Study Evaluating the Safety and Efficacy of Eribulin Mesilate in Combination With Irinotecan Hydrochloride in Children With Refractory or Recurrent Solid Tumors

• Sponsor: Eisai Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03245450
• Collaborator: (none)
• Enrollment: 40
• Locations: 39
• Arm: 1
• Actual Duration (Months): 38.4
• Patients Per Site: 1
• Patients Per Site Per Month: 0

Study Details

Study Description

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).

Condition or Disease	Intervention/Treatment	Phase
Refractory or Recurrent Solid Tumors; Rhabdomyosarcoma; Non-Rhabdomyosarcoma Soft Tissue Sarcoma; Ewing Sarcoma	Drug: Eribulin mesilate; Drug: Irinotecan hydrochloride	Phase 1/Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 40 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official 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
• Actual Study Start Date: Mar 5, 2018
• Actual Primary Completion Date: May 17, 2021
• Actual Study Completion Date: May 17, 2021

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Eribulin mesilate plus irinotecan hydrochloride 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.

Drug: Eribulin mesilate; IV infusion; Other Names: E7389 ; Drug: Irinotecan hydrochloride; IV infusion; Other Names: (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

Outcome Measures

Primary Outcome Measures

1. Phase 1: Recommended Phase 2 Dose (RP2D) of Eribulin Mesilate in Combination With Irinotecan Hydrochloride [First dose of study drug up to Cycle 1 (Cycle length=21 days)]

   The RP2D was evaluated based on a review of the outcomes of safety (including dose limiting toxicities [DLTs]), tumor assessments, and pharmacokinetic (PK) in Phase 1 by investigators and the study team.

2. Phase 2: Objective Response Rate (ORR) [From date of first dose of study drug until disease progression, development of unacceptable toxicity, withdrawal of consent, or up to approximately 2 years 4 months]

   ORR was defined as the percentage of participants achieving 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 defined as 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.

Secondary Outcome Measures

1. Number of Participants With Treatment-Emergent Adverse Events (TEAEs) [From first dose of study drug up to approximately 2 years 4 months]

   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 participant administered a drug; it does not necessarily have to have a causal relationship with this treatment.

2. Number of Participants With Serious Adverse Event (SAE) [Up to approximately 2 years and 4 months]

   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.

3. Phase 1, Cmax: Maximum Observed Plasma Concentration of Eribulin, Irinotecan and Its Active Metabolite SN-38 [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)]

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

5. Phase 1, T1/2: Half-life of Eribulin, Irinotecan and Its Active Metabolite SN-38 [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)]

   Half-life for irinotecan and metabolite SN-38 could not be estimated for phase 1:schedule A, eribulin mesilate 1.4 mg/m^2 + irinotecan 20 mg/m^2 and phase 1: schedule A, eribulin mesilate 1.4 mg/m^2 + irinotecan 40 mg/m^2 arm as the slope of the terminal phase of the concentration-time profiles could not be determined.

6. Phase 1, Total Clearance (CL) of Eribulin and Irinotecan [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)]

   CL for irinotecan could not be estimated for phase 1:schedule A, eribulin mesilate 1.4 mg/m^2 + irinotecan 20 mg/m^2 and phase 1: schedule A, eribulin mesilate 1.4 mg/m^2 + irinotecan 40 mg/m^2 arm because it was not possible to calculate half-life as the slope of the terminal phase of the concentration-time profiles could not be determined.

7. Phase 1, Volume of Distribution (Vz) of Eribulin and Irinotecan [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)]

   Vz for irinotecan could not be estimated for phase 1: schedule A, eribulin mesilate 1.4 mg/m^2 + irinotecan 20 mg/m^2 and phase 1: schedule A, eribulin mesilate 1.4 mg/m^2 + irinotecan 40 mg/m^2 arm because it was not possible to calculate half-life as the slope of the terminal phase of the concentration-time profiles could not be determined.

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

9. 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 [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)]

   AUC(0-inf) for irinotecan and metabolite SN-38 could not be estimated for phase 1: schedule A, eribulin mesilate 1.4 mg/m^2 + irinotecan 20 mg/m^2 and phase 1: schedule A, eribulin mesilate 1.4 mg/m^2 + irinotecan 40 mg/m^2 arm because it was not possible to calculate half-life as the slope of the terminal phase of the concentration-time profiles could not be determined.

10. Phase 2: Progression Free Survival (PFS) [From the date of first dose to the date of first documentation of PD, or date of death, whichever occurred first up to approximately 2 years 4 months]

    PFS was defined as the time from date of first dose to the date of disease progression (PD). PFS was assessed based on the investigators' assessments utilizing RECIST 1.1. PD was defined as at least 20% increase or 5 mm increase in the sum of diameters of target lesions recorded since the treatment started or the appearance of 1 or more new lesions. PFS was estimated and analyzed using Kaplan-Meier method.

11. Phase 2: Clinical Benefit Rate (CBR) [From the date of first dose to the date of first documentation of PD, or date of death, whichever occurred first up to approximately 2 years 4 months]

    CBR was defined as the percentage of participants with 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 defined as 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 defined as at least 30% decrease in the SOD of target lesions, taking as reference the baseline sum diameters.

12. Model Predicted Apparent Total Body Clearance (CL) of Eribulin [Cycle 1 Day 1: 0.5-120 hours after eribulin infusion; Cycle 1 Day 8: pre-dose and at the end of the eribulin infusion (cycle length=21 days)]

    Per the planned PK analysis, PK samples were collected and analyzed using a population PK approach to estimate PK parameters. Eribulin plasma concentration data from this study were pooled from studies (NCT00069264, NCT00069277, NCT00326950, NCT00706095, NCT01000376, NCT01106248, NCT02171260, NCT00413192, NCT01458249, NCT03441360 and NCT01327885), and a population PK model was applied to the pooled dataset. The data presented are the CL parameter estimates, with Measure Type "Number" defining the eribulin PK model. They are population PK model predictions and have been estimated using non-linear mixed effects model.

13. Volume of Distribution Estimates From the Population PK Model for Eribulin [Cycle 1 Day 1: 0.5-120 hours after eribulin infusion; Cycle 1 Day 8: pre-dose and at the end of the eribulin infusion (cycle length=21 days)]

    Per the planned PK analysis, PK samples were collected and analyzed using a population PK approach to estimate PK parameters. Eribulin plasma concentration data from this study were pooled from studies (NCT00069264, NCT00069277, NCT00326950, NCT00706095, NCT01000376, NCT01106248, NCT02171260, NCT00413192, NCT01458249, NCT03441360 and NCT01327885), and a population PK model was applied to the pooled dataset. Data presented are the volume of distribution of the central compartment (V1), volume of distribution of the first peripheral compartment (V2), and volume of distribution of the second peripheral compartment (V3) parameter estimates with Measure Type "Number" defining the eribulin PK model. They are population PK model predictions and have been estimated using non-linear mixed effects model.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 6 Months to 25 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Participants must be

• =12 months to less than or equal to (<=) 25 years old at the time of consent [no more than 25 percent (%) of participants between the ages of 18 and 25 years will be enrolled in this study].

• In Phase 1, >6 months and <12 months at the time of consent (Schedule A only) participants will be enrolled one dose level behind the >=12 months participant in order to maximize safety for infant participants. In Phase 2, participants aged >6 months and <12 months at the time of consent will be enrolled to Schedule A with a modified dose of eribulin with the irinotecan dose maintained in order to maximize safety for infant participants.

Inclusion Criteria:

• Phase 1: Participants must be diagnosed with histologically confirmed solid tumors (excluding CNS tumors), which is relapsed or refractory, and for which there are no currently available therapies.

• Phase 2: Participants must be diagnosed with histologically confirmed RMS, NRSTS or EWS which is relapsed or refractory having received at least 1 prior therapy, including primary treatment.

• Phase 1: Participants must have either measurable or evaluable disease as per RECIST 1.1.

• Phase 2: Participants must have measurable disease as per RECIST 1.1.

• Participant's current disease state must be one for which there is no known curative therapy.

• Participant's performance score must be >=50% Karnofsky (for participants >16 years of age) or Lansky (for participants <=16 years of age).Participants 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.

• Participants must have fully recovered from the acute toxic effects of all prior anticancer treatments prior to study drug administration:

• Must not have received myelosuppressive chemotherapy within 21 days prior to study drug administration (42 days if prior nitrosourea).

• Must not have received a long-acting growth factor (example, Neulasta) within 14 days or a short-acting growth factor within 7 days.

• Must not have received an antineoplastic targeted therapy within 14 days.

• Must not have received immunotherapy, example, tumor vaccines, within 42 days.

• Must not have received monoclonal antibodies within at least 3 half-lives of the antibody after its last dose.

• Must not have received radiotherapy (XRT) within 14 days prior to study drug administration (small field) or 42 days for craniospinal XRT, or if >=50% radiation of pelvis.

• At least 84 days must have elapsed after stem cell infusion prior to study drug administration

• No evidence of active graft-versus-host disease (GVHD) and at least 100 days must have elapsed after allogeneic bone marrow transplant or stem cell infusion prior to study drug administration

• Participants must have adequate bone marrow function, defined as:

• Peripheral absolute neutrophil count (ANC) >=1.0*10^9/liter (L).

• Platelet count >=100*10^9/L (not receiving platelet transfusions within a 7-day period prior to study drug administration).

• Hemoglobin (Hb) at least 8.0 grams per deciliter (g/dL) at baseline (blood transfusions are allowed during the screening period to correct Hb values <8.0 g/dL).

• Participants must have adequate renal function, defined as:

• A serum creatinine based on age/gender, derived from the Schwartz formula for estimating glomerular filtration rate (GFR), per protocol-specified criteria.

• Serum creatinine clearance or GFR >=50 milliliters/minute/1.73 m^2, based on a 12 or 24 hours (h) urine creatinine collection.

• Participants must have adequate liver function, defined as:

• Bilirubin (sum of conjugated + unconjugated) <=1.5 times the upper limit of normal (ULN) for age.

• Alkaline phosphatase, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <=3ULN (in the case of liver metastases <=5ULN), 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.

• All participants and/or their parents or guardians must sign a written informed consent.

• Participants must be willing to comply with all aspects of the protocol.

Exclusion Criteria:

• Females who are breastfeeding or pregnant at Screening or Baseline. A separate baseline assessment is required if a negative screening pregnancy test was obtained more than 72 h 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, that is:

• 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.

• Males who have not had a successful vasectomy (confirmed azoospermia) or they and their female partners do not meet the criteria above (that is, 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.

• Concomitant Medications:

• Participants receiving corticosteroids who have not been on a stable dose for at least 7 days prior to study drug administration.

• Participants who are currently receiving other anticancer agents.

• Participants who are receiving cyclosporine, tacrolimus or other agents to prevent GVHD post bone marrow transplant.

• Participants who are receiving strong cytochrome P450 3A4 (CYP3A4) inhibitors and inducers including traditional herbal medicinal products (example, St. John's Wort).

• 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, participants can be included if there was no tumor progression during irinotecan therapy).

• 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.

• Has hypersensitivity to either study drug or any of the excipients.

• 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

• Has >Grade 1 peripheral sensory neuropathy or >Grade 1 peripheral motor neuropathy graded according to the Modified ("Balis") Pediatric Scale of Peripheral Neuropathies.

• Has cardiac pathology, defined as:

• Participants with known congestive heart failure, symptomatic or Left ventricular (LV) ejection fraction <50% or shortening fraction <27% and participants with congenital long QT syndrome, bradyarrhythmias, or QT interval (QTc)>480 milliseconds on at least 2 separate electrocardiograms (ECGs).

• Has CNS disease: Participants 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 and have discontinued the use of corticosteroids for this indication for at least 28 days prior to study drug administration. Participants must be clinically stable. It is not the intention of this protocol to treat participants with active brain metastases.

Note: Screening CNS imaging for participants with a known history of CNS disease is required.

• Have had or are planning to have the following invasive procedures:

• Major surgical procedure or significant traumatic injury within 28 days prior to study drug administration.

• Laparoscopic procedure or open biopsy within 7 days prior to study drug administration

• Central line placement or subcutaneous port placement is not considered major surgery.

• 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.

• Participants with known human immunodeficiency virus (HIV); due to lack of available safety data for eribulin therapy in HIV infected participants.

• Has any serious concomitant illness that in the opinion of the investigator(s) could affect the participant's safety or interfere with the study assessments (including active or severe chronic inflammatory bowel disease or bowel obstruction).

• 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Hopitaux de La Timone	Marseille	Bouches-du-Rhône	France	13385
2	Centre Oscar Lambret	Lille	Nord	France	59020
3	Centre Léon Berard	Lyon	Rhône	France	69008
4	Eisai Trial Site 4	Freiburg	Baden-Württemberg	Germany	79106
5	Eisai Trial Site 2	Frankfurt	Hessen	Germany	60590
6	Eisai Trial Site 5	Gottingen	Niedersachsen	Germany	37075
7	Eisai Trial Site 1	Aachen	Nordrhein-Westfalen	Germany	52074
8	Eisai Trial Site 3	Berlin		Germany	13353
9	Eisai Trial Site 6	Essen		Germany	45122
10	Aghia Sophia' Children's General Hospital of Athens	Athens	Attiki	Greece	115 27
11	AHEPA University General Hospital of Thessaloniki	Thessaloníki		Greece	546 36
12	Azienda Ospedaliero Universitaria Di Bologna - Policlinico S Orsola Malpighi	Bologna	Emilia-Romagna	Italy	40138
13	Ospedale Pediatrico Bambino Gesù	Roma	Lazio	Italy	00165
14	Fondazione Policlinico Universitario A Gemelli	Roma	Lazio	Italy	00168
15	Istituto G Gaslini Ospedale Pediatrico IRCCS	Genova	Liguria	Italy	16147
16	Ospedale Infantile Regina Margherita	Torino	Piemonte	Italy	10126
17	Azienda Ospedaliera A Meyer	Firenze	Toscana	Italy	50139
18	Azienda Ospedaliera Di Padova	Padova	Veneto	Italy	35128
19	Istituto Nazionale Dei Tumori	Milan		Italy	20133
20	Uniwersytecki Szpital Kliniczny im. Jana Mikulicza Radeckiego we Wroclawiu	Wrocław	Dolnoslaskie	Poland	50-556
21	Instytut Pomnik Centrum Zdrowia Dziecka	Warszawa	Mazowieckie	Poland	04-730
22	Hospital Universitario Vall d'Hebron - PPDS	Barcelona	Cataluña	Spain	08035
23	Hospital Sant Joan de Deu	Esplugues De Llobregat	Cataluña	Spain	08950
24	Hospital Infantil Universitario Niño Jesus	Madrid		Spain	28009
25	Hospital Universitario La Paz	Madrid		Spain	28046
26	Hospital Universitario Virgen del Rocio	Sevilla		Spain	41013
27	Hospital Universitari i Politecnic La Fe de Valencia	Valencia		Spain	46026
28	Kinderspital Zürich - Eleonorenstiftung	Zürich		Switzerland	CH-8032
29	Addenbrooke's Hospital	Cambridge	Cambridgeshire	United Kingdom	CB2 0QQ
30	Southampton General Hospital	Southampton	Hampshire	United Kingdom	SO16 6YD
31	Alder Hey Childrens Hospital	Liverpool	Merseyside	United Kingdom	L12 2AP
32	John Radcliffe Hospital	Oxford	Oxfordshire	United Kingdom	OX3 9DU
33	Royal Marsden Hospital - Surrey	Sutton	Surrey	United Kingdom	SM2 5PT
34	Birmingham Children's Hospital	Birmingham	West Midlands	United Kingdom	B4 6NH
35	The Leeds Teaching Hospitals Charitable Foundation - Leeds Childrens Hospital (LCH)	Leeds	Yorkshire	United Kingdom	LS1 3EX
36	University College London	London		United Kingdom	NW1 2BU
37	Royal Manchester Childrens Hospital	Manchester		United Kingdom	M13 9WL
38	The Christie NHS Foundation Trust	Manchester		United Kingdom	M20 4BX
39	Royal Victoria Infirmary	Newcastle		United Kingdom	NE1 4LP

Sponsors and Collaborators

• Eisai Inc.

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Mar 29, 2021
• Statistical Analysis Plan - Jun 25, 2021

More Information

Publications

None provided.

• Responsible Party: Eisai Inc.
• ClinicalTrials.gov Identifier: NCT03245450
• Other Study ID Numbers: E7389-G000-213; 2016-003352-67
• First Posted: Aug 10, 2017
• Last Update Posted: Jun 28, 2022
• Last Verified: Jun 1, 2021

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Eisai Inc.: eribulin mesilate; irinotecan; combination therapy; children
• Additional relevant MeSH terms: Sarcoma; Rhabdomyosarcoma; Sarcoma, Ewing; Recurrence; Irinotecan

Study Results

Participant Flow

Recruitment Details	Participants took part in the study at 22 investigative sites in France, Germany, Greece, Italy, Poland, Spain and United Kingdom from 05 March 2018 to 17 May 2021.
Pre-assignment Detail	A total of 46 participants were screened, out of which 13 participants were treated in the Phase 1 and 27 participants were treated in Phase 2 (9 participants each in the relapsed/refractory rhabdomyosarcoma [RMS], non-rhabdomyosarcoma soft tissue sarcoma [NRSTS], and Ewing sarcoma [EWS] cohorts).

Arm/Group Title	Phase 1: Schedule A, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 20 mg/m^2	Phase 1: Schedule A, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2	Phase 1: Schedule B, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 100 mg/m^2	Phase 1: Schedule B, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 125 mg/m^2	Phase 2: RMS Cohort, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2	Phase 2: NRSTS Cohort, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2	Phase 2: EWS Cohort, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2
Arm/Group Description	Participants received eribulin mesilate 1.4 mg/m^2 (milligram per square meter) intravenous infusion on Days 1 and 8 and irinotecan hydrochloride 20 mg/m^2, intravenous infusion on Days 1 to 5 in every 21 days treatment cycle until disease progression, development of intolerable toxicity or withdrawal of consent.	Participants received eribulin mesilate 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 every 21 days treatment cycle until disease progression, development of intolerable toxicity or withdrawal of consent.	Participants received eribulin mesilate 1.4 mg/m^2 and irinotecan hydrochloride 100 mg/m^2 intravenous infusion on Days 1 and 8 in every 21 days treatment cycle until disease progression, development of intolerable toxicity or withdrawal of consent.	Participants received eribulin mesilate 1.4 mg/m^2 and irinotecan hydrochloride 125 mg/m^2 intravenous infusion on Days 1 and 8 in every 21 days treatment cycle until disease progression, development of intolerable toxicity or withdrawal of consent.	Participants with RMS received eribulin mesilate 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 every 21 days treatment cycle until disease progression, development of intolerable toxicity or withdrawal of consent.	Participants with NRSTS received eribulin mesilate 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 every 21 days treatment cycle until disease progression, development of unacceptable toxicity or withdrawal of consent.	Participants with EWS received eribulin mesilate 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 every 21 days treatment cycle until disease progression, development of unacceptable toxicity or withdrawal of consent.
Period Title: Overall Study
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

Baseline Characteristics

Arm/Group Title	Phase 1: Schedule A, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 20 mg/m^2	Phase 1: Schedule A, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2	Phase 1: Schedule B, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 100 mg/m^2	Phase 1: Schedule B, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 125 mg/m^2	Phase 2: RMS Cohort, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2	Phase 2: NRSTS Cohort, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2	Phase 2: EWS Cohort, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2	Total
Arm/Group Description	Participants received eribulin mesilate 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 every 21 days treatment cycle until disease progression, development of intolerable toxicity or withdrawal of consent.	Participants received eribulin mesilate 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 every 21 days treatment cycle until disease progression, development of intolerable toxicity or withdrawal of consent.	Participants received eribulin mesilate 1.4 mg/m^2 and irinotecan hydrochloride 100 mg/m^2 intravenous infusion on Days 1 and 8 in every 21 days treatment cycle until disease progression, development of intolerable toxicity or withdrawal of consent.	Participants received eribulin mesilate 1.4 mg/m^2 and irinotecan hydrochloride 125 mg/m^2 intravenous infusion on Days 1 and 8 in every 21 days treatment cycle until disease progression, development of intolerable toxicity or withdrawal of consent.	Participants with RMS received eribulin mesilate 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 every 21 days treatment cycle until disease progression, development of intolerable toxicity or withdrawal of consent.	Participants with NRSTS received eribulin mesilate 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 every 21 days treatment cycle until disease progression, development of unacceptable toxicity or withdrawal of consent.	Participants with EWS received eribulin mesilate 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 every 21 days treatment cycle until disease progression, development of unacceptable toxicity or withdrawal of consent.	Total of all reporting groups
Overall Participants	3	4	3	3	9	9	9	40
Age (years) [Mean (Standard Deviation) ]
Phase 1	10.94 (6.583)	7.33 (2.540)	13.97 (4.231)	8.06 (4.997)	9.87 (4.842)
Phase 2	11.05 (3.845)	12.71 (4.348)	11.59 (3.753)	11.78 (3.899)
Age, Customized (Count of Participants)
Children (2-11 years)	1 33.3%	4 100%	1 33.3%	2 66.7%	5 55.6%	3 33.3%	4 44.4%	20 50%
Adolescents (12-17 years)	2 66.7%	0 0%	2 66.7%	1 33.3%	4 44.4%	6 66.7%	5 55.6%	20 50%
Sex: Female, Male (Count of Participants)
Female	2 66.7%	1 25%	2 66.7%	2 66.7%	5 55.6%	2 22.2%	5 55.6%	19 47.5%
Male	1 33.3%	3 75%	1 33.3%	1 33.3%	4 44.4%	7 77.8%	4 44.4%	21 52.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	1 25%	0 0%	0 0%	0 0%	1 11.1%	0 0%	2 5%
Not Hispanic or Latino	3 100%	3 75%	3 100%	3 100%	9 100%	8 88.9%	9 100%	38 95%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	1 33.3%	0 0%	0 0%	0 0%	0 0%	1 2.5%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%	0 0%	0 0%	1 11.1%	0 0%	1 2.5%
White	3 100%	4 100%	2 66.7%	3 100%	5 55.6%	8 88.9%	8 88.9%	33 82.5%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	4 44.4%	0 0%	1 11.1%	5 12.5%

Outcome Measures

1. Primary Outcome

Title	Phase 1: Recommended Phase 2 Dose (RP2D) of Eribulin Mesilate in Combination With Irinotecan Hydrochloride
Description	The RP2D was evaluated based on a review of the outcomes of safety (including dose limiting toxicities [DLTs]), tumor assessments, and pharmacokinetic (PK) in Phase 1 by investigators and the study team.
Time Frame	First dose of study drug up to Cycle 1 (Cycle length=21 days)

Outcome Measure Data

Analysis Population Description

The Dose Evaluable Set (DES) for Phase 1 included all the participants who completed Cycle 1 treatment and were evaluated for DLTs and those who discontinued treatment during Cycle 1 due to DLTs.

Arm/Group Title	Phase 1: All Participants
Arm/Group Description	All participants received eribulin mesilate 1.4 mg/m^2 intravenous infusion on Days 1 and 8 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 21-day treatment cycle until disease progression, development of intolerable toxicity or withdrawal of consent.
Measure Participants	12
Eribulin Mesilate	1.4
Irinotecan Hydrochloride	40

2. Primary Outcome

Title	Phase 2: Objective Response Rate (ORR)
Description	ORR was defined as the percentage of participants achieving 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 defined as 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.
Time Frame	From date of first dose of study drug until disease progression, development of unacceptable toxicity, withdrawal of consent, or up to approximately 2 years 4 months

Outcome Measure Data

Analysis Population Description

Full analysis set included all participants who received at least 1 dose of either study drug.

Arm/Group Title	Phase 2: RMS Cohort, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2	Phase 2: NRSTS Cohort, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2	Phase 2: EWS Cohort, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2
Arm/Group Description	Participants with RMS received eribulin mesilate 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 every 21 days treatment cycle until disease progression, development of intolerable toxicity or withdrawal of consent.	Participants with NRSTS received eribulin mesilate 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 every 21 days treatment cycle until disease progression, development of unacceptable toxicity or withdrawal of consent.	Participants with EWS received eribulin mesilate 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 every 21 days treatment cycle until disease progression, development of unacceptable toxicity or withdrawal of consent.
Measure Participants	9	9	9
Number (90% Confidence Interval) [percentage of participants]	11.1 (0.6) 370%	11.1 (0.6) 277.5%	11.1 (0.6) 370%

3. Secondary Outcome

Title	Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
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 participant administered a drug; it does not necessarily have to have a causal relationship with this treatment.
Time Frame	From first dose of study drug up to approximately 2 years 4 months

Outcome Measure Data

Analysis Population Description

Safety analysis set included all participants who received at least 1 dose of either study drug.

Arm/Group Title	Phase 1: Schedule A, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 20 mg/m^2	Phase 1: Schedule A, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2	Phase 1: Schedule B, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 100 mg/m^2	Phase 1: Schedule B, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 125 mg/m^2	Phase 2: RMS Cohort, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2	Phase 2: NRSTS Cohort, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2	Phase 2: EWS Cohort, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2
Arm/Group Description	Participants received eribulin mesilate 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 every 21 days treatment cycle until disease progression, development of intolerable toxicity or withdrawal of consent.	Participants received eribulin mesilate 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 every 21 days treatment cycle until disease progression, development of intolerable toxicity or withdrawal of consent.	Participants received eribulin mesilate 1.4 mg/m^2 and irinotecan hydrochloride 100 mg/m^2 intravenous infusion on Days 1 and 8 in every 21 days treatment cycle until disease progression, development of intolerable toxicity or withdrawal of consent.	Participants received eribulin mesilate 1.4 mg/m^2 and irinotecan hydrochloride 125 mg/m^2 intravenous infusion on Days 1 and 8 in every 21 days treatment cycle until disease progression, development of intolerable toxicity or withdrawal of consent.	Participants with RMS received eribulin mesilate 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 every 21 days treatment cycle until disease progression, development of intolerable toxicity or withdrawal of consent.	Participants with NRSTS received eribulin mesilate 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 every 21 days treatment cycle until disease progression, development of unacceptable toxicity or withdrawal of consent.	Participants with EWS received eribulin mesilate 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 every 21 days treatment cycle until disease progression, development of unacceptable toxicity or withdrawal of consent.
Measure Participants	3	4	3	3	9	9	9
Count of Participants [Participants]	3 100%	4 100%	3 100%	3 100%	9 100%	9 100%	9 100%

4. Secondary Outcome

Title	Number of Participants With Serious Adverse Event (SAE)
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.
Time Frame	Up to approximately 2 years and 4 months

Outcome Measure Data

Analysis Population Description

Safety analysis set included all participants who received at least 1 dose of either study drug.

Arm/Group Title	Phase 1: Schedule A, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 20 mg/m^2	Phase 1: Schedule A, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2	Phase 1: Schedule B, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 100 mg/m^2	Phase 1: Schedule B, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 125 mg/m^2	Phase 2: RMS Cohort, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2	Phase 2: NRSTS Cohort, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2	Phase 2: EWS Cohort, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2
Arm/Group Description	Participants received eribulin mesilate 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 every 21 days treatment cycle until disease progression, development of intolerable toxicity or withdrawal of consent.	Participants received eribulin mesilate 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 every 21 days treatment cycle until disease progression, development of intolerable toxicity or withdrawal of consent.	Participants received eribulin mesilate 1.4 mg/m^2 and irinotecan hydrochloride 100 mg/m^2 intravenous infusion on Days 1 and 8 in every 21 days treatment cycle until disease progression, development of intolerable toxicity or withdrawal of consent.	Participants received eribulin mesilate 1.4 mg/m^2 and irinotecan hydrochloride 125 mg/m^2 intravenous infusion on Days 1 and 8 in every 21 days treatment cycle until disease progression, development of intolerable toxicity or withdrawal of consent.	Participants with RMS received eribulin mesilate 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 every 21 days treatment cycle until disease progression, development of intolerable toxicity or withdrawal of consent.	Participants with NRSTS received eribulin mesilate 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 every 21 days treatment cycle until disease progression, development of unacceptable toxicity or withdrawal of consent.	Participants with EWS received eribulin mesilate 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 every 21 days treatment cycle until disease progression, development of unacceptable toxicity or withdrawal of consent.
Measure Participants	3	4	3	3	9	9	9
Count of Participants [Participants]	1 33.3%	3 75%	0 0%	1 33.3%	5 55.6%	4 44.4%	3 33.3%

5. Secondary Outcome

Title	Phase 1, Cmax: Maximum Observed Plasma Concentration of Eribulin, Irinotecan and Its Active Metabolite SN-38
Time Frame	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)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Phase 1: Schedule A, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 20 mg/m^2	Phase 1: Schedule A, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2	Phase 1: Schedule B, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 100 mg/m^2	Phase 1: Schedule B, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 125 mg/m^2
Arm/Group Description	Participants received eribulin mesilate 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 every 21 days treatment cycle until disease progression, development of intolerable toxicity or withdrawal of consent.	Participants received eribulin mesilate 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 every 21 days treatment cycle until disease progression, development of intolerable toxicity or withdrawal of consent.	Participants received eribulin mesilate 1.4 mg/m^2 and irinotecan hydrochloride 100 mg/m^2 intravenous infusion on Days 1 and 8 in every 21 days treatment cycle until disease progression, development of intolerable toxicity or withdrawal of consent.	Participants received eribulin mesilate 1.4 mg/m^2 and irinotecan hydrochloride 125 mg/m^2 intravenous infusion on Days 1 and 8 in every 21 days treatment cycle until disease progression, development of intolerable toxicity or withdrawal of consent.
Measure Participants	3	4	3	3
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)

6. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Phase 1: Schedule A, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 20 mg/m^2	Phase 1: Schedule A, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2	Phase 1: Schedule B, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 100 mg/m^2	Phase 1: Schedule B, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 125 mg/m^2
Arm/Group Description	Participants received eribulin mesilate 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 every 21 days treatment cycle until disease progression, development of intolerable toxicity or withdrawal of consent.	Participants received eribulin mesilate 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 every 21 days treatment cycle until disease progression, development of intolerable toxicity or withdrawal of consent.	Participants received eribulin mesilate 1.4 mg/m^2 and irinotecan hydrochloride 100 mg/m^2 intravenous infusion on Days 1 and 8 in every 21 days treatment cycle until disease progression, development of intolerable toxicity or withdrawal of consent.	Participants received eribulin mesilate 1.4 mg/m^2 and irinotecan hydrochloride 125 mg/m^2 intravenous infusion on Days 1 and 8 in every 21 days treatment cycle until disease progression, development of intolerable toxicity or withdrawal of consent.
Measure Participants	3	4	3	3
Eribulin	0.080 (0.03)	0.135 (0.03)	0.080 (0)	0.050 (0.01)
Irinotecan	0.250 (0.07)	0.305 (0)	0.300 (0.03)	0.170 (0.13)
Active Metabolite SN-38	0.420 (0.25)	0.305 (0)	0.330 (0.3)	0.250 (0.13)

7. Secondary Outcome

Title	Phase 1, T1/2: Half-life of Eribulin, Irinotecan and Its Active Metabolite SN-38
Description	Half-life for irinotecan and metabolite SN-38 could not be estimated for phase 1:schedule A, eribulin mesilate 1.4 mg/m^2 + irinotecan 20 mg/m^2 and phase 1: schedule A, eribulin mesilate 1.4 mg/m^2 + irinotecan 40 mg/m^2 arm as the slope of the terminal phase of the concentration-time profiles could not be determined.
Time Frame	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)

Outcome Measure Data

Analysis Population Description

PK analysis set included participants who had documented dosing history and at least one post-dosing quantifiable drug concentration. Here 'N' (overall number of participants analyzed) included all participants who were evaluable for this outcome measure and 'n' (number analyzed) included all participants who were evaluable for each category.

Arm/Group Title	Phase 1: Schedule A, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 20 mg/m^2	Phase 1: Schedule A, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2	Phase 1: Schedule B, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 100 mg/m^2	Phase 1: Schedule B, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 125 mg/m^2
Arm/Group Description	Participants received eribulin mesilate 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 every 21 days treatment cycle until disease progression, development of intolerable toxicity or withdrawal of consent.	Participants received eribulin mesilate 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 every 21 days treatment cycle until disease progression, development of intolerable toxicity or withdrawal of consent.	Participants received eribulin mesilate 1.4 mg/m^2 and irinotecan hydrochloride 100 mg/m^2 intravenous infusion on Days 1 and 8 in every 21 days treatment cycle until disease progression, development of intolerable toxicity or withdrawal of consent.	Participants received eribulin mesilate 1.4 mg/m^2 and irinotecan hydrochloride 125 mg/m^2 intravenous infusion on Days 1 and 8 in every 21 days treatment cycle until disease progression, development of intolerable toxicity or withdrawal of consent.
Measure Participants	3	3	3	2
Eribulin	27.50	34.70	30.00	25.30
Irinotecan	5.140	4.430
Metabolite SN-38	12.000	10.390

8. Secondary Outcome

Title	Phase 1, Total Clearance (CL) of Eribulin and Irinotecan
Description	CL for irinotecan could not be estimated for phase 1:schedule A, eribulin mesilate 1.4 mg/m^2 + irinotecan 20 mg/m^2 and phase 1: schedule A, eribulin mesilate 1.4 mg/m^2 + irinotecan 40 mg/m^2 arm because it was not possible to calculate half-life as the slope of the terminal phase of the concentration-time profiles could not be determined.
Time Frame	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)

Outcome Measure Data

Analysis Population Description

PK analysis set included participants who had documented dosing history and at least one post-dosing quantifiable drug concentration. Here 'N' (overall number of participants analyzed) included all participants who were evaluable for this outcome measure and 'n' (number analyzed) included all participants who were evaluable for each category.

Arm/Group Title	Phase 1: Schedule A, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 20 mg/m^2	Phase 1: Schedule A, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2	Phase 1: Schedule B, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 100 mg/m^2	Phase 1: Schedule B, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 125 mg/m^2
Arm/Group Description	Participants received eribulin mesilate 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 every 21 days treatment cycle until disease progression, development of intolerable toxicity or withdrawal of consent.	Participants received eribulin mesilate 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 every 21 days treatment cycle until disease progression, development of intolerable toxicity or withdrawal of consent.	Participants received eribulin mesilate 1.4 mg/m^2 and irinotecan hydrochloride 100 mg/m^2 intravenous infusion on Days 1 and 8 in every 21 days treatment cycle until disease progression, development of intolerable toxicity or withdrawal of consent.	Participants received eribulin mesilate 1.4 mg/m^2 and irinotecan hydrochloride 125 mg/m^2 intravenous infusion on Days 1 and 8 in every 21 days treatment cycle until disease progression, development of intolerable toxicity or withdrawal of consent.
Measure Participants	3	3	3	2
Eribulin	3.1781 (43.9)	2.4581 (8.0)	2.9060 (32.8)	1.7521 (136.6)
Irinotecan	27.27 (23.2)	30.30 (60.7)

9. Secondary Outcome

Title	Phase 1, Volume of Distribution (Vz) of Eribulin and Irinotecan
Description	Vz for irinotecan could not be estimated for phase 1: schedule A, eribulin mesilate 1.4 mg/m^2 + irinotecan 20 mg/m^2 and phase 1: schedule A, eribulin mesilate 1.4 mg/m^2 + irinotecan 40 mg/m^2 arm because it was not possible to calculate half-life as the slope of the terminal phase of the concentration-time profiles could not be determined.
Time Frame	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)

Outcome Measure Data

Analysis Population Description

PK analysis set included participants who had documented dosing history and at least one post-dosing quantifiable drug concentration. Here 'N' (overall number of participants analyzed) included all participants who were evaluable for this outcome measure and 'n' (number analyzed) included all participants who were evaluable for each category.

Arm/Group Title	Phase 1: Schedule A, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 20 mg/m^2	Phase 1: Schedule A, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2	Phase 1: Schedule B, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 100 mg/m^2	Phase 1: Schedule B, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 125 mg/m^2
Arm/Group Description	Participants received eribulin mesilate 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 every 21 days treatment cycle until disease progression, development of intolerable toxicity or withdrawal of consent.	Participants received eribulin mesilate 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 every 21 days treatment cycle until disease progression, development of intolerable toxicity or withdrawal of consent.	Participants received eribulin mesilate 1.4 mg/m^2 and irinotecan hydrochloride 100 mg/m^2 intravenous infusion on Days 1 and 8 in every 21 days treatment cycle until disease progression, development of intolerable toxicity or withdrawal of consent.	Participants received eribulin mesilate 1.4 mg/m^2 and irinotecan hydrochloride 125 mg/m^2 intravenous infusion on Days 1 and 8 in every 21 days treatment cycle until disease progression, development of intolerable toxicity or withdrawal of consent.
Measure Participants	3	3	3	2
Eribulin	124.70 (41.5)	126.96 (18.1)	130.78 (35.9)	63.35 (101.8)
Irinotecan	248.5 (16.1)	195.1 (69.0)

10. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Phase 1: Schedule A, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 20 mg/m^2	Phase 1: Schedule A, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2	Phase 1: Schedule B, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 100 mg/m^2	Phase 1: Schedule B, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 125 mg/m^2
Arm/Group Description	Participants received eribulin mesilate 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 every 21 days treatment cycle until disease progression, development of intolerable toxicity or withdrawal of consent.	Participants received eribulin mesilate 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 every 21 days treatment cycle until disease progression, development of intolerable toxicity or withdrawal of consent.	Participants received eribulin mesilate 1.4 mg/m^2 and irinotecan hydrochloride 100 mg/m^2 intravenous infusion on Days 1 and 8 in every 21 days treatment cycle until disease progression, development of intolerable toxicity or withdrawal of consent.	Participants received eribulin mesilate 1.4 mg/m^2 and irinotecan hydrochloride 125 mg/m^2 intravenous infusion on Days 1 and 8 in every 21 days treatment cycle until disease progression, development of intolerable toxicity or withdrawal of consent.
Measure Participants	3	4	3	3
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)

11. Secondary Outcome

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
Description	AUC(0-inf) for irinotecan and metabolite SN-38 could not be estimated for phase 1: schedule A, eribulin mesilate 1.4 mg/m^2 + irinotecan 20 mg/m^2 and phase 1: schedule A, eribulin mesilate 1.4 mg/m^2 + irinotecan 40 mg/m^2 arm because it was not possible to calculate half-life as the slope of the terminal phase of the concentration-time profiles could not be determined.
Time Frame	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)

Outcome Measure Data

Analysis Population Description

PK analysis set included participants who had documented dosing history and at least one post-dosing quantifiable drug concentration. Here 'N' (overall number of participants analyzed) included all participants who were evaluable for this outcome measure and 'n' (number analyzed) included all participants who were evaluable for each category.

Arm/Group Title	Phase 1: Schedule A, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 20 mg/m^2	Phase 1: Schedule A, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2	Phase 1: Schedule B, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 100 mg/m^2	Phase 1: Schedule B, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 125 mg/m^2
Arm/Group Description	Participants received eribulin mesilate 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 every 21 days treatment cycle until disease progression, development of intolerable toxicity or withdrawal of consent.	Participants received eribulin mesilate 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 every 21 days treatment cycle until disease progression, development of intolerable toxicity or withdrawal of consent.	Participants received eribulin mesilate 1.4 mg/m^2 and irinotecan hydrochloride 100 mg/m^2 intravenous infusion on Days 1 and 8 in every 21 days treatment cycle until disease progression, development of intolerable toxicity or withdrawal of consent.	Participants received eribulin mesilate 1.4 mg/m^2 and irinotecan hydrochloride 125 mg/m^2 intravenous infusion on Days 1 and 8 in every 21 days treatment cycle until disease progression, development of intolerable toxicity or withdrawal of consent.
Measure Participants	3	3	3	2
Eribulin	438.1 (39.0)	506.0 (16.6)	666.9 (69.0)	576.9 (133.6)
Irinotecan	5036.1 (70.9)	3698.5 (39.2)
Metabolite SN-38	169.0 (51.4)	149.4 (4.3)

12. Secondary Outcome

Title	Phase 2: Progression Free Survival (PFS)
Description	PFS was defined as the time from date of first dose to the date of disease progression (PD). PFS was assessed based on the investigators' assessments utilizing RECIST 1.1. PD was defined as at least 20% increase or 5 mm increase in the sum of diameters of target lesions recorded since the treatment started or the appearance of 1 or more new lesions. PFS was estimated and analyzed using Kaplan-Meier method.
Time Frame	From the date of first dose to the date of first documentation of PD, or date of death, whichever occurred first up to approximately 2 years 4 months

Outcome Measure Data

Analysis Population Description

Full analysis set included all participants who received at least 1 dose of either study drug.

Arm/Group Title	Phase 2: RMS Cohort, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2	Phase 2: NRSTS Cohort, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2	Phase 2: EWS Cohort, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2
Arm/Group Description	Participants with RMS received eribulin mesilate 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 every 21 days treatment cycle until disease progression, development of intolerable toxicity or withdrawal of consent.	Participants with NRSTS received eribulin mesilate 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 every 21 days treatment cycle until disease progression, development of unacceptable toxicity or withdrawal of consent.	Participants with EWS received eribulin mesilate 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 every 21 days treatment cycle until disease progression, development of unacceptable toxicity or withdrawal of consent.
Measure Participants	9	9	9
Median (90% Confidence Interval) [months]	2.69 (1.28)	1.35 (1.15)	6.70 (1.38)

13. Secondary Outcome

Title	Phase 2: Clinical Benefit Rate (CBR)
Description	CBR was defined as the percentage of participants with 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 defined as 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 defined as at least 30% decrease in the SOD of target lesions, taking as reference the baseline sum diameters.
Time Frame	From the date of first dose to the date of first documentation of PD, or date of death, whichever occurred first up to approximately 2 years 4 months

Outcome Measure Data

Analysis Population Description

Full analysis set included all participants who received at least 1 dose of either study drug.

Arm/Group Title	Phase 2: RMS Cohort, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2	Phase 2: NRSTS Cohort, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2	Phase 2: EWS Cohort, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2
Arm/Group Description	Participants with RMS received eribulin mesilate 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 every 21 days treatment cycle until disease progression, development of intolerable toxicity or withdrawal of consent.	Participants with NRSTS received eribulin mesilate 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 every 21 days treatment cycle until disease progression, development of unacceptable toxicity or withdrawal of consent.	Participants with EWS received eribulin mesilate 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 every 21 days treatment cycle until disease progression, development of unacceptable toxicity or withdrawal of consent.
Measure Participants	5	3	5
Number (90% Confidence Interval) [percentage of participants]	55.6 (25.1) 1853.3%	33.3 (9.8) 832.5%	55.6 (25.1) 1853.3%

14. Secondary Outcome

Title	Model Predicted Apparent Total Body Clearance (CL) of Eribulin
Description	Per the planned PK analysis, PK samples were collected and analyzed using a population PK approach to estimate PK parameters. Eribulin plasma concentration data from this study were pooled from studies (NCT00069264, NCT00069277, NCT00326950, NCT00706095, NCT01000376, NCT01106248, NCT02171260, NCT00413192, NCT01458249, NCT03441360 and NCT01327885), and a population PK model was applied to the pooled dataset. The data presented are the CL parameter estimates, with Measure Type "Number" defining the eribulin PK model. They are population PK model predictions and have been estimated using non-linear mixed effects model.
Time Frame	Cycle 1 Day 1: 0.5-120 hours after eribulin infusion; Cycle 1 Day 8: pre-dose and at the end of the eribulin infusion (cycle length=21 days)

Outcome Measure Data

Analysis Population Description

PK analysis set included all participants who had documented dosing history had at least one postdosing quantifiable drug concentration. Analysis population for this outcome measure included participants from current study E7389-G000-213 and from studies (NCT00069264,NCT00069277,NCT00326950,NCT00706095,NCT01000376,NCT01106248,NCT02171260, NCT00413192,NCT01458249,NCT03441360,NCT01327885)."Overall number of participants analyzed" signifies participants who were evaluable for this outcome measure.

Arm/Group Title	Eribulin Mesilate - All Participants
Arm/Group Description	All participants who received eribulin mesilate intravenous infusion over the dose range 0.25 to 4.0 mg/m^2 in current study (E7389-G000-213) and studies (NCT00069264, NCT00069277, NCT00326950, NCT00706095, NCT01000376, NCT01106248, NCT02171260, NCT00413192, NCT01458249, NCT03441360 and NCT01327885).
Measure Participants	561
Number (95% Confidence Interval) [L/hr]	2.89

15. Secondary Outcome

Title	Volume of Distribution Estimates From the Population PK Model for Eribulin
Description	Per the planned PK analysis, PK samples were collected and analyzed using a population PK approach to estimate PK parameters. Eribulin plasma concentration data from this study were pooled from studies (NCT00069264, NCT00069277, NCT00326950, NCT00706095, NCT01000376, NCT01106248, NCT02171260, NCT00413192, NCT01458249, NCT03441360 and NCT01327885), and a population PK model was applied to the pooled dataset. Data presented are the volume of distribution of the central compartment (V1), volume of distribution of the first peripheral compartment (V2), and volume of distribution of the second peripheral compartment (V3) parameter estimates with Measure Type "Number" defining the eribulin PK model. They are population PK model predictions and have been estimated using non-linear mixed effects model.
Time Frame	Cycle 1 Day 1: 0.5-120 hours after eribulin infusion; Cycle 1 Day 8: pre-dose and at the end of the eribulin infusion (cycle length=21 days)

Outcome Measure Data

Analysis Population Description

PK analysis set included all participants who had documented dosing history had at least one postdosing quantifiable drug concentration. Analysis population for this outcome measure included participants from current study E7389-G000-213 and from studies (NCT00069264,NCT00069277,NCT00326950,NCT00706095,NCT01000376,NCT01106248,NCT02171260, NCT00413192,NCT01458249,NCT03441360,NCT01327885)."Overall number of participants analyzed" signifies participants who were evaluable for this outcome measure.

Arm/Group Title	Eribulin Mesilate - All Participants
Arm/Group Description	All participants who received eribulin mesilate intravenous infusion over the dose range 0.25 to 4.0 mg/m^2 in current study (E7389-G000-213) and in studies (NCT00069264, NCT00069277, NCT00326950, NCT00706095, NCT01000376, NCT01106248, NCT02171260, NCT00413192, NCT01458249, NCT03441360 and NCT01327885).
Measure Participants	561
V1	4.08
V2	2.03
V3	106

Adverse Events

Time Frame	From first dose of study drug up to approximately 2 year 4 months
Arm/Group Title	Phase 1: Schedule A, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 20 mg/m^2		Phase 1: Schedule A, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2		Phase 1: Schedule B, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 100 mg/m^2		Phase 1: Schedule B, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 125 mg/m^2		Phase 2: RMS Cohort, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2		Phase 2: NRSTS Cohort, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2		Phase 2: EWS Cohort, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2
Arm/Group Description	Participants received eribulin mesilate 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 every 21 days treatment cycle until disease progression, development of intolerable toxicity or withdrawal of consent.		Participants received eribulin mesilate 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 every 21 days treatment cycle until disease progression, development of intolerable toxicity or withdrawal of consent.		Participants received eribulin mesilate 1.4 mg/m^2 and irinotecan hydrochloride 100 mg/m^2 intravenous infusion on Days 1 and 8 in every 21 days treatment cycle until disease progression, development of intolerable toxicity or withdrawal of consent.		Participants received eribulin mesilate 1.4 mg/m^2 and irinotecan hydrochloride 125 mg/m^2 intravenous infusion on Days 1 and 8 in every 21 days treatment cycle until disease progression, development of intolerable toxicity or withdrawal of consent.		Participants with RMS received eribulin mesilate 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 every 21 days treatment cycle until disease progression, development of intolerable toxicity or withdrawal of consent.		Participants with NRSTS received eribulin mesilate 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 every 21 days treatment cycle until disease progression, development of unacceptable toxicity or withdrawal of consent.		Participants with EWS received eribulin mesilate 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 every 21 days treatment cycle until disease progression, development of unacceptable toxicity or withdrawal of consent.
All Cause Mortality
	Phase 1: Schedule A, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 20 mg/m^2		Phase 1: Schedule A, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2		Phase 1: Schedule B, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 100 mg/m^2		Phase 1: Schedule B, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 125 mg/m^2		Phase 2: RMS Cohort, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2		Phase 2: NRSTS Cohort, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2		Phase 2: EWS Cohort, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/3 (33.3%)		2/4 (50%)		1/3 (33.3%)		1/3 (33.3%)		4/9 (44.4%)		3/9 (33.3%)		3/9 (33.3%)
Serious Adverse Events
	Phase 1: Schedule A, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 20 mg/m^2		Phase 1: Schedule A, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2		Phase 1: Schedule B, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 100 mg/m^2		Phase 1: Schedule B, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 125 mg/m^2		Phase 2: RMS Cohort, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2		Phase 2: NRSTS Cohort, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2		Phase 2: EWS Cohort, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/3 (33.3%)		3/4 (75%)		0/3 (0%)		1/3 (33.3%)		5/9 (55.6%)		4/9 (44.4%)		3/9 (33.3%)
Blood and lymphatic system disorders
Febrile neutropenia	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/9 (0%)	0	1/9 (11.1%)	1	1/9 (11.1%)	1
Gastrointestinal disorders
Abdominal pain	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/9 (11.1%)	1	0/9 (0%)	0	0/9 (0%)	0
General disorders
Pyrexia	1/3 (33.3%)	1	2/4 (50%)	2	0/3 (0%)	0	0/3 (0%)	0	1/9 (11.1%)	1	0/9 (0%)	0	0/9 (0%)	0
Infections and infestations
Bacteraemia	1/3 (33.3%)	1	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/9 (0%)	0	0/9 (0%)	0	0/9 (0%)	0
Device related infection	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/9 (11.1%)	1	0/9 (0%)	0	0/9 (0%)	0
Sepsis	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/9 (0%)	0	0/9 (0%)	0	1/9 (11.1%)	1
Upper respiratory tract infection	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/9 (11.1%)	1	0/9 (0%)	0	0/9 (0%)	0
Metabolism and nutrition disorders
Malnutrition	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/9 (0%)	0	1/9 (11.1%)	1	0/9 (0%)	0
Musculoskeletal and connective tissue disorders
Pain in jaw	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/9 (0%)	0	0/9 (0%)	0	1/9 (11.1%)	2
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Malignant neoplasm progression	0/3 (0%)	0	1/4 (25%)	1	0/3 (0%)	0	1/3 (33.3%)	1	1/9 (11.1%)	2	2/9 (22.2%)	2	0/9 (0%)	0
Malignant pleural effusion	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/9 (11.1%)	2	1/9 (11.1%)	1	0/9 (0%)	0
Respiratory, thoracic and mediastinal disorders
Dyspnoea	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/9 (11.1%)	1	0/9 (0%)	0	0/9 (0%)	0
Other (Not Including Serious) Adverse Events
	Phase 1: Schedule A, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 20 mg/m^2		Phase 1: Schedule A, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2		Phase 1: Schedule B, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 100 mg/m^2		Phase 1: Schedule B, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 125 mg/m^2		Phase 2: RMS Cohort, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2		Phase 2: NRSTS Cohort, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2		Phase 2: EWS Cohort, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/3 (100%)		4/4 (100%)		3/3 (100%)		3/3 (100%)		9/9 (100%)		9/9 (100%)		9/9 (100%)
Blood and lymphatic system disorders
Anaemia	2/3 (66.7%)	3	2/4 (50%)	14	1/3 (33.3%)	6	1/3 (33.3%)	1	3/9 (33.3%)	9	4/9 (44.4%)	8	5/9 (55.6%)	29
Leukopenia	1/3 (33.3%)	4	1/4 (25%)	14	2/3 (66.7%)	15	1/3 (33.3%)	12	0/9 (0%)	0	1/9 (11.1%)	1	3/9 (33.3%)	32
Lymphopenia	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	3	0/9 (0%)	0	0/9 (0%)	0	0/9 (0%)	0
Neutropenia	3/3 (100%)	39	2/4 (50%)	8	3/3 (100%)	18	1/3 (33.3%)	12	3/9 (33.3%)	15	2/9 (22.2%)	10	4/9 (44.4%)	52
Thrombocytopenia	0/3 (0%)	0	1/4 (25%)	1	1/3 (33.3%)	3	1/3 (33.3%)	1	0/9 (0%)	0	0/9 (0%)	0	5/9 (55.6%)	17
Leukocytosis	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/9 (11.1%)	1	0/9 (0%)	0	0/9 (0%)	0
Cardiac disorders
Tachycardia	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/9 (0%)	0	2/9 (22.2%)	2	0/9 (0%)	0
Ear and labyrinth disorders
Ear pain	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/9 (0%)	0	0/9 (0%)	0	1/9 (11.1%)	1
Gastrointestinal disorders
Abdominal pain	1/3 (33.3%)	1	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	7/9 (77.8%)	9	2/9 (22.2%)	3	2/9 (22.2%)	2
Abdominal pain upper	1/3 (33.3%)	1	0/4 (0%)	0	2/3 (66.7%)	2	0/3 (0%)	0	0/9 (0%)	0	1/9 (11.1%)	1	0/9 (0%)	0
Constipation	2/3 (66.7%)	3	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	2/9 (22.2%)	2	0/9 (0%)	0	2/9 (22.2%)	2
Diarrhoea	1/3 (33.3%)	1	1/4 (25%)	12	0/3 (0%)	0	0/3 (0%)	0	4/9 (44.4%)	24	5/9 (55.6%)	11	5/9 (55.6%)	9
Nausea	1/3 (33.3%)	2	1/4 (25%)	1	2/3 (66.7%)	2	0/3 (0%)	0	4/9 (44.4%)	5	6/9 (66.7%)	8	1/9 (11.1%)	1
Oral pain	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/9 (0%)	0	0/9 (0%)	0	0/9 (0%)	0
Toothache	1/3 (33.3%)	2	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/9 (11.1%)	1	0/9 (0%)	0	0/9 (0%)	0
Vomiting	0/3 (0%)	0	2/4 (50%)	2	3/3 (100%)	10	1/3 (33.3%)	3	6/9 (66.7%)	8	2/9 (22.2%)	2	1/9 (11.1%)	4
Abdominal distension	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/9 (11.1%)	2	0/9 (0%)	0	0/9 (0%)	0
Anal fissure	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/9 (0%)	0	1/9 (11.1%)	1	0/9 (0%)	0
Anal inflammation	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/9 (0%)	0	0/9 (0%)	0	1/9 (11.1%)	1
Aphthous ulcer	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/9 (0%)	0	1/9 (11.1%)	1	0/9 (0%)	0
Gingival pain	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/9 (11.1%)	1	1/9 (11.1%)	1	0/9 (0%)	0
Haematemesis	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/9 (11.1%)	1	0/9 (0%)	0	0/9 (0%)	0
Haematochezia	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/9 (0%)	0	0/9 (0%)	0	1/9 (11.1%)	1
Hypoaesthesia oral	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/9 (11.1%)	4	0/9 (0%)	0	0/9 (0%)	0
Mouth ulceration	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/9 (11.1%)	4	1/9 (11.1%)	1	0/9 (0%)	0
Odynophagia	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/9 (0%)	0	0/9 (0%)	0	1/9 (11.1%)	1
Proctalgia	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/9 (0%)	0	1/9 (11.1%)	1	0/9 (0%)	0
Stomatitis	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	2/9 (22.2%)	5	0/9 (0%)	0	1/9 (11.1%)	4
Tongue ulceration	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/9 (0%)	0	1/9 (11.1%)	1	0/9 (0%)	0
General disorders
Asthenia	0/3 (0%)	0	0/4 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	2/9 (22.2%)	2	3/9 (33.3%)	3	0/9 (0%)	0
Catheter site pain	1/3 (33.3%)	1	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/9 (0%)	0	0/9 (0%)	0	0/9 (0%)	0
Non-cardiac chest pain	1/3 (33.3%)	1	0/4 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/9 (0%)	0	0/9 (0%)	0	1/9 (11.1%)	2
Pyrexia	1/3 (33.3%)	1	0/4 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	1/9 (11.1%)	1	2/9 (22.2%)	3	5/9 (55.6%)	8
Catheter site pruritus	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/9 (11.1%)	1	0/9 (0%)	0	0/9 (0%)	0
Fatigue	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	2/9 (22.2%)	5	3/9 (33.3%)	3	2/9 (22.2%)	4
Gait disturbance	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/9 (0%)	0	0/9 (0%)	0	1/9 (11.1%)	1
Oedema peripheral	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/9 (0%)	0	1/9 (11.1%)	1	1/9 (11.1%)	1
Pain	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/9 (11.1%)	1	1/9 (11.1%)	2	1/9 (11.1%)	1
Infections and infestations
Conjunctivitis	0/3 (0%)	0	1/4 (25%)	1	0/3 (0%)	0	0/3 (0%)	0	0/9 (0%)	0	0/9 (0%)	0	0/9 (0%)	0
Rhinitis	1/3 (33.3%)	1	0/4 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	3/9 (33.3%)	3	0/9 (0%)	0	1/9 (11.1%)	2
Tonsillitis	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/9 (0%)	0	0/9 (0%)	0	0/9 (0%)	0
Vascular device infection	1/3 (33.3%)	1	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/9 (0%)	0	0/9 (0%)	0	0/9 (0%)	0
Bacterial infection	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/9 (11.1%)	1	0/9 (0%)	0	0/9 (0%)	0
COVID-19	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/9 (0%)	0	1/9 (11.1%)	1	0/9 (0%)	0
Device related infection	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/9 (11.1%)	1	0/9 (0%)	0	0/9 (0%)	0
Ear infection	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/9 (0%)	0	0/9 (0%)	0	1/9 (11.1%)	1
Herpes simplex	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/9 (11.1%)	1	0/9 (0%)	0	0/9 (0%)	0
Influenza	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/9 (0%)	0	1/9 (11.1%)	1	0/9 (0%)	0
Nasopharyngitis	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/9 (0%)	0	1/9 (11.1%)	1	0/9 (0%)	0
Oral candidiasis	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/9 (0%)	0	1/9 (11.1%)	1	1/9 (11.1%)	1
Pneumonia	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/9 (0%)	0	0/9 (0%)	0	1/9 (11.1%)	1
Respiratory tract infection	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/9 (0%)	0	0/9 (0%)	0	1/9 (11.1%)	1
Upper respiratory tract infection	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/9 (0%)	0	1/9 (11.1%)	1	0/9 (0%)	0
Urinary tract infection	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/9 (0%)	0	1/9 (11.1%)	1	0/9 (0%)	0
Injury, poisoning and procedural complications
Procedural nausea	1/3 (33.3%)	1	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/9 (11.1%)	1	0/9 (0%)	0	0/9 (0%)	0
Urostomy complication	0/3 (0%)	0	1/4 (25%)	1	0/3 (0%)	0	0/3 (0%)	0	0/9 (0%)	0	0/9 (0%)	0	0/9 (0%)	0
Contusion	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/9 (11.1%)	1	0/9 (0%)	0	0/9 (0%)	0
Fall	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/9 (0%)	0	0/9 (0%)	0	1/9 (11.1%)	1
Mouth injury	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/9 (11.1%)	1	0/9 (0%)	0	0/9 (0%)	0
Wound dehiscence	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/9 (11.1%)	2	0/9 (0%)	0	0/9 (0%)	0
Investigations
Alanine aminotransferase increased	0/3 (0%)	0	0/4 (0%)	0	1/3 (33.3%)	2	0/3 (0%)	0	1/9 (11.1%)	10	1/9 (11.1%)	2	2/9 (22.2%)	9
Aspartate aminotransferase increased	0/3 (0%)	0	1/4 (25%)	2	0/3 (0%)	0	0/3 (0%)	0	1/9 (11.1%)	4	0/9 (0%)	0	1/9 (11.1%)	5
C-reactive protein increased	0/3 (0%)	0	0/4 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	1/9 (11.1%)	1	0/9 (0%)	0	0/9 (0%)	0
Lymphocyte count decreased	0/3 (0%)	0	1/4 (25%)	1	0/3 (0%)	0	1/3 (33.3%)	1	1/9 (11.1%)	8	0/9 (0%)	0	2/9 (22.2%)	5
Neutrophil count decreased	0/3 (0%)	0	3/4 (75%)	8	0/3 (0%)	0	2/3 (66.7%)	7	6/9 (66.7%)	21	3/9 (33.3%)	22	5/9 (55.6%)	46
Weight decreased	0/3 (0%)	0	1/4 (25%)	1	1/3 (33.3%)	1	0/3 (0%)	0	2/9 (22.2%)	2	0/9 (0%)	0	1/9 (11.1%)	1
White blood cell count decreased	0/3 (0%)	0	3/4 (75%)	7	0/3 (0%)	0	1/3 (33.3%)	1	1/9 (11.1%)	20	1/9 (11.1%)	6	0/9 (0%)	0
Blood albumin decreased	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/9 (0%)	0	1/9 (11.1%)	1	0/9 (0%)	0
Blood calcium decreased	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/9 (11.1%)	1	0/9 (0%)	0	0/9 (0%)	0
Blood creatinine increased	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/9 (0%)	0	0/9 (0%)	0	1/9 (11.1%)	1
Blood phosphorus decreased	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/9 (11.1%)	1	0/9 (0%)	0	0/9 (0%)	0
Blood potassium decreased	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/9 (11.1%)	1	0/9 (0%)	0	0/9 (0%)	0
Blood sodium decreased	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/9 (0%)	0	1/9 (11.1%)	2	0/9 (0%)	0
Blood urea increased	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/9 (11.1%)	1	0/9 (0%)	0	0/9 (0%)	0
Electrocardiogram QT prolonged	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/9 (0%)	0	1/9 (11.1%)	2	1/9 (11.1%)	2
Gamma-glutamyltransferase increased	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/9 (0%)	0	0/9 (0%)	0	1/9 (11.1%)	1
Haematocrit decreased	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/9 (11.1%)	7	0/9 (0%)	0	0/9 (0%)	0
Metamyelocyte count increased	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/9 (11.1%)	1	0/9 (0%)	0	0/9 (0%)	0
Myelocyte count increased	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/9 (11.1%)	1	0/9 (0%)	0	0/9 (0%)	0
Red blood cell count decreased	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/9 (11.1%)	5	0/9 (0%)	0	0/9 (0%)	0
Metabolism and nutrition disorders
Decreased appetite	0/3 (0%)	0	1/4 (25%)	1	0/3 (0%)	0	0/3 (0%)	0	4/9 (44.4%)	5	3/9 (33.3%)	3	0/9 (0%)	0
Hypophosphataemia	1/3 (33.3%)	1	0/4 (0%)	0	1/3 (33.3%)	2	0/3 (0%)	0	0/9 (0%)	0	0/9 (0%)	0	1/9 (11.1%)	3
Vitamin D deficiency	0/3 (0%)	0	0/4 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/9 (0%)	0	0/9 (0%)	0	0/9 (0%)	0
Hypokalaemia	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	2/9 (22.2%)	7	0/9 (0%)	0	2/9 (22.2%)	10
Hypomagnesaemia	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/9 (11.1%)	2	1/9 (11.1%)	1	0/9 (0%)	0
Refeeding syndrome	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/9 (0%)	0	1/9 (11.1%)	1	0/9 (0%)	0
Musculoskeletal and connective tissue disorders
Back pain	0/3 (0%)	0	0/4 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	1/9 (11.1%)	1	2/9 (22.2%)	4	0/9 (0%)	0
Bone pain	0/3 (0%)	0	0/4 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/9 (0%)	0	0/9 (0%)	0	3/9 (33.3%)	3
Muscle spasms	0/3 (0%)	0	0/4 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	2/9 (22.2%)	2	0/9 (0%)	0	0/9 (0%)	0
Musculoskeletal chest pain	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/9 (0%)	0	0/9 (0%)	0	2/9 (22.2%)	2
Spinal pain	0/3 (0%)	0	0/4 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	1/9 (11.1%)	1	0/9 (0%)	0	0/9 (0%)	0
Arthralgia	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/9 (11.1%)	2	2/9 (22.2%)	5	2/9 (22.2%)	5
Groin pain	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/9 (0%)	0	1/9 (11.1%)	2	0/9 (0%)	0
Neck pain	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/9 (0%)	0	0/9 (0%)	0	1/9 (11.1%)	1
Pain in extremity	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/9 (11.1%)	1	2/9 (22.2%)	3	1/9 (11.1%)	4
Pain in jaw	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/9 (11.1%)	4	0/9 (0%)	0	1/9 (11.1%)	3
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cancer pain	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/9 (11.1%)	1	0/9 (0%)	0	0/9 (0%)	0
Tumour pain	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/9 (11.1%)	1	0/9 (0%)	0	0/9 (0%)	0
Nervous system disorders
Headache	1/3 (33.3%)	1	0/4 (0%)	0	1/3 (33.3%)	1	1/3 (33.3%)	1	4/9 (44.4%)	6	0/9 (0%)	0	1/9 (11.1%)	2
Paraesthesia	0/3 (0%)	0	1/4 (25%)	1	0/3 (0%)	0	0/3 (0%)	0	0/9 (0%)	0	0/9 (0%)	0	0/9 (0%)	0
Neuralgia	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/9 (0%)	0	0/9 (0%)	0	1/9 (11.1%)	1
Peripheral sensorimotor neuropathy	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/9 (11.1%)	1	0/9 (0%)	0	1/9 (11.1%)	3
Peripheral sensory neuropathy	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/9 (0%)	0	1/9 (11.1%)	4	1/9 (11.1%)	1
Syncope	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/9 (11.1%)	1	0/9 (0%)	0	0/9 (0%)	0
Psychiatric disorders
Insomnia	0/3 (0%)	0	1/4 (25%)	3	0/3 (0%)	0	0/3 (0%)	0	1/9 (11.1%)	1	1/9 (11.1%)	1	1/9 (11.1%)	1
Agitation	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/9 (0%)	0	1/9 (11.1%)	1	0/9 (0%)	0
Anxiety	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/9 (11.1%)	1	0/9 (0%)	0	0/9 (0%)	0
Depressed mood	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/9 (11.1%)	8	0/9 (0%)	0	0/9 (0%)	0
Negative thoughts	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/9 (11.1%)	1	0/9 (0%)	0	0/9 (0%)	0
Tearfulness	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/9 (11.1%)	3	0/9 (0%)	0	0/9 (0%)	0
Renal and urinary disorders
Acute kidney injury	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/9 (0%)	0	0/9 (0%)	0	1/9 (11.1%)	1
Haematuria	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/9 (11.1%)	1	1/9 (11.1%)	1	1/9 (11.1%)	3
Urinary tract pain	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/9 (11.1%)	1	0/9 (0%)	0	0/9 (0%)	0
Respiratory, thoracic and mediastinal disorders
Cough	1/3 (33.3%)	1	0/4 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	2/9 (22.2%)	3	0/9 (0%)	0	1/9 (11.1%)	1
Hypoxia	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/9 (0%)	0	0/9 (0%)	0	0/9 (0%)	0
Pleuritic pain	0/3 (0%)	0	1/4 (25%)	1	0/3 (0%)	0	0/3 (0%)	0	0/9 (0%)	0	0/9 (0%)	0	1/9 (11.1%)	1
Respiratory distress	0/3 (0%)	0	1/4 (25%)	1	0/3 (0%)	0	0/3 (0%)	0	0/9 (0%)	0	0/9 (0%)	0	0/9 (0%)	0
Allergic cough	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/9 (0%)	0	1/9 (11.1%)	1	0/9 (0%)	0
Dyspnoea	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/9 (11.1%)	1	0/9 (0%)	0	0/9 (0%)	0
Epistaxis	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	2/9 (22.2%)	2	1/9 (11.1%)	2	0/9 (0%)	0
Haemoptysis	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/9 (11.1%)	1	0/9 (0%)	0	0/9 (0%)	0
Laryngeal inflammation	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/9 (11.1%)	1	0/9 (0%)	0	0/9 (0%)	0
Oropharyngeal pain	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	2/9 (22.2%)	3	0/9 (0%)	0	0/9 (0%)	0
Pneumothorax	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/9 (0%)	0	1/9 (11.1%)	1	1/9 (11.1%)	1
Pulmonary embolism	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/9 (0%)	0	1/9 (11.1%)	1	0/9 (0%)	0
Rhinorrhoea	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/9 (11.1%)	1	0/9 (0%)	0	0/9 (0%)	0
Skin and subcutaneous tissue disorders
Alopecia	1/3 (33.3%)	1	0/4 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	2/9 (22.2%)	3	0/9 (0%)	0	0/9 (0%)	0
Dermatitis	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/9 (0%)	0	0/9 (0%)	0	1/9 (11.1%)	1
Dry skin	0/3 (0%)	0	0/4 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/9 (0%)	0	0/9 (0%)	0	0/9 (0%)	0
Rash	1/3 (33.3%)	1	0/4 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	1/9 (11.1%)	1	0/9 (0%)	0	0/9 (0%)	0
Skin oedema	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/9 (0%)	0	0/9 (0%)	0	0/9 (0%)	0
Leukonychia	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/9 (11.1%)	1	0/9 (0%)	0	0/9 (0%)	0
Palmar-plantar erythrodysaesthesia syndrome	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/9 (0%)	0	1/9 (11.1%)	1	0/9 (0%)	0
Papule	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/9 (11.1%)	1	0/9 (0%)	0	0/9 (0%)	0
Pruritus	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/9 (0%)	0	0/9 (0%)	0	2/9 (22.2%)	2

Limitations/Caveats

[Not Specified]

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.