Please select the eligibility criteria that correspond to the clinical trial below.
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
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.


Options:
A: 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.
B: Inclusion Criteria:

* Female patients with histologically proven, core-biopsied, invasive breast cancer of any clinical and/or radiological T-stage (except for T4d)
* Age 18-70 years
* WHO performance status ≤ 2
* No prior or current neoplasm except for curatively treated non-melanoma skin cancer, in situ carcinoma of the cervix
* No distant disease / secondary carcinoma judged clinically and at least by chest X-ray, liver sonography, and bone scan upon randomization
* No medical and/or cardiologic contraindication to receive an anthracycline- and taxane-containing chemotherapy regimen. Normal cardiac function must be confirmed by LVEF (echocardiography or Muga scan). The result must be above 50% or above the institution's ULN
* Results of the following assessments at the time of randomization must be available:

  1. chest wall CT, abdomen CT, bilateral mammography: within 4 weeks before enrolment;
  2. laboratory requirements: within 2 weeks before enrolment
  3. hematology: neutrophils ≥ 4.0 x 109/l, platelets ≥ 150 x 109/l, haemoglobin ≥ 13 g/dl
  4. hepatic function: total bilirubin \< 1 x ULN, ASAT (SGOT) and ALAT (SGPT) \< 1x ULN, alkaline phosphatase \< 1 x ULN. In case of abnormal values, liver function tests have to be repeated within 3 days before study treatment.
  5. renal function: creatinine ≤ 1 x ULN,
  6. histology, grading, hormone receptor status, HER-2/neu status
* Signed and dated informed consent before the start of specific protocol procedures
* Negative pregnancy test in the presence of childbearing potential

Exclusion Criteria:

* Stage T4d / inflammatory breast cancer
* Pregnant or lactating patients; patients of childbearing potential must implement adequate contraceptive measures during study participation
* Pre-existing motor or sensory neurotoxicity of a severity ≥ WHO grade 2
* Preoperative local treatment for breast cancer (i.e. incomplete surgery, radiotherapy)
* Prior or concomitant systemic antitumor therapy
* Other serious illness or medical condition

  1. congestive heart failure or unstable angina pectoris, even if medically controlled.

     Previous history of myocardial infarction within 1 year from study entry, uncontrolled hypertension or high-risk uncontrolled arrythmias
  2. history of significant neurologic or psychiatric disorders, including psychotic disorders, dementia or seizures that would prohibit the understanding and giving of informed consent
  3. active uncontrolled infection
  4. unstable peptic ulcer, unstable diabetes mellitus or other contraindication for the use of corticosteroids
* Concurrent treatment with corticosteroids except as use for the prophylactic regimen, inhalational use, treatment of acute hypersensitivity reactions, treatment of nausea/vomiting or chronic treatment (initiated \> 6 months prior to study entry) at low dose (≤ 20 mg methylprednisolone or equivalent)
* Known hypersensitivity against taxanes and/or epirubicin and/or fluorouracil/capecitabine
* Known dihydropyrimidine-dehydrogenase (DPD) deficit
* Treatment with an investigational drug within 30 days prior to study entry
* Legally incapacitated and/or other circumstances which make it unfeasible for the subject to understand the nature, meaning and consequences of the clinical study
* Concurrent psychiatric illness according to ICD (alcohol addiction) at the time of study entry
C: 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.
D: DISEASE CHARACTERISTICS:

* Histological diagnosis of invasive breast carcinoma

  * Cytological proof of malignancy alone is not sufficient
  * Early stage disease (T0-3, N0-2, M0) without clinical suspicion or evidence of distant metastases on routine staging
  * No locally advanced breast cancer (T4 and/or N3 disease)
* Completely resected disease by breast-conserving surgery with axillary node clearance or modified radical mastectomy within the past 4-8 weeks

  * Negative surgical margins required, unless either of the following are true:

    * Deep surgical margins after full thickness resection
    * Noninvasive cancer at surgical margins for which a mastectomy is planned after completion of study chemotherapy
  * No contraindication for or refusal of postoperative radiotherapy in patients who underwent prior breast-conserving surgery
* Definite indication for adjuvant chemotherapy
* No prior or current invasive breast cancer or bilateral breast cancer

  * Prior surgically-treated ductal carcinoma in situ or lobular carcinoma in situ allowed
* Hormone receptor status:

  * Estrogen receptor- and/or progesterone receptor-positive or -negative tumor

PATIENT CHARACTERISTICS:

* Sex: male or female
* Menopausal status: premenopausal or postmenopausal
* No previous malignancy except basal cell carcinoma, carcinoma in situ of the cervix, or any cancer from which the patient has been disease-free for 10 years and for which treatment consisted solely of resection
* ECOG status 0 or 1
* Hemoglobin \> 9 g/dL
* WBC \> 3,000/mm³
* Platelet count \> 10,000/mm³
* Bilirubin normal (unless due to known Gilbert's disease)
* AST and ALT ≤ 1.5 times upper limit of normal (ULN)
* Albumin normal
* Creatinine ≤ 1.5 times ULN
* Creatinine clearance \> 50 mL/min
* No active, uncontrolled infection
* Not pregnant or nursing
* Fertile patients must use effective contraception
* No concurrent medical, psychiatric, or geographic problems that might prevent completion of treatment or follow-up
* Available for a minimum of 5 years' follow-up
* No known serious viral infection such as active hepatitis B, hepatitis C, or HIV
* No significant cardiac disease, such as impaired left ventricular function or active angina requiring regular anti-anginal medication and/or resulting in restricted physical activity
* No history of significant renal impairment or disease

PRIOR CONCURRENT THERAPY:

* No simultaneous participation in the active intervention phase of another treatment trial
* Not being approached or recruited for another trial within 2 months of study entry
* No previous chemotherapy, hormonal therapy or radiotherapy for the treatment of pre-invasive or invasive cancer except for either of the following:

  * Previous radiotherapy for basal cell carcinoma
  * Previous preoperative endocrine therapy, provided there was no evidence of progression during this therapy, it lasted for less than 6 weeks in duration, and it was stopped at least one month prior to trial entry
* Concurrent luteinizing hormone-releasing hormone analog therapy allowed for premenopausal patients
* More than 4 weeks since prior hormone replacement therapy (HRT) or pre-operative endocrine therapy
* No prior breast conserving surgery if there is a contradiction for or refusal of postoperative radiotherapy

Answer: A