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.

- Arm I: 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.

- Arm II: 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