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
1. Female patients with histologically or cytologically confirmed carcinoma of the
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
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
- 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
- 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
10. Patients willing and able to comply with the study protocol for the duration of the
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.
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
16. Patients who participated in a prior E7389 clinical trial whether or not E7389 was
17. Patients with other significant disease or disorders that, in the Investigator's
opinion, would exclude the patient from the study.