D
recommend phase 2 dose
SAE
serious adverse event
SAP
statistical analysis plan
SD
stable disease
SI
Système International
SOC
system organ class 
TEAE
treatment-emergent adverse event
TLG
tables, listings, and graphs
Tmax
time of maximum observed plasma concentration
WHO DD
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-
G000-213 titled “A Phase 1/2 single-arm study evaluating the safety and efficacy of eribulin 
mesilate in combination with irinotecan in children with refractory or recurrent solid 
tumors”.
3.1
Study Objectives
3.1.1
Primary Objective(s)
The primary objectives are: 
Phase 1: To determine the maximum tolerated dose (MTD) and Recommended Phase 2 Dose 
(RP2D) of eribulin mesilate in combination with weekly and daily irinotecan hydrochloride in 
pediatric subjects with relapsed/refractory solid tumors, excluding CNS. 
Phase 2: To assess the objective response rate (ORR) and duration of response (DOR) of 
eribulin mesilate in combination with irinotecan hydrochloride in pediatric subjects with 
relapsed/refractory rhabdomyosarcoma (RMS), non-rhabdomyosarcoma soft tissue sarcoma 
(NRSTS) and Ewing sarcoma (EWS).
3.1.2
Secondary Objective(s)
Phase 1:

To assess the safety and tolerability of eribulin mesilate in combination with irinotecan 
hydrochloride in pediatric subjects

To determine the optimal schedule of irinotecan hydrochloride when administered with 
standard schedule (Days 1 and 8) of eribulin mesilate in pediatric subjects
Phase 2:

To assess Progression Free Survival (PFS) of eribulin mesilate in combination with 
irinotecan hydrochloride in pediatric subjects 

To assess the Clinical Benefit Rate (CBR) of eribulin mesilate in combination with 
irinotecan hydrochloride in pediatric subjects 
Phase 1 & 2:
To evaluate the pharmacokinetic (PK) profile of eribulin, irinotecan and its active 
metabolite and compare to appropriate historical data. 


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3.1.3
Exploratory Objective(s)
The exploratory objective of Phase 1 & 2 is:

To explore the relationship between model-derived exposure to eribulin and the 
active metabolite for irinotecan (SN 38) in terms of area under the curve and AEs and 
efficacy endpoints using a model-based approach
3.2
Overall Study Design and Plan
This study is divided into 2 phases.
3.2.1 Phase 1
Phase 1 will determine the MTD/RP2D and optimal schedule of eribulin mesilate in 
combination with irinotecan hydrochloride in pediatric subjects with relapsed/refractory solid 
tumors, excluding CNS.
Eribulin mesilate will be administered as an intravenous (IV) infusion on Days 1 and 8 of each 
21-day cycle, at the RP2D determined in the single-agent dose finding study E7389-A001-113 
(1.4 mg/m2)
Irinotecan hydrochloride will be administered as an IV infusion using 2 different dose 
schedules:

Schedule A: Days 1-5 of a 21-day cycle at the following doses: 20 mg/m2 and 40 mg/m2
And 

Schedule B: Days 1 and 8 of a 21-day cycle at the following doses: 100 mg/m2 and 125
mg/m2. 
Table1Study Medication Dose Levels by Schedule
Dose Level
Eribulin mesilate (mg/m2)
Irinotecan hydrochloride (mg/m2)
Schedule A
-2#
0.8
20
-1
1.1
20
0*
1.4
20
1
1.4
40
Schedule B


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Table1Study Medication Dose Levels by Schedule
Dose Level
Eribulin mesilate (mg/m2)
Irinotecan hydrochloride (mg/m2)
-1
1.1
100
0*
1.4
100
1
1.4
125
*Dose level 0 refers to the starting dose.
#Dose level -2 is a further dose reduction in Schedule A for subjects <12 months only.
Dose Escalation 
The traditional 3+3 design will be used for the conduct of Phase 1 part of this study.
The MTD is defined as the highest dose level at which less than 1/3 of subjects experience a 
DLT during Cycle 1 of therapy. The MTD will be determined based on the incidence of DLTs 
in Cycle 1 of each dose level.  Subjects who do not complete Cycle 1 for any reason other than 
toxicity, ie, DLT, will be replaced in that cohort in order to complete the number necessary (up 
to 6) to assess the safety of the dose level cohort. 
Toxicities subsequent to Cycle 1 will also be reviewed, but will not count towards 
determination of dose escalation and MTD/RP2D.  If protocol-defined DLTs are observed in 
a subject after the first cycle at any dose level, the dose will be reduced to the next lower dose 
level for subsequent cycles.
Definition of DLT 
DLTs are defined as any of the following using the National Cancer Institute Common 
Terminology Criteria for Adverse Events (CTCAE Version 5.0) during Cycle 1:
Hematological:
1. Neutropenia Grade 4 that lasts > 7 days
2. Thrombocytopenia Grade 4 on 2 separate days, or requiring a platelet transfusion on 2 
separate days, within a 7-day period 
3. Thrombocytopenia Grade 3 complicated by bleeding or requiring platelet or blood 
transfusion 
4. Neutropenia Grade 3 or 4 complicated by fever and/or infection (ANC <1.0 × 109/L, fever 
≥38.0°C). 
5. Myelosuppression that causes a delay of >14 days between treatment cycles


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6. Grade 4 neutropenia or platelets < 75,000/mm3 on Day 8 that does not resolve to ANC 
≥750/mm3 and platelets ≥ 75,000/mm3 (transfusion independent) by Day 11 will be 
considered dose-limiting.
Non-hematological:
1. Grade 3 or 4 non-hematological toxicities related to study drug except for:
-
inadequately treated nausea and/or vomiting,
-
Grade 3 liver enzyme elevation (including ALT/AST),
-
Grade 3 fever or Grade 3infection,
-
Grade 3 hypophosphatemia, hypokalemia, hypocalcemia or hypomagnesemia 
responsive to oral supplementation
2. Grade 3 or above diarrhea despite adequate treatment 
3. Non-hematological toxicity that causes a delay of ≥14 days between treatment cycles 
4. Day 8 dose omission or interruption for more than 2 weeks due to non-recovery of any 
toxicity related to the study drug 
5. For subjects <12 months (at the time of DLT), any ≥Grade 2 drug-related non-
hematological toxicity
6. DLT exception:  Allergic reactions that lead to discontinuation of study drug during Cycle 
1.
MTDs will be obtained for both Schedule A and Schedule B and the most appropriate schedule 
will be taken forward to Phase 2 and will represent the RP2D (See Section 9.4.1 in the protocol
for details on schedule selection).
3.2.2
Phase 2
Phase 2 will evaluate the safety and efficacy of eribulin mesilate in combination with irinotecan 
hydrochloride in pediatric subjects with relapsed/refractory RMS, NRSTS, and EWS, using 
the combination dose and schedule determined in Phase 1 (RP2D).  The RP2D as determined 
from the phase 1 portion of the study was Schedule A Dose Level 1, ie, eribulin (1.4 mg/m2) 
Day 1 and Day 8 and irinotecan (40 mg/m2) Days 1-5.
Up to approximately 75 pediatric subjects (approximately 25 subjects per histology type of
RMS, NRSTS, and EWS) who meet all the inclusion criteria and none of the exclusion criteria, 
will be enrolled on to Phase 2, using a Simon’s two-stage design (Simon, 1989).  
Trial schema of Phase 2


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Outline

Subjects will be enrolled on to the RMS, NRSTS, or EWS histology type; the 
proportion of the responders (ORR) will be estimated. 

Subjects will continue with their treatment until progression of disease, intolerable 
toxicity or withdrawal of consent.

Each tumor histology type will have a futility analysis after 9 subjects are treated.  
Recruitment will be suspended for up to 24 weeks after 9 subjects have been enrolled 
to complete ORR assessment.  If more than 2 responses (partial responses [PR] or 
complete responses [CR]) are observed and documented in that histology type, then 
recruitment will continue, and that histology type will expand to approximately 25 
subjects in total.  If 2 or fewer responses (PR or CR) are observed, recruitment to that 
histology type will close.  

The study will enroll a minimum of 27 (ie, 9 for each negative histology type) and a 
maximum of approximately 75 (ie, approximately 25 for each positive histology type) 
subjects.
Pretreatment Phase:
The Pretreatment Phase will last for up to 28 days and will include a Screening Period and a Baseline 
Period. Day -28 to -1, computerized 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: 


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The Treatment Phase will start on Day 1 (D1) of Cycle 1 (C1).  Subjects will receive eribulin
mesilate by IV infusion on Days 1 and 8 of a 21-day cycle together with IV irinotecan 
hydrochloride administered on either:

Day 1-5
or

Days 1 and 8 of a 21-day cycle (See Study Design of Phase 1)
The most appropriate schedule will be taken forward to Phase 2 and will represent the RP2D
(See Study Design of Phase 2).
Follow-up
All subjects will have an off-treatment visit within 28 days after the last dose of study 
medication. After discontinuation from study treatment and completing the off-treatment visit, 
subjects will be followed up at least 4 weeks later (ie, greater than or equal to 28 days after last dose 
but no more than 1 year) unless they withdraw consent. Subjects who discontinue without objective 
evidence of disease progression will continue to have tumor assessments performed as per the 
Schedule of Assessments until disease progression, death, or another anticancer therapy is 
initiated, whichever occurs first, unless study is terminated.  Follow-up data will be required 
unless consent is withdrawn.
4
DETERMINATION OF SAMPLE SIZE
Phase 1: Up to 6 subjects can be enrolled in up to 3 dose levels, there are 2 schedules being 
evaluated (Schedule A and Schedule B).  Therefore, a maximum of 36 subjects are anticipated 
to be enrolled on this phase (not including subjects <12 months). Note:  Subjects <12 months 
will not contribute to the determination of MTD/RP2D and data is for descriptive purposes 
only.
Phase 2: Up to approximately 75 subjects (approximately 25 in each histology group) will be 
enrolled.  Simon’s two-stage design will be used for each histology group.  The following 
hypothesis will be tested at a one-sided 5% significance level: 
Ho: p ≤30%         Vs            Ha: p ≥ 55%.
In the first stage, 9 subjects will be accrued.  If there are 2 or fewer responses in these 9 subjects, 
the enrollment to this histology type (RMS, NRSTS, and EWS) will be stopped.  Otherwise, 
16 additional subjects will be enrolled in the second stage for a total of 25 subjects.  The null 
hypothesis will be rejected if 12 or more responses are observed in 25 subjects. This design 
yields a type I error rate of 0.05 (one-sided) and the power of 80% when the true response rate 
is 55%.


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5
STATISTICAL METHODS
Unless otherwise stated, tables, listings, and figures will be presented by dose level for Phase 
1, and by histology type for Phase 2.
Descriptive statistics for continuous variables include: 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. 
5.1
Study Endpoints
5.1.1
Primary Endpoint(s)
The primary endpoints are:

Phase 1: The MTD/RP2D of eribulin mesilate in combination with irinotecan 
hydrochloride in pediatric subjects with relapsed/refractory solid tumors, excluding 
CNS tumors. Note: Subjects <12 months will not contribute to the determination of 
MTD/RP2D and data is for descriptive purposes only. 

Phase 2: Objective response rate (ORR): defined as the proportion of subjects achieving 
a best overall response of confirmed partial or complete response, as determined by 
investigator assessment. Duration of response (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).
5.1.2
Secondary Endpoint(s)
Phase 1 & 2:

Safety and tolerability: adverse events (AEs), serious adverse events, clinical 
laboratory values, ECG parameters, vital sign measurements and physical 
examinations.

The pharmacokinetic profile of eribulin, irinotecan, and its active metabolite
Phase 2:

Progression-free survival (PFS): defined as the time from the first dose date to the date 
of disease progression as determined by investigator assessment or death. 

The Clinical Benefit Rate (CBR): defined as the proportion of subjects with best overall 
response (BOR) of CR, PR, or durable SD based on RECIST 1.1 (durable SD is defined 
as SD with duration of >11 weeks). 


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5.2
Study Subjects
5.2.1
Definitions of Analysis Sets
The following analysis sets will be defined:

Full Analysis Set (FAS) will consist of subjects who receive at least 1 dose of either 
study drug. 

Safety Analysis Set will consist of subjects who receive at least 1 dose of either study 
drug.  

Pharmacokinetic Analysis Set (PAS) will include subjects who have documented 
dosing history and at least one post-dosing quantifiable drug concentration.

Dose Evaluable Set (DES) for Phase 1 will consist of all subjects who completed 
Cycle 1 treatment and were evaluated for DLT, and those who discontinued during 
Cycle 1 due to DLT. DES will be used for evaluation of each dose level for dose-
escalation and for determination of MTD.
5.2.2
Subject Disposition
The number and percentage of subjects who discontinue the study treatment will be 
tabulated, along with the primary reason for 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 will be summarized for the FAS using 
descriptive statistics. They will include age (year), age group, race [White, Black or African 
American, Asian (Japanese, Chinese, Other Asian), American Indian or Alaska Native, Native 
Hawaiian or other Pacific Islander, and Other], ethnicity (Hispanic or Latino, not Hispanic or 
Latino), height (cm), weight (kg), and BSA (body surface area), as well as Karnofsky
performance score (for subjects >16 years of age) or Lansky play-performance score (for 
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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.
MEDICAL HISTORY
The number and percentage of subjects reporting a history of any medical condition will be 
summarized for the FAS.  Listing of medical history 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 (WHO DD) 2017 or current
(WHODDMAR18_HD_B2). The number (percentage) of subjects who have taken prior and 
concomitant medications will be summarized by Anatomical Therapeutic Chemical (ATC) 
class (ie, anatomical class, therapeutic class) and WHO drug 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 up to 28 days after the subject’s last dose. All medications 
will be presented in subject data listings.
A medication that cannot be determined as prior/concomitant/post-treatment due to 
missing/incomplete dates will be regarded as a concomitant medication. The summary of prior 
and concomitant medications will be summarized respectively. All medications will be 
presented in subject data listings.
5.2.6
Treatment Compliance
Subjects with treatment related protocol deviations/violations will be summarized by treatment 
group.
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.


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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.
5.3.6
Other Considerations
Not applicable.
5.4
Efficacy Analyses
The primary efficacy analyses (ORR) for Phase 2 will be performed at the time of data cutoff, 
ie, when all subjects have discontinued the treatment or completed at least 6 months of 
treatment.
ORR, DOR, PFS, and CBR will be summarized descriptively on the FAS for Phase 2. 
Endpoints related to tumor assessments will be based on investigator assessments.
5.4.1
Primary Efficacy Analyses
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 (Eisenhauer, et al., 2009). Confirmed 
response will be used. Subjects who do not have a clinical response assessment for any reason 
will be considered non-responders and will be included in the denominator when calculating 
the response rate.
ORR and the corresponding 90% confidence interval (CI) will be estimated and summarized 
for each histology type.  Simon’s two stage design will be used within each histology type.  
The following hypothesis will be tested at a one-sided 5% significance level:
Ho: p ≤ 30%         Vs            Ha: p ≥ 55%.
The first stage will enroll 9 subjects.  A futility analysis will be performed when the data for 
the 9 subjects is available.  If there are 2 or less responders (CR or PR) among the 9 subjects, 
the enrollment in this histology type will be stopped.  If there are 3 or more responders (CR or 
PR), the enrollment will continue to be up to approximately 25 subjects in the second stage.  If 
there are 12 or more responders out of 25 subjects, the null hypothesis will be rejected.  
Efficacy endpoints of tumor assessment and tumor response will be presented in subject data 
listings.
Duration of response (DOR) will be calculated for responders and summarized descriptively
using Kaplan-Meier method.


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5.4.2
Secondary Efficacy Analyses
Progression-Free Survival
Progression-free survival (PFS) is defined as the time from the first study dose date to the date 
of disease progression (PD) as determined by investigator review or death (whichever occurs 
first). If a subject has not experienced PD or death, then the subject’s data will be censored at 
the date of the last adequate radiologic assessment.
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 2 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
Nonstudy anticancer treatment 
initiated before progression or 
death
Date of last adequate tumor
assessment* prior to or on 
date of nonstudy 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 at regular interval as defined in the 
protocol.
Data cutoff generally refers to the data scope at each analysis (e.g., dry run or final analysis), 
from an executed cutoff or as of the final study data.
The distribution of PFS and time curve will be estimated using Kaplan–Meier method (Kaplan
and Meier, 1958).  Median survival time and the corresponding 90% CI will be estimated using 
Kaplan–Meier method for each histology type. PFS will also be graphically summarized by 
Kaplan-Meier curves for each histology type.


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Clinical Benefit Rate
Clinical benefit rate (CBR) defined as the number of subjects with best overall response (BOR)
of CR, PR, or durable SD based on RECIST 1.1, divided by the number of subjects in FAS, 
and corresponding confidence interval will be calculated.  Durable SD is defined as SD with 
duration of more than 11 weeks. 
The count and percentage of subjects with clinical benefit as well as exact 90% CI for the CBR 
will be summarized for each histology type.
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
PK analysis will be based on PK Analysis Set.
Phase 1:
Blood samples will be collected for PK analysis of both irinotecan (and its metabolite, SN-
38) and eribulin as follows:
For subjects ≥12 months of age and >10 kg:

Cycle 1, Day 1: At the end of the irinotecan infusion (irinotecan is administered first), 
and at the end of the eribulin infusion, then at 1, 2, 4, 6, and 24 hours post-eribulin 
infusion.  Both irinotecan (and its metabolite, SN-38) and eribulin will be assayed.

At 72 and 120 hours post-eribulin infusion, eribulin only will be assayed. 
Please note that eribulin will be administered immediately after the end of irinotecan infusion 
and PK blood sample draw.
Subjects <12 months of age as well as those ≥12 months of age and ≤10 kg (subjects under 6
kg will not have PK samples taken):

Cycle 1, Day 1: At the end of the irinotecan infusion (irinotecan is administered first) 
and then immediately after the end of the eribulin infusion (ie, 10 ± 5 minutes from 
the start of the eribulin infusion).

Cycle 1, Day 4 or 5: During the collection of the first twice weekly CBC sample.

Cycle 1, Day 8: Before the eribulin infusion and then immediately after the end of the 
eribulin infusion (ie, 10 ± 5 minutes from the start of the eribulin infusion).


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Please note that eribulin will be administered immediately after the end of irinotecan infusion 
and PK blood sample draw.
Plasma concentrations of eribulin, irinotecan and its active metabolite SN-38 will be tabulated 
and summarized by dose level, day and time.  PK parameters for eribulin, irinotecan, and SN-
38 will be derived from plasma concentrations by noncompartmental analysis using actual 
times. Minimally, the following PK parameters will be calculated: maximum observed plasma 
concentration (Cmax), time of maximum observed concentration following drug administration 
(tmax), area under the concentration-time curve (AUC).
Phase 2:
Eribulin will be assessed on Cycle 1 Day 1 (at the end of infusion, 0.5 to 6 hours and 24 to 120 
hours after eribulin infusion) and on Cycle 1 Day 8 (pre-dose of eribulin and at the end of the 
infusion).
The Phase 2 PK data will be assessed using a PopPK approach. A population PK model for 
eribulin will be developed using non-linear mixed effect modelling. The model will be 
parameterized in terms of clearance and volume of distribution.
5.5.2 Pharmacokinetic Analyses and Pharmacodynamic Analyses
Exploratory/graphical analysis will be conducted for PK/pharmacocodynamic evaluations, ie, 
dose and/or exposure effect relationships will be explored for the effects of eribulin mesilate 
on tumor responses as determined by RECIST 1.1 (CR, PR and SD), PFS and ORR, as well as
AEs/dose reductions, and may be followed by model-based analysis. Further details will be
documented separately.
5.5.3 Pharmacodynamic, Pharmacogenomic, and Other Biomarker Analyses
Not applicable.
5.6
Safety Analyses
The primary endpoint for Phase 1, the incidence of DLTs, will be summarized by dose level 
for the DES using frequency and percentage. All other evaluation of safety will be performed 
on the Safety Analysis Set. Safety data that will be evaluated include adverse events, clinical
laboratory results, ECG, vital signs, and Karnofsky/Lansky performance status score.
Descriptive summary statistics (e.g., n, mean, standard deviation, median, 25th percentile (Q1), 
75th percentile (Q3), minimum, and maximum for continuous variables; n [%] for categorical 
variables) of clinical laboratory test results, vital signs measurements, ECG parameters, and 
changes from baseline will be presented.


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5.6.1
Extent of Exposure
Descriptive summary statistics will be presented for the number of cycles/weeks on treatment, 
total dose (mg/m2) per subject, actual dose intensity (mg/m2/week) per subject, and relative 
dose intensity per subject.
Duration of treatment (weeks), dose intensity (mg/m2/week), and relative dose intensity (%)
will be calculated as the following: 
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 / Planned dose intensity × 100.
The number of subjects with study drug dose reduction, treatment interruption, and 
discontinuation due to adverse events will be summarized.
5.6.2 Dose Limiting Toxicities
The primary objective for phase 1 is to determine MTD and RP2D. The MTD is defined as 
the highest dose level at which less than 1/3 of subjects experience a DLT during Cycle 1 of 
therapy. The MTD will be determined based on the incidence of DLTs in Cycle 1 of each dose 
level.
MTDs will be obtained for both Schedule A and Schedule B and the most appropriate schedule 
will be taken forward to Phase 2 and will represent the RP2D (See Section 9.4.1 in the protocol 
for details on schedule selection).
The primary endpoint for Phase 1, ie, the incidence of DLTs will be summarized by dose level 
for the Dose Evaluable Set (DES) using frequency and percentage.
5.6.3
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 22.0 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, or 


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
Reemerges during treatment, having been present at pre-treatment (Baseline) but 
stopped before treatment, or

Worsens 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.
The incidence of TEAEs will be reported as the number (percentage) of subjects with TEAEs
by SOC and PT. A subject will be counted only once within an SOC and PT, even if the subject 
experienced more than 1 TEAE within a specific SOC and PT. The number (percentage) of 
subjects with TEAEs will also be summarized by highest CTCAE grade (CTCAE v5.0).
The number (percentage) of subjects with treatment-related TEAEs will also be summarized.
The number (percentage) of subjects with treatment-emergent serious adverse events (SAEs)
will be summarized by MedDRA SOC and PT. A subject data listing of all SAEs will be
provided.
The number (percentage) of subjects with TEAEs of 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 (percentage) of subjects with TEAEs leading to discontinuation from study drug
will be summarized by MedDRA SOC and PT. A subject data listing of all AEs leading to
discontinuation from study drug will be provided.
5.6.4
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 9.5.1.4.3, 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 data will be listed.
5.6.5
Vital Signs
Descriptive statistics for vital signs parameters (ie, systolic and diastolic blood pressure (BP), 
heart rate, temperature, weight/BSA, and height) and changes from baseline will be presented 
by visit.


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A listing of all vital sign measurements will be provided.
5.6.6
Electrocardiograms
Resting 12-lead electrocardiogram (ECG) assessments will be performed at screening, during
Cycle 1 (pre- and post-infusion Day 1 and Day 8) and as clinically indicated during subsequent 
cycles and during off-treatment Visit (within 28 days after the last dose of drug). 
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 (HR). Descriptive 
statistics for electrocardiogram parameters and changes from baseline will be presented by 
visit.
Shift tables will present changes from baseline in ECG interpretation (categorized as normal; 
abnormal, not clinically significant; and abnormal, clinically significant) to worst post-baseline 
categories.
In addition, the number (percentage) of subjects with at least 1 post-baseline abnormal ECG 
result in QTcF during the treatment period will be summarized.  Clinically abnormal ECG 
results in QTcF 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 increases from baseline > 30 ms

QTc interval increases from baseline > 60 ms
5.6.7
Other Safety Analyses
The changes of Karnofsky and Lansky performance status scores from baseline to worst post-
baseline will be presented in shift tables.


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5.7
Other Analyses
Not applicable.
5.8
Exploratory Analyses
No exploratory analyses are planned for this study.
6
INTERIM ANALYSES
There will be an interim analysis to define MTD and RP2D prior to initiating Phase 2 of the 
study.  It is anticipated that selection of the RP2D will be based on an integrated evaluation of 
safety, efficacy, and PK data. In Phase 2, for each histology (RMS, NRSTS and EWS), there 
will be 1 futility analysis of efficacy: this is planned after data from the first 9 subjects is 
available. At the futility analysis, if there are 2 or fewer responses, then enrollment to that 
histology will be discontinued. Enrollment to that histology will be suspended for up to 24 
weeks after 9 subjects have been enrolled to complete ORR assessment. An assessment of 
tolerability will also be conducted at this time.
7
CHANGES IN THE PLANNED ANALYSES
If the SAP needs to be revised after its finalization prior to the database lock, 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.
8
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING
The Baseline value will be defined as the last non-missing measurement prior to the first dose 
of the study drug.
Descriptive statistics for continuous variables include number of non-missing measurements 
(n), mean, standard deviation, median, 25th percentile (Q1), 75th percentile (Q3), minimum,
and maximum. 
Descriptive statistics for categorical variables will be summarized as number (percentage) of 
subjects. 
Confidence intervals for proportions will be reported as two-sided and calculated using 
Clopper-Pearson method (Clopper and Pearson, 1934).
Time-to-event variables will be 
estimated using Kaplan-Meier product-limit method.
9
PROGRAMMING SPECIFICATIONS
The rules for programming derivations and dataset specifications are provided in separate 
documents.


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10 STATISTICAL SOFTWARE
All statistical analyses will be performed using SAS v9.4 or later.
11 MOCK TABLES, LISTINGS, AND GRAPHS
The study TLG shells will be provided in a separate document, which will show the content 
and format of all tables, listings, and graphs in detail.
12 REFERENCES
1. Clopper, CJ and Pearson, ES. The Use of Confidence or Fiducial Limits Illustrated in 
the Case of the Binomial. Biometrika. 1934; 26: 404–413.
2. 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).  European Journal of Cancer 2009; 45(2): 228-47. 
3. Kaplan, E. L.; Meier, P. (1958). Nonparametric estimation from incomplete 
observations, J. Amer. Statist. Assn. 53 (282): 457–481.  
4. Simon R., Optimal two-stage designs for phase II clinical trials, Controlled Clinical 
Trials 1989; 10: 1 – 10.  


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13 APPENDICES
13.1
Sponsor’s Grading for Determining Markedly Abnormal Laboratory 
Results
The following table of Sponsor’s Grading for Laboratory Values is copied from the protocol, 
Appendix 1.
Sponsor’s Grading for Laboratory Values
Grade 1
Grade 2
Grade 3
Grade 4
BLOOD/BONE MARROW
Anaemia (Hemoglobin)
<LLN – 10.0 g/dL
<LLN – 100 g/L
<LLN – 6.2 mmol/L
<10.0 – 8.0 g/dL
<100 – 80 g/L
<6.2 – 4.9 mmol/L
<8.0 g/dL
<80 g/L
<4.9 mmol/L; 
transfusion 
life-threatening 
consequences; urgent 
intervention indicated
White blood cell 
(Leukocytes) decreased
<LLN – 3.0109/L
<LLN – 3000/mm3
<3.0 – 2.0109/L
<3000 – 2000/mm3
<2.0 – 1.0109/L
<2000 – 1000/mm3
<1.0109/L
<1000/mm3
Lymphocyte count decreased
<LLN – 800/mm3
<LLN – 0.8109/L
<800 – 500/mm3
<0.8 – 0.5109/L
<500 – 200/mm3
<0.5 – 0.2109/L
<200/mm3
<0.2109/L
Neutrophil count decreased
<LLN – 1.5109/L
<LLN – 1500/mm3
<1.5 – 1.0109/L
<1500 – 1000/mm3
<1.0 – 0.5109/L
<1000 – 500/mm3
<0.5109/L
<500/mm3
Platelet count decreased
<LLN – 75.0109/L
<LLN – 75,000/mm3
<75.0 – 50.0109/L
<75,000 – 50,000/mm3
<50.0 – 25.0109/L
<50,000 – 25,000/mm3
<25.0109/L
<25,000/mm3
METABOLIC/LABORATORY
Albumin, serum- low 
(hypoalbuminemia)
<LLN – 3 g/dL
<LLN – 30 g/L
<3 – 2 g/dL
<30 – 20 g/L
<2 g/dL
<20 g/L
life-threatening 
consequences; urgent 
intervention indicated
Alkaline phosphatase increased
>ULN - 2.5 x ULN if
baseline was normal;
2.0 - 2.5 x baseline if 
baseline was 
abnormal
>2.5 - 5.0 x ULN if
baseline was normal;
>2.5 - 5.0 x baseline 
if baseline was 
abnormal
>5.0 – 20.0ULN 
ifbaseline was normal;
>5.0 - 20.0 x baseline 
if baseline was 
abnormal
>20.0ULN if
baseline was normal;
>20.0 x baseline if 
baseline was 
abnormal
ALT
>ULN - 3.0 x ULN if
baseline was normal;
1.5 - 3.0 x baseline if 
baseline was 
abnormal
>3.0 - 5.0 x ULN if
baseline was normal;
>3.0 - 5.0 x baseline if 
baseline was 
abnormal
>5.0 - 20.0 x ULN if
baseline was normal;
>5.0 - 20.0 x baseline 
if baseline was 
abnormal
>20.0 x ULN if
baseline was normal;
>20.0 x baseline if 
baseline was 
abnormal
AST
>ULN - 3.0 x ULN if
baseline was normal;
1.5 - 3.0 x baseline if 
baseline was 
abnormal
>3.0 - 5.0 x ULN if
baseline was normal;
>3.0 - 5.0 x baseline if 
baseline was 
abnormal
>5.0 - 20.0 x ULN if
baseline was normal;
>5.0 - 20.0 x baseline 
if baseline was 
abnormal
>20.0 x ULN if
baseline was normal;
>20.0 x baseline if 
baseline was 
abnormal
Bilirubin (hyperbilirubinemia)
>ULN - 1.5 x ULN if
baseline was normal;
> 1.0 - 1.5 x baseline 
if baseline was 
abnormal
>1.5 - 3.0 x ULN if
baseline was normal;
>1.5 - 3.0 x baseline if 
baseline was 
abnormal
>3.0 - 10.0 x ULN if
baseline was normal;
>3.0 - 10.0 x baseline 
if baseline was 
abnormal
>10.0 x ULN if
baseline was normal;
>10.0 x baseline if 
baseline was 
abnormal


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Calcium, serum-low (hypocalcemia) <LLN – 8.0 mg/dL
<LLN – 2.0 mmol/L
<8.0 – 7.0 mg/dL
<2.0 – 1.75 mmol/L
<7.0 – 6.0 mg/dL
<1.75 – 1.5 mmol/L
<6.0 mg/dL
<1.5 mmol/L
Calcium, serum-high 
(hypercalcemia)
>ULN – 11.5 mg/dL
>ULN – 2.9 mmol/L
>11.5 – 12.5 mg/dL
>2.9 – 3.1 mmol/L
>12.5 – 13.5 mg/dL
>3.1 – 3.4 mmol/L
>13.5 mg/dL
>3.4 mmol/L
Cholesterol, serum-
high(hypercholester
olemia)
>ULN – 300 mg/dL
>ULN – 7.75 mmol/L
>300 – 400 mg/dL
>7.75 – 10.34 mmol/L
>400 – 500 mg/dL
>10.34 – 12.92 mmol/L
>500 mg/dL
>12.92 mmol/L
Creatinine
>ULN – 1.5ULN
>1.5 – 3.0ULN
>3.0 – 6.0ULN
>6.0ULN
GGT (γ-glutamyltranspeptidase)
>ULN – 3.0ULN
>3.0 – 5.0ULN
>5.0 – 20.0ULN
>20.0ULN
Glucose, serum-high 
(hyperglycemia)
Abnormal glucose 
above baseline with 
no medical 
intervention
Change in daily 
management from 
baseline for a diabetic; 
oral antiglycemic 
agent initiated; workup 
for diabetes
Insulin therapy 
initiated; 
hospitalization 
indicated
Life-threatening 
consequences; urgent 
intervention indicated
Glucose, serum-low (hypoglycemia) <LLN – 55 mg/dL
<LLN – 3.0 mmol/L
<55 – 40 mg/dL
<3.0 – 2.2 mmol/L
<40 – 30 mg/dL
<2.2 – 1.7 mmol/L
<30 mg/dL
<1.7 mmol/L
life-threatening 
consequences; 
seizures
Magnesium, serum-
high 
(hypermagnesemia)
>ULN - 3.0 mg/dL;
>ULN - 1.23 mmol/L
N/A
>3.0 - 8.0 mg/dL;
>1.23 - 3.30 mmol/L
>8.0 mg/dL;
>3.30 mmol/L;
life-threatening 
consequences
Magnesium, serum-low 
(hypomagnesemia)
<LLN - 1.2 mg/dL;
<LLN - 0.5 mmol/L
<1.2 - 0.9 mg/dL;
<0.5 - 0.4 mmol/L
<0.9 - 0.7 mg/dL;
<0.4 - 0.3 mmol/L
<0.7 mg/dL;
<0.3 mmol/L;
life-threatening 
consequences
Phosphate, serum-low 
(hypophosphatemia)
Laboratory finding 
only and intervention 
not indicated
Oral 
replacement 
therapy 
indicated
Severe or medically 
significant but not 
immediately life-
threatening; 
hospitalization or 
prolongation of 
existing hospitalization 
indicated
life-threatening 
consequences
Potassium, serum-high 
(hyperkalemia)
>ULN – 5.5 mmol/L
>5.5 – 6.0 mmol/L; 
intervention 
initiated
>6.0 – 7.0 mmol/L 
hospitalization 
indicated
>7.0 mmol/L
life-threatening 
consequences
Potassium, serum-low 
(hypokalemia)
<LLN – 3.0 mmol/L
<LLN – 3.0
mmol/Lsymptomatic; 
intervention 
indicated
<3.0 – 2.5 mmol/L 
hospitalization 
indicated
<2.5 mmol/L
life-threatening 
consequences
Sodium, serum-high 
(hypernatremia)
>ULN – 150 mmol/L
>150 – 155 mmol/L 
intervention 
initiated
>155 – 160 mmol/L 
hospitalization 
indicated
>160 mmol/L
life-threatening 
consequences
Sodium, serum-low (hyponatremia)
<LLN – 130 mmol/L
125-129 mmol/L 
and asymptomatic
125-129 mmol/L
symptomatic; 120-
124 mmol/L 
regardless of 
symptoms
<120 mmol/L
life-threatening 
consequences


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Triglyceride, serum-
high 
(hypertriglyceridemi
a)
150 – 300 mg/dL
1.71 – 3.42 mmol/L
>300 – 500 mg/dL
>3.42 – 5.7 mmol/L
>500 – 1000 mg/dL
>5.7 – 11.4 mmol/L
>1000 mg/dL
>11.4 mmol/L
life-threatening 
consequences
Uric acid, serum-high 
(hyperuricemia)
>ULN 
without 
physiologic 
consequences
N/A
>ULN with 
physiologic 
consequences
life-threatening 
consequences
ALT = alanine aminotransferase (serum glutamic pyruvic transaminase), AST = aspartate aminotransferase (serum glutamic 
oxaloacetictransaminase), GGT = γ-glutamyltranspeptidase, N/A = not applicable, LLN = lower limit of normal, ULN = upper limit of 
normal, WBC = white blood cell.
Based on Common Terminology Criteria for Adverse events (CTCAE) Version 5.0. Published: Nov 27, 2017.


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13.2
Measurements of Performance Status
The following table of Karnofsky Performance Status and Lansky Play-Performance Scale for 
Pediatric Patients is copied from the protocol, Appendix 2.
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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SIGNATURE PAGE
Author(s):  
Oncology Business Group, Eisai, Inc.
Date
Approval:
Oncology Business Group, Eisai, Inc.
Date
Oncology Business Group, Eisai, Ltd.
Date
PPD
PPD
PPD
PPD