Trial of Ixabepilone in Patients With HER-2 Negative Metastatic Breast Cancer (HIT)

Phase II Randomized Trial of Ixabepilone Administered Weekly or Every Three Weeks in Patients With HER-2 Negative Metastatic Breast Cancer Previously Treated With Chemotherapy in the Neo-adjuvant or Adjuvant Setting

This is a Phase II Randomized, Open Label, Non-comparative Trial (Parallel Assignment and Efficacy Study) for patients with HER-2 Negative Metastatic Breast Cancer Previously Treated With chemotherapy in the Neo-Adjuvant or Adjuvant Setting.Patients will be randomized to receive Ixabepilone either every three weeks, or weekly for three weeks followed by one week off. Patients will be treated until consent withdrawal, intolerable toxicity or documented disease progression

Patients with measurable metastatic breast cancer that have been treated in the adjuvant or neo-adjuvant setting with chemotherapy will be considered for this study. Subjects must not have received cytotoxic chemotherapy for locally recurrent/metastatic disease. Patients who fulfil the eligibility criteria, and have signed inform consent for the trial will be centrally randomized by electronic means to one of two ixabepilone treatment arms. Stratification factors will include: time to recurrence from adjuvant treatment, calculated from the date of the last dose of adjuvant treatment to the date of relapse (≤ 1 year vs. > 1 year); and previous chemotherapy with taxane regimen in the neo-adjuvant or adjuvant setting (yes vs. no). Randomization will be balanced by site.Treatment Protocol· Arm A [standard once every three weeks schedule]:Ixabepilone [BMS-247550] will be administered on Day 1 (D1) every three weeks as a 3-hour infusion at a dose of 40 mg/m2. · Arm B [weekly schedule]:Ixabepilone [BMS-247550] will be administered weekly for three weeks as a 3-hour infusion at a dose of 20 mg/m2, followed by one week-off.Treatment can be continued until consent withdrawal by the patient, intolerable toxicity or documented disease progression.

Inclusion Criteria:

• Written informed consent
• Female patients aged 18 to 75 years inclusive
• Prior chemotherapy in the adjuvant or neo-adjuvant setting
• Diagnosis of HER-2 negative (HER-2 <2+ by immunohistochemistry and/or FISH negative) metastatic breast adenocarcinoma confirmed by the pathology department of the enrolling institution
• Eastern Cooperative Oncology Group performance status of 0 or 1
• Life expectancy of at least 12 weeks
• Measurable disease by the Response Criteria in Solid Tumors (RECIST) method
• Laboratory values within the specified ranges within 1 week of study enrolment:
• Absolute neutrophil count of ≥ 1.5 x 109/L
• Thrombocyte count of ≥ 100 x 109/L
• Subjects must not have received cytotoxic chemotherapy for locally recurrent/metastatic disease
• Prior hormonal therapy for locally recurrent or metastatic disease allowed
• AST and ALT ≤ 2.5 x ULN
• Bilirubin ≤ 1.5 x ULN
• Recovery from prior palliative radiotherapy for bone metastases

Exclusion Criteria:

• Because of concerns that ixabepilone metabolism may be inhibited by potent cytochrome P450 3A4 inhibitors, patients must not receive the following medications, up to 72 hours prior to initiation of study therapy and until they come off treatment with ixabepilone: amprenavir, delavirdine, voriconazole, erythromycin, cyclosporine, troleandomycin, terfenadine, ketoconazole, nelfinavir, and ritonavir
• Patients with CTC grade 2 or greater neuropathy at baseline
• Patients with any history or evidence of brain an/or leptomenigneal metastasis
• Patients with clinically significant cardiac disease (e.g. unstable angina, congestive heart failure, myocardial infarction) within 6 months from study entry
• Psychiatric disorders or other conditions rendering the subject incapable of complying with the requirements of the protocol
• Any concurrent active malignancy other than non-melanoma skin cancer or in situ carcinoma of the cervix (subjects with a history of previous malignancies but without evidence of disease for 5 years will be allowed to enter the trial)
• Prior severe HSR to agents containing Cremophor EL
• Women of childbearing potential (WOCBP) who are unwilling or unable to use an adequate method of contraception to avoid pregnancy throughout the study and for up to 12 weeks from the last dose of ixabepilone, in such a manner that the risk of pregnancy is minimized WOCBP include: any female who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation or bilateral oophorectomy) or is not postmenopausal (defined as amenorrhea ≥ 12 consecutive months; women on hormone replacement therapy with documented FSH level > 35mIU/mL. Even women who are practising abstinence or whom their partner is sterile (e.g. vasectomy) should be considered of childbearing potential.
• Women who are pregnant or breastfeeding
• Women with a positive pregnancy test on enrolment or prior to study therapy
• No other concomitant chemotherapy, endocrine therapy, immunotherapy, radiation therapy (except for palliative radiotherapy for bone metastases) or investigational treatments are allowed during subject's participation in the study