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
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
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
- Regimens must have included an anthracycline (e.g., doxorubicin, epirubicin) and
a taxane (e.g., paclitaxel, docetaxel), either in combination or in separate
- 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
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.
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
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
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.