Safety and Efficacy Comparison of Docetaxel and Ixabepilone in Non Metastatic Poor Prognosis Breast Cancer

OBJECTIVES:

Primary

• To evaluate the benefit from sequential administration of 3 courses of combination chemotherapy (FEC100) followed by 3 courses of ixabepilone versus docetaxel on the 5-year disease-free survival of women with nonmetastatic, poor-prognosis breast cancer.

Secondary

• To compare the 5-year distant metastasis-free survival.
• To compare the 5-year event-free survival.
• To compare the 5-year overall survival.
• To compare the safety profiles for the two chemotherapy regimens.
• To identify and/or validate predictive-gene expression profiles of clinical response/resistance to the two treatment regimens.
• To bank frozen and fixed tumor and frozen serum prospectively for future translational studies in both genomics and proteomics (transcriptome and proteome analyses, tissue array analyses).
• To compare the cost-effectiveness of these 2 regimens.
• To compare the quality-of-life of patients treated with these 2 regimens.

OUTLINE: This is a multicenter study. Patients are stratified according to participating center, menopausal status (pre- vs post-menopausal), and tumor hormone-receptor status (triple-negative vs progesterone-receptor negative, HER negative, and estrogen-receptor [ER] positive). Patients are randomized to 1 of 2 treatment arms.

• Docetaxel Arm: Patients receive epirubicin hydrochloride IV, fluorouracil IV, and cyclophosphamide IV every 3 weeks in courses 1-3 and docetaxel IV alone every 3 weeks in courses 4-6.
• Ixabepilone Arm: Patients receive treatment in courses 1-3 as in arm I and ixabepilone IV alone every 3 weeks in courses 4-6.

In both arms, courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Patients also complete a quality of life questionnaire periodically.

After completion of study treatment, patients are followed periodically for up to 10 years.

DISEASE CHARACTERISTICS:

Inclusion criteria

• Histologically proven invasive unilateral breast cancer (regardless of the type)

• Initial clinical condition compatible with complete initial resection
• No residual macro or microscopic tumor after surgical excision
• Node-positive disease (i.e., positive sentinel node or positive axillary clearance) (N+) or node-negative disease (-) meeting the following criteria :

• Stage II or III disease
• pT >20 mm (T1-4)
• Patients must meet 1 of the following hormone-receptor criteria:

• Node-positive patients: triple-negative* tumor (HER2 negative, estrogen-receptor [ER] negative, and progesterone receptor [PR] negative) OR double-negative (HER2 negative, PR negative, and ER+)
• Node-negative patients: triple-negative* tumor only
• NOTE: *Hormone-receptor negativity is defined as ER <10% and PR <10% by IHC and HER2 negativity is defined as IHC 0-1+ OR IHC 2+ and FISH or CISH negative
• Must be able to begin chemotherapy no later than day 49 after the initial surgery

Exclusion criteria

• Clinically or radiologically detectable metastases (M0)
• Bilateral breast cancer or contralateral ductal carcinoma in situ
• Any metastatic impairment, including homolateral subclavicular node involvement, regardless of its type
• Any tumor ≥T4a (cutaneous invasion, deep adherence, inflammatory breast cancer)
• HER 2 overexpression defined as IHC 3+ OR IHC 2+ and FISH or CISH positive
• Any clinically or radiologically suspect and non-explored damage to the contralateral breast

PATIENT CHARACTERISTICS:

Inclusion criteria

• Female
• Pre- or postmenopausal
• ECOG performance status 0-1
• Peripheral neuropathy ≤grade 1
• Neutrophil count ≥2,000/mm³
• Platelet count ≥100,000/mm³
• Hemoglobin >9 g/dL
• AST and ALT ≤1.5 times upper limit of normal (ULN)
• Alkaline phosphatase ≤2.5 times ULN
• Total bilirubin ≤1.0 times ULN
• Serum creatinine ≤1.5 times ULN
• LVEF ≥50% by MUGA scan or echocardiography
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for up to 8 weeks after completion of study treatment

Exclusion criteria

• Previous cancer (except cutaneous baso-cellular epithelioma or uterine peripheral epithelioma) in the preceding 5 years, including invasive contralateral breast cancer
• Patients with any other concurrent severe and/or uncontrolled medical disease or infection that could compromise participation in the study
• Clinically significant cardiovascular disease within the past 6 months including any of the following:

• Unstable angina
• Congestive heart failure
• Uncontrolled hypertension (i.e., blood pressure >150/90 mm Hg)
• Myocardial infarction
• Cerebral vascular accidents
• Known prior severe hypersensitivity reactions to agents containing Cremophor EL
• Patients with any psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol and follow-up schedule
• Patients deprived of liberty or placed under the authority of a tutor

PRIOR CONCURRENT THERAPY:

• At least 2 weeks since prior minor surgery (excluding breast biopsy) and adequately recovered
• At least 3 weeks since prior major surgery and adequately recovered
• No prior chemotherapy, hormonal therapy, or radiotherapy
• More than 72 hours since prior and no concurrent treatment with any of the following strong inhibitors of CYP3A4:

• Amiodarone
• Clarithromycin
• Amprenavir
• Delavirdine
• Voriconazole
• Erythromycin
• Fluconazole
• Itraconazole
• Ketoconazole
• Indinavir
• Nelfinavir
• Ritonavir
• Saquinavir
• No concurrent participation in another therapeutic trial involving an experimental drug