Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Phase III Randomized Study Evaluating the Efficacy and Safety of Continued and Re-induced Bevacizumab in Combination With Chemotherapy for Patients With Locally Recurrent or Metastatic Breast Cancer After First-line Chemotherapy and Bevacizumab Treatment
Brief Summary: This randomized, open-label, parallel-group study will assess the efficacy and s afety of Avastin (bevacizumab) in combination with chemotherapy versus chemother apy alone as second- and third-line therapy in patients with locally recurrent o r metastatic breast cancer progressing after first-line therapy with Avastin and chemotherapy. Patients will be randomized to receive either Avastin (15 mg/kg e very 3 weeks or 10 mg/kg every 2 weeks intravenously) plus standard chemotherapy or chemotherapy alone. Anticipated time on study treatment is until third-line disease progression or unacceptable toxicity occurs.


Options:
A: Inclusion Criteria:

* Female patients, \>/= 18 years of age
* Histologically confirmed HER2-negative breast cancer
* Disease progression during or following first-line treatment with Avastin and chemotherapy for locally recurrent or metastatic breast cancer
* Avastin treatment in first-line setting must have been a minimum of 4 cycles (15 mg/kg) or 6 cycles (10 mg/kg) in combination with chemotherapy
* ECOG performance status 0-2
* At least 28 days since prior radiation therapy or surgery and recovery from treatment

Exclusion Criteria:

* Anti-angiogenic therapy or anti-vascular endothelial growth factors other than Avastin for first-line treatment
* Active malignancy other than superficial basal cell and superficial squamous cell carcinoma of the skin, or in situ carcinoma of the cervix or breast within the last 5 years
* Inadequate renal function
* Clinically relevant cardio-vascular disease
* Known CNS disease except for treated brain metastases
* Chronic daily treatment with high-dose aspirin (\>325 mg/day) or clopidogrel (\>75 mg/day)
* Pregnant or lactating women
B: DISEASE CHARACTERISTICS:

* Histologically confirmed unilateral or bilateral primary breast cancer

  * Meets 1 of the following staging criteria:

    * Clinical stage T4 or T3 disease
    * Clinical stage T1 and pathologic stage N+ by sentinel lymph node biopsy OR clinical stage T2, N+ disease AND estrogen receptor (ER) or progesterone receptor (PR) positive tumor
    * ER and PR negative tumor (T1-4, N0-3, M0)
* Disease confirmed by core biopsy

  * No fine-needle aspiration or incisional biopsy
* Bidimensionally measurable disease\*

  * Tumor lesion palpable and measures ≥ 2 cm OR tumor lesion ≥ 1 cm in maximum diameter by sonography

    * For inflammatory disease, extent of inflammation can be used as measurable lesion NOTE: \*In patients with multifocal or multicentric breast cancer, the largest lesion should be measured
* Candidate for adjuvant chemotherapy

  * No low- or moderate-risk patients who are doubtful candidates for adjuvant chemotherapy and do not fulfill the staging criteria
* Known HER-2/neu status by core biopsy

  * HER-2/neu positive tumor is defined as +3 by immunohistochemistry \[IHC\] OR positive by fluorescence in situ hybridization (FISH)
* No evidence of distant metastasis
* Hormone receptor status:

  * ER- or PR-positive tumor OR ER- and PR-negative tumor

PATIENT CHARACTERISTICS:

* No male patients
* Menopausal status not specified
* Karnofsky performance status 80-100%
* Life expectancy ≥ 10 years (disregarding diagnosis of cancer)
* Normal cardiac function confirmed by ECG
* LVEF ≥ 55% by cardiac ultrasound
* Neutrophil count ≥ 2,000/mm\^3
* Platelet count ≥ 100,000/mm\^3
* Hemoglobin ≥ 10 g/dL
* Bilirubin normal
* AST and ALT ≤ 2.5 times upper limit of normal (ULN)
* Alkaline phosphatase (AP) ≤ 5 times ULN OR
* AP ≤ 2.5 times ULN AND AST and/or ALT ≤ 1.5 times ULN
* Creatinine ≤ 2 mg/dL
* Creatinine clearance ≥ 50 mL/min
* Not pregnant or nursing
* Negative pregnancy test
* Fertile patients must use effective nonhormonal contraception
* No motor or sensory neuropathy ≥ grade 2
* No other malignancy within the past 5 years except carcinoma in situ of the cervix or nonmelanoma skin cancer
* No New York Heart Association class II-IV congestive heart failure
* No coronary artery disease
* No history of myocardial infarction
* No uncontrolled arterial hypertension (i.e., blood pressure ≥ 160/90 mm Hg despite antihypertensive therapy)
* No rhythm abnormalities requiring permanent therapy
* No history of significant neurological or psychiatric disorders including psychotic disorders, dementia, or seizures that would preclude giving informed consent
* No active infection
* No active peptic ulcer
* No unstable diabetes mellitus or insulin-dependent type II diabetes mellitus
* No other serious illness or medical condition
* No known hypersensitivity reaction to investigational compounds or incorporated substances
* No definite contraindications for the use of corticosteroids
* No known dihydropyrimidine dehydrogenase deficiency
* Must be fit for anthracycline/taxane-containing chemotherapy

PRIOR CONCURRENT THERAPY:

* No prior chemotherapy for any malignancy
* No prior radiation therapy for breast cancer
* No concurrent bisphosphonates during chemotherapy

  * Bisphosphonates allowed postoperatively
* No chronic treatment with corticosteroids unless it is initiated \> 6 months prior to study entry and is given at low doses (≤ 20 mg methylprednisolone or equivalent)
* No concurrent amifostine during chemotherapy
* No concurrent cardioprotectors (e.g., dexrazoxane) during chemotherapy
* No concurrent sex hormone therapy
* No concurrent virostatic agents (e.g., sorivudine or brivudine)
* No concurrent aminoglycosides
* No other concurrent experimental drugs or anticancer therapy
* At least 30 days since prior participation in another clinical trial with any investigational (not marketed) drug
C: Inclusion Criteria:

* Written informed consent must be obtained and documented according to the local regulatory requirements prior to beginning specific protocol procedures.
* Complete baseline documentation sent to SKM CRS.
* Unilateral or bilateral primary carcinoma of the breast, confirmed histologically by core biopsy. Fine-needle aspiration is not sufficient. Incisional biopsy is not allowed. In case of bilateral cancer the investigator has to decide prospectively which side will be evaluated for the primary endpoint.
* Tumor lesion in the breast with a palpable size of \> 2 cm in maximum diameter. The leasion has to be measurable in two-dimensions by sonography. In case of inflammatory disease the extent of inflammation can be used as measurable lesion. The following tumor stages are eligible:

  * Palpable breast tumor size of \> 2 cm without involvement of the skin or muscle or evidence of inflammatory disease (T2-3). Clinical N0-2. (Study population I)
  * Primary tumor with clinical involvement of skin or muscle or clinically evidence of inflammatory breast cancer (T4 a-d) or clinical N3 including supraclavicular nodes. (Study population II). In patients with multifocal or multicentric breast cancer, the largest lesion should be measured.
* Age \> 18 years.
* Karnofsky Performance status index \> 80%.
* Normal cardiac function must be confirmed by LVEF or shortening fraction (echocardiography or MUGA scan respectively) within 3 months prior to registration. The result must be above the normal limit of the institution.
* Laboratory requirements (within 14 days prior to registration):

  * Hematology:

    * Neutrophils \> 2.0 x 109/L and
    * Platelets \> 100 x 109/L and
    * Hemoglobin \> 10 g/dL
  * Hepatic function:

    * Total bilirubin \< 1 x UNL and
    * ASAT (SGOT) and ALAT (SGPT) \< 2.5 x UNL and
    * Alkaline phosphatase \< 5 UNL. Patients with ASAT and/or ALAT \> 1.5 x UNL associated with alkaline phosphatase \> 2.5 x UNL are not eligible for the study.
  * Renal function:

    * Creatinine \< 175 µmol/L (2 mg/dL)
* Tissue block centrally available for further biological tests.
* Negative pregnancy test (urine or serum) within 14 days prior to registration for all women of childbearing potential.
* Complete staging work-up within 3 months prior to registration. All patients must have bilateral mammography, breast ultrasound, breast MRI (optional), chest X-ray (PA and lateral), abdominal ultrasound and/or CT scan, and bone scan. In case of positive bone scan, bone X-ray is mandatory. Other tests may be performed as clinically indicated.
* Patients must be available and compliant for treatment and follow-up. Patients registered on this trial must be treated and followed up at the participating center which can be the Principal or the Co- Investigator's site.

Exclusion Criteria:

* Early breast cancer with a tumor size of \< 2 cm measured by palpation.
* Patients with low or moderate risk. These patients are defined as having none of the following risk factors: Age \< 36 years, cT\> 5cm, ER and PR negative, cN+, or Grade III.
* Evidence of distant metastasis.
* Prior chemotherapy for any malignancy.
* Pregnant or lactating patients. Patients of childbearing potential must implement adequate non-hormonal contraceptive measures during study treatment.
* Pre-existing motor or sensory neuropathy of a severity \> grade 2 by NCI criteria.
* Other serious illness or medical condition:

  * previous malignant disease with a disease-free survival of less than 5 years (except CIS of the Cervix and non-melanomatous skin cancer.
  * congestive heart failure or unstable angina pectoris, previous history of myocardial infarction within 1 year prior to study entry, uncontrolled arterial hypertension or high-risk uncontrolled arrhythmias.
  * history of significant neurologic or psychiatric disorders including psychotic disorders, dementia or seizures that would prohibit the understanding and giving of informed consent.
  * active uncontrolled infection.
  * active peptic ulcer, unstable diabetes mellitus.
* Chronic treatment with corticosteroids unless initiated \> 6 months prior to study entry and at low dose (\</= 20 mg methylprednisolone or equivalent).
* Concurrent treatment with sex hormones. Prior treatment must be stopped before study entry.
* Definite contraindications for the use of corticosteroids.
* Concurrent treatment with other experimental drugs. Participation in another clinical trial with any investigational not marketed drug within 30 days prior to study entry.
* Concurrent treatment with any other anti-cancer therapy.
* Known hypersensitivity reaction to one of the investigational compounds or incorporated substances.
* Male patients.
D: 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.

Answer: A