E7389 Versus Capecitabine in Patients With Locally Advanced or Metastatic Breast Cancer Previously Treated With Anthracyclines and Taxanes

Metastatic Breast Cancer Clinical Trial

Official title:

A Phase III Open Label, Randomized Two-Parallel-Arm Multicenter Study of E7389 Versus Capecitabine in Patients With Locally Advanced or Metastatic Breast Cancer Previously Treated With Anthracyclines and Taxanes

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00337103
• Other study ID #: E7389-G000-301
• Status: Completed
• Phase: Phase 3
• Start date: September 20, 2006
• Est. completion date: December 11, 2017

Study information

• Verified date: January 2018
• Source: Eisai Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1276
• Est. completion date: December 11, 2017
• Est. primary completion date: March 12, 2012
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Breast Neoplasms
• Metastatic Breast Cancer

Intervention

Drug:
• Eribulin Mesylate
1.4 mg/m^2 intravenous (IV) infusion given over 2-5 minutes on Days 1 and 8 every 21 days
• Capecitabine
Capecitabine 2.5 g/m^2/day administered orally twice daily in two equal doses on Days 1 to 14 every 21 days

Locations

Country	Name	City	State
Argentina	Hospital General de Agudos Teodoro Alvarez	Ciudad Autonoma	Buenos Aires
Argentina	Hospital Italiano de Buenos Aires	Ciudad Autonoma de Buenos Aires
Argentina	Instituto Argentino de Diagnostico y Tratamiento	Cuidad Autonoma de Buenos Aires	Buenos Aires
Argentina	Corporacion Medica General San Martin	San Martin	Buenos Aires
Australia	Ashford Cancer Centre	Adelaide	South Australia
Australia	Bankstown Hospital, Oncology Trials Unit	Bankstown	New South Wales
Australia	Epworth Freemasons Hospital	East Melbourne
Australia	Saint Vincent's Hospital	Fitzroy	Victoria
Australia	Royal Hobart Hospital	Hobart	Tasmania
Australia	Liverpool Hospital, Cancer Therapy Centre	Liverpool	New South Wales
Australia	Sir Charles Gairdner Hospital, Dept. of Medical Oncology	Nedlands
Australia	Royal Perth Hospital	Perth	Western Australia
Australia	Mater Adult Hospital	South Brisbane
Belgium	OLVZ Aalst, Oncology Service	Aalst
Belgium	Institut Jules Bordet, Medical Oncology Unit	Brussels
Belgium	Algemeen Ziekenhuis Sint Lucas	Ghent
Belgium	Centre Hosptialier Universitaire Sart Tilman Liege	Liege
Brazil	Associacao Hospital de Caridade Ijui	Ijui
Brazil	Instituto de Oncologia Ltda	Jundiai
Brazil	Proonco Centro de Tratamento Oncologico	Londrina
Brazil	Hospital de Clinicas de Porto Alegre, Servicio de Oncologia	Porto Alegre
Brazil	Hospital Nossa Senhora da Conceicao	Porto Alegre
Brazil	Servico de Quimioterapia de Pernambuco-SEQUIPE	Recife
Brazil	Instituto Ribeiraopretano de Combate ao Cancer	Ribeirao Preto
Brazil	Nucleo de Oncologia da Bahia	Salvador
Brazil	Faculdade de Medicina do ABC	Santo Andre
Brazil	Grupo Paulista de Oncologia Integrada Ltda	Sao Paulo
Brazil	Hospital das Clinicas de Faculdade de Medicina da Universidade de Sao	Sao Paulo
Brazil	Hospital do Cancer de Sao Paulo-AC Camargo	Sao Paulo
Brazil	Hospital do Cancer de Sao Paulo-AC. Camargo	Sao Paulo
Brazil	Instituto Brasileiro de Controle do Cancer-IBCC	Sao Paulo
Canada	Centre Hospitalier Universitaire de Montreal, Hopital Notre Dame	Montreal
Canada	Hopital du Sacre-Coeur de Montreal	Montreal	Quebec
Canada	Montreal General Hospital	Montreal	Quebec
Canada	Thunder Bay Regional Health Science Centre Northwestern Ontario	Thunder Bay
Czechia	Nemocnice Ceske Budejovice, a.s.	Ceske Budejovice
Czechia	Onkologicka Klinika, Fakutni Nemocnice	Olomouc
Czechia	1. LF UK, Ustav radiacnej onkologie	Prague 8
Czechia	Krajska nemocnice T. Bati	Zlin Poiters
France	Centre Hospitalier La Roche sur Yon, CHD les Oudairies	La Roche sur Yon
France	CHU de Poitiers, Service d'Oncologie Medicale	Poitiers Cedex
France	Hopital Nord Saint-Etienne	Saint Priest en Jarez
Germany	Augusta-Kranken-Anstalt, Klinik fur Hamatologie und Onkologie	Bochum
Germany	Universitatsfrauenklinik Magdeburg	Magdeburg
Hungary	Debrecen University	Debrecen
Hungary	Pecsi Tudomanyegyetem, Onkoterapias Intezet	Pecs
Israel	Barzilai Medical Center	Ashkelon
Israel	Soroka Medical Center	Beer Sheva
Israel	Sharet Institute of Oncology	Jerusalem
Israel	Meir Hospital, Sapir Medical Center	Kfar Saba
Israel	Rabin Medical Center	Petach Tikva
Israel	Kaplan Medical Center	Rechovot
Israel	The Chaim Sheba Medical Center	Tel Hashomer
Italy	Unita Operativa de Oncologia	Lugo
Italy	Azienda Ospedaliera San Salvatore	Pesaro
Italy	Ospedale Civile S. Maria delle Croci	Ravenna
Italy	UO di Onco-ematologia	Rimini
Mexico	Centro Estatal de Cancerologia	Chihuahua
Mexico	Consultorio del Dr. Trigueros	Morelia
Poland	Regionalny Osrodek Onkologii	Bialystok
Poland	Wojewodzkie Centrum Onkologii	Gdansk
Poland	Wojewodzki Szpital Specjalistyczny	Wroclaw
Romania	Spitalul Militar Central Bucuresti	Bucharest
Romania	Centrul de Oncologie Medicala	Iasi
Romania	Spitalul Clinic Judetean Sibiu	Sibiu
Russian Federation	Blokhin Cancer Research Centre	Moscow
Russian Federation	Regional Oncology Dispensary	Yaroslavl	Yaroslavlr
South Africa	Panorama Medical Centre	Cape Town

Sponsors (1)

Lead Sponsor	Collaborator
Eisai Inc.

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Belgium,  Brazil,  Bulgaria,  Canada,  Czechia,  France,  Germany,  Greece,  Hungary,  Israel,  Italy,  Mexico,  Poland,  Romania,  Russian Federation,  Singapore,  South Africa,  Spain,  Taiwan,  Ukraine, 

Outcome

Type	Measure	Description	Time frame	Safety issue
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.	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
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.	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
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.	Baseline and Week 6
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.	Baseline and Week 6
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.	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
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.	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
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.	From the date of randomization to Year 1, 2 and 3
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.	First dose of study drug (Baseline) up to 30 days after last dose of study drug (up to approximately 6 years 3 months)
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	First dose of study drug (Baseline) up to 30 days after last dose of study drug (up to approximately 6 years 3 months)
Secondary	Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)	TEAEs included both SAEs as well as non-SAEs.	First dose of study drug (Baseline) up to 30 days after last dose of study drug (up to approximately 6 years 3 months)
Secondary	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)
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.	First dose of study drug (Baseline) up to 30 days after last dose of study drug (up to approximately 6 years 3 months)
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.	Up to approximately 6 years for primary analysis completion stage, Up to approximately 6 years 2 months for final analysis completion stage
Secondary	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)