Metastatic Breast Cancer
Conditions
Brief summary
The purpose of this study is to compare E7389 versus capecitabine in patients with locally advanced or metastatic breast cancer who are refractory to the most recent chemotherapy. This is an open-label, randomized, two-parallel arm study. Patients will be randomized to receive either E7389 or capecitabine on a one-to-one ratio.
Interventions
DRUGEribulin Mesylate
1.4 mg/m\^2 intravenous (IV) infusion given over 2-5 minutes on Days 1 and 8 every 21 days
DRUGCapecitabine
Capecitabine 2.5 g/m\^2/day administered orally twice daily in two equal doses on Days 1 to 14 every 21 days
Sponsors
Eisai Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Female patients with histologically or cytologically confirmed carcinoma of the breast. Every effort should be made to ensure that paraffin embedded tissue or slides from the diagnostic biopsy or surgical specimen are available for confirmation of diagnosis. 2. Patients with locally advanced or metastatic disease who have received up to three prior chemotherapy regimens, and no more than two prior regimens for advanced and/or metastatic disease. * Regimens must have included an anthracycline (e.g., doxorubicin, epirubicin) and a taxane (e.g., paclitaxel, docetaxel), either in combination or in separate regimens. * Patients with known human epidermal growth factor 2 (HER2/neu) over-expressing tumors may additionally have been treated with trastuzumab in centers where this treatment is available. * Patients with known estrogen and/or progesterone receptor-expressing tumors may have additionally been treated with hormonal therapy. 3. Resolution of all chemotherapy or radiation-related toxicities to Grade 1 severity or lower, except for stable sensory neuropathy \<= Grade 2 and alopecia. 4. Age \>= 18 years. 5. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2. 6. Life expectancy of \>= 3 months. 7. Adequate renal function as evidenced by serum creatinine \<1.5 mg/dL or calculated creatinine clearance \> 50 mL/minute (min) per the Cockcroft and Gault formula. 8. Adequate bone marrow function as evidenced by absolute neutrophil count (ANC) \>= 1.5 x 10\^9/L, hemoglobin \>= 10.0 g/dL (a hemoglobin \< 10.0 g/dL acceptable if it is corrected by growth factor or transfusion), and platelet count \>= 100 x 10\^9/L. 9. Adequate liver function as evidenced by bilirubin \<= 1.5 times the upper limits of normal (ULN) and alkaline phosphatase, alanine transaminase (ALT), and aspartate transaminase (AST) \<= 3 x ULN (in the case of liver metastases \<= 5 x ULN), or in case of bone metastases, liver specific alkaline phosphatase \<= 3 x ULN. 10. Patients willing and able to complete the EORTC (European Organization for Research on the Treatment of Cancer) quality of life questionnaire (QLQ-C30 with breast cancer module QLQ-BR23) and to record their pain level on the Visual Analog Scale (VAS). 11. Patients willing and able to comply with the study protocol for the duration of the study. 12. Written informed consent prior to any study-specific screening procedures with the understanding that the patient may withdraw consent at any time without prejudice.
Exclusion criteria
1. Patients who have received more than three prior chemotherapy regimens for their disease, including adjuvant therapies, or patients who have received more than two prior chemotherapy regimens for advanced disease (other therapies are allowed e.g., anti-estrogens, trastuzumab and radiotherapy). 2. Patients who have received capecitabine as a prior therapy for their disease. 3. Patients who have received chemotherapy, radiation, or biological therapy within two weeks, or hormonal therapy, within one week before study treatment start, or any investigational drug within four weeks before study treatment start. 4. Radiation therapy encompassing \> 30% of marrow. 5. Prior treatment with mitomycin C or nitrosourea. 6. Pulmonary lymphangitic involvement that results in pulmonary dysfunction requiring active treatment, including the use of oxygen. 7. Patients with brain or subdural metastases are not eligible, unless they have completed local therapy and have discontinued the use of corticosteroids for this indication for at least 4 weeks before starting treatment with study treatment. Any symptoms attributed to brain metastases must be stable for at least 4 weeks before starting study treatment; radiographic stability should be determined by comparing a contrast-enhanced Computed Tomography Scan (CT) or Magnetic Resonance Imaging (MRI) brain scan performed during screening to a prior scan performed at least 4 weeks earlier. 8. Patients with meningeal carcinomatosis. 9. Patients who are receiving anti-coagulant therapy with warfarin or related compounds, other than for line patency, and cannot be changed to heparin-based therapy, are not eligible. If a patient is to continue on mini-dose warfarin, then the prothrombin time (PT)/international normalized ratio (INR) must be closely monitored. 10. Women who are pregnant or breast-feeding; women of childbearing potential with either a positive pregnancy test at screening or no pregnancy test; women of childbearing potential unless (1) surgically sterile or (2) using adequate measures of contraception (considered to be two methods of contraception, one of which must be a barrier method, e.g. condom, diaphragm or cervical cap). Perimenopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential. 11. Severe/uncontrolled intercurrent illness/infection. 12. Significant cardiovascular impairment (history of congestive heart failure \> New York Heart Association \[NYHA\] Grade II, unstable angina or myocardial infarction within the past six months, or serious cardiac arrhythmia). 13. Patients with organ allografts requiring immunosuppression. 14. Patients with known positive human immunodeficiency virus (HIV) status. 15. Patients who have had a prior malignancy, other than carcinoma in situ of the cervix, or non-melanoma skin cancer, unless the prior malignancy was diagnosed and definitively treated \>= 5 years previously with no subsequent evidence of recurrence. 16. Patients with pre-existing neuropathy \> Grade 2. 17. Patients with a hypersensitivity to halichondrin B and/or halichondrin B chemical derivative. 18. Patients who participated in a prior E7389 clinical trial. 19. Patients with other significant disease or disorders that, in the Investigator's opinion, would exclude the patient from the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | 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 | OS was measured from the date of randomization until the date of death from any cause, or the last date the participant was known to be alive. Participants 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 participant was still alive at data cutoff, the date of data cutoff was considered the end date, and 2) if the participant was lost to follow-up before data cutoff, the date they were last known to be alive was considered the end date. Participants 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. |
| Progression Free Survival (PFS) | 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 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR): Independent Review | 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 | ORR was defined as the percentage of participants 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. |
| Duration of Response (DOR): Independent Review | From first documented CR or PR until date of recurrent or progressive disease or death, assessed up to data cutoff of date of 12 Mar 2012 or up to approximately 6 years | DOR was defined as the time from first documented CR or PR until disease progression or death from any cause for those participants 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. |
| Overall Survival Rate | From the date of randomization to Year 1, 2 and 3 | One-, two-, and three- year's survival rates were defined as the percentage of participants who were alive at one, two, and three years respectively, and estimated using the Kaplan-Meier method and Greenwood Formula. |
| Change From Baseline in Pain Intensity by Visual Analog Scale (VAS) Until 30 Days After the Last Dose of Study Drug | First dose of study drug (Baseline) up to 30 days after last dose of study drug (up to approximately 6 years 3 months) | 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. |
| Number of Participants With Consumption of Analgesics During the Study | First dose of study drug (Baseline) up to 30 days after last dose of study drug (up to approximately 6 years 3 months) | Participants 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 |
| 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 | Baseline and Week 6 | EORTC-QLQ-C30:cancer-specific instrument with 30 questions to assess the participant QoL. First 28 questions used to evaluate 5 functional scales (physical, role, cognitive, emotional, social), 3 symptom scales (fatigue, nausea and vomiting, pain) and other single items(dyspnoea, 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. |
| Number of Participants With Treatment-emergent Markedly Abnormal Laboratory Parameter Values | First dose of study drug (Baseline) up to 30 days after last dose of study drug (up to approximately 6 years 3 months) | — |
| Number of Participants Who Took at Least One Concomitant Medication | First dose of study drug (Baseline) up to 30 days after last dose of study drug (up to approximately 6 years 3 months) | 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. |
| Duration of Eribulin Mesylate Exposure | Up to approximately 6 years for primary analysis completion stage, Up to approximately 6 years 2 months for final analysis completion stage | 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 participants were still receiving study treatment. |
| Plasma Concentrations of Eribulin Mesylate | 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) | — |
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | First dose of study drug (Baseline) up to 30 days after last dose of study drug (up to approximately 6 years 3 months) | TEAEs included both SAEs as well as non-SAEs. |
| 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 | Baseline and Week 6 | 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. |
Countries
Argentina, Australia, Belgium, Brazil, Bulgaria, Canada, Czechia, France, Germany, Greece, Hungary, Israel, Italy, Mexico, Poland, Romania, Russia, Singapore, South Africa, Spain, Taiwan, Ukraine, United States
Participant flow
Pre-assignment 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.
Participants by arm
| Arm | Count |
|---|---|
| Eribulin Mesylate 1.4 mg/m^2 Eribulin mesylate 1.4 mg/m\^2 intravenous (IV) infusion given over 2-5 minutes on Days 1 and 8 every 21 days. | 554 |
| Capecitabine 2.5 g/m^2/Day Capecitabine : Capecitabine 2.5 g/m\^2/day administered orally twice daily in two equal doses on Days 1 to 14 every 21 days. | 548 |
| Total | 1,102 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 45 | 59 |
| Overall Study | Clinical Progression | 27 | 24 |
| Overall Study | Death | 1 | 0 |
| Overall Study | Entry Criteria Not Met | 4 | 1 |
| Overall Study | Lost to Follow-up | 1 | 2 |
| Overall Study | Other | 5 | 6 |
| Overall Study | Physician Decision | 15 | 14 |
| Overall Study | Progressive Disease | 414 | 410 |
| Overall Study | Subject Choice | 34 | 27 |
| Overall Study | Withdrawal by Subject | 8 | 5 |
Baseline characteristics
| Characteristic | Capecitabine 2.5 g/m^2/Day | Total | Eribulin Mesylate 1.4 mg/m^2 |
|---|---|---|---|
| Age, Continuous | 52.8 years STANDARD_DEVIATION 10.2 | 53.3 years STANDARD_DEVIATION 10.29 | 53.8 years STANDARD_DEVIATION 10.37 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 18 Participants | 36 Participants | 18 Participants |
| Race (NIH/OMB) Black or African American | 16 Participants | 31 Participants | 15 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 19 Participants | 44 Participants | 25 Participants |
| Race (NIH/OMB) White | 495 Participants | 991 Participants | 496 Participants |
| Sex: Female, Male Female | 548 Participants | 1102 Participants | 554 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 442 / 544 | 459 / 546 |
| other Total, other adverse events | 509 / 544 | 489 / 546 |
| serious Total, serious adverse events | 95 / 544 | 115 / 546 |
Outcome results
Primary
Overall Survival (OS)
OS was measured from the date of randomization until the date of death from any cause, or the last date the participant was known to be alive. Participants 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 participant was still alive at data cutoff, the date of data cutoff was considered the end date, and 2) if the participant was lost to follow-up before data cutoff, the date they were last known to be alive was considered the end date. Participants 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.
Time frame: 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
Population: Data was analyzed using the Intent-to-Treat (ITT) Population defined as all participants who were randomized.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Eribulin Mesylate 1.4 mg/m^2 | Overall Survival (OS) | 484 days |
| Capecitabine 2.5 g/m^2/Day | Overall Survival (OS) | 440 days |
Primary
Progression Free Survival (PFS)
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.
Time frame: 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
Population: Data was analyzed using the ITT Population defined as all participants who were randomized.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Eribulin Mesylate 1.4 mg/m^2 | Progression Free Survival (PFS) | 126 Days |
| Capecitabine 2.5 g/m^2/Day | Progression Free Survival (PFS) | 129 Days |
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
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.
Time frame: Baseline and Week 6
Population: Data was analyzed using the ITT Population defined as all participants who were randomized. Here,number analyzed signifies the participants who were evaluable for this outcome measure for individual row.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Eribulin Mesylate 1.4 mg/m^2 | 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 | Body Image | 0.7 units on a scale | Standard Deviation 21.26 |
| Eribulin Mesylate 1.4 mg/m^2 | 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 | Sexual functioning | 1.2 units on a scale | Standard Deviation 14.75 |
| Eribulin Mesylate 1.4 mg/m^2 | 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 | Sexual enjoyment | 0.8 units on a scale | Standard Deviation 21.58 |
| Eribulin Mesylate 1.4 mg/m^2 | 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 | Future perspective | 7.7 units on a scale | Standard Deviation 28.48 |
| Eribulin Mesylate 1.4 mg/m^2 | 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 | Systemic therapy side effects | 4.5 units on a scale | Standard Deviation 15.55 |
| Eribulin Mesylate 1.4 mg/m^2 | 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 | Breast Symptoms | -3.4 units on a scale | Standard Deviation 16.55 |
| Eribulin Mesylate 1.4 mg/m^2 | 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 | Arm Symptoms | -4.2 units on a scale | Standard Deviation 17.94 |
| Eribulin Mesylate 1.4 mg/m^2 | 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 | Upset by hair loss | -4.4 units on a scale | Standard Deviation 32.66 |
| Capecitabine 2.5 g/m^2/Day | 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 | Upset by hair loss | -10.1 units on a scale | Standard Deviation 29.76 |
| Capecitabine 2.5 g/m^2/Day | 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 | Body Image | 4.8 units on a scale | Standard Deviation 21.8 |
| Capecitabine 2.5 g/m^2/Day | 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 | Systemic therapy side effects | -1.2 units on a scale | Standard Deviation 14.73 |
| Capecitabine 2.5 g/m^2/Day | 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 | Sexual functioning | -0.1 units on a scale | Standard Deviation 16.62 |
| Capecitabine 2.5 g/m^2/Day | 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 | Arm Symptoms | -3.4 units on a scale | Standard Deviation 18.65 |
| Capecitabine 2.5 g/m^2/Day | 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 | Sexual enjoyment | 3.1 units on a scale | Standard Deviation 17.49 |
| Capecitabine 2.5 g/m^2/Day | 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 | Breast Symptoms | -3.6 units on a scale | Standard Deviation 16.2 |
| Capecitabine 2.5 g/m^2/Day | 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 | Future perspective | 10.0 units on a scale | Standard Deviation 30.84 |
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
EORTC-QLQ-C30:cancer-specific instrument with 30 questions to assess the participant QoL. First 28 questions used to evaluate 5 functional scales (physical, role, cognitive, emotional, social), 3 symptom scales (fatigue, nausea and vomiting, pain) and other single items(dyspnoea, 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.
Time frame: Baseline and Week 6
Population: Data was analyzed using the ITT Population defined as all participants who were randomized. Here,overall number of participants analyzed are the participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Eribulin Mesylate 1.4 mg/m^2 | 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 | 0.1 units on a scale | Standard Deviation 19.23 |
| Capecitabine 2.5 g/m^2/Day | 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 | 1.7 units on a scale | Standard Deviation 20.69 |
Secondary
Change From Baseline in Pain Intensity by Visual Analog Scale (VAS) Until 30 Days After the Last Dose of Study Drug
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.
Time frame: First dose of study drug (Baseline) up to 30 days after last dose of study drug (up to approximately 6 years 3 months)
Population: Data was analyzed using the ITT Population defined as all participants who were randomized. Here, overall number of participants analyzed are the participants who were evaluable for the outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Eribulin Mesylate 1.4 mg/m^2 | Change From Baseline in Pain Intensity by Visual Analog Scale (VAS) Until 30 Days After the Last Dose of Study Drug | -3.7 units on a scale | Standard Deviation 22.8 |
| Capecitabine 2.5 g/m^2/Day | Change From Baseline in Pain Intensity by Visual Analog Scale (VAS) Until 30 Days After the Last Dose of Study Drug | 0.4 units on a scale | Standard Deviation 22.9 |
Secondary
Duration of Eribulin Mesylate Exposure
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 participants were still receiving study treatment.
Time frame: Up to approximately 6 years for primary analysis completion stage, Up to approximately 6 years 2 months for final analysis completion stage
Population: Data was analyzed using safety population defined as all participants who received at least one dose of study treatment. Here, number analyzed signifies the participants who were evaluable at individual stage for this outcome measure.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Eribulin Mesylate 1.4 mg/m^2 | Duration of Eribulin Mesylate Exposure | At primary analysis completion stage | 125.0 days |
| Eribulin Mesylate 1.4 mg/m^2 | Duration of Eribulin Mesylate Exposure | At final analysis completion stage | 1743.0 days |
| Capecitabine 2.5 g/m^2/Day | Duration of Eribulin Mesylate Exposure | At primary analysis completion stage | 119.0 days |
| Capecitabine 2.5 g/m^2/Day | Duration of Eribulin Mesylate Exposure | At final analysis completion stage | 1506.0 days |
Secondary
Duration of Response (DOR): Independent Review
DOR was defined as the time from first documented CR or PR until disease progression or death from any cause for those participants 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.
Time frame: From first documented CR or PR until date of recurrent or progressive disease or death, assessed up to data cutoff of date of 12 Mar 2012 or up to approximately 6 years
Population: Data was analyzed using for a subset of participants in the ITT Population who had a response. Here, overall number of participants analyzed are the participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Eribulin Mesylate 1.4 mg/m^2 | Duration of Response (DOR): Independent Review | 198 days |
| Capecitabine 2.5 g/m^2/Day | Duration of Response (DOR): Independent Review | 330 days |
Secondary
Number of Participants Who Took at Least One Concomitant Medication
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.
Time frame: First dose of study drug (Baseline) up to 30 days after last dose of study drug (up to approximately 6 years 3 months)
Population: Data was analyzed using safety population defined as all participants who received at least one dose of study treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Eribulin Mesylate 1.4 mg/m^2 | Number of Participants Who Took at Least One Concomitant Medication | 496 Participants |
| Capecitabine 2.5 g/m^2/Day | Number of Participants Who Took at Least One Concomitant Medication | 483 Participants |
Secondary
Number of Participants With Consumption of Analgesics During the Study
Participants 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
Time frame: First dose of study drug (Baseline) up to 30 days after last dose of study drug (up to approximately 6 years 3 months)
Population: Data was analyzed using safety population defined as all participants who received at least one dose of study treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Eribulin Mesylate 1.4 mg/m^2 | Number of Participants With Consumption of Analgesics During the Study | 222 Participants |
| Capecitabine 2.5 g/m^2/Day | Number of Participants With Consumption of Analgesics During the Study | 196 Participants |
Secondary
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
TEAEs included both SAEs as well as non-SAEs.
Time frame: First dose of study drug (Baseline) up to 30 days after last dose of study drug (up to approximately 6 years 3 months)
Population: Data was analyzed using safety population defined as all participants who received at least one dose of study treatment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Eribulin Mesylate 1.4 mg/m^2 | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | TEAEs | 512 Participants |
| Eribulin Mesylate 1.4 mg/m^2 | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | SAEs | 95 Participants |
| Capecitabine 2.5 g/m^2/Day | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | TEAEs | 494 Participants |
| Capecitabine 2.5 g/m^2/Day | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | SAEs | 115 Participants |
Secondary
Number of Participants With Treatment-emergent Markedly Abnormal Laboratory Parameter Values
Time frame: First dose of study drug (Baseline) up to 30 days after last dose of study drug (up to approximately 6 years 3 months)
Population: Data was analyzed using safety population defined as all participants who received at least one dose of study treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Eribulin Mesylate 1.4 mg/m^2 | Number of Participants With Treatment-emergent Markedly Abnormal Laboratory Parameter Values | 362 Participants |
| Capecitabine 2.5 g/m^2/Day | Number of Participants With Treatment-emergent Markedly Abnormal Laboratory Parameter Values | 224 Participants |
Secondary
Objective Response Rate (ORR): Independent Review
ORR was defined as the percentage of participants 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.
Time frame: 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
Population: Data was analyzed using the ITT Population defined as all participants who were randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Eribulin Mesylate 1.4 mg/m^2 | Objective Response Rate (ORR): Independent Review | 11.0 percentage of participants |
| Capecitabine 2.5 g/m^2/Day | Objective Response Rate (ORR): Independent Review | 11.5 percentage of participants |
Secondary
Overall Survival Rate
One-, two-, and three- year's survival rates were defined as the percentage of participants who were alive at one, two, and three years respectively, and estimated using the Kaplan-Meier method and Greenwood Formula.
Time frame: From the date of randomization to Year 1, 2 and 3
Population: Data was analyzed using the ITT Population defined as all participants who were randomized.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Eribulin Mesylate 1.4 mg/m^2 | Overall Survival Rate | At 1-year | 0.644 percentage of participants |
| Eribulin Mesylate 1.4 mg/m^2 | Overall Survival Rate | At 2-years | 0.328 percentage of participants |
| Eribulin Mesylate 1.4 mg/m^2 | Overall Survival Rate | At 3-years | 0.178 percentage of participants |
| Capecitabine 2.5 g/m^2/Day | Overall Survival Rate | At 1-year | 0.580 percentage of participants |
| Capecitabine 2.5 g/m^2/Day | Overall Survival Rate | At 2-years | 0.298 percentage of participants |
| Capecitabine 2.5 g/m^2/Day | Overall Survival Rate | At 3-years | 0.145 percentage of participants |
Secondary
Plasma Concentrations of Eribulin Mesylate
Time frame: 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)
Population: Pharmacokinetic (PK) analysis set included all participants who have received at least one dose of E7389 and have at least one quantifiable E7389 concentration. Here, number analyzed signifies the participants who were evaluable for this outcome measure for given time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Eribulin Mesylate 1.4 mg/m^2 | Plasma Concentrations of Eribulin Mesylate | 4-8 hours | 10.0 nanogram per milliliter (ng/mL) | Standard Deviation 5.4 |
| Eribulin Mesylate 1.4 mg/m^2 | Plasma Concentrations of Eribulin Mesylate | 10-24 hours | 5.8 nanogram per milliliter (ng/mL) | Standard Deviation 3.72 |
| Eribulin Mesylate 1.4 mg/m^2 | Plasma Concentrations of Eribulin Mesylate | 5-10 minutes | 415.8 nanogram per milliliter (ng/mL) | Standard Deviation 719.5 |
| Eribulin Mesylate 1.4 mg/m^2 | Plasma Concentrations of Eribulin Mesylate | 15-30 minutes | 152.6 nanogram per milliliter (ng/mL) | Standard Deviation 70.51 |
| Eribulin Mesylate 1.4 mg/m^2 | Plasma Concentrations of Eribulin Mesylate | 30-60 minutes | 95.5 nanogram per milliliter (ng/mL) | Standard Deviation 87.9 |
| Eribulin Mesylate 1.4 mg/m^2 | Plasma Concentrations of Eribulin Mesylate | 60-90 minutes | 52.7 nanogram per milliliter (ng/mL) | Standard Deviation 79.33 |
| Eribulin Mesylate 1.4 mg/m^2 | Plasma Concentrations of Eribulin Mesylate | 2-4 hours | 20.7 nanogram per milliliter (ng/mL) | Standard Deviation 32.81 |
| Eribulin Mesylate 1.4 mg/m^2 | Plasma Concentrations of Eribulin Mesylate | 48-72 hours | 3.7 nanogram per milliliter (ng/mL) | Standard Deviation 2.58 |
| Eribulin Mesylate 1.4 mg/m^2 | Plasma Concentrations of Eribulin Mesylate | 72-96 hours | 2.4 nanogram per milliliter (ng/mL) | Standard Deviation 1.6 |
| Eribulin Mesylate 1.4 mg/m^2 | Plasma Concentrations of Eribulin Mesylate | 96-120 hours | 7.6 nanogram per milliliter (ng/mL) | Standard Deviation 38.75 |