Clinical trial NCT00388726: E7389 Versus Treatment of Physician's Choice in Patients With Locally Recurrent or Metastatic Breast Cancer
Official title: The "EMBRACE" Trial: Eisai Metastatic Breast Cancer Study Assessing Physician's Choice Versus E7389. A Phase III Open-Label, Randomized, Parallel, Two-arm, Multi-center Study of E7389 Versus "Treatment of Physician's Choice" in Patients With Locally Recurrent, Metastatic Breast Cancer, Previously Treated With At Least Two and a Maximum of Five Prior Chemotherapy Regimens, Including an Anthracycline and a Taxane
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Breast Cancer
Keywords: Locally recurrent breast cancer
metastatic breast cancer
Lead sponsor: Eisai Inc.
Sponsor class: INDUSTRY
Collaborators: name: Eisai Limited
First posted: 2006-10-17
Enrollment: 762
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 Overall Survival (OS), Progression Free Survival (PFS), objective tumor response rate, duration of response, and safety in patients treated with E7389 versus the Treatment of Physician's Choice (TPC) in patients with locally recurrent or metastatic breast cancer.


Eligibility criteria: Inclusion Criteria:

1. Female patients with histologically or cytologically confirmed carcinoma of the breast.

   Every effort should be made to make paraffin embedded tissue or slides from the diagnostic biopsy or surgical specimen available for confirmation of diagnosis.
2. Patients with locally recurrent or metastatic disease who have received at least two (and not more than five) prior chemotherapeutic regimens for breast cancer, at least two of which were administered for treatment of locally recurrent and/or metastatic disease.

   Prior therapy must be documented by the following criteria prior to entry onto study:
   * Regimens must have included an anthracycline (e.g., doxorubicin, epirubicin) and a taxane (e.g., paclitaxel, docetaxel) in any combination or order. Treatment with any of these agents is not required if they are contraindicated for a certain patient.
   * One or two of these regimens may have been administered as adjuvant and/or neoadjuvant therapy, but at least 2 must have been given for relapsed or metastatic disease.
   * Patients must have proved refractory to the most recent chemotherapy, documented by progression on or within six (6) months of therapy.
   * Patients with Human Epidermal Growth Factor 2 (HER2/neu) positive tumors may additionally have been treated with trastuzumab.
   * Patients may have additionally been treated with anti-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 to 2.
6. Life expectancy of \>= 3 months.
7. Adequate renal function as evidenced by serum creatinine \<= 2.0 mg/dL or calculated creatinine clearance \>= 40 mL/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 is 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 aminotransferase (ALT), and aspartate aminotransferase (AST) \<= 3 x ULN (in the case of liver metastases \<= 5 x ULN), unless there are bone metastases, in which case liver specific alkaline phosphatase must be separated from the total and used to assess the liver function instead of the total alkaline phosphatase. In case alkaline phosphatase is \>3 x ULN (in absence of liver metastases) or \> 5 x ULN (in presence of liver metastases) AND patient is known to have bone metastases, the liver specific alkaline phosphatase must be separated from the total and used to assess the liver function instead of the total alkaline phosphatase.
10. Patients willing and able to comply with the study protocol for the duration of the study.
11. 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 any of the following treatments within the specified period before E7389 or TPC treatment start:

   * chemotherapy, radiation, trastuzumab or hormonal therapy within three weeks.
   * any investigational drug within four weeks.
2. Radiation therapy encompassing \> 30% of marrow.
3. Prior treatment with mitomycin C or nitrosourea.
4. Pulmonary lymphangitic involvement that results in pulmonary dysfunction requiring active treatment, including the use of oxygen.
5. 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 in this study. Any signs (e.g., radiologic) and/or symptoms of 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 or magnetic resonance imaging brain scan performed during screening to a prior scan performed at least 4 weeks earlier.
6. Patients with meningeal carcinomatosis.
7. 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 if randomized to E7389 are not eligible. If a patient is to continue on mini-dose warfarin, then the prothrombin time (PT) or international normalized ratio (INR) must be closely monitored.
8. 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 in the opinion of the Investigator. Perimenopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential.
9. Severe/uncontrolled intercurrent illness/infection.
10. Significant cardiovascular impairment (history of congestive heart failure \> New York Heart Association grade II, unstable angina or myocardial infarction within the past six months, or serious cardiac arrhythmia).
11. Patients with organ allografts requiring immunosuppression.
12. Patients with known positive HIV status.
13. Patients who have had a prior malignancy, other than previous breast cancer, 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.
14. Patients with pre-existing neuropathy \> Grade 2.
15. Patients with a hypersensitivity to halichondrin B and/or halichondrin B chemical derivative.
16. Patients who participated in a prior E7389 clinical trial whether or not E7389 was received.
17. 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
timeFrame: From date of randomization until death from any cause
Secondary outcomes:
measure: Progression-Free Survival.
timeFrame: Until disease progression or death.
measure: Best Overall Response
timeFrame: Until Day 30 or every 3 months during Follow-up period for patients who complete study without PD.
measure: Duration of Response.
timeFrame: From first documented CR or PR until disease progression or death.
measure: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
timeFrame: From start of study drug administration up to 30 days after the last dose of study drug (approximately up to 42 months)
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: US Oncology St. Vincent's Hospital - Bruno Cancer Center
state: Alabama
city: Bellflower
country: United States
facility: Bellflower Satellite
state: California
city: Gilroy
country: United States
facility: Research Center
state: California
city: Denver
country: United States
facility: US Oncology
state: Colorado
city: Davie
country: United States
facility: Florida Cancer Research Institute
state: Florida
city: Miami
country: United States
facility: Innovative Medical Research of South Florida, Inc.
state: Florida
city: Atlanta
country: United States
facility: Peachtree Hematology/Oncology Consultants, PC
state: Georgia
city: Niles
country: United States
facility: US Oncology
state: Illinois
city: Indianapolis
country: United States
facility: US Oncology
state: Indiana
city: Iowa City
country: United States
facility: University of Iowa Hospital and Clinic
state: Iowa
city: Baton Rouge
country: United States
facility: Hematology Oncology Clinic
state: Louisiana
city: Saint Joseph
country: United States
facility: Oncology Care Associates, P.L.L.C.
state: Michigan
city: Columbia
country: United States
facility: US Oncology
state: Missouri
city: Missoula
country: United States
facility: Montana Cancer Specialists
state: Montana
city: Las Vegas
country: United States
facility: US Oncology
state: Nevada
city: Albany
country: United States
facility: US Oncology
state: New York
city: East Setauket
country: United States
facility: North Shore Hematology/Oncology Associates
state: New York
city: New York
country: United States
facility: Weill Cornell Breast Cancer Center
state: New York
city: Charlotte
country: United States
facility: Carolina Hematology Oncology Associates
state: North Carolina
city: Raleigh
country: United States
facility: US Oncology
state: North Carolina
city: Eugene
country: United States
facility: US Oncology
state: Oregon
city: Portland
country: United States
facility: St. Vincent Medical Center
state: Oregon
city: Bedford
country: United States
facility: US Oncology
state: Texas
city: Dallas
country: United States
facility: US Oncology
state: Texas
city: Houston
country: United States
facility: US Oncology
state: Texas
city: McAllen
country: United States
facility: US Oncology
state: Texas
city: Midland
country: United States
facility: US Oncology
state: Texas
city: Tyler
country: United States
facility: US Oncology
state: Texas
city: Spokane
country: United States
facility: US Oncology
state: Washington
city: Tacoma
country: United States
facility: Northwest Medical Specialists
state: Washington
city: Vancouver
country: United States
facility: US Oncology
state: Washington
city: Yakima
country: United States
facility: US Oncology
state: Washington
city: Bahia Blanca
country: Argentina
facility: Instituto Oncologico "Las Heras"
state: Buenos Aires
city: C.a.b.a
country: Argentina
facility: Hospital Britanico
state: Buenos Aires
city: La Plata
country: Argentina
facility: Instituto FIDES especialidades Medicas
state: Buenos Aires
city: La Plata
country: Argentina
facility: Breast Clinica de la Mama
state: Buenos Aires
city: Quilmes Oeste
country: Argentina
facility: CER Instituto Medico
state: Buenos Aires
city: Quilmes
country: Argentina
facility: CITEM
state: Buenos Aires
city: Rosario
country: Argentina
facility: Instituto CAICI
state: Pcia. Santa Fe
city: Tucuman
country: Argentina
facility: Centro Medico San Roque
state: San Miguel De Tucuman
city: Buenos Aires
country: Argentina
facility: Hosptial Interzonal General de Mar del Plata
city: Cordoba
country: Argentina
facility: Clinica Universitaria Privada Reina Fabiola
city: Cordoba
country: Argentina
facility: Sanatorio Frances
city: Rosario Santa Fe
country: Argentina
facility: Instituto de Oncologia y Especialidades Medicas
city: Santa Fe
country: Argentina
facility: Clinica Especializada ISIS
city: Southport
country: Australia
facility: The Queen Elizabeth Hospital
state: Queensland
city: Woodville South
country: Australia
facility: Servicio De Oncologia
state: South Australia
city: Melbourne
country: Australia
facility: Maroondah Breast Clinic
city: North Sydney
country: Australia
facility: Mater Medical Centre
city: Perth
country: Australia
facility: Mount Hospital
city: Perth
country: Australia
facility: Royal Perth Hospital, Department of Medical Oncology
city: Graz Steiermark
country: Austria
facility: Medizinische Universitatsklinik Graz
city: Salzburg
country: Austria
facility: Salzburger Landeskliniken Universitatsklinik fur Innere medizin III
city: Brussels
country: Belgium
facility: Institut Jules Bordet
city: Bruxelles
country: Belgium
facility: Cliniques Universitaires Saint-Luc
city: Charleroi
country: Belgium
facility: Centre Hospitalier Notre-Dame - Reine Fabiola
city: Gent
country: Belgium
facility: UZ Gent
city: Kortrijk
country: Belgium
facility: AZ Groeninge, Campus Maria's Voorzienigheid
city: Fortaleza
country: Brazil
facility: Centro Regional Integrado de Oncologia-CRIO
state: CE
city: Giana
country: Brazil
facility: Centro de Pesquisas e Estudios do Centro Goiano
state: GO
city: Curitiba
country: Brazil
facility: Hospital Erasto Gaertner
state: PA
city: Rio De Janiero
country: Brazil
facility: Instituto Nacional do Cancer-Unidade III (INCA III)
state: RJ
city: Porto Alegre
country: Brazil
facility: CPO-Centro de Pesquisas em Oncologia
state: RS
city: Santo Andre
country: Brazil
facility: CEPHO-Centro de Estudos e Pesquisa de Hematologia e oncologia
state: SP
city: Santo Andre
country: Brazil
facility: Santo Andre Diagnosticos e Tratamentos
state: SP
city: Sao Paulo
country: Brazil
facility: Clinica de Oncologia Medica
state: SP
city: Vila Assis
country: Brazil
facility: Hospital Amaral Carvalho
state: SP
city: Ottawa
country: Canada
facility: The Ottawa Hospital Regional Cancer Center
state: Ontario
city: Toronto
country: Canada
facility: Sunnybrook Odette Cancer Centre
state: Ontario
city: Montreal
country: Canada
facility: McGill University Health Centre, Department of Oncology, Gerald Bronfman Center
state: Quebec
city: Osijek
country: Croatia
facility: Clinical Hospital Osijek
city: Zagreb
country: Croatia
facility: University Hospital Center Zagreb
city: Zagreb
country: Croatia
facility: University Hospital for Tumors Zagreb
city: Brno
country: Czechia
facility: Masaryk Memorial Cancer Institute
city: Jihlava
country: Czechia
facility: Hospital Jihlava
city: Prague
country: Czechia
facility: General Faculty Hospital Prague
city: Prague
country: Czechia
facility: Fakultni Thomayerova Nemocnice
city: Praha 10
country: Czechia
facility: Clinic of Radiotherapy and Oncology
city: Praha
country: Czechia
facility: Ustav radia ni onkologie 1. LF UK a FNB
city: Agners Cedex 01
country: France
facility: Centre Paul Papin
city: Besancon
country: France
facility: Hopital Jean Minjoz
city: Bordeaux
country: France
facility: Polyclinique Boredaux Nord Aquitaine
city: Caen Cedex 05
country: France
facility: Centre Francois Baclesse Caen
city: Clermont-Ferrand Cedex 01
country: France
facility: Centre Jean Perrin - CRLC
city: Dijon Cedex
country: France
facility: Centre Georges-Francois Lecierc
city: Lyon
country: France
facility: Hopital Edourad Herriot
city: Paris
country: France
facility: Institut Curie
city: Saint Brieuc Cedex
country: France
facility: Clinique Armoricaine de Radiologie
city: Tours Cedex
country: France
facility: Hopital Bretonneau
city: Budapest
country: Hungary
facility: Semmelweis Medical University, III. Dep. of Internal Med.
city: Debrecen
country: Hungary
facility: Debrecen Medical University, Department of Oncology
city: Pecs
country: Hungary
facility: University of Pecs
city: Szombathely
country: Hungary
facility: Markusovszky Teaching Hospital, Dept. of Oncoradiology, Sec. Med. Oncology
city: Firenze (FI)
country: Italy
facility: Azienda Ospedaliera Careggi
city: Genova
country: Italy
facility: Ospedale San Martino
city: Lecce (LE)
country: Italy
facility: Ospedale "Vito Fazzi" - Lecce
city: Milano
country: Italy
facility: Istituto Scientifico San Raffaele
city: Roma
country: Italy
facility: Ospedale San Filippo Neri
city: Rozzano
country: Italy
facility: Istituto Clinico Humanitas
city: Sora
country: Italy
facility: UO di Oncologia
city: Gdansk
country: Poland
facility: Akademickie Centrum Kliniczne Szpital Akademii Medycznej w
city: Gdynia
country: Poland
facility: Szpital Morski im PCK w Gdyni Gdynskie Centrum Onkologii
city: Gilwice
country: Poland
facility: Centrum Onkologii Instytut M. Sklodowskiej Curie w Warszawie Oddzial Gilwice
city: Krakow
country: Poland
facility: Centrum Onkologii Instytut M Sklodowskiej Curie, Oddzial w Krakowie
city: Poznan
country: Poland
facility: Szpital Kiniczny Przemienienia Panskiego Uniwersyteu Medycznego im Karola Marcinkowskiego w Poznaniu
city: Szczecin
country: Poland
facility: Zachodniopomorski e Centrum
city: Warszawa
country: Poland
facility: Centrum Onkologii Instytut im M. Sklodowskiej Curie w Warszawie
city: Izhervsk Udmurtia
country: Russian Federation
facility: Republic Clinical Oncology Dispensary
city: Kazan
country: Russian Federation
facility: Kazan State Medical University
city: Krasnodar
country: Russian Federation
facility: Krasnodar Territory Clinical Oncology Center
city: Moscow
country: Russian Federation
facility: Burdenko Main Military Hospital
city: Nizhny Novgorod
country: Russian Federation
facility: Nizhniy Novgorod City Oncology Center
city: Novosibirisk
country: Russian Federation
facility: City Clinical Hospital #1
city: Petrozavodsk
country: Russian Federation
facility: Republican Oncology Center
city: Pyatigorsk
country: Russian Federation
facility: State Institution of Healthcare Stavropol Region clinical Oncology dispensary
city: St Petersburg
country: Russian Federation
facility: St Petersburg City Oncology Center
city: St. Petersburg
country: Russian Federation
facility: Pavlov Medical University
city: St. Petersburg
country: Russian Federation
facility: NN Petrov Research Institute of Oncology
city: Tomsk
country: Russian Federation
facility: Tomsk Regional Oncology Dispensary
city: Yaroslavl
country: Russian Federation
facility: GUZ YO Regional Clinical Oncology Hospital
city: Panorama
country: South Africa
facility: Panorama Medical Centre
state: Cape Town
city: Port Elizabeth
country: South Africa
facility: Eastern Cape Oncology Centre, GVI, St Georges Hospital
state: Eastern Cape
city: Johannesburg
country: South Africa
facility: Sandton Oncology Centre
city: Pretoria
country: South Africa
facility: Pretoria Academic Hospital
city: Barcelona
country: Spain
facility: Hospital Vall d Hebron
city: Barcelona
country: Spain
facility: Hospital Mutua de Terrassa
city: Gerona
country: Spain
facility: Hospital Universitario de Girona Dr. Josep Trueta
city: Jaen
country: Spain
facility: Complejo Hospitalario de Jaen
city: Salamanca
country: Spain
facility: Hospital Unversitatio de Salamanca
city: Santa Cruz de Tenerife
country: Spain
facility: Hospital Universitario de Canarias
city: Sevilla
country: Spain
facility: Hospital General Virgen del Rocio
city: Zanagoza
country: Spain
facility: Hospital Clinico de Zaragoza
city: Aarau
country: Switzerland
facility: Kantonsspital Aarau
city: Bern Bern
country: Switzerland
facility: Inselspital Bern
city: St. Gallen
country: Switzerland
facility: Kantonsspital Oncology Haematology
city: Thun
country: Switzerland
facility: Spital Thun-Simmental AG
city: Winterhur
country: Switzerland
facility: Kantonsspital Winterhur
Study officials:
References:
citation: Hoon SN, Lau PK, White AM, Bulsara MK, Banks PD, Redfern AD. Capecitabine for hormone receptor-positive versus hormone receptor-negative breast cancer. Cochrane Database Syst Rev. 2021 May 26;5(5):CD011220. doi: 10.1002/14651858.CD011220.pub2.
citation: Miyoshi Y, Yoshimura Y, Saito K, Muramoto K, Sugawara M, Alexis K, Nomoto K, Nakamura S, Saeki T, Watanabe J, Perez-Garcia JM, Cortes J. High absolute lymphocyte counts are associated with longer overall survival in patients with metastatic breast cancer treated with eribulin-but not with treatment of physician's choice-in the EMBRACE study. Breast Cancer. 2020 Jul;27(4):706-715. doi: 10.1007/s12282-020-01067-2. Epub 2020 Mar 5.
citation: Wedam SB, Beaver JA, Amiri-Kordestani L, Bloomquist E, Tang S, Goldberg KB, Sridhara R, Ibrahim A, Kim G, Kluetz P, McKee A, Pazdur R. US Food and Drug Administration Pooled Analysis to Assess the Impact of Bone-Only Metastatic Breast Cancer on Clinical Trial Outcomes and Radiographic Assessments. J Clin Oncol. 2018 Apr 20;36(12):1225-1231. doi: 10.1200/JCO.2017.74.6917. Epub 2018 Mar 9.
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: Muss H, Cortes J, Vahdat LT, Cardoso F, Twelves C, Wanders J, Dutcus CE, Yang J, Seegobin S, O'Shaughnessy J. Eribulin monotherapy in patients aged 70 years and older with metastatic breast cancer. Oncologist. 2014 Apr;19(4):318-27. doi: 10.1634/theoncologist.2013-0282. Epub 2014 Mar 28.
citation: Cortes J, O'Shaughnessy J, Loesch D, Blum JL, Vahdat LT, Petrakova K, Chollet P, Manikas A, Dieras V, Delozier T, Vladimirov V, Cardoso F, Koh H, Bougnoux P, Dutcus CE, Seegobin S, Mir D, Meneses N, Wanders J, Twelves C; EMBRACE (Eisai Metastatic Breast Cancer Study Assessing Physician's Choice Versus E7389) investigators. Eribulin monotherapy versus treatment of physician's choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study. Lancet. 2011 Mar 12;377(9769):914-23. doi: 10.1016/S0140-6736(11)60070-6. Epub 2011 Mar 2.
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.