E7389 Versus Treatment of Physician's Choice in Patients With Locally Recurrent or Metastatic Breast Cancer
Condition: Breast Cancer
MeSH terms: Breast Neoplasms
Intervention: E7389; Physician's Choice
Intervention description: 1.4 mg/m^2 intravenous (IV) infusion given over 2-5 minutes on Days 1 and 8 every 21 days.; Treatment of the Physician's Choice defined as any single agent chemotherapy, hormonal treatment or biological therapy approved for the treatment of cancer; or palliative treatment or radiotherapy, administered according to local practice, if applicable.
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 762.0
Sex: Female
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Locally recurrent breast cancer; metastatic breast cancer

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.