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Clinical Trial Results:
A Phase III Open Label, Randomized Two-Parallel-Arm Multicenter Study of E7389 versus Capecitabine in subjects with Locally Advanced or Metastatic Breast Cancer Previously Treated with Anthracyclines and Taxanes

Summary
EudraCT number
 2005-004009-26
Trial protocol
 HU   BE   CZ   LT   DE   FR   IT   GR   BG   ES  
Global end of trial date
11 Dec 2017

Results information
Results version number
 v2(current)
This version publication date
13 Jun 2020
First version publication date
20 Feb 2019
Other versions
 v1
Version creation reason
  • New data added to full data set
Results were initially posted at primary completion date cut-off. Updated version includes new data added to full data set at study completion date.

Trial information

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Trial identification
Sponsor protocol code
E7389-G000-301
Additional study identifiers
ISRCTN number
 -
US NCT number
 NCT00337103
WHO universal trial number (UTN)
 -
Sponsors
Sponsor organisation name
Eisai Inc.
Sponsor organisation address
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
Paediatric regulatory details
Is trial part of an agreed paediatric investigation plan (PIP)
No
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
No
Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
No
Results analysis stage
Analysis stage
Interim
Date of interim/final analysis
12 Mar 2012
Is this the analysis of the primary completion data?
Yes
Primary completion date
12 Mar 2012
Global end of trial reached?
Yes
Global end of trial date
11 Dec 2017
Was the trial ended prematurely?
No
General information about the trial
Main objective of the trial
To compare the efficacy of E7389 versus capecitabine monotherapy, in terms of overall survival (OS) and progression-free survival (PFS) in subjetcs with locally advanced or metastatic breast cancer.
Protection of trial subjects
This study was conducted in accordance with standard operating procedures (SOPs) of the sponsor (or designee), which are designed to ensure adherence to Good Clinical Practice (GCP) guidelines as required by the following: - Principles of the World Medical Association Declaration of Helsinki (World Medical Association, 2008) - 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 for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use - Title 21 of the United States (US) Code of Federal Regulations (US 21 CFR) regarding clinical studies, including Part 50 and Part 56 concerning informed subject consent and Institutional Review Board (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 suspected unexpected serious adverse reactions were reported, as required, to the Competent Authorities of all involved EU member states. - Article 14, Paragraph 3, and Article 80-2 of the Pharmaceutical Affairs Law (Law No. 145, 1960) for studies conducted in Japan, in addition to Japan’s GCP Subject Information and Informed Consent.
Background therapy
 -
Evidence for comparator
 -
Actual start date of recruitment
20 Sep 2006
Long term follow-up planned
Yes
Long term follow-up rationale
 Safety
Long term follow-up duration
 3 Months
Independent data monitoring committee (IDMC) involvement?
Yes
Population of trial subjects
Number of subjects enrolled per country
Country: Number of subjects enrolled
South Africa: 12
Country: Number of subjects enrolled
Spain: 63
Country: Number of subjects enrolled
Taiwan: 19
Country: Number of subjects enrolled
Ukraine: 122
Country: Number of subjects enrolled
United States: 62
Country: Number of subjects enrolled
Argentina: 67
Country: Number of subjects enrolled
Australia: 14
Country: Number of subjects enrolled
Belgium: 42
Country: Number of subjects enrolled
Brazil: 120
Country: Number of subjects enrolled
Bulgaria: 15
Country: Number of subjects enrolled
Canada: 25
Country: Number of subjects enrolled
Croatia: 9
Country: Number of subjects enrolled
Czech Republic: 23
Country: Number of subjects enrolled
France: 8
Country: Number of subjects enrolled
Germany: 2
Country: Number of subjects enrolled
Greece: 3
Country: Number of subjects enrolled
Hungary: 42
Country: Number of subjects enrolled
Israel: 17
Country: Number of subjects enrolled
Italy: 8
Country: Number of subjects enrolled
Lithuania: 6
Country: Number of subjects enrolled
Mexico: 22
Country: Number of subjects enrolled
Poland: 41
Country: Number of subjects enrolled
Romania: 34
Country: Number of subjects enrolled
Russian Federation: 300
Country: Number of subjects enrolled
Serbia: 20
Country: Number of subjects enrolled
Singapore: 6
Worldwide total number of subjects
1102
EEA total number of subjects
296
Number of subjects enrolled per age group
In utero
0
Preterm newborn - gestational age
0
Newborns (0-27 days)
0
Infants and toddlers (28 days-23 months)
0
Children (2-11 years)
0
Adolescents (12-17 years)
0
Adults (18-64 years)
944
From 65 to 84 years
158
85 years and over
0

Subject disposition

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Recruitment
Recruitment details
 Subjects took part in the study at 210 sites across geographic regions (6 regions: North America, Western Europe, Eastern Europe, Latin America, South Africa and Asia) from 01 Apr 2006 to 12 Mar 2012.

Pre-assignment
Screening details
 A total of 1276 participants were enrolled and screened, of which 174 were screen failures and 1102 were randomized in the study. Of the randomized participants, 1090 participants received the study treatment.

Period 1
Period 1 title
Overall study (overall period)
Is this the baseline period?
 Yes
Allocation method
Randomised - controlled
Blinding used
 Not blinded

Arms
Are arms mutually exclusive
Yes

Arm title
 Eribulin Mesylate 1.4 mg/m^2
Arm description
 Eribulin mesylate 1.4 milligram per square meter (mg/m^2) intravenous (IV) infusion given over 2-5 minutes on Days 1 and 8 every 21 days.
Arm type
 Experimental

Investigational medicinal product name
Eribulin Mesylate
Investigational medicinal product code
E7389
Other name
Halaven
Pharmaceutical forms
Infusion
Routes of administration
Intravascular use
Dosage and administration details
Eribulin mesylate 1.4 mg/m^2 IV infusion given over 2-5 minutes on Days 1 and 8 every 21 days.

Arm title
 Capecitabine 2.5 g/m^2/Day
Arm description
 Capecitabine : Capecitabine 2.5 gram per square meter (g/m^2) per (/) day administered orally twice daily in two equal doses on Days 1 to 14 every 21 days.
Arm type
 Active comparator

Investigational medicinal product name
Capecitabine
Investigational medicinal product code
Other name
Pharmaceutical forms
Film-coated tablet
Routes of administration
Oral use
Dosage and administration details
Capecitabine 2.5 g/m^2/day administered orally twice daily in two equal doses on Days 1 to 14 every 21 days.

Number of subjects in period 1
Eribulin Mesylate 1.4 mg/m^2 Capecitabine 2.5 g/m^2/Day
Started
554
548
Treated (Safety Population)
544
546
Completed
0
0
Not completed
554
548
     Death
1
-
     Physician decision
15
14
     Not specified
5
6
     Subject Choice
34
27
     Entry Criteria Not Met
4
1
     Adverse event, non-fatal
45
59
     Progressive Disease
414
410
     Consent withdrawn by subject
8
5
     Lost to follow-up
1
2
     Clinical Progression
27
24

Baseline characteristics

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Baseline characteristics reporting groups
Reporting group title
Eribulin Mesylate 1.4 mg/m^2
Reporting group description
 Eribulin mesylate 1.4 milligram per square meter (mg/m^2) intravenous (IV) infusion given over 2-5 minutes on Days 1 and 8 every 21 days.

Reporting group title
Capecitabine 2.5 g/m^2/Day
Reporting group description
 Capecitabine : Capecitabine 2.5 gram per square meter (g/m^2) per (/) day administered orally twice daily in two equal doses on Days 1 to 14 every 21 days.

Reporting group values
 Eribulin Mesylate 1.4 mg/m^2 Capecitabine 2.5 g/m^2/Day Total
Number of subjects
 554 548 1102
Age categorical
Units: Subjects
Age continuous
Units: years
    arithmetic mean (standard deviation)
 53.8 ± 10.37 52.8 ± 10.20 -
Gender categorical
Units: Subjects
    Female
 554 548 1102
    Male
 0 0 0
Race
Units: Subjects
    American Indian or Alaska Native
 0 0 0
    Asian
 18 18 36
    Native Hawaiian or Other Pacific Islander
 0 0 0
    Black or African American
 15 16 31
    White
 496 495 991
    More than one race
 0 0 0
    Unknown or Not Reported
 25 19 44

End points

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End points reporting groups
Reporting group title
Eribulin Mesylate 1.4 mg/m^2
Reporting group description
 Eribulin mesylate 1.4 milligram per square meter (mg/m^2) intravenous (IV) infusion given over 2-5 minutes on Days 1 and 8 every 21 days.

Reporting group title
Capecitabine 2.5 g/m^2/Day
Reporting group description
 Capecitabine : Capecitabine 2.5 gram per square meter (g/m^2) per (/) day administered orally twice daily in two equal doses on Days 1 to 14 every 21 days.

Primary: Overall Survival (OS)

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End point title
 Overall Survival (OS) [1]
End point description
OS was measured from the date of randomization until the date of death from any cause, or the last date the subject was known to be alive. Subjects who were lost to follow-up or who were alive at the date of data cutoff were censored. The censoring rules for OS were as follows: 1) if the subject was still alive at data cutoff, the date of data cutoff was considered the end date, and 2) if the subject was lost to follow-up before data cutoff, the date they were last known to be alive was considered the end date. Subjects who survived past the end of the study were counted as in the full study period. If death occurred after data cutoff, the end date was to be censored at the time of data cutoff. Data was analyzed using the Intent-to-Treat (ITT) Population defined as all subject who were randomized.
End point type
Primary
End point timeframe
From date of randomization until date of death from any cause, assessed up to data cutoff date of 12 Mar 2012, or up to approximately 6 years
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 analysed for this endpoint.
End point values
 Eribulin Mesylate 1.4 mg/m^2 Capecitabine 2.5 g/m^2/Day
Number of subjects analysed
554
548
Units: Days
    median (confidence interval 95%)
484 (462 to 536)
440 (400 to 487)
No statistical analyses for this end point

Primary: Progression Free Survival (PFS)

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End point title
 Progression Free Survival (PFS) [2]
End point description
PFS was defined as the time (in days) from the date of randomization to the date of the first sign of disease progression based on Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1 (v 1.1) or date of death, regardless of cause. Disease progression was measured by computed tomography (CT) and magnetic resonance imaging (MRI) performed on lesions targeted at baseline for tumor assessment. Disease progression (as assessed by independent review of the imaging scans) per RECIST v 1.1 was defined as at least a 20% increase in the sum of the diameters of the target lesions (taking as reference the smallest sum on study, including the baseline sum if that is the smallest), and an absolute increase of at least 5 millimeter (mm). Note that the appearance of one or more new lesions was also considered as disease progression. Data was analyzed using the ITT Population defined as all subject who were randomized.
End point type
Primary
End point timeframe
From date of randomization to the date of disease progression or death (whichever occurred first), assessed up to data cutoff date of 12 Mar 2012 or up to approximately 6 years
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 analysed for this endpoint.
End point values
 Eribulin Mesylate 1.4 mg/m^2 Capecitabine 2.5 g/m^2/Day
Number of subjects analysed
554
548
Units: Days
    median (confidence interval 95%)
126 (106 to 131)
129 (120 to 147)
No statistical analyses for this end point

Secondary: Change From Baseline in Global Health Status/Quality of Life (QoL) Measured by European Organization for the Treatment of Cancer Quality of Life Core Questionnaire Scores Based on Core 30 Items (EORTC-QLQ-C30) at Week 6

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End point title
 Change From Baseline in Global Health Status/Quality of Life (QoL) Measured by European Organization for the Treatment of Cancer Quality of Life Core Questionnaire Scores Based on Core 30 Items (EORTC-QLQ-C30) at Week 6
End point description
EORTCQLQ-C30:cancer-specific instrument with 30 questions to assess the subject QoL. First 28 questions used to evaluate 5 functional scales(physical, role, cognitive, emotional, social),3 symptom scales(fatigue, nausea and vomiting, pain)and single items(dysponea, appetite loss, insomnia, constipation, diarrhea, financial difficulties).Each of these 28 questions assessed on 4-point scale(1=not at all, 2=a little, 3=quite a bit, 4=very much);functional scales: higher score=better level of functioning; symptom scale: higher score=more severe symptoms; for single items: higher score=more severe problem. Last 2 questions used to evaluate global health status(GHS)/QoL. Each question was assessed on 7-point scale(1=very poor to 7=excellent). Scores averaged, transformed to 0-100 scale; higher score=better quality of life/better level of functioning. ITT Population: subjects who were randomized. Here, overall number of subjects analyzed are those who were evaluable for this outcome measure.
End point type
Secondary
End point timeframe
Baseline and Week 6
End point values
 Eribulin Mesylate 1.4 mg/m^2 Capecitabine 2.5 g/m^2/Day
Number of subjects analysed
438
406
Units: units on a scale
    arithmetic mean (standard deviation)
0.1 ± 19.23
1.7 ± 20.69
No statistical analyses for this end point

Secondary: Change From Baseline in European Organization for the Treatment of Cancer Quality of Life Core Questionnaire Scores Based on Breast Cancer Specific 23 Items (EORTC-QLQ- BR 23) at Week 6

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End point title
 Change From Baseline in European Organization for the Treatment of Cancer Quality of Life Core Questionnaire Scores Based on Breast Cancer Specific 23 Items (EORTC-QLQ- BR 23) at Week 6
End point description
EORTC-QLQ-BR23:disease-specific module for breast cancer developed as a supplement for the EORTC-QLQ-C30 to assess quality of life of participants with breast cancer. The scores from 23 items of QLQ-BR23 included functional scales (body image, sexual functioning, sexual enjoyment, future perspective), symptom scales (systemic therapy side effects, breast symptoms, arm symptoms, upset by hair loss). Each item was rated on a scale of 1 to 4 to record level of intensity (1= not at all, 2= a little, 3= quite a bit, 4= very much) within each scales. Scores averaged and transformed to 0-100 scale. High score indicated high/better level of functioning/healthy functioning. Negative change from Baseline indicated deterioration in QOL and positive change from Baseline indicated an improvement in QOL. ITT Population: all subjects who were randomized. Here, “number analyzed” signifies the subjects who were evaluable for this outcome measure for individual row.
End point type
Secondary
End point timeframe
Baseline and Week 6
End point values
 Eribulin Mesylate 1.4 mg/m^2 Capecitabine 2.5 g/m^2/Day
Number of subjects analysed
554
548
Units: units on a scale
arithmetic mean (standard deviation)
    Body Image: (n=441, 411)
0.7 ± 21.26
4.8 ± 21.80
    Sexual functioning: (n=418, 381)
1.2 ± 14.75
-0.1 ± 16.62
    Sexual enjoyment: (n=82, 96)
0.8 ± 21.58
3.1 ± 17.49
    Future perspective: (n=439, 410)
7.7 ± 28.48
10.0 ± 30.84
    Systemic therapy side effects: (n=440, 415)
4.5 ± 15.55
-1.2 ± 14.73
    Breast Symptoms: (n=434, 407)
-3.4 ± 16.55
-3.6 ± 16.20
    Arm Symptoms: (n=437, 411)
-4.2 ± 17.94
-3.4 ± 18.65
    Upset by hair loss: (n=91, 56)
-4.4 ± 32.66
-10.1 ± 29.76
No statistical analyses for this end point

Secondary: Objective Response Rate (ORR): Independent Review

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End point title
 Objective Response Rate (ORR): Independent Review
End point description
ORR was defined as the percentage of subjects with a best overall response of complete response (CR) or partial response (PR) based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (v 1.1). CR is defined as disappearance of all target legions and non-target lesions. All pathological lymph nodes (whether target and non-target), must have reduction in their short axis to less than 10 mm. PR is defined as at least 30% decrease in the sum of the long diameter LD (hereafter referred to as sum of LD) of all target lesions, as compared with Baseline summed LD.
End point type
Secondary
End point timeframe
From date of randomization until date of first documentation of CR or PR, assessed up to data cutoff date of 12 Mar 2012 or up to approximately 6 years
End point values
 Eribulin Mesylate 1.4 mg/m^2 Capecitabine 2.5 g/m^2/Day
Number of subjects analysed
554
548
Units: percentage of subjects
    number (confidence interval 90%)
11.0 (8.5 to 13.9)
11.5 (8.9 to 14.5)
No statistical analyses for this end point

Secondary: Duration of Response (DOR): Independent Review

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End point title
 Duration of Response (DOR): Independent Review
End point description
DOR was defined as the time from first documented CR or PR until disease progression or death from any cause for those subjects with a confirmed PR or CR measured by RECIST v1.1. CR defined as disappearance of all target and non-target lesions . All pathological lymph nodes(whether target and non-target), must have reduction in their short axis to less than 10 mm. PR defined as at least 30% decrease in the sum of the long diameter LD (hereafter referred to as sum of LD) of all target lesions, as compared with Baseline summed LD. Data was analyzed using for a subset of subjects in the ITT Population who had a response. Here, “overall number of subjects analyzed” are the subjects who were evaluable for this outcome measure.
End point type
Secondary
End point timeframe
From first documented CR or PR until date of recurrent or progressive disease or death, assessed up to data cutoff date of 12 Mar 2012 or up to approximately 6 years
End point values
 Eribulin Mesylate 1.4 mg/m^2 Capecitabine 2.5 g/m^2/Day
Number of subjects analysed
61
63
Units: days
    median (confidence interval 95%)
198 (150 to 273)
330 (208 to 541)
No statistical analyses for this end point

Secondary: Overall Survival Rate

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End point title
 Overall Survival Rate
End point description
One-, two-, and three- year’s survival rates were defined as the percentage of subjects who were alive at one, two, and three years respectively, and estimated using the Kaplan−Meier method and Greenwood Formula. ITT population included all subjects who were randomized.
End point type
Secondary
End point timeframe
From the date of randomization to Year 1, 2 and 3
End point values
 Eribulin Mesylate 1.4 mg/m^2 Capecitabine 2.5 g/m^2/Day
Number of subjects analysed
554
548
Units: percentage of subjects
number (confidence interval 95%)
    At 1-year
0.644 (0.604 to 0.684)
0.580 (0.538 to 0.622)
    At 2-years
0.328 (0.289 to 0.368)
0.298 (0.259 to 0.337)
    At 3-years
0.178 (0.144 to 0.212)
0.145 (0.113 to 0.177)
No statistical analyses for this end point

Secondary: Change From Baseline in Pain Intensity by Visual Analog Scale (VAS) until 30 Days after the Last Dose of Study Drug

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End point title
 Change From Baseline in Pain Intensity by Visual Analog Scale (VAS) until 30 Days after the Last Dose of Study Drug
End point description
Pain intensity was measured by marking a single vertical line that crosses a 1-100 mm unmarked VAS scale. The left-end of the visual analog scale was labelled “least possible pain” and the right-end of the visual analog scale was labelled “worst possible pain”. The pain rating ranged from 0 to 100, with a higher score indicating more pain. A negative change score indicated improvement. ITT Population included all subjects who were randomized. Here, “overall number of subjects analyzed” are the subjects who were evaluable for the outcome measure.
End point type
Secondary
End point timeframe
First dose of study drug (Baseline) up to 30 days after last dose of study drug (up to approximately 6 years 3 months)
End point values
 Eribulin Mesylate 1.4 mg/m^2 Capecitabine 2.5 g/m^2/Day
Number of subjects analysed
431
431
Units: units on a scale
    arithmetic mean (standard deviation)
-3.7 ± 22.80
0.4 ± 22.90
No statistical analyses for this end point

Secondary: Number of Subjects With Consumption of Analgesics During the Study

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End point title
 Number of Subjects With Consumption of Analgesics During the Study
End point description
Subjects took analgesics as concomitant pain medications which are defined as pain medications that (1) started before the first dose of study drug and were continuing at the time of the first dose of study drug, or (2) started on/after the day of the first dose of study drug up to 30 days after the last dose of study drug medication.Safety population included all subjects who received at least one dose of study treatment.
End point type
Secondary
End point timeframe
First dose of study drug (Baseline) up to 30 days after last dose of study drug (up to approximately 6 years 3 months)
End point values
 Eribulin Mesylate 1.4 mg/m^2 Capecitabine 2.5 g/m^2/Day
Number of subjects analysed
544
546
Units: subjects
222
196
No statistical analyses for this end point

Secondary: Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)

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End point title
 Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
End point description
Safety population defined as all subjects who received at least one dose of study treatment. TEAEs included both SAEs as well as non-SAEs.
End point type
Secondary
End point timeframe
First dose of study drug (Baseline) up to 30 days after last dose of study drug (up to approximately 6 years 3 months)
End point values
 Eribulin Mesylate 1.4 mg/m^2 Capecitabine 2.5 g/m^2/Day
Number of subjects analysed
544
546
Units: subjects
    TEAEs
512
494
    SAEs
95
115
No statistical analyses for this end point

Secondary: Number of Subjects With Treatment-emergent Markedly Abnormal Parameter Values

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End point title
 Number of Subjects With Treatment-emergent Markedly Abnormal Parameter Values
End point description
Safety population defined as all subjects who received at least one dose of study treatment.
End point type
Secondary
End point timeframe
First dose of study drug (Baseline) up to 30 days after last dose of study drug (up to approximately 6 years 3 months)
End point values
 Eribulin Mesylate 1.4 mg/m^2 Capecitabine 2.5 g/m^2/Day
Number of subjects analysed
544
546
Units: subjects
362
224
No statistical analyses for this end point

Secondary: Number of Subjects Who Took at Least One Concomitant Medication

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End point title
 Number of Subjects Who Took at Least One Concomitant Medication
End point description
Concomitant medications included medications that either (1) started before the first dose of study drug and were continuing at the time of the first dose of study drug, or (2) started on or after the first dose of study drug up to 30 days after the last dose of study drug. Safety population included all subjects who received at least one dose of study treatment.
End point type
Secondary
End point timeframe
First dose of study drug (Baseline) up to 30 days after last dose of study drug (up to approximately 6 years 3 months)
End point values
 Eribulin Mesylate 1.4 mg/m^2 Capecitabine 2.5 g/m^2/Day
Number of subjects analysed
544
546
Units: subjects
496
483
No statistical analyses for this end point

Secondary: Duration of Eribulin mesylate Exposure

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End point title
 Duration of Eribulin mesylate Exposure
End point description
Data have been reported per primary analysis completion stage and final analysis completion stage. After primary analysis completion (at cutoff date of 12 March 2012), only 10 subjects were still receiving study treatment.
End point type
Secondary
End point timeframe
Up to approximately 6 years for primary analysis completion stage, Up to approximately 6 years 2 months for final analysis completion stage
End point values
 Eribulin Mesylate 1.4 mg/m^2 Capecitabine 2.5 g/m^2/Day
Number of subjects analysed
554
548
Units: days
median (full range (min-max))
    At primary analysis completion stage (n= 544, 546)
125.0 (21 to 1372)
119.0 (21 to 1442)
    At final analysis completion stage (n=5, 5)
1743.0 (1561 to 2219)
1506.0 (1175 to 2296)
No statistical analyses for this end point

Secondary: Plasma Concentrations of Eribulin mesylate

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End point title
 Plasma Concentrations of Eribulin mesylate [3]
End point description
Pharmacokinetic (PK) analysis set included all subjects who have received at least one dose of E7389 and have at least one quantifiable E7389 concentration. Here, “number analyzed” signifies the subjects who were evaluable for this outcome measure for given time points.
End point type
Secondary
End point timeframe
Cycle 1 Day 1: 5-10 minutes(min), 15-30 min, 30-60 min, 60-90 min, 2-4 hours(hrs), 4-8 hrs, 10-24 hrs, 48-72 hrs, 72-96 hrs, 96-120 hrs after the start of infusion of Eribulin mesylate (Duration of each cycle is 21 days)
Notes
[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: Only descriptive data was planned to be analysed for this endpoint.
End point values
 Eribulin Mesylate 1.4 mg/m^2
Number of subjects analysed
173
Units: nanogram per milliliter (ng/mL)
arithmetic mean (standard deviation)
    5-10 minutes (n=172)
415.8 ± 719.5
    15-30 minutes (n=57)
152.6 ± 70.51
    30-60 minutes (n=58)
95.5 ± 87.90
    60-90 minutes (n=58)
52.7 ± 79.33
    2-4 hours (n=85)
20.7 ± 32.81
    4-8 hours (n=78)
10.0 ± 5.40
    10-24 hours (n=44)
5.8 ± 3.72
    48-72 hours (n=40)
3.7 ± 2.58
    72-96 hours (n=37)
2.4 ± 1.60
    96-120 hours (n=41)
7.6 ± 38.75
No statistical analyses for this end point

Adverse events

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Adverse events information
Timeframe for reporting adverse events
First dose of study drug (Baseline) up to 30 days after last dose of study drug (up to approximately 6 years 3 months)
Adverse event reporting additional description
Data was analyzed using Safety Population defined as all subjects who received at least one dose of study treatment.
Assessment type
 Systematic
Dictionary used for adverse event reporting
Dictionary name
 MedDRA
Dictionary version
14.1
Reporting groups
Reporting group title
Eribulin Mesylate 1.4 mg/m^2
Reporting group description
 Eribulin mesylate 1.4 mg/m^2 IV infusion given over 2-5 minutes on Days 1 and 8 every 21 days.

Reporting group title
Capecitabine 2.5 g/m^2/Day
Reporting group description
 Capecitabine : Capecitabine 2.5 g/m^2/day administered orally twice daily in two equal doses on Days 1 to 14 every 21 days.

Serious adverse events
 Eribulin Mesylate 1.4 mg/m^2 Capecitabine 2.5 g/m^2/Day
Total subjects affected by serious adverse events
     subjects affected / exposed
95 / 544 (17.46%)
115 / 546 (21.06%)
     number of deaths (all causes)
442
459
     number of deaths resulting from adverse events
26
36
Vascular disorders
Deep Vein Thrombosis
     subjects affected / exposed
2 / 544 (0.37%)
3 / 546 (0.55%)
     occurrences causally related to treatment / all
0 / 2
1 / 3
     deaths causally related to treatment / all
0 / 0
0 / 0
Hypertension
     subjects affected / exposed
0 / 544 (0.00%)
1 / 546 (0.18%)
     occurrences causally related to treatment / all
0 / 0
1 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
Hypotension
     subjects affected / exposed
1 / 544 (0.18%)
1 / 546 (0.18%)
     occurrences causally related to treatment / all
0 / 1
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
Shock haemorrhagic
     subjects affected / exposed
0 / 544 (0.00%)
1 / 546 (0.18%)
     occurrences causally related to treatment / all
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 1
Thrombophlebitis
     subjects affected / exposed
1 / 544 (0.18%)
0 / 546 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Thrombosis
     subjects affected / exposed
0 / 544 (0.00%)
1 / 546 (0.18%)
     occurrences causally related to treatment / all
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
Haemorrhage
     subjects affected / exposed
0 / 544 (0.00%)
1 / 546 (0.18%)
     occurrences causally related to treatment / all
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
Surgical and medical procedures
Malignant Breast Lump Removal
     subjects affected / exposed
0 / 544 (0.00%)
1 / 546 (0.18%)
     occurrences causally related to treatment / all
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Malignant Ascites
     subjects affected / exposed
0 / 544 (0.00%)
1 / 546 (0.18%)
     occurrences causally related to treatment / all
0 / 0
0 / 2
     deaths causally related to treatment / all
0 / 0
0 / 0
Malignant Pleural Effusion
     subjects affected / exposed
0 / 544 (0.00%)
1 / 546 (0.18%)
     occurrences causally related to treatment / all
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
Metastases to Central Nervous System
     subjects affected / exposed
0 / 544 (0.00%)
1 / 546 (0.18%)
     occurrences causally related to treatment / all
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
Metastases to Liver
     subjects affected / exposed
1 / 544 (0.18%)
1 / 546 (0.18%)
     occurrences causally related to treatment / all
0 / 1
0 / 1
     deaths causally related to treatment / all
0 / 1
0 / 1
Metastases to Meninges
     subjects affected / exposed
1 / 544 (0.18%)
0 / 546 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Metastases to Ovary
     subjects affected / exposed
1 / 544 (0.18%)
0 / 546 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Metastases to Peritoneum
     subjects affected / exposed
1 / 544 (0.18%)
0 / 546 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Metastases to Pleura
     subjects affected / exposed
0 / 544 (0.00%)
1 / 546 (0.18%)
     occurrences causally related to treatment / all
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
Neoplasm Malignant
     subjects affected / exposed
7 / 544 (1.29%)
4 / 546 (0.73%)
     occurrences causally related to treatment / all
0 / 8
0 / 4
     deaths causally related to treatment / all
0 / 6
0 / 4
Oncologic Complication
     subjects affected / exposed
0 / 544 (0.00%)
2 / 546 (0.37%)
     occurrences causally related to treatment / all
0 / 0
0 / 2
     deaths causally related to treatment / all
0 / 0
0 / 1
Rectal Cancer
     subjects affected / exposed
0 / 544 (0.00%)
1 / 546 (0.18%)
     occurrences causally related to treatment / all
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
Tumour Pain
     subjects affected / exposed
0 / 544 (0.00%)
2 / 546 (0.37%)
     occurrences causally related to treatment / all
0 / 0
0 / 2
     deaths causally related to treatment / all
0 / 0
0 / 0
Immune system disorders
Hypersensitivity
     subjects affected / exposed
1 / 544 (0.18%)
1 / 546 (0.18%)
     occurrences causally related to treatment / all
1 / 1
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
General disorders and administration site conditions
Asthenia
     subjects affected / exposed
3 / 544 (0.55%)
4 / 546 (0.73%)
     occurrences causally related to treatment / all
1 / 5
0 / 4
     deaths causally related to treatment / all
0 / 0
0 / 0
Death
     subjects affected / exposed
2 / 544 (0.37%)
2 / 546 (0.37%)
     occurrences causally related to treatment / all
1 / 2
0 / 2
     deaths causally related to treatment / all
1 / 2
0 / 2
Extravasation
     subjects affected / exposed
1 / 544 (0.18%)
0 / 546 (0.00%)
     occurrences causally related to treatment / all
1 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Fatigue
     subjects affected / exposed
3 / 544 (0.55%)
4 / 546 (0.73%)
     occurrences causally related to treatment / all
2 / 3
1 / 4
     deaths causally related to treatment / all
0 / 0
0 / 0
General Physical Health Deterioration
     subjects affected / exposed
2 / 544 (0.37%)
3 / 546 (0.55%)
     occurrences causally related to treatment / all
2 / 2
0 / 4
     deaths causally related to treatment / all
0 / 0
0 / 1
Generalized Oedema
     subjects affected / exposed
0 / 544 (0.00%)
1 / 546 (0.18%)
     occurrences causally related to treatment / all
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
Influenza Like Illness
     subjects affected / exposed
1 / 544 (0.18%)
0 / 546 (0.00%)
     occurrences causally related to treatment / all
1 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Injection Site Extravasation
     subjects affected / exposed
0 / 544 (0.00%)
1 / 546 (0.18%)
     occurrences causally related to treatment / all
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
Mucosal Inflammation
     subjects affected / exposed
0 / 544 (0.00%)
2 / 546 (0.37%)
     occurrences causally related to treatment / all
0 / 0
2 / 2
     deaths causally related to treatment / all
0 / 0
0 / 0
Multi-Organ Failure
     subjects affected / exposed
1 / 544 (0.18%)
2 / 546 (0.37%)
     occurrences causally related to treatment / all
0 / 1
0 / 2
     deaths causally related to treatment / all
0 / 1
0 / 2
Oedema peripheral
     subjects affected / exposed
0 / 544 (0.00%)
1 / 546 (0.18%)
     occurrences causally related to treatment / all
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
Pyrexia
     subjects affected / exposed
3 / 544 (0.55%)
5 / 546 (0.92%)
     occurrences causally related to treatment / all
1 / 3
3 / 5
     deaths causally related to treatment / all
0 / 0
0 / 0
Sudden Death
     subjects affected / exposed
1 / 544 (0.18%)
0 / 546 (0.00%)
     occurrences causally related to treatment / all
1 / 1
0 / 0
     deaths causally related to treatment / all
1 / 1
0 / 0
Psychiatric disorders
Confusional state
     subjects affected / exposed
2 / 544 (0.37%)
0 / 546 (0.00%)
     occurrences causally related to treatment / all
2 / 2
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Mental status changes
     subjects affected / exposed
2 / 544 (0.37%)
1 / 546 (0.18%)
     occurrences causally related to treatment / all
0 / 2
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
Reproductive system and breast disorders
Vaginal Haemorrhage
     subjects affected / exposed
0 / 544 (0.00%)
1 / 546 (0.18%)
     occurrences causally related to treatment / all
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
Injury, poisoning and procedural complications
Accidental Overdose
     subjects affected / exposed
1 / 544 (0.18%)
1 / 546 (0.18%)
     occurrences causally related to treatment / all
1 / 1
1 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
Femoral Neck Fracture
     subjects affected / exposed
1 / 544 (0.18%)
1 / 546 (0.18%)
     occurrences causally related to treatment / all
0 / 1
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
Femur Fracture
     subjects affected / exposed
1 / 544 (0.18%)
2 / 546 (0.37%)
     occurrences causally related to treatment / all
0 / 1
0 / 2
     deaths causally related to treatment / all
0 / 0
0 / 0
Hip Fracture
     subjects affected / exposed
1 / 544 (0.18%)
0 / 546 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Humerus Fracture
     subjects affected / exposed
1 / 544 (0.18%)
0 / 546 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Joint Dislocation
     subjects affected / exposed
0 / 544 (0.00%)
1 / 546 (0.18%)
     occurrences causally related to treatment / all
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
Lumbar Vertebral Fracture
     subjects affected / exposed
1 / 544 (0.18%)
0 / 546 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Investigations
Aspartate Aminotransferase Increased
     subjects affected / exposed
0 / 544 (0.00%)
1 / 546 (0.18%)
     occurrences causally related to treatment / all
0 / 0
1 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
Hemoglobin Decreased
     subjects affected / exposed
1 / 544 (0.18%)
0 / 546 (0.00%)
     occurrences causally related to treatment / all
1 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Hepatic Enzyme Increased
     subjects affected / exposed
0 / 544 (0.00%)
1 / 546 (0.18%)
     occurrences causally related to treatment / all
0 / 0
1 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
Troponin Increased
     subjects affected / exposed
0 / 544 (0.00%)
1 / 546 (0.18%)
     occurrences causally related to treatment / all
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
Cardiac disorders
Acute Myocardial Infarction
     subjects affected / exposed
0 / 544 (0.00%)
1 / 546 (0.18%)
     occurrences causally related to treatment / all
0 / 0
0 / 2
     deaths causally related to treatment / all
0 / 0
0 / 0
Angina Pectoris
     subjects affected / exposed
1 / 544 (0.18%)
0 / 546 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Bradycardia
     subjects affected / exposed
0 / 544 (0.00%)
1 / 546 (0.18%)
     occurrences causally related to treatment / all
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
Cardiac Failure
     subjects affected / exposed
0 / 544 (0.00%)
2 / 546 (0.37%)
     occurrences causally related to treatment / all
0 / 0
0 / 2
     deaths causally related to treatment / all
0 / 0
0 / 1
Cardiac Tamponade
     subjects affected / exposed
0 / 544 (0.00%)
1 / 546 (0.18%)
     occurrences causally related to treatment / all
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
Cardio-respiratory Arrest
     subjects affected / exposed
0 / 544 (0.00%)
1 / 546 (0.18%)
     occurrences causally related to treatment / all
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 1
Cardiogenic Shock
     subjects affected / exposed
0 / 544 (0.00%)
1 / 546 (0.18%)
     occurrences causally related to treatment / all
0 / 0
1 / 1
     deaths causally related to treatment / all
0 / 0
1 / 1
Cardiopulmonary Failure
     subjects affected / exposed
1 / 544 (0.18%)
1 / 546 (0.18%)
     occurrences causally related to treatment / all
0 / 1
0 / 1
     deaths causally related to treatment / all
0 / 1
0 / 1
Left Ventricular Dysfunction
     subjects affected / exposed
1 / 544 (0.18%)
0 / 546 (0.00%)
     occurrences causally related to treatment / all
1 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Myocardial Infarction
     subjects affected / exposed
1 / 544 (0.18%)
1 / 546 (0.18%)
     occurrences causally related to treatment / all
1 / 1
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
Pericardial Effusion
     subjects affected / exposed
1 / 544 (0.18%)
1 / 546 (0.18%)
     occurrences causally related to treatment / all
2 / 2
0 / 1
     deaths causally related to treatment / all
1 / 1
0 / 0
Tachycardia
     subjects affected / exposed
1 / 544 (0.18%)
0 / 546 (0.00%)
     occurrences causally related to treatment / all
1 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Respiratory, thoracic and mediastinal disorders
Acute Respiratory Failure
     subjects affected / exposed
1 / 544 (0.18%)
1 / 546 (0.18%)
     occurrences causally related to treatment / all
0 / 1
1 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
Cough
     subjects affected / exposed
0 / 544 (0.00%)
1 / 546 (0.18%)
     occurrences causally related to treatment / all
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
Dyspnoea
     subjects affected / exposed
13 / 544 (2.39%)
17 / 546 (3.11%)
     occurrences causally related to treatment / all
4 / 20
2 / 22
     deaths causally related to treatment / all
0 / 4
0 / 3
Dyspnoea exertional
     subjects affected / exposed
0 / 544 (0.00%)
1 / 546 (0.18%)
     occurrences causally related to treatment / all
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
Epistaxis
     subjects affected / exposed
1 / 544 (0.18%)
0 / 546 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Hydrothorax
     subjects affected / exposed
1 / 544 (0.18%)
2 / 546 (0.37%)
     occurrences causally related to treatment / all
0 / 1
0 / 2
     deaths causally related to treatment / all
0 / 0
0 / 0
Pleural Effusion
     subjects affected / exposed
2 / 544 (0.37%)
2 / 546 (0.37%)
     occurrences causally related to treatment / all
0 / 2
0 / 2
     deaths causally related to treatment / all
0 / 0
0 / 0
Pneumothorax
     subjects affected / exposed
0 / 544 (0.00%)
1 / 546 (0.18%)
     occurrences causally related to treatment / all
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
Pulmonary Embolism
     subjects affected / exposed
1 / 544 (0.18%)
3 / 546 (0.55%)
     occurrences causally related to treatment / all
0 / 1
1 / 3
     deaths causally related to treatment / all
0 / 0
0 / 0
Respiratory Distress
     subjects affected / exposed
0 / 544 (0.00%)
2 / 546 (0.37%)
     occurrences causally related to treatment / all
0 / 0
0 / 2
     deaths causally related to treatment / all
0 / 0
0 / 1
Respiratory Failure
     subjects affected / exposed
5 / 544 (0.92%)
7 / 546 (1.28%)
     occurrences causally related to treatment / all
0 / 8
0 / 9
     deaths causally related to treatment / all
0 / 4
0 / 5
Tracheal Stenosis
     subjects affected / exposed
1 / 544 (0.18%)
0 / 546 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Wheezing
     subjects affected / exposed
0 / 544 (0.00%)
1 / 546 (0.18%)
     occurrences causally related to treatment / all
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
Blood and lymphatic system disorders
Anaemia
     subjects affected / exposed
3 / 544 (0.55%)
0 / 546 (0.00%)
     occurrences causally related to treatment / all
2 / 3
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Febrile Neutropenia
     subjects affected / exposed
7 / 544 (1.29%)
4 / 546 (0.73%)
     occurrences causally related to treatment / all
7 / 8
4 / 4
     deaths causally related to treatment / all
0 / 0
0 / 0
Leukopenia
     subjects affected / exposed
4 / 544 (0.74%)
0 / 546 (0.00%)
     occurrences causally related to treatment / all
4 / 4
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Neutropenia
     subjects affected / exposed
10 / 544 (1.84%)
1 / 546 (0.18%)
     occurrences causally related to treatment / all
10 / 10
1 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
Pancytopenia
     subjects affected / exposed
1 / 544 (0.18%)
1 / 546 (0.18%)
     occurrences causally related to treatment / all
0 / 1
2 / 2
     deaths causally related to treatment / all
0 / 0
1 / 1
Thrombocytopenia
     subjects affected / exposed
0 / 544 (0.00%)
1 / 546 (0.18%)
     occurrences causally related to treatment / all
0 / 0
1 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
Nervous system disorders
Aphasia
     subjects affected / exposed
0 / 544 (0.00%)
1 / 546 (0.18%)
     occurrences causally related to treatment / all
0 / 0
0 / 2
     deaths causally related to treatment / all
0 / 0
0 / 1
Cerebellar Infarction
     subjects affected / exposed
0 / 544 (0.00%)
1 / 546 (0.18%)
     occurrences causally related to treatment / all
0 / 0
0 / 2
     deaths causally related to treatment / all
0 / 0
0 / 1
Cerebrovascular Accident
     subjects affected / exposed
2 / 544 (0.37%)
2 / 546 (0.37%)
     occurrences causally related to treatment / all
1 / 2
0 / 2
     deaths causally related to treatment / all
0 / 1
0 / 1
Coma Hepatic
     subjects affected / exposed
0 / 544 (0.00%)
1 / 546 (0.18%)
     occurrences causally related to treatment / all
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 1
Convulsion
     subjects affected / exposed
1 / 544 (0.18%)
2 / 546 (0.37%)
     occurrences causally related to treatment / all
1 / 1
0 / 2
     deaths causally related to treatment / all
0 / 0
0 / 1
Depressed Level of Consciousness
     subjects affected / exposed
0 / 544 (0.00%)
2 / 546 (0.37%)
     occurrences causally related to treatment / all
0 / 0
0 / 2
     deaths causally related to treatment / all
0 / 0
0 / 0
Dizziness
     subjects affected / exposed
1 / 544 (0.18%)
0 / 546 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Dysgeusia
     subjects affected / exposed
0 / 544 (0.00%)
1 / 546 (0.18%)
     occurrences causally related to treatment / all
0 / 0
1 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
Facial Paresis
     subjects affected / exposed
1 / 544 (0.18%)
0 / 546 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Headache
     subjects affected / exposed
2 / 544 (0.37%)
4 / 546 (0.73%)
     occurrences causally related to treatment / all
1 / 2
0 / 4
     deaths causally related to treatment / all
0 / 0
0 / 0
Intracranial Pressure Increased
     subjects affected / exposed
0 / 544 (0.00%)
1 / 546 (0.18%)
     occurrences causally related to treatment / all
0 / 0
0 / 2
     deaths causally related to treatment / all
0 / 0
0 / 1
Lethargy
     subjects affected / exposed
0 / 544 (0.00%)
1 / 546 (0.18%)
     occurrences causally related to treatment / all
0 / 0
0 / 2
     deaths causally related to treatment / all
0 / 0
0 / 0
Myoclonic Epilepsy
     subjects affected / exposed
1 / 544 (0.18%)
0 / 546 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Partial Seizures
     subjects affected / exposed
1 / 544 (0.18%)
0 / 546 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Peripheral Motor Neuropathy
     subjects affected / exposed
1 / 544 (0.18%)
0 / 546 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Peripheral Sensory Neuropathy
     subjects affected / exposed
1 / 544 (0.18%)
0 / 546 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Simple Partial Seizures
     subjects affected / exposed
0 / 544 (0.00%)
1 / 546 (0.18%)
     occurrences causally related to treatment / all
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
Somnolence
     subjects affected / exposed
0 / 544 (0.00%)
1 / 546 (0.18%)
     occurrences causally related to treatment / all
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
Spinal Cord Compression
     subjects affected / exposed
2 / 544 (0.37%)
2 / 546 (0.37%)
     occurrences causally related to treatment / all
0 / 2
0 / 2
     deaths causally related to treatment / all
0 / 0
0 / 0
Syncope
     subjects affected / exposed
1 / 544 (0.18%)
0 / 546 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Transient Ischaemic Attack
     subjects affected / exposed
1 / 544 (0.18%)
0 / 546 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Ear and labyrinth disorders
Vertigo
     subjects affected / exposed
1 / 544 (0.18%)
0 / 546 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Gastrointestinal disorders
Abdominal Pain
     subjects affected / exposed
2 / 544 (0.37%)
1 / 546 (0.18%)
     occurrences causally related to treatment / all
0 / 2
1 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
Constipation
     subjects affected / exposed
0 / 544 (0.00%)
1 / 546 (0.18%)
     occurrences causally related to treatment / all
0 / 0
1 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
Diarrhoea
     subjects affected / exposed
1 / 544 (0.18%)
15 / 546 (2.75%)
     occurrences causally related to treatment / all
1 / 1
14 / 15
     deaths causally related to treatment / all
0 / 0
0 / 0
Dysphagia
     subjects affected / exposed
0 / 544 (0.00%)
2 / 546 (0.37%)
     occurrences causally related to treatment / all
0 / 0
1 / 2
     deaths causally related to treatment / all
0 / 0
0 / 0
Gastrointestinal Haemorrhage
     subjects affected / exposed
1 / 544 (0.18%)
0 / 546 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Haemorrhoids
     subjects affected / exposed
1 / 544 (0.18%)
0 / 546 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Intestinal ischaemia
     subjects affected / exposed
1 / 544 (0.18%)
0 / 546 (0.00%)
     occurrences causally related to treatment / all
0 / 2
0 / 0
     deaths causally related to treatment / all
0 / 1
0 / 0
Nausea
     subjects affected / exposed
1 / 544 (0.18%)
7 / 546 (1.28%)
     occurrences causally related to treatment / all
0 / 1
8 / 8
     deaths causally related to treatment / all
0 / 0
0 / 0
Stomatitis
     subjects affected / exposed
1 / 544 (0.18%)
1 / 546 (0.18%)
     occurrences causally related to treatment / all
1 / 1
1 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
Vomiting
     subjects affected / exposed
2 / 544 (0.37%)
9 / 546 (1.65%)
     occurrences causally related to treatment / all
0 / 2
6 / 9
     deaths causally related to treatment / all
0 / 0
0 / 0
Haematochezia
     subjects affected / exposed
1 / 544 (0.18%)
0 / 546 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Haematemesis
     subjects affected / exposed
1 / 544 (0.18%)
0 / 546 (0.00%)
     occurrences causally related to treatment / all
1 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Intestinal obstruction
     subjects affected / exposed
1 / 544 (0.18%)
0 / 546 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Renal and urinary disorders
Haematuria
     subjects affected / exposed
0 / 544 (0.00%)
1 / 546 (0.18%)
     occurrences causally related to treatment / all
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
Hydronephrosis
     subjects affected / exposed
0 / 544 (0.00%)
1 / 546 (0.18%)
     occurrences causally related to treatment / all
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
Renal Failure
     subjects affected / exposed
1 / 544 (0.18%)
1 / 546 (0.18%)
     occurrences causally related to treatment / all
3 / 3
0 / 1
     deaths causally related to treatment / all
1 / 1
0 / 0
Renal Failure Acute
     subjects affected / exposed
1 / 544 (0.18%)
1 / 546 (0.18%)
     occurrences causally related to treatment / all
0 / 1
2 / 2
     deaths causally related to treatment / all
0 / 0
0 / 0
Hepatobiliary disorders
Cholelithiasis
     subjects affected / exposed
1 / 544 (0.18%)
0 / 546 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Hepatic Failure
     subjects affected / exposed
1 / 544 (0.18%)
1 / 546 (0.18%)
     occurrences causally related to treatment / all
1 / 1
0 / 2
     deaths causally related to treatment / all
0 / 0
0 / 1
Hepatitis Toxic
     subjects affected / exposed
1 / 544 (0.18%)
0 / 546 (0.00%)
     occurrences causally related to treatment / all
1 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Skin and subcutaneous tissue disorders
Palmar-Plantar Erythrodysaesthesia Syndrome
     subjects affected / exposed
0 / 544 (0.00%)
2 / 546 (0.37%)
     occurrences causally related to treatment / all
0 / 0
2 / 2
     deaths causally related to treatment / all
0 / 0
0 / 0
Musculoskeletal and connective tissue disorders
Arthralgia
     subjects affected / exposed
0 / 544 (0.00%)
1 / 546 (0.18%)
     occurrences causally related to treatment / all
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
Back Pain
     subjects affected / exposed
2 / 544 (0.37%)
0 / 546 (0.00%)
     occurrences causally related to treatment / all
0 / 2
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Bone Pain
     subjects affected / exposed
0 / 544 (0.00%)
1 / 546 (0.18%)
     occurrences causally related to treatment / all
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
Muscular Weakness
     subjects affected / exposed
1 / 544 (0.18%)
0 / 546 (0.00%)
     occurrences causally related to treatment / all
1 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Pathological Fracture
     subjects affected / exposed
1 / 544 (0.18%)
0 / 546 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Metabolism and nutrition disorders
Decreased Appetite
     subjects affected / exposed
1 / 544 (0.18%)
1 / 546 (0.18%)
     occurrences causally related to treatment / all
0 / 1
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
Dehydration
     subjects affected / exposed
1 / 544 (0.18%)
9 / 546 (1.65%)
     occurrences causally related to treatment / all
1 / 1
4 / 10
     deaths causally related to treatment / all
0 / 0
0 / 0
Electrolyte Imbalance
     subjects affected / exposed
0 / 544 (0.00%)
1 / 546 (0.18%)
     occurrences causally related to treatment / all
0 / 0
1 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
Hypercalcaemia
     subjects affected / exposed
1 / 544 (0.18%)
1 / 546 (0.18%)
     occurrences causally related to treatment / all
0 / 1
0 / 2
     deaths causally related to treatment / all
0 / 0
0 / 1
Hyperglycaemia
     subjects affected / exposed
1 / 544 (0.18%)
2 / 546 (0.37%)
     occurrences causally related to treatment / all
1 / 1
1 / 2
     deaths causally related to treatment / all
0 / 0
0 / 0
Hypokalaemia
     subjects affected / exposed
0 / 544 (0.00%)
1 / 546 (0.18%)
     occurrences causally related to treatment / all
0 / 0
1 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
Hyponatremia
     subjects affected / exposed
0 / 544 (0.00%)
1 / 546 (0.18%)
     occurrences causally related to treatment / all
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
Infections and infestations
Bronchitis
     subjects affected / exposed
0 / 544 (0.00%)
3 / 546 (0.55%)
     occurrences causally related to treatment / all
0 / 0
0 / 3
     deaths causally related to treatment / all
0 / 0
0 / 0
Bronchopneumonia
     subjects affected / exposed
1 / 544 (0.18%)
1 / 546 (0.18%)
     occurrences causally related to treatment / all
1 / 1
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
Cellulitis
     subjects affected / exposed
0 / 544 (0.00%)
2 / 546 (0.37%)
     occurrences causally related to treatment / all
0 / 0
1 / 2
     deaths causally related to treatment / all
0 / 0
0 / 0
Hepatitis C
     subjects affected / exposed
1 / 544 (0.18%)
0 / 546 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Lung Infection
     subjects affected / exposed
1 / 544 (0.18%)
0 / 546 (0.00%)
     occurrences causally related to treatment / all
1 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Pneumonia
     subjects affected / exposed
4 / 544 (0.74%)
4 / 546 (0.73%)
     occurrences causally related to treatment / all
1 / 4
3 / 5
     deaths causally related to treatment / all
0 / 0
1 / 1
Pneumonia Klebsiella
     subjects affected / exposed
1 / 544 (0.18%)
0 / 546 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Respiratory Tract Infection
     subjects affected / exposed
1 / 544 (0.18%)
0 / 546 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Sepsis
     subjects affected / exposed
2 / 544 (0.37%)
4 / 546 (0.73%)
     occurrences causally related to treatment / all
2 / 4
4 / 5
     deaths causally related to treatment / all
1 / 2
1 / 1
Soft Tissue Infection
     subjects affected / exposed
1 / 544 (0.18%)
0 / 546 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Staphylococcal Infection
     subjects affected / exposed
0 / 544 (0.00%)
1 / 546 (0.18%)
     occurrences causally related to treatment / all
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
Subcutaneous Abscess
     subjects affected / exposed
0 / 544 (0.00%)
1 / 546 (0.18%)
     occurrences causally related to treatment / all
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
Upper Respiratory Tract Infection
     subjects affected / exposed
1 / 544 (0.18%)
0 / 546 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Urinary Tract Infection
     subjects affected / exposed
1 / 544 (0.18%)
0 / 546 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Frequency threshold for reporting non-serious adverse events: 5%
Non-serious adverse events
 Eribulin Mesylate 1.4 mg/m^2 Capecitabine 2.5 g/m^2/Day
Total subjects affected by non serious adverse events
     subjects affected / exposed
509 / 544 (93.57%)
489 / 546 (89.56%)
Investigations
Alanine aminotransferase increased
     subjects affected / exposed
47 / 544 (8.64%)
23 / 546 (4.21%)
     occurrences all number
103
41
Aspartate aminotransferase increased
     subjects affected / exposed
43 / 544 (7.90%)
27 / 546 (4.95%)
     occurrences all number
113
49
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumour pain
     subjects affected / exposed
29 / 544 (5.33%)
22 / 546 (4.03%)
     occurrences all number
38
43
Respiratory, thoracic and mediastinal disorders
Cough
     subjects affected / exposed
45 / 544 (8.27%)
44 / 546 (8.06%)
     occurrences all number
56
61
Dyspnoea
     subjects affected / exposed
49 / 544 (9.01%)
51 / 546 (9.34%)
     occurrences all number
62
77
Blood and lymphatic system disorders
Anaemia
     subjects affected / exposed
102 / 544 (18.75%)
96 / 546 (17.58%)
     occurrences all number
237
194
Leukopenia
     subjects affected / exposed
171 / 544 (31.43%)
57 / 546 (10.44%)
     occurrences all number
537
170
Neutropenia
     subjects affected / exposed
292 / 544 (53.68%)
87 / 546 (15.93%)
     occurrences all number
914
211
Thrombocytopenia
     subjects affected / exposed
27 / 544 (4.96%)
29 / 546 (5.31%)
     occurrences all number
48
42
Nervous system disorders
Dizziness
     subjects affected / exposed
30 / 544 (5.51%)
29 / 546 (5.31%)
     occurrences all number
38
31
Headache
     subjects affected / exposed
67 / 544 (12.32%)
55 / 546 (10.07%)
     occurrences all number
133
94
Peripheral sensory neuropathy
     subjects affected / exposed
73 / 544 (13.42%)
38 / 546 (6.96%)
     occurrences all number
131
47
General disorders and administration site conditions
Asthenia
     subjects affected / exposed
83 / 544 (15.26%)
79 / 546 (14.47%)
     occurrences all number
165
113
Fatigue
     subjects affected / exposed
91 / 544 (16.73%)
82 / 546 (15.02%)
     occurrences all number
193
116
Mucosal inflammation
     subjects affected / exposed
26 / 544 (4.78%)
35 / 546 (6.41%)
     occurrences all number
37
60
Oedema peripheral
     subjects affected / exposed
35 / 544 (6.43%)
36 / 546 (6.59%)
     occurrences all number
42
41
Pyrexia
     subjects affected / exposed
67 / 544 (12.32%)
27 / 546 (4.95%)
     occurrences all number
124
33
Gastrointestinal disorders
Abdominal Pain
     subjects affected / exposed
32 / 544 (5.88%)
46 / 546 (8.42%)
     occurrences all number
51
68
Abdominal Pain Upper
     subjects affected / exposed
31 / 544 (5.70%)
39 / 546 (7.14%)
     occurrences all number
38
52
Constipation
     subjects affected / exposed
42 / 544 (7.72%)
46 / 546 (8.42%)
     occurrences all number
70
58
Diarrhoea
     subjects affected / exposed
77 / 544 (14.15%)
154 / 546 (28.21%)
     occurrences all number
124
363
Nausea
     subjects affected / exposed
121 / 544 (22.24%)
131 / 546 (23.99%)
     occurrences all number
259
226
Stomatitis
     subjects affected / exposed
27 / 544 (4.96%)
31 / 546 (5.68%)
     occurrences all number
38
42
Vomiting
     subjects affected / exposed
63 / 544 (11.58%)
89 / 546 (16.30%)
     occurrences all number
87
141
Hepatobiliary disorders
Hyperbilirubinaemia
     subjects affected / exposed
9 / 544 (1.65%)
38 / 546 (6.96%)
     occurrences all number
12
82
Skin and subcutaneous tissue disorders
Alopecia
     subjects affected / exposed
188 / 544 (34.56%)
22 / 546 (4.03%)
     occurrences all number
263
24
Palmar-plantar erythrodysaesthesia syndrome
     subjects affected / exposed
1 / 544 (0.18%)
244 / 546 (44.69%)
     occurrences all number
1
735
Musculoskeletal and connective tissue disorders
Arthralgia
     subjects affected / exposed
42 / 544 (7.72%)
31 / 546 (5.68%)
     occurrences all number
76
53
Back pain
     subjects affected / exposed
55 / 544 (10.11%)
43 / 546 (7.88%)
     occurrences all number
86
75
Bone pain
     subjects affected / exposed
50 / 544 (9.19%)
42 / 546 (7.69%)
     occurrences all number
94
75
Myalgia
     subjects affected / exposed
30 / 544 (5.51%)
8 / 546 (1.47%)
     occurrences all number
38
9
Pain in extremity
     subjects affected / exposed
47 / 544 (8.64%)
37 / 546 (6.78%)
     occurrences all number
91
68
Metabolism and nutrition disorders
Decreased appetite
     subjects affected / exposed
68 / 544 (12.50%)
80 / 546 (14.65%)
     occurrences all number
91
120
Infections and infestations
Urinary tract infection
     subjects affected / exposed
29 / 544 (5.33%)
26 / 546 (4.76%)
     occurrences all number
35
32

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Substantial protocol amendments (globally)
Were there any global substantial amendments to the protocol? Yes
Date
Amendment
14 Dec 2005
Amendment 01: The protocol was amended to update PFS from secondary objective to primary objective, pharmacogenomic analysis was deleted and Eastern Cooperative Oncology Group (ECOG) performance status was removed from symptom assessments and included as a separate assessment.
02 Mar 2006
Amendment 02: The protocol was amended to update number of subjects included in the PK analysis to include a minimum of 200 subjects, requirement for previous exposure to trastuzumab was modified to allow subjects to participate in the study without previous exposure to trastuzumab, confirmation of the frequency of additional bone scans, stability data for E7389, addition of more comprehensive information regarding bone marrow exposure in relation to exclusion criterion #4 and provisions under which the use of bisphosphonates was permitted during the study.
11 May 2006
Amendment 03: Storage conditions for E7389 were updated according to new stability data.
05 Dec 2006
Amendment 04: The protocol was amended to include all subjects, not just those subjects who had measurable lesions for imaging review process by independent review, eligibility criteria were changed to include a more complete representation of the breast cancer population, level of renal function was changed for greater than (>) 50 milliliter/minute creatinine clearance in order to administer the full 2.5 g/m2 starting dose of capecitabine, washout period was added for prior experimental treatments, removed restriction on subjects with prior high dose chemotherapy, added requirement for confirmation of stable brain metastases by scan at screening to ensure scan is available for independent review and allowed for continuation of treatment with E7389 for as long as subjects continue to experience clinical benefit.
31 Oct 2007
Amendment 05: The protocol was amendment to update The number of sites participating in the study was increased from 180 to 210. Storage conditions for E7389 were updated to reflect new stability data.
06 Mar 2008
Amendment 06: The protocol was amended to update title of the study to remove the requirement for subject’s tumors to be refractory to the most recent chemotherapy, eligibility for enrollment into the study was widened to comply with current medical practices in the use of capecitabine, allowed inclusion of subjects with ECOG performance status of up to 2 and complete response (CR) or partial response (PR) was to be assessed a minimum of 5 weeks after start of treatment with a subsequent PD without a confirmation of PR or CR at least 4 weeks later by follow-up scans, allowed investigator more discretion for dose reductions of capecitabine on the first instance of Grade 2 toxicity and specified requirements for bone lesion assessment to note the use of x-ray to confirm whether or not lesions are malignant. Complete response or PR was to be assessed a minimum of 5 weeks after start of treatment with a subsequent PD without a confirmation of PR or CR at least 4 weeks later by follow-up scans but having a subsequent PD assessment was considered SD for the best response. However, CR or PR assessed less than 5 weeks of start of treatment with a subsequent PD was considered PD for the best response.
03 Mar 2009
Amendment 07: The protocol was amended to update study timeline to change the date of the end of the study from 31 Mar 2010 to Apr 2012.
15 Sep 2014
Amendment 08: The protocol was amended to update that no further collection of survival follow-up data, quality of life data, pain intensity data, and images by the independent imaging vendor was deemed necessary for the study. 

Interruptions (globally)
Were there any global interruptions to the trial? No

Limitations and caveats
Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
None reported

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