Clinical trial NCT00337103: E7389 Versus Capecitabine in Patients With Locally Advanced or Metastatic Breast Cancer Previously Treated With Anthracyclines and Taxanes
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Metastatic Breast Cancer
Lead sponsor: Eisai Inc.
Sponsor class: INDUSTRY
First posted: 2006-06-15
Enrollment: 1276
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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.

Primary outcomes:
measure: Overall Survival (OS)
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
measure: Progression Free Survival (PFS)
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
Secondary outcomes:
measure: 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
timeFrame: Baseline and Week 6
measure: 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
timeFrame: Baseline and Week 6
measure: Objective Response Rate (ORR): Independent Review
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
measure: Duration of Response (DOR): Independent Review
timeFrame: 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
measure: Overall Survival Rate
timeFrame: From the date of randomization to Year 1, 2 and 3
measure: Change From Baseline in Pain Intensity by Visual Analog Scale (VAS) Until 30 Days After the Last Dose of Study Drug
timeFrame: First dose of study drug (Baseline) up to 30 days after last dose of study drug (up to approximately 6 years 3 months)
measure: Number of Participants With Consumption of Analgesics During the Study
timeFrame: First dose of study drug (Baseline) up to 30 days after last dose of study drug (up to approximately 6 years 3 months)
measure: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
timeFrame: First dose of study drug (Baseline) up to 30 days after last dose of study drug (up to approximately 6 years 3 months)
measure: Number of Participants With Treatment-emergent Markedly Abnormal Laboratory Parameter Values
timeFrame: First dose of study drug (Baseline) up to 30 days after last dose of study drug (up to approximately 6 years 3 months)
measure: Number of Participants Who Took at Least One Concomitant Medication
timeFrame: First dose of study drug (Baseline) up to 30 days after last dose of study drug (up to approximately 6 years 3 months)
measure: Duration of Eribulin Mesylate Exposure
timeFrame: Up to approximately 6 years for primary analysis completion stage, Up to approximately 6 years 2 months for final analysis completion stage
measure: Plasma Concentrations of Eribulin Mesylate
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)
Other outcomes:
Locations:
city: Anaheim
country: United States
state: California
city: La Verne
country: United States
state: California
city: Poway
country: United States
state: California
city: Centralia
country: United States
state: Illinois
city: Augusta
country: United States
state: Maine
city: Boston
country: United States
state: Massachusetts
city: Jefferson City
country: United States
state: Missouri
city: Lebanon
country: United States
state: New Hampshire
city: Ephrata
country: United States
state: Pennsylvania
city: Cookeville
country: United States
state: Tennessee
city: Germantown
country: United States
state: Tennessee
city: Amarillo
country: United States
state: Texas
city: Wenatchee
country: United States
state: Washington
city: Ciudad Autonoma
country: Argentina
facility: Hospital General de Agudos Teodoro Alvarez
state: Buenos Aires
city: Cuidad Autonoma de Buenos Aires
country: Argentina
facility: Instituto Argentino de Diagnostico y Tratamiento
state: Buenos Aires
city: La Plata
country: Argentina
state: Buenos Aires
city: La Plata
country: Argentina
state: Buenos Aires
city: Pilar
country: Argentina
state: Buenos Aires
city: San Martin
country: Argentina
facility: Corporacion Medica General San Martin
state: Buenos Aires
city: Rosario
country: Argentina
state: Santa Fe
city: San Miguel de Tucuman
country: Argentina
state: Tucuman
city: Bahia Blanca
country: Argentina
city: Buenos Aires
country: Argentina
city: Buenos Aires
country: Argentina
city: Ciudad Autonoma de Buenos Aires
country: Argentina
facility: Hospital Italiano de Buenos Aires
city: Ciudad Autonoma
country: Argentina
city: Mendoza
country: Argentina
city: Santa Fe
country: Argentina
city: Bankstown
country: Australia
facility: Bankstown Hospital, Oncology Trials Unit
state: New South Wales
city: Hornsby
country: Australia
state: New South Wales
city: Liverpool
country: Australia
facility: Liverpool Hospital, Cancer Therapy Centre
state: New South Wales
city: Adelaide
country: Australia
facility: Ashford Cancer Centre
state: South Australia
city: Hobart
country: Australia
facility: Royal Hobart Hospital
state: Tasmania
city: Fitzroy
country: Australia
facility: Saint Vincent's Hospital
state: Victoria
city: Perth
country: Australia
facility: Royal Perth Hospital
state: Western Australia
city: East Melbourne
country: Australia
facility: Epworth Freemasons Hospital
city: Nedlands
country: Australia
facility: Sir Charles Gairdner Hospital, Dept. of Medical Oncology
city: South Brisbane
country: Australia
facility: Mater Adult Hospital
city: Aalst
country: Belgium
facility: OLVZ Aalst, Oncology Service
city: Brussels
country: Belgium
facility: Institut Jules Bordet, Medical Oncology Unit
city: Ghent
country: Belgium
facility: Algemeen Ziekenhuis Sint Lucas
city: Liege
country: Belgium
facility: Centre Hosptialier Universitaire Sart Tilman Liege
city: Florianopolis
country: Brazil
city: Ijui
country: Brazil
facility: Associacao Hospital de Caridade Ijui
city: Jundiai
country: Brazil
facility: Instituto de Oncologia Ltda
city: Londrina
country: Brazil
facility: Proonco Centro de Tratamento Oncologico
city: Porto Alegre
country: Brazil
facility: Hospital de Clinicas de Porto Alegre, Servicio de Oncologia
city: Porto Alegre
country: Brazil
facility: Hospital Nossa Senhora da Conceicao
city: Recife
country: Brazil
facility: Servico de Quimioterapia de Pernambuco-SEQUIPE
city: Ribeirao Preto
country: Brazil
facility: Instituto Ribeiraopretano de Combate ao Cancer
city: Salvador
country: Brazil
facility: Nucleo de Oncologia da Bahia
city: Santo Andre
country: Brazil
facility: Faculdade de Medicina do ABC
city: Sao Paulo
country: Brazil
facility: Grupo Paulista de Oncologia Integrada Ltda
city: Sao Paulo
country: Brazil
facility: Hospital das Clinicas de Faculdade de Medicina da Universidade de Sao
city: Sao Paulo
country: Brazil
facility: Hospital do Cancer de Sao Paulo-AC Camargo
city: Sao Paulo
country: Brazil
facility: Hospital do Cancer de Sao Paulo-AC. Camargo
city: Sao Paulo
country: Brazil
facility: Instituto Brasileiro de Controle do Cancer-IBCC
city: Burgas
country: Bulgaria
city: Gabrovo
country: Bulgaria
city: Pleven
country: Bulgaria
city: Plovdiv
country: Bulgaria
city: Ruse
country: Bulgaria
city: Shumen
country: Bulgaria
city: Sofia
country: Bulgaria
city: Stara Zagora
country: Bulgaria
city: Varna
country: Bulgaria
city: Kingston
country: Canada
state: Ontario
city: Montreal
country: Canada
facility: Montreal General Hospital
state: Quebec
city: Montreal
country: Canada
facility: Hopital du Sacre-Coeur de Montreal
state: Quebec
city: Montreal
country: Canada
facility: Centre Hospitalier Universitaire de Montreal, Hopital Notre Dame
city: Thunder Bay
country: Canada
facility: Thunder Bay Regional Health Science Centre Northwestern Ontario
city: Ceske Budejovice
country: Czechia
facility: Nemocnice Ceske Budejovice, a.s.
city: Olomouc
country: Czechia
facility: Onkologicka Klinika, Fakutni Nemocnice
city: Prague 8
country: Czechia
facility: 1. LF UK, Ustav radiacnej onkologie
city: Zlin Poiters
country: Czechia
facility: Krajska nemocnice T. Bati
city: La Roche sur Yon
country: France
facility: Centre Hospitalier La Roche sur Yon, CHD les Oudairies
city: Poitiers Cedex
country: France
facility: CHU de Poitiers, Service d'Oncologie Medicale
city: Saint Priest en Jarez
country: France
facility: Hopital Nord Saint-Etienne
city: Bochum
country: Germany
facility: Augusta-Kranken-Anstalt, Klinik fur Hamatologie und Onkologie
city: Hamburg
country: Germany
city: Homburg
country: Germany
city: Magdeburg
country: Germany
facility: Universitatsfrauenklinik Magdeburg
city: Rostock
country: Germany
city: Patra
country: Greece
city: Gyor
country: Hungary
state: Budapest
city: Debrecen
country: Hungary
facility: Debrecen University
city: Debrecen
country: Hungary
city: Gyula
country: Hungary
city: Pecs
country: Hungary
facility: Pecsi Tudomanyegyetem, Onkoterapias Intezet
city: Szeged
country: Hungary
city: Veszprem
country: Hungary
city: Ashkelon
country: Israel
facility: Barzilai Medical Center
city: Beer Sheva
country: Israel
facility: Soroka Medical Center
city: Jerusalem
country: Israel
facility: Sharet Institute of Oncology
city: Kfar Saba
country: Israel
facility: Meir Hospital, Sapir Medical Center
city: Petach Tikva
country: Israel
facility: Rabin Medical Center
city: Rechovot
country: Israel
facility: Kaplan Medical Center
city: Tel Hashomer
country: Israel
facility: The Chaim Sheba Medical Center
city: Ancona
country: Italy
city: Lugo
country: Italy
facility: Unita Operativa de Oncologia
city: Meldola
country: Italy
city: Modena
country: Italy
city: Pesaro
country: Italy
facility: Azienda Ospedaliera San Salvatore
city: Ravenna
country: Italy
facility: Ospedale Civile S. Maria delle Croci
city: Rimini
country: Italy
facility: UO di Onco-ematologia
city: Sassari
country: Italy
city: Chihuahua
country: Mexico
facility: Centro Estatal de Cancerologia
city: Monterrey
country: Mexico
city: Morelia
country: Mexico
facility: Consultorio del Dr. Trigueros
city: Bialystok
country: Poland
facility: Regionalny Osrodek Onkologii
city: Bytom
country: Poland
city: Elblag
country: Poland
city: Gdansk
country: Poland
facility: Wojewodzkie Centrum Onkologii
city: Krakow
country: Poland
city: Olsztyn
country: Poland
city: Rybnik
country: Poland
city: Torun
country: Poland
city: Wroclaw
country: Poland
facility: Wojewodzki Szpital Specjalistyczny
city: Cluj-Napoca
country: Romania
state: Cluj
city: Bucharest
country: Romania
facility: Spitalul Militar Central Bucuresti
city: Bucuresti
country: Romania
city: Cluj-Napoca
country: Romania
city: Iasi
country: Romania
facility: Centrul de Oncologie Medicala
city: Sibiu
country: Romania
facility: Spitalul Clinic Judetean Sibiu
city: Timisoara
country: Romania
city: Yaroslavl
country: Russian Federation
facility: Regional Oncology Dispensary
state: Yaroslavlr
city: Barnaul
country: Russian Federation
city: Kazan
country: Russian Federation
city: Kirov
country: Russian Federation
city: Krasnodar
country: Russian Federation
city: Moscow
country: Russian Federation
facility: Blokhin Cancer Research Centre
city: Moscow
country: Russian Federation
city: Nizhny Novgorod
country: Russian Federation
city: Obninsk
country: Russian Federation
city: Rostov-on-Don
country: Russian Federation
city: Saint Petersburg
country: Russian Federation
city: Saratov
country: Russian Federation
city: Sochi
country: Russian Federation
city: Tomsk
country: Russian Federation
city: Vladimir
country: Russian Federation
city: Singapore
country: Singapore
city: Mayville
country: South Africa
state: Durban
city: Pretoria
country: South Africa
state: Gaunteng
city: Groenkloof
country: South Africa
state: Pretoria
city: Cape Town
country: South Africa
facility: Panorama Medical Centre
city: Durban
country: South Africa
city: Johannesburg
country: South Africa
city: Sandton
country: South Africa
city: Barakaldo
country: Spain
state: Vizcaya
city: Barcelona
country: Spain
city: Guadalajara
country: Spain
city: La Coruna
country: Spain
city: Sevilla
country: Spain
city: Valencia
country: Spain
city: Changhua
country: Taiwan
city: Taichung
country: Taiwan
city: Tainan City
country: Taiwan
city: Taipei
country: Taiwan
city: Yung-Kang City
country: Taiwan
city: Chernigov
country: Ukraine
city: Dnepropetrovsk
country: Ukraine
city: Donetsk
country: Ukraine
city: Kharkov
country: Ukraine
city: Khmelnytskyi
country: Ukraine
city: Kiev
country: Ukraine
city: Kryvyi Rih
country: Ukraine
city: Kyiv
country: Ukraine
city: Lvov
country: Ukraine
city: Odessa
country: Ukraine
Study officials:
References:
citation: Twelves C, Awada A, Cortes J, Yelle L, Velikova G, Olivo MS, Song J, Dutcus CE, Kaufman PA. Subgroup Analyses from a Phase 3, Open-Label, Randomized Study of Eribulin Mesylate Versus Capecitabine in Pretreated Patients with Advanced or Metastatic Breast Cancer. Breast Cancer (Auckl). 2016 Jun 28;10:77-84. doi: 10.4137/BCBCR.S39615. eCollection 2016.
citation: Cortes J, Hudgens S, Twelves C, Perez EA, Awada A, Yelle L, McCutcheon S, Kaufman PA, Forsythe A, Velikova G. Health-related quality of life in patients with locally advanced or metastatic breast cancer treated with eribulin mesylate or capecitabine in an open-label randomized phase 3 trial. Breast Cancer Res Treat. 2015 Dec;154(3):509-20. doi: 10.1007/s10549-015-3633-7. Epub 2015 Nov 14.
citation: Kaufman PA, Awada A, Twelves C, Yelle L, Perez EA, Velikova G, Olivo MS, He Y, Dutcus CE, Cortes J. Phase III open-label randomized study of eribulin mesylate versus capecitabine in patients with locally advanced or metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol. 2015 Feb 20;33(6):594-601. doi: 10.1200/JCO.2013.52.4892. Epub 2015 Jan 20.
citation: Twelves C, Cortes J, Kaufman PA, Yelle L, Awada A, Binder TA, Olivo M, Song J, O'Shaughnessy JA, Jove M, Perez EA. "New" metastases are associated with a poorer prognosis than growth of pre-existing metastases in patients with metastatic breast cancer treated with chemotherapy. Breast Cancer Res. 2015 Dec 9;17(1):150. doi: 10.1186/s13058-015-0657-1.
citation: Twelves C, Cortes J, Vahdat LT, Wanders J, Akerele C, Kaufman PA. Phase III trials of eribulin mesylate (E7389) in extensively pretreated patients with locally recurrent or metastatic breast cancer. Clin Breast Cancer. 2010 Apr;10(2):160-3. doi: 10.3816/CBC.2010.n.023.