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Clinical Trial Results:
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.

Summary
EudraCT number	2016-003352-67
Trial protocol	DE GB ES PL IT
Global end of trial date	17 May 2021

Results information
Results version number	v1
This version publication date	02 Dec 2021
First version publication date	02 Dec 2021
Other versions	v2

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

E7389-G000-213

ISRCTN number

US NCT number

NCT03245450

WHO universal trial number (UTN)

Sponsor organisation name

Eisai Inc.

Sponsor organisation address

155 Tice Boulevard, Woodcliff Lake, New Jersey, United States, 07677

Public contact

Eisai Medical Information, Eisai Inc., 1 888-274-2378, esi_oncmedinfo@eisai.com

Scientific contact

Eisai Medical Information, Eisai Inc., 1 888-274-2378, esi_oncmedinfo@eisai.com

Is trial part of an agreed paediatric investigation plan (PIP)

Yes

EMA paediatric investigation plan number(s)

EMEA-001261-PIP01-11

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Yes

Analysis stage

Final

Date of interim/final analysis

09 Jul 2021

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

17 May 2021

Was the trial ended prematurely?

Main objective of the trial

The primary objective of the study was 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 central nervous system (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 rhabdomyosarcoma (RMS), non-rhabdomyosarcoma soft tissue sarcoma (NRSTS), and Ewing sarcoma (EWS).

Protection of trial subjects

This study was 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; - International Council on Harmonisation (ICH) E6 Guideline for GCP (CPMP/ICH/135/95) of the European Agency for the Evaluation of Medicinal Products, Committee for Proprietary Medicinal Products,International Council 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 European Union (EU) country. All SUSARs will be reported, as required, to the Competent Authorities of all involved EU member states.

Background therapy

Evidence for comparator

Actual start date of recruitment

05 Mar 2018

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Germany: 3

Country: Number of subjects enrolled

Greece: 1

Country: Number of subjects enrolled

Italy: 12

Country: Number of subjects enrolled

Spain: 14

Country: Number of subjects enrolled

France: 4

Country: Number of subjects enrolled

Poland: 1

Country: Number of subjects enrolled

United Kingdom: 5

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Subjects took part in the study at 22 investigative sites in France, Germany, Greece, Italy, Poland, Spain and United Kingdom.

Screening details

A total of 46 subjects were screened and signed inform consent form, of which 13 subjects were treated in the Phase 1 and 27 subjects were treated in Phase 2.

Period 1 title

Overall (overall period)

Is this the baseline period?

Yes

Allocation method

Non-randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Phase 1: Schedule A, Eribulin Mesylate + Irinotecan 20 mg/m^2

Arm description

Subjects received eribulin mesylate 1.4 milligram per square meter (mg/m^2) intravenous infusion on Days 1 and 8 and irinotecan hydrochloride 20 mg/m^2, intravenous infusion on Days 1 to 5 in a 21 day treatment cycle until MTD was reached. The MTD was determined based on the incidence of dose limiting toxicities (DLTs) in cycle 1.

Arm type

Experimental

Investigational medicinal product name

Irinotecan 20 mg/m^2

Investigational medicinal product code

Other name

Irinotecan

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Subjects received irinotecan hydrochloride 20 mg/m^2, intravenous infusion on Days 1 to 5 in a 21 day treatment cycle.

Investigational medicinal product name

Eribulin Mesilate 1.4 mg/m^2

Investigational medicinal product code

Other name

E7389, HALAVEN

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Subjects received eribulin mesylate 1.4 mg/m^2, intravenous infusion on Days 1 and 8 in a 21 day treatment cycle.

Phase 1: Schedule A, Eribulin Mesylate + Irinotecan 40 mg/m^2

Arm description

Subjects received eribulin mesylate 1.4 mg/m^2, intravenous infusion on Days 1 and 8 and irinotecan hydrochloride 40 mg/m^2, intravenous infusion on Days 1 to 5 in a 21 day treatment cycle until MTD was reached. The MTD was determined based on the incidence of DLTs in cycle 1.

Arm type

Experimental

Investigational medicinal product name

Irinotecan 40 mg/m^2

Investigational medicinal product code

Other name

Irinotecan

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Subjects received irinotecan hydrochloride 40 mg/m^2, intravenous infusion on Days 1 to 5 in a 21 day treatment cycle.

Investigational medicinal product name

Eribulin Mesilate 1.4 mg/m^2

Investigational medicinal product code

Other name

E7389, HALAVEN

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Subjects received eribulin mesylate 1.4 mg/m^2, intravenous infusion on Days 1 and 8 in a 21 day treatment cycle.

Phase 1: Schedule B, Eribulin Mesylate + Irinotecan 100 mg/m^2

Arm description

Subjects received eribulin mesylate 1.4 mg/m^2 and irinotecan hydrochloride 100 mg/m^2 intravenous infusion on Days 1 and 8 in a 21 day treatment cycle until MTD was reached. The MTD was determined based on the incidence of DLTs in cycle 1.

Arm type

Experimental

Investigational medicinal product name

Irinotecan 100 mg/m^2

Investigational medicinal product code

Other name

Irinotecan

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Subjects received irinotecan hydrochloride 100 mg/m^2 intravenous infusion on Days 1 and 8 in a 21 day treatment cycle.

Investigational medicinal product name

Eribulin Mesilate 1.4 mg/m^2

Investigational medicinal product code

Other name

E7389, HALAVEN

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Subjects received eribulin mesylate 1.4 mg/m^2 intravenous infusion on Days 1 and 8 in a 21 day treatment cycle.

Phase 1: Schedule B, Eribulin Mesylate + Irinotecan 125 mg/m^2

Arm description

Subjects received eribulin mesylate 1.4 mg/m^2 and irinotecan hydrochloride 125 mg/m^2 intravenous infusion on Days 1 and 8 in a 21 day treatment cycle until MTD was reached. The MTD was determined based on the incidence of DLTs in cycle 1.

Arm type

Experimental

Investigational medicinal product name

Irinotecan 125 mg/m^2

Investigational medicinal product code

Other name

Irinotecan

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Subjects received irinotecan hydrochloride 125 mg/m^2 intravenous infusion on Days 1 and 8 in a 21 day treatment cycle.

Investigational medicinal product name

Eribulin Mesilate 1.4 mg/m^2

Investigational medicinal product code

Other name

E7389, HALAVEN

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Subjects received eribulin mesylate 1.4 mg/m^2 intravenous infusion on Days 1 and 8 in a 21 day treatment cycle.

Phase 2: RMS Cohort, Eribulin Mesylate + Irinotecan 40 mg/m^2

Arm description

Subjects with RMS received eribulin mesylate 1.4 mg/m^2, intravenous infusion on Days 1 and 8 and irinotecan hydrochloride 40 mg/m^2, intravenous infusion on Days 1 to 5 in a 21 day treatment cycle until disease progression, development of unacceptable toxicity or withdrawal of consent (approximately 39 months).

Arm type

Experimental

Investigational medicinal product name

Irinotecan 40 mg/m^2

Investigational medicinal product code

Other name

Irinotecan

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Subjects with RMS received irinotecan hydrochloride 40 mg/m^2, intravenous infusion on Days 1 to 5 in a 21 day treatment cycle until disease progression, development of unacceptable toxicity or withdrawal of consent (39 months).

Investigational medicinal product name

Eribulin Mesilate 1.4 mg/m^2

Investigational medicinal product code

Other name

E7389, HALAVEN

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Subjects with RMS received eribulin mesylate 1.4 mg/m^2, intravenous infusion on Days 1 and 8 in a 21 day treatment cycle until disease progression, development of unacceptable toxicity or withdrawal of consent (39 months).

Phase 2: NRSTS Cohort, Eribulin Mesylate+Irinotecan 40 mg/m^2

Arm description

Subjects with NRSTS received eribulin mesylate 1.4 mg/m^2, intravenous infusion on Days 1 and 8 and irinotecan hydrochloride 40 mg/m^2, intravenous infusion on Days 1 to 5 in a 21 day treatment cycle until disease progression, development of unacceptable toxicity or withdrawal of consent (approximately 39 months).

Arm type

Experimental

Investigational medicinal product name

Irinotecan 40 mg/m^2

Investigational medicinal product code

Other name

Irinotecan

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Subjects with NRSTS received irinotecan hydrochloride 40 mg/m^2, intravenous infusion on Days 1 to 5 in a 21 day treatment cycle until disease progression, development of unacceptable toxicity or withdrawal of consent (39 months).

Investigational medicinal product name

Eribulin Mesilate 1.4 mg/m^2

Investigational medicinal product code

Other name

E7389, HALAVEN

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Subjects with NRSTS received eribulin mesylate 1.4 mg/m^2, intravenous infusion on Days 1 and 8 in a 21 day treatment cycle until disease progression, development of unacceptable toxicity or withdrawal of consent (39 months).

Phase 2: EWS Cohort, Eribulin Mesylate + Irinotecan 40 mg/m^2

Arm description

Subjects with EWS received eribulin mesylate 1.4 mg/m^2, intravenous infusion on Days 1 and 8 and Irinotecan hydrochloride 40 mg/m^2, intravenous infusion on Days 1 to 5 in a 21 day treatment cycle until disease progression, development of unacceptable toxicity or withdrawal of consent (approximately 39 months).

Arm type

Experimental

Investigational medicinal product name

Irinotecan 40 mg/m^2

Investigational medicinal product code

Other name

Irinotecan

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Subjects with EWS received irinotecan hydrochloride 40 mg/m^2, intravenous infusion on Days 1 to 5 in a 21 day treatment cycle until disease progression, development of unacceptable toxicity or withdrawal of consent (39 months).

Investigational medicinal product name

Eribulin Mesilate 1.4 mg/m^2

Investigational medicinal product code

Other name

E7389, HALAVEN

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Subjects with EWS received eribulin mesylate 1.4 mg/m^2, intravenous infusion on Days 1 and 8 in a 21 day treatment cycle until disease progression, development of unacceptable toxicity or withdrawal of consent (39 months).

Number of subjects in period 1	Phase 1: Schedule A, Eribulin Mesylate + Irinotecan 20 mg/m^2	Phase 1: Schedule A, Eribulin Mesylate + Irinotecan 40 mg/m^2	Phase 1: Schedule B, Eribulin Mesylate + Irinotecan 100 mg/m^2	Phase 1: Schedule B, Eribulin Mesylate + Irinotecan 125 mg/m^2	Phase 2: RMS Cohort, Eribulin Mesylate + Irinotecan 40 mg/m^2	Phase 2: NRSTS Cohort, Eribulin Mesylate+Irinotecan 40 mg/m^2	Phase 2: EWS Cohort, Eribulin Mesylate + Irinotecan 40 mg/m^2
Started	3	4	3	3	9	9	9
Completed	0	0	0	0	0	0	0
Not completed	3	4	3	3	9	9	9
Adverse event, serious fatal	-	-	-	-	1	-	2
Consent withdrawn by subject	-	1	-	-	-	-	-
Not specified	-	-	-	1	1	1	1
Clinical disease progression	-	-	1	-	-	2	-
Radiological disease progression	3	3	2	2	7	6	6

Baseline characteristics

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Reporting group title

Phase 1: Schedule A, Eribulin Mesylate + Irinotecan 20 mg/m^2

Reporting group description

Reporting group title

Phase 1: Schedule A, Eribulin Mesylate + Irinotecan 40 mg/m^2

Reporting group description

Reporting group title

Phase 1: Schedule B, Eribulin Mesylate + Irinotecan 100 mg/m^2

Reporting group description

Reporting group title

Phase 1: Schedule B, Eribulin Mesylate + Irinotecan 125 mg/m^2

Reporting group description

Reporting group title

Phase 2: RMS Cohort, Eribulin Mesylate + Irinotecan 40 mg/m^2

Reporting group description

Reporting group title

Phase 2: NRSTS Cohort, Eribulin Mesylate+Irinotecan 40 mg/m^2

Reporting group description

Reporting group title

Phase 2: EWS Cohort, Eribulin Mesylate + Irinotecan 40 mg/m^2

Reporting group description

Reporting group values	Phase 1: Schedule A, Eribulin Mesylate + Irinotecan 20 mg/m^2	Phase 1: Schedule A, Eribulin Mesylate + Irinotecan 40 mg/m^2	Phase 1: Schedule B, Eribulin Mesylate + Irinotecan 100 mg/m^2	Phase 1: Schedule B, Eribulin Mesylate + Irinotecan 125 mg/m^2	Phase 2: RMS Cohort, Eribulin Mesylate + Irinotecan 40 mg/m^2	Phase 2: NRSTS Cohort, Eribulin Mesylate+Irinotecan 40 mg/m^2	Phase 2: EWS Cohort, Eribulin Mesylate + Irinotecan 40 mg/m^2	Total
Number of subjects	3	4	3	3	9	9	9	40
Age Categorical
Units: Subjects
In utero	0	0	0	0	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0	0	0	0	0
Newborns (0-27 days)	0	0	0	0	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0	0	0	0	0
Children (2-11 years)	1	4	1	2	5	3	4	20
Adolescents (12-17 years)	2	0	2	1	4	6	5	20
Adults (18-64 years)	0	0	0	0	0	0	0	0
From 65-84 years	0	0	0	0	0	0	0	0
85 years and over	0	0	0	0	0	0	0	0
Age Continuous
Units: years
arithmetic mean (standard deviation)	10.94 ( 6.583 )	7.33 ( 2.540 )	13.97 ( 4.231 )	8.06 ( 4.9997 )	11.05 ( 3.845 )	12.71 ( 4.348 )	11.59 ( 3.753 )	-
Gender Categorical
Units: Subjects
Male	1	3	1	1	4	7	4	21
Female	2	1	2	2	5	2	5	19
Race
Units: Subjects
White	3	4	2	3	5	8	8	33
Asian	0	0	1	0	0	1	0	2
Black or African American	0	0	0	0	0	0	0	0
Other	0	0	0	0	2	0	0	2
Missing	0	0	0	0	2	0	1	3
Ethnicity
Units: Subjects
Hispanic or Latino	0	1	0	0	0	1	0	2
Not Hispanic or Latino	3	3	3	3	9	8	9	38

End points

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Reporting group title

Phase 1: Schedule A, Eribulin Mesylate + Irinotecan 20 mg/m^2

Reporting group description

Reporting group title

Phase 1: Schedule A, Eribulin Mesylate + Irinotecan 40 mg/m^2

Reporting group description

Reporting group title

Phase 1: Schedule B, Eribulin Mesylate + Irinotecan 100 mg/m^2

Reporting group description

Reporting group title

Phase 1: Schedule B, Eribulin Mesylate + Irinotecan 125 mg/m^2

Reporting group description

Reporting group title

Phase 2: RMS Cohort, Eribulin Mesylate + Irinotecan 40 mg/m^2

Reporting group description

Reporting group title

Phase 2: NRSTS Cohort, Eribulin Mesylate+Irinotecan 40 mg/m^2

Reporting group description

Reporting group title

Phase 2: EWS Cohort, Eribulin Mesylate + Irinotecan 40 mg/m^2

Reporting group description

Subject analysis set title

Phase 1: All Subjects (Dose Evaluable Set)

Subject analysis set type

Sub-group analysis

Subject analysis set description

All subjects received eribulin mesylate 1.4 mg/m^2 intravenous infusion on Days 1 and 8 (schedule A and B) and irinotecan hydrochloride 20 mg/m^2 or 40 mg/m^2 intravenous infusion on Days 1 to 5 (schedule A) and irinotecan hydrochloride 100 mg/m^2 or 125 mg/m^2 intravenous infusion on Days 1 and 8 (schedule B) in a 21 day treatment cycle until MTD was reached. The MTD was determined based on the incidence of dose limiting toxicities (DLTs) in cycle 1. Dose Evaluable Set (DES) was used for evaluation of each dose level for dose escalation and for determination of MTD.

Primary: Phase 1: Maximum Tolerated Dose (MTD) of Eribulin Mesylate in Combination with Irinotecan Hydrochloride

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End point title

Phase 1: Maximum Tolerated Dose (MTD) of Eribulin Mesylate in Combination with Irinotecan Hydrochloride ^[1]

End point description

The MTD was defined as the highest dose level at which less than 1/3 of subjects experience a DLT during Cycle 1 of therapy. DES for Phase 1 included all subjects who completed Cycle 1 treatment and were evaluated for DLT, and those who discontinued during Cycle 1 due to DLT. DES was used for evaluation of each dose level for dose escalation and for determination of MTD.

End point type

Primary

End point timeframe

First dose of study drug up to Cycle 1 (Cycle length=21 days)

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive data was planned to be analyzed.

End point values	Phase 1: All Subjects (Dose Evaluable Set)
Number of subjects analysed	12
Units: mg/m^2
number (not applicable)
Eribulin Mesylate	1.4
Irinotecan Hydrochloride	40

No statistical analyses for this end point

Primary: Phase 2: Objective response rate (ORR)

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End point title

Phase 2: Objective response rate (ORR) ^[2] ^[3]

End point description

ORR was defined as the percentage of subjects with a best overall response (BOR) of confirmed partial response (PR) or complete response (CR) determined by investigator assessment per Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1. CR was disappearance of all target and non-target lesions. All pathological (whether target or non-target) must have a reduction in their short axis less than (<) 10 millimeter (mm). PR was at least a 30 percent (%) decrease in the sum of diameter (SOD) of target lesions, taking as reference the baseline sum diameters. Full analysis set included subjects who received at least 1 dose of either study drug.

End point type

Primary

End point timeframe

From date of first dose of study drug until disease progression, development of unacceptable toxicity, withdrawal of consent, or up to approximately 3 years 3 months

Notes
[2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive data was planned to be analyzed.
[3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was assessed in Phase 2 only.

End point values	Phase 2: RMS Cohort, Eribulin Mesylate + Irinotecan 40 mg/m^2	Phase 2: NRSTS Cohort, Eribulin Mesylate+Irinotecan 40 mg/m^2	Phase 2: EWS Cohort, Eribulin Mesylate + Irinotecan 40 mg/m^2
Number of subjects analysed	9	9	9
Units: percentage of subjects
number (confidence interval 90%)	11.1 (0.6 to 42.9)	11.1 (0.6 to 42.9)	11.1 (0.6 to 42.9)

No statistical analyses for this end point

Secondary: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs)

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End point title

Number of Subjects With Treatment-Emergent Adverse Events (TEAEs)

End point description

A TEAE was defined as an AE that emerged during treatment, having been absent at pretreatment, or reemerged during treatment, having been present at pre-treatment (baseline) but stopped before treatment, or worsened in severity during treatment relative to the pretreatment state, when the AE was continuous. AE was defined as any untoward medical occurrence in a clinical investigation subject administered a drug; it does not necessarily have to have a causal relationship with this treatment. Safety Analysis Set included subjects who received at least 1 dose of either study drug.

End point type

Secondary

End point timeframe

From first dose of study drug up to approximately 3 years 3 months

End point values	Phase 1: Schedule A, Eribulin Mesylate + Irinotecan 20 mg/m^2	Phase 1: Schedule A, Eribulin Mesylate + Irinotecan 40 mg/m^2	Phase 1: Schedule B, Eribulin Mesylate + Irinotecan 100 mg/m^2	Phase 1: Schedule B, Eribulin Mesylate + Irinotecan 125 mg/m^2	Phase 2: RMS Cohort, Eribulin Mesylate + Irinotecan 40 mg/m^2	Phase 2: NRSTS Cohort, Eribulin Mesylate+Irinotecan 40 mg/m^2	Phase 2: EWS Cohort, Eribulin Mesylate + Irinotecan 40 mg/m^2
Number of subjects analysed	3	4	3	3	9	9	9
Units: subjects	3	4	3	3	9	9	9

No statistical analyses for this end point

Secondary: Number of Subjects With Serious Adverse Event (SAE)

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End point title

Number of Subjects With Serious Adverse Event (SAE)

End point description

SAE was defined as any untoward medical occurrence at any dose if it resulted in death or life-threatening AE or required inpatient hospitalization or prolongation of existing hospitalization or resulted in persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions or was a congenital anomaly/birth defect. Safety analysis set included subjects who received at least 1 dose of either study drug.

End point type

Secondary

End point timeframe

Up to approximately 3 years and 3 months

End point values	Phase 1: Schedule A, Eribulin Mesylate + Irinotecan 20 mg/m^2	Phase 1: Schedule A, Eribulin Mesylate + Irinotecan 40 mg/m^2	Phase 1: Schedule B, Eribulin Mesylate + Irinotecan 100 mg/m^2	Phase 1: Schedule B, Eribulin Mesylate + Irinotecan 125 mg/m^2	Phase 2: RMS Cohort, Eribulin Mesylate + Irinotecan 40 mg/m^2	Phase 2: NRSTS Cohort, Eribulin Mesylate+Irinotecan 40 mg/m^2	Phase 2: EWS Cohort, Eribulin Mesylate + Irinotecan 40 mg/m^2
Number of subjects analysed	3	4	3	3	9	9	9
Units: subjects	1	3	0	1	5	4	3

No statistical analyses for this end point

Secondary: Phase 1, Cmax: Maximum Observed Plasma Concentration of Eribulin, Irinotecan and its Active Metabolite SN-38

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End point title

Phase 1, Cmax: Maximum Observed Plasma Concentration of Eribulin, Irinotecan and its Active Metabolite SN-38 ^[4]

End point description

Pharmacokinetic analysis set included subjects who had documented dosing history and at least one post-dosing quantifiable drug concentration.

End point type

Secondary

End point timeframe

For eribulin, Cycle 1 Day 1: 0-120 hours post-eribulin infusion; For irinotecan and its metabolite, Cycle 1 Day 1: 0-24 hours post-irinotecan infusion (cycle length=21 days)

Notes
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was assessed in Phase 1 only.

End point values	Phase 1: Schedule A, Eribulin Mesylate + Irinotecan 20 mg/m^2	Phase 1: Schedule A, Eribulin Mesylate + Irinotecan 40 mg/m^2	Phase 1: Schedule B, Eribulin Mesylate + Irinotecan 100 mg/m^2	Phase 1: Schedule B, Eribulin Mesylate + Irinotecan 125 mg/m^2
Number of subjects analysed	3	4	3	3
Units: nanogram/milliliter (ng/mL)
geometric mean (geometric coefficient of variation)
Eribulin	369.3 ( 58.0 )	179.4 ( 136.1 )	348.7 ( 25.0 )	323.3 ( 20.6 )
Irinotecan	538.8 ( 165.9 )	399.5 ( 19.1 )	1168.1 ( 39.8 )	1555.4 ( 39.5 )
Active Metabolite SN-38	6.518 ( 9.4 )	17.170 ( 39.7 )	25.409 ( 51.6 )	18.614 ( 74.3 )

No statistical analyses for this end point

Secondary: Phase 1, Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) of Eribulin, Irinotecan and its Active Metabolite SN-38

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End point title

Phase 1, Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) of Eribulin, Irinotecan and its Active Metabolite SN-38 ^[5]

End point description

Pharmacokinetic analysis set included subjects who had documented dosing history and at least one post-dosing quantifiable drug concentration.

End point type

Secondary

End point timeframe

For eribulin, Cycle 1 Day 1: 0-120 hours post-eribulin infusion; For irinotecan and its metabolite, Cycle 1 Day 1: 0-24 hours post-irinotecan infusion (cycle length=21 days)

Notes
[5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was assessed in Phase 1 only.

End point values	Phase 1: Schedule A, Eribulin Mesylate + Irinotecan 20 mg/m^2	Phase 1: Schedule A, Eribulin Mesylate + Irinotecan 40 mg/m^2	Phase 1: Schedule B, Eribulin Mesylate + Irinotecan 100 mg/m^2	Phase 1: Schedule B, Eribulin Mesylate + Irinotecan 125 mg/m^2
Number of subjects analysed	3	4	3	3
Units: hours
median (full range (min-max))
Eribulin	0.080 (0.03 to 0.22)	0.135 (0.03 to 1)	0.080 (0 to 0.12)	0.050 (0.01 to 0.12)
Irinotecan	0.250 (0.07 to 0.42)	0.305 (0 to 24)	0.300 (0.03 to 0.33)	0.170 (0.13 to 0.25)
Active Metabolite SN-38	0.420 (0.25 to 1.03)	0.305 (0 to 24)	0.330 (0.3 to 0.53)	0.250 (0.13 to 0.55)

No statistical analyses for this end point

Secondary: Phase 1, T1/2: Half-life of Eribulin, Irinotecan and its Active Metabolite SN-38

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End point title

Phase 1, T1/2: Half-life of Eribulin, Irinotecan and its Active Metabolite SN-38 ^[6]

End point description

Pharmacokinetic analysis set included subjects who had documented dosing history and at least one post-dosing quantifiable drug concentration. Here 'N' (overall number of subjects analyzed) included all subjects who were evaluable for this outcome measure and 'n' (number analyzed) included all subjects who were evaluable for each category. Here '99999' signifies that no subject was analyzed.

End point type

Secondary

End point timeframe

For eribulin, Cycle 1 Day 1: 0-120 hours post-eribulin infusion; For irinotecan and its metabolite, Cycle 1 Day 1: 0-24 hours post-irinotecan infusion (cycle length=21 days)

Notes
[6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was assessed in Phase 1 only.

End point values	Phase 1: Schedule A, Eribulin Mesylate + Irinotecan 20 mg/m^2	Phase 1: Schedule A, Eribulin Mesylate + Irinotecan 40 mg/m^2	Phase 1: Schedule B, Eribulin Mesylate + Irinotecan 100 mg/m^2	Phase 1: Schedule B, Eribulin Mesylate + Irinotecan 125 mg/m^2
Number of subjects analysed	3	3	3	2
Units: hours
median (full range (min-max))
Eribulin(n=3,3,3,2)	27.50 (26.5 to 27.7)	34.70 (32.9 to 40.4)	30.00 (23.4 to 43.3)	25.30 (22.1 to 28.5)
Irinotecan(n=0,0,3,3)	99999 (99999 to 99999)	99999 (99999 to 99999)	5.140 (5.1 to 9.61)	4.430 (3.95 to 5.08)
Metabolite SN-38(n=0,0,3,2)	99999 (99999 to 99999)	99999 (99999 to 99999)	12.000 (9.9 to 13.9)	10.390 (9.68 to 11.1)

No statistical analyses for this end point

Secondary: Phase 1, Total Clearance (CL) of Eribulin and Irinotecan

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End point title

Phase 1, Total Clearance (CL) of Eribulin and Irinotecan ^[7]

End point description

End point type

Secondary

End point timeframe

For eribulin, Cycle 1 Day 1: 0-120 hours post-eribulin infusion; For irinotecan, Cycle 1 Day 1: 0-24 hours post-irinotecan infusion (cycle length=21 days)

Notes
[7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was assessed in Phase 1 only.

End point values	Phase 1: Schedule A, Eribulin Mesylate + Irinotecan 20 mg/m^2	Phase 1: Schedule A, Eribulin Mesylate + Irinotecan 40 mg/m^2	Phase 1: Schedule B, Eribulin Mesylate + Irinotecan 100 mg/m^2	Phase 1: Schedule B, Eribulin Mesylate + Irinotecan 125 mg/m^2
Number of subjects analysed	3	3	3	2
Units: liter per hour (L/h)
geometric mean (geometric coefficient of variation)
Eribulin(n=3,3,3,2)	3.1781 ( 43.9 )	2.4581 ( 8.0 )	2.9060 ( 32.8 )	1.7521 ( 136.6 )
Irinotecan(n=0,0,3,3)	99999 ( 99999 )	99999 ( 99999 )	27.27 ( 23.2 )	30.30 ( 60.7 )

No statistical analyses for this end point

Secondary: Phase 1, Volume of Distribution (Vz) of Eribulin and Irinotecan

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End point title

Phase 1, Volume of Distribution (Vz) of Eribulin and Irinotecan ^[8]

End point description

End point type

Secondary

End point timeframe

For eribulin, Cycle 1 Day 1: 0-120 hours post-eribulin infusion; For irinotecan, Cycle 1 Day 1: 0-24 hours post-irinotecan infusion (cycle length=21 days)

Notes
[8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was assessed in Phase 1 only.

End point values	Phase 1: Schedule A, Eribulin Mesylate + Irinotecan 20 mg/m^2	Phase 1: Schedule A, Eribulin Mesylate + Irinotecan 40 mg/m^2	Phase 1: Schedule B, Eribulin Mesylate + Irinotecan 100 mg/m^2	Phase 1: Schedule B, Eribulin Mesylate + Irinotecan 125 mg/m^2
Number of subjects analysed	3	3	3	2
Units: liter
geometric mean (geometric coefficient of variation)
Eribulin(n=3,3,3,2)	124.70 ( 41.5 )	126.96 ( 18.1 )	130.78 ( 35.9 )	63.35 ( 101.8 )
Irinotecan(n=0,0,3,3)	99999 ( 99999 )	99999 ( 99999 )	248.5 ( 16.1 )	195.1 ( 69.0 )

No statistical analyses for this end point

Secondary: Phase 1, AUC(0-t): Area Under the Concentration-time Curve From Zero (Pre-dose) to Time of Last Quantifiable Concentration of of Eribulin, Irinotecan and its Active Metabolite SN-38

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End point title

Phase 1, AUC(0-t): Area Under the Concentration-time Curve From Zero (Pre-dose) to Time of Last Quantifiable Concentration of of Eribulin, Irinotecan and its Active Metabolite SN-38 ^[9]

End point description

Pharmacokinetic analysis set included subjects who had documented dosing history and at least one post-dosing quantifiable drug concentration.

End point type

Secondary

End point timeframe

For eribulin, Cycle 1 Day 1: 0-120 hours post-eribulin infusion; For irinotecan and its metabolite, Cycle 1 Day 1: 0-24 hours post-irinotecan infusion (cycle length=21 days)

Notes
[9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was assessed in Phase 1 only.

End point values	Phase 1: Schedule A, Eribulin Mesylate + Irinotecan 20 mg/m^2	Phase 1: Schedule A, Eribulin Mesylate + Irinotecan 40 mg/m^2	Phase 1: Schedule B, Eribulin Mesylate + Irinotecan 100 mg/m^2	Phase 1: Schedule B, Eribulin Mesylate + Irinotecan 125 mg/m^2
Number of subjects analysed	3	4	3	3
Units: hournanogram per milliliter (hng/mL)
geometric mean (geometric coefficient of variation)
Eribulin	422.5 ( 40.0 )	403.7 ( 32.1 )	616.9 ( 66.1 )	603.5 ( 87.3 )
Irinotecan	1812.6 ( 13.5 )	3686.1 ( 36.4 )	4693.9 ( 66.1 )	3633.7 ( 38.9 )
Metabolite SN-38	68.00 ( 19.7 )	145.04 ( 11.6 )	138.22 ( 42.2 )	65.47 ( 153.2 )

No statistical analyses for this end point

Secondary: Phase 1, AUC(0-inf): Area Under the Concentration-time Curve From Zero (Pre-dose) Extrapolated to Infinite Time of Eribulin, Irinotecan and its Active Metabolite SN-38

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End point title

Phase 1, AUC(0-inf): Area Under the Concentration-time Curve From Zero (Pre-dose) Extrapolated to Infinite Time of Eribulin, Irinotecan and its Active Metabolite SN-38 ^[10]

End point description

Pharmacokinetic analysis set included subjects who had documented dosing history and at least one post-dosing quantifiable drug concentration. Here 'N' (overall number of subjects analyzed) included all subjects who were evaluable for this outcome measure and 'n' (number analyzed) included all subjects who were evaluable at specified timepoints for this outcome measure. Here '99999' signifies that no subject was analyzed.

End point type

Secondary

End point timeframe

For eribulin, Cycle 1 Day 1: 0-120 hours post-eribulin infusion; For irinotecan and its metabolite, Cycle 1 Day 1: 0-24 hours post-irinotecan infusion (cycle length=21 days)

Notes
[10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was assessed in Phase 1 only.

End point values	Phase 1: Schedule A, Eribulin Mesylate + Irinotecan 20 mg/m^2	Phase 1: Schedule A, Eribulin Mesylate + Irinotecan 40 mg/m^2	Phase 1: Schedule B, Eribulin Mesylate + Irinotecan 100 mg/m^2	Phase 1: Schedule B, Eribulin Mesylate + Irinotecan 125 mg/m^2
Number of subjects analysed	3	3	3	2
Units: h*ng/mL
geometric mean (geometric coefficient of variation)
Eribulin(n=3,3,3,2)	438.1 ( 39.0 )	506.0 ( 16.6 )	666.9 ( 69.0 )	576.9 ( 133.6 )
Irinotecan(0,0,3,3)	99999 ( 99999 )	99999 ( 99999 )	5036.1 ( 70.9 )	3698.5 ( 39.2 )
Metabolite SN-38(0,0,2,2)	99999 ( 99999 )	99999 ( 99999 )	169.0 ( 51.4 )	149.4 ( 4.3 )

No statistical analyses for this end point

Secondary: Phase 2: Progression Free Survival (PFS)

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End point title

Phase 2: Progression Free Survival (PFS) ^[11]

End point description

PFS was defined as the time from date of first dose to the date of disease progression (PD) as determined by investigator assessment or death. PFS was assessed based on the investigators' assessments utilizing RECIST 1.1. PD was defined as at least a 20% increase or 5 mm increase in the sum of diameters of target lesions (taking as reference the smallest sum on study) recorded since the treatment started or the appearance of 1 or more new lesions. PFS was estimated and analyzed using Kaplan-Meier method. Full analysis set included subjects who received at least 1 dose of either study drug.

End point type

Secondary

End point timeframe

From the date of first dose to the date of first documentation of PD, or date of death, whichever occurred first up to approximately 3 years 3 months

Notes
[11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was assessed in Phase 2 only.

End point values	Phase 2: RMS Cohort, Eribulin Mesylate + Irinotecan 40 mg/m^2	Phase 2: NRSTS Cohort, Eribulin Mesylate+Irinotecan 40 mg/m^2	Phase 2: EWS Cohort, Eribulin Mesylate + Irinotecan 40 mg/m^2
Number of subjects analysed	9	9	9
Units: months
median (confidence interval 90%)	2.69 (1.28 to 8.87)	1.35 (1.15 to 2.79)	6.70 (1.38 to 8.84)

No statistical analyses for this end point

Secondary: Phase 2: Clinical Benefit Rate (CBR)

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End point title

Phase 2: Clinical Benefit Rate (CBR) ^[12]

End point description

CBR was defined as the percentage of subjects with best overall response (BOR) of CR, PR, or durable stable disease (SD) based on RECIST 1.1 (durable SD was defined as SD with duration of greater than [>] 11 weeks). CR was disappearance of all target and non-target lesions. All pathological (whether target or non-target) must have a reduction in their short axis <10 mm. PR was at least a 30% decrease in the SOD of target lesions, taking as reference the baseline sum diameters. Full analysis set included subjects who received at least 1 dose of either study drug. Here 'N' (overall number of subjects analyzed) included all subjects who had CR, PR or SD.

End point type

Secondary

End point timeframe

From the date of first dose to the date of first documentation of PD, or date of death, whichever occurred first up to approximately 3 years 3 months

Notes
[12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was assessed in Phase 2 only.

End point values	Phase 2: RMS Cohort, Eribulin Mesylate + Irinotecan 40 mg/m^2	Phase 2: NRSTS Cohort, Eribulin Mesylate+Irinotecan 40 mg/m^2	Phase 2: EWS Cohort, Eribulin Mesylate + Irinotecan 40 mg/m^2
Number of subjects analysed	5	3	5
Units: percentage of subject
number (confidence interval 90%)	55.6 (25.1 to 83.1)	33.3 (9.8 to 65.5)	55.6 (25.1 to 83.1)

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Baseline up to 28 days after last dose of study drug (approximately 3 years 3 months)

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

24.0

Reporting group title

Phase 1: Schedule A, Eribulin Mesylate + Irinotecan 20 mg/m^2

Reporting group description

Subjects received eribulin mesylate 1.4 mg/m^2 intravenous infusion on Days 1 and 8 and irinotecan hydrochloride 20 mg/m^2, intravenous infusion on Days 1 to 5 in a 21 day treatment cycle until MTD was reached. The MTD was determined based on the incidence of DLTs in cycle 1.

Reporting group title

Phase 1: Schedule A, Eribulin Mesylate + Irinotecan 40 mg/m^2

Reporting group description

Reporting group title

Phase 1: Schedule B, Eribulin Mesylate + Irinotecan 100 mg/m^2

Reporting group description

Reporting group title

Phase 1: Schedule B, Eribulin Mesylate + Irinotecan 125 mg/m^2

Reporting group description

Reporting group title

Phase 2: RMS Cohort, Eribulin Mesylate + Irinotecan 40 mg/m^2

Reporting group description

Reporting group title

Phase 2: NRSTS Cohort, Eribulin Mesylate+Irinotecan 40 mg/m^2

Reporting group description

Reporting group title

Phase 2: EWS Cohort, Eribulin Mesylate + Irinotecan 40 mg/m^2

Reporting group description

Subjects with EWS received eribulin mesylate 1.4 mg/m^2, intravenous infusion on Days 1 and 8 and irinotecan hydrochloride 40 mg/m^2, intravenous infusion on Days 1 to 5 in a 21 day treatment cycle until disease progression, development of unacceptable toxicity or withdrawal of consent (approximately 39 months).

Serious adverse events	Phase 1: Schedule A, Eribulin Mesylate + Irinotecan 20 mg/m^2	Phase 1: Schedule A, Eribulin Mesylate + Irinotecan 40 mg/m^2	Phase 1: Schedule B, Eribulin Mesylate + Irinotecan 100 mg/m^2	Phase 1: Schedule B, Eribulin Mesylate + Irinotecan 125 mg/m^2	Phase 2: RMS Cohort, Eribulin Mesylate + Irinotecan 40 mg/m^2	Phase 2: NRSTS Cohort, Eribulin Mesylate+Irinotecan 40 mg/m^2	Phase 2: EWS Cohort, Eribulin Mesylate + Irinotecan 40 mg/m^2
Total subjects affected by serious adverse events
subjects affected / exposed	1 / 3 (33.33%)	3 / 4 (75.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	5 / 9 (55.56%)	4 / 9 (44.44%)	3 / 9 (33.33%)
number of deaths (all causes)	0	1	0	1	3	2	0
number of deaths resulting from adverse events	0	1	0	1	3	2	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Malignant neoplasm progression
subjects affected / exposed	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 9 (11.11%)	2 / 9 (22.22%)	0 / 9 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 2	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1	0 / 2	0 / 0
Malignant pleural effusion
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	1 / 9 (11.11%)	0 / 9 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	1 / 3 (33.33%)	2 / 4 (50.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 9 (0.00%)
occurrences causally related to treatment / all	1 / 1	1 / 2	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Febrile neutropenia
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	1 / 9 (11.11%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 9 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Dyspnoea
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 9 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Pain in jaw
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Bacteraemia
subjects affected / exposed	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Device related infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 9 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Upper respiratory tract infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 9 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Malnutrition
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 0%

Non-serious adverse events	Phase 1: Schedule A, Eribulin Mesylate + Irinotecan 20 mg/m^2	Phase 1: Schedule A, Eribulin Mesylate + Irinotecan 40 mg/m^2	Phase 1: Schedule B, Eribulin Mesylate + Irinotecan 100 mg/m^2	Phase 1: Schedule B, Eribulin Mesylate + Irinotecan 125 mg/m^2	Phase 2: RMS Cohort, Eribulin Mesylate + Irinotecan 40 mg/m^2	Phase 2: NRSTS Cohort, Eribulin Mesylate+Irinotecan 40 mg/m^2	Phase 2: EWS Cohort, Eribulin Mesylate + Irinotecan 40 mg/m^2
Total subjects affected by non serious adverse events
subjects affected / exposed	3 / 3 (100.00%)	4 / 4 (100.00%)	3 / 3 (100.00%)	3 / 3 (100.00%)	9 / 9 (100.00%)	9 / 9 (100.00%)	9 / 9 (100.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cancer pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Tumour pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	1	0	0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	2 / 9 (22.22%)	3 / 9 (33.33%)	0 / 9 (0.00%)
occurrences all number	0	0	1	0	2	3	0
Catheter site pain
subjects affected / exposed	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Non-cardiac chest pain
subjects affected / exposed	1 / 3 (33.33%)	0 / 4 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)
occurrences all number	1	0	1	0	0	0	2
Pyrexia
subjects affected / exposed	1 / 3 (33.33%)	0 / 4 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 9 (11.11%)	2 / 9 (22.22%)	5 / 9 (55.56%)
occurrences all number	1	0	1	0	1	3	8
Catheter site pruritus
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Gait disturbance
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	0	0	1
Fatigue
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 9 (22.22%)	3 / 9 (33.33%)	2 / 9 (22.22%)
occurrences all number	0	0	0	0	5	3	4
Oedema peripheral
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	0	1	1
Pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	1 / 9 (11.11%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	1	2	1
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	1 / 3 (33.33%)	0 / 4 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	2 / 9 (22.22%)	0 / 9 (0.00%)	1 / 9 (11.11%)
occurrences all number	1	0	1	0	3	0	1
Hypoxia
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Pleuritic pain
subjects affected / exposed	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	1	0	0	0	0	1
Respiratory distress
subjects affected / exposed	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Allergic cough
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Dyspnoea
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Epistaxis
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 9 (22.22%)	1 / 9 (11.11%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	2	2	0
Haemoptysis
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Laryngeal inflammation
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Oropharyngeal pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 9 (22.22%)	0 / 9 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	3	0	0
Pneumothorax
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	0	1	1
Pulmonary embolism
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Rhinorrhoea
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Psychiatric disorders
Insomnia
subjects affected / exposed	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	1 / 9 (11.11%)	1 / 9 (11.11%)
occurrences all number	0	3	0	0	1	1	1
Agitation
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Anxiety
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Depressed mood
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	8	0	0
Negative thoughts
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Tearfulness
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	3	0	0
Investigations
Aspartate aminotransferase increased
subjects affected / exposed	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	2	0	0	4	0	5
Alanine aminotransferase increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 9 (11.11%)	1 / 9 (11.11%)	2 / 9 (22.22%)
occurrences all number	0	0	2	0	10	2	9
C-reactive protein increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	1	0	1	0	0
Lymphocyte count decreased
subjects affected / exposed	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 9 (11.11%)	0 / 9 (0.00%)	2 / 9 (22.22%)
occurrences all number	0	1	0	1	8	0	5
Weight decreased
subjects affected / exposed	0 / 3 (0.00%)	1 / 4 (25.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	2 / 9 (22.22%)	0 / 9 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	1	1	0	2	0	1
Neutrophil count decreased
subjects affected / exposed	0 / 3 (0.00%)	3 / 4 (75.00%)	0 / 3 (0.00%)	2 / 3 (66.67%)	6 / 9 (66.67%)	3 / 9 (33.33%)	5 / 9 (55.56%)
occurrences all number	0	8	0	7	21	22	46
White blood cell count decreased
subjects affected / exposed	0 / 3 (0.00%)	3 / 4 (75.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 9 (11.11%)	1 / 9 (11.11%)	0 / 9 (0.00%)
occurrences all number	0	7	0	1	20	6	0
Blood albumin decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Blood calcium decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Blood creatinine increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	0	0	1
Blood phosphorus decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Blood potassium decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Blood sodium decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	2	0
Blood urea increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Electrocardiogram QT prolonged
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	0	2	2
Gamma-glutamyltransferase increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	0	0	1
Haematocrit decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	7	0	0
Metamyelocyte count increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Myelocyte count increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Red blood cell count decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	5	0	0
Injury, poisoning and procedural complications
Procedural nausea
subjects affected / exposed	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	0	1	0	0
Urostomy complication
subjects affected / exposed	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Contusion
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Fall
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	0	0	1
Mouth injury
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Wound dehiscence
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	2	0	0
Cardiac disorders
Tachycardia
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	2 / 9 (22.22%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	2	0
Nervous system disorders
Headache
subjects affected / exposed	1 / 3 (33.33%)	0 / 4 (0.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	4 / 9 (44.44%)	0 / 9 (0.00%)	1 / 9 (11.11%)
occurrences all number	1	0	1	1	6	0	2
Paraesthesia
subjects affected / exposed	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Neuralgia
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	0	0	1
Peripheral sensorimotor neuropathy
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	1	0	3
Peripheral sensory neuropathy
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	0	4	1
Syncope
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	2 / 3 (66.67%)	2 / 4 (50.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	3 / 9 (33.33%)	4 / 9 (44.44%)	5 / 9 (55.56%)
occurrences all number	3	14	6	1	9	8	29
Leukopenia
subjects affected / exposed	1 / 3 (33.33%)	1 / 4 (25.00%)	2 / 3 (66.67%)	1 / 3 (33.33%)	0 / 9 (0.00%)	1 / 9 (11.11%)	3 / 9 (33.33%)
occurrences all number	4	14	15	12	0	1	32
Lymphopenia
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	3	0	0	0
Neutropenia
subjects affected / exposed	3 / 3 (100.00%)	2 / 4 (50.00%)	3 / 3 (100.00%)	1 / 3 (33.33%)	3 / 9 (33.33%)	2 / 9 (22.22%)	4 / 9 (44.44%)
occurrences all number	39	8	18	12	15	10	52
Thrombocytopenia
subjects affected / exposed	0 / 3 (0.00%)	1 / 4 (25.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 9 (0.00%)	0 / 9 (0.00%)	5 / 9 (55.56%)
occurrences all number	0	1	3	1	0	0	17
Leukocytosis
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Ear and labyrinth disorders
Ear pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	0	0	1
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	7 / 9 (77.78%)	2 / 9 (22.22%)	2 / 9 (22.22%)
occurrences all number	1	0	0	0	9	3	2
Abdominal pain upper
subjects affected / exposed	1 / 3 (33.33%)	0 / 4 (0.00%)	2 / 3 (66.67%)	0 / 3 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)
occurrences all number	1	0	2	0	0	1	0
Constipation
subjects affected / exposed	2 / 3 (66.67%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 9 (22.22%)	0 / 9 (0.00%)	2 / 9 (22.22%)
occurrences all number	3	0	0	0	2	0	2
Diarrhoea
subjects affected / exposed	1 / 3 (33.33%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	4 / 9 (44.44%)	5 / 9 (55.56%)	5 / 9 (55.56%)
occurrences all number	1	12	0	0	24	11	9
Nausea
subjects affected / exposed	1 / 3 (33.33%)	1 / 4 (25.00%)	2 / 3 (66.67%)	0 / 3 (0.00%)	4 / 9 (44.44%)	6 / 9 (66.67%)	1 / 9 (11.11%)
occurrences all number	2	1	2	0	5	8	1
Oral pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Toothache
subjects affected / exposed	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 9 (0.00%)
occurrences all number	2	0	0	0	1	0	0
Vomiting
subjects affected / exposed	0 / 3 (0.00%)	2 / 4 (50.00%)	3 / 3 (100.00%)	1 / 3 (33.33%)	6 / 9 (66.67%)	2 / 9 (22.22%)	1 / 9 (11.11%)
occurrences all number	0	2	10	3	8	2	4
Abdominal distension
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	2	0	0
Anal inflammation
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	0	0	1
Anal fissure
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Aphthous ulcer
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Gingival pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	1 / 9 (11.11%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	1	1	0
Haematemesis
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Haematochezia
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	0	0	1
Hypoaesthesia oral
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	4	0	0
Mouth ulceration
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	1 / 9 (11.11%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	4	1	1
Odynophagia
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	0	0	1
Proctalgia
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Stomatitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 9 (22.22%)	0 / 9 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	5	0	4
Tongue ulceration
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Skin and subcutaneous tissue disorders
Alopecia
subjects affected / exposed	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	2 / 9 (22.22%)	0 / 9 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	1	3	0	0
Dermatitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	1	0	0	1
Dry skin
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Skin oedema
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Rash
subjects affected / exposed	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	1	1	0	0
Leukonychia
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Palmar-plantar erythrodysaesthesia syndrome
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Papule
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Pruritus
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	2 / 9 (22.22%)
occurrences all number	0	0	0	0	0	0	2
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	0	0	1
Haematuria
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	1 / 9 (11.11%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	1	1	3
Urinary tract pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 9 (11.11%)	2 / 9 (22.22%)	0 / 9 (0.00%)
occurrences all number	0	0	1	0	1	4	0
Bone pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	3 / 9 (33.33%)
occurrences all number	0	0	1	0	0	0	3
Muscle spasms
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	2 / 9 (22.22%)	0 / 9 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	1	0	2	0	0
Musculoskeletal chest pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 9 (0.00%)	0 / 9 (0.00%)	2 / 9 (22.22%)
occurrences all number	0	0	0	1	0	0	2
Spinal pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	1	0	1	0	0
Arthralgia
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	2 / 9 (22.22%)	2 / 9 (22.22%)
occurrences all number	0	0	0	0	2	5	5
Groin pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	2	0
Pain in extremity
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	2 / 9 (22.22%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	1	3	4
Pain in jaw
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	4	0	3
Neck pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	0	0	1
Infections and infestations
Conjunctivitis
subjects affected / exposed	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Rhinitis
subjects affected / exposed	1 / 3 (33.33%)	0 / 4 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	3 / 9 (33.33%)	0 / 9 (0.00%)	1 / 9 (11.11%)
occurrences all number	1	0	1	0	3	0	2
Tonsillitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Vascular device infection
subjects affected / exposed	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Bacterial infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	1	0	0
COVID-19
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Device related infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Ear infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	0	0	1
Herpes simplex
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Influenza
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Nasopharyngitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Pneumonia
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	0	0	1
Oral candidiasis
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	0	1	1
Upper respiratory tract infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Respiratory tract infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	0	0	1
Urinary tract infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	4 / 9 (44.44%)	3 / 9 (33.33%)	0 / 9 (0.00%)
occurrences all number	0	1	0	0	5	3	0
Hypophosphataemia
subjects affected / exposed	1 / 3 (33.33%)	0 / 4 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)
occurrences all number	1	0	2	0	0	0	3
Vitamin D deficiency
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Hypokalaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 9 (22.22%)	0 / 9 (0.00%)	2 / 9 (22.22%)
occurrences all number	0	0	0	0	7	0	10
Hypomagnesaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	1 / 9 (11.11%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	2	1	0
Refeeding syndrome
subjects affected / exposed	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	1	0

More information

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Were there any global substantial amendments to the protocol? Yes

10 May 2018

Amendment 01: Up to approximately 50 study sites was added. Ewing sarcoma (EWS) as a treatment group was added. Included duration of response (DOR) as part of the primary objective for Phase 2. Expanded maximum number of subjects for Phase 2 of study from 50 to 75, consistent with addition of an EWS treatment group. 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. Eligibility criteria was amended. PK sampling schedule for subjects <12 months was included. Updated Principles of the World Medical Association Declaration of Helsinki from 2008 to 2013. Included storage and labeling information for irinotecan hydrochloride as an Investigational Product. schedule of assessments was amended.

02 Aug 2018

Amendment 02: Added restriction to concomitant use with St. John's Wort in exclusion criterion #2. Added criteria for study drug discontinuation. Added new Tables (Tables 3 and 8) which list the criteria for study drug discontinuation. 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.

12 Oct 2018

Amendment 03: 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’. Clarification that the duration of treatment up to 1 year is from the ‘start of study treatment’. ECG and electrolyte monitoring will occur ‘more frequently in consultation with cardiologist advice and in line with local practice’. For neuroblastoma subjects (Phase 1 only), included MIBG assessments and when to perform them. Updated interim analyses to include an assessment of tolerability. Removed ‘safety summaries may be provided periodically’ due to this update. Included monthly pregnancy tests are required for all sexually active subjects. Removed assessment for globulin. Updated sponsor’s grading for CTCAE laboratory values.

10 Jul 2019

Amendment 04: Updated description of sample size for Phase 2 to ‘approximately 75’ or ‘approximately 25 per histology’ and updated trial schema. Updated inclusion criterion #8 to remove the use of radioisotope for the measurement of the glomerular filtration rate (GFR). 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. Updated exclusion criterion #9. Added FDG-PET scans. Updated details of MIBG scans for neuroblastoma patients. Updated the description of safety data analysis in statistical methods section. Updated estimated study LSLV date (to Mar 2021). Updated description of laboratory analysis values, ECG and other safety analyses. Minor administrative changes.

14 Jul 2020

Amendment 05: Extended study duration from 36 to 42 months. 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. Updated Inclusion Criterion 1a. Updated Exclusion Criterion 10. Criteria for administration of study drug; Day 8 Bowel function deteriorated since pretreatment/ baseline and requires antidiarrheal medications for within 24 hours before the next administration of irinotecan hydrochloride. Included dose levels specifically for the Phase 2 portion of the study. 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. Included ‘irrespective of dose delays’ 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”.

29 Mar 2021

Amendment 06: 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. Amended Inclusion Criterion 1b to include subjects >6 months and <12 months of age in Phase 2. For subjects >6 months and <12 months of age in Phase 2, further dose reductions have been included 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. Vital signs, physical examination, and chemistry assessments during Phase 2 for the >6 months and <12 months age group will be weekly. 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.

Were there any global interruptions to the trial? Yes

Date	Interruption	Restart date
01 Apr 2020	New screening or enrollment was temporarily halted on all sites on study for the period of 01 Apr 2020 to 30 Apr 2020 to reduce the risk of potential COVID-19 exposure.	-

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results: 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.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Phase 1: Maximum Tolerated Dose (MTD) of Eribulin Mesylate in Combination with Irinotecan Hydrochloride

Primary: Phase 1: Maximum Tolerated Dose (MTD) of Eribulin Mesylate in Combination with Irinotecan Hydrochloride

Primary: Phase 2: Objective response rate (ORR)

Primary: Phase 2: Objective response rate (ORR)

Secondary: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs)

Secondary: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs)

Secondary: Number of Subjects With Serious Adverse Event (SAE)

Secondary: Number of Subjects With Serious Adverse Event (SAE)

Secondary: Phase 1, Cmax: Maximum Observed Plasma Concentration of Eribulin, Irinotecan and its Active Metabolite SN-38

Secondary: Phase 1, Cmax: Maximum Observed Plasma Concentration of Eribulin, Irinotecan and its Active Metabolite SN-38

Secondary: Phase 1, Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) of Eribulin, Irinotecan and its Active Metabolite SN-38

Secondary: Phase 1, Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) of Eribulin, Irinotecan and its Active Metabolite SN-38

Secondary: Phase 1, T1/2: Half-life of Eribulin, Irinotecan and its Active Metabolite SN-38

Secondary: Phase 1, T1/2: Half-life of Eribulin, Irinotecan and its Active Metabolite SN-38

Secondary: Phase 1, Total Clearance (CL) of Eribulin and Irinotecan

Secondary: Phase 1, Total Clearance (CL) of Eribulin and Irinotecan

Secondary: Phase 1, Volume of Distribution (Vz) of Eribulin and Irinotecan

Secondary: Phase 1, Volume of Distribution (Vz) of Eribulin and Irinotecan

Secondary: Phase 1, AUC(0-t): Area Under the Concentration-time Curve From Zero (Pre-dose) to Time of Last Quantifiable Concentration of of Eribulin, Irinotecan and its Active Metabolite SN-38

Secondary: Phase 1, AUC(0-t): Area Under the Concentration-time Curve From Zero (Pre-dose) to Time of Last Quantifiable Concentration of of Eribulin, Irinotecan and its Active Metabolite SN-38

Secondary: Phase 1, AUC(0-inf): Area Under the Concentration-time Curve From Zero (Pre-dose) Extrapolated to Infinite Time of Eribulin, Irinotecan and its Active Metabolite SN-38

Secondary: Phase 1, AUC(0-inf): Area Under the Concentration-time Curve From Zero (Pre-dose) Extrapolated to Infinite Time of Eribulin, Irinotecan and its Active Metabolite SN-38

Secondary: Phase 2: Progression Free Survival (PFS)

Secondary: Phase 2: Progression Free Survival (PFS)

Secondary: Phase 2: Clinical Benefit Rate (CBR)

Secondary: Phase 2: Clinical Benefit Rate (CBR)

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
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.