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

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) and giving them after surgery may kill any tumor cells remaining after surgery. It is not yet known whether docetaxel is more effective than ixabepilone when given after surgery and combination chemotherapy in treating breast cancer. PURPOSE: This randomized phase III trial is studying giving combination chemotherapy followed by docetaxel or ixabepilone to compare how well they work in treating patients who have undergone surgery for nonmetastatic breast cancer.

Detailed Description
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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.

Official Title
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Randomized, Open Label, Multicentric Phase III Evaluating the Benefit of a Sequential Regimen Associating FEC 100 and Ixabepilone in Adjuvant Treatment of Non Metastatic, Poor Prognosis Breast Cancer Defined as Triple-negative Tumor [HER2 Negative - ER Negative - PR Negative] or [HER2 Negative and PR Negative] Tumor; in Node Positive or Node Negative Patients.

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: cyclophosphamide
* Drug: Docetaxel
* Drug: epirubicin hydrochloride
* Drug: fluorouracil
* Drug: ixabepilone


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Docetaxel<br>3 cycles of FEC100 (F and C, each at 500 mg/m², E 100 mg/m², every 3 weeks) followed by 3 cycles of D (100 mg/m² every 3 weeks) | Drug: cyclophosphamide<br>* 500 mg/m² every 3 weeks<br>Drug: Docetaxel<br>* 100 mg/m² every 3 weeks<br>Drug: epirubicin hydrochloride<br>* 100 mg/m² every 3 weeks<br>Drug: fluorouracil<br>* 500 mg/m² every 3 weeks<br>|
| Experimental: Ixabepilone<br>3 cycles of FEC100 (F and C, each at 500 mg/m², E 100 mg/m², every 3 weeks) followed by 3 cycles of Ixabepilone (40 mg/m² every 3 weeks); | Drug: cyclophosphamide<br>* 500 mg/m² every 3 weeks<br>Drug: epirubicin hydrochloride<br>* 100 mg/m² every 3 weeks<br>Drug: fluorouracil<br>* 500 mg/m² every 3 weeks<br>Drug: ixabepilone<br>* 40 mg/m² every 3 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Disease-free Survival (DFS) | DFS is defined as the interval between the date of randomization and the date of breast cancer relapse (local, regional or distant) or the date of invasive contralateral breast cancer or death from any cause, whichever occurs first | At 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Disease-free Survival Events for Triple-negative Subgroup | DFS is defined as the interval between the date of randomization and the date of breast cancer relapse (local, regional or distant) or the date of invasive contralateral breast cancer or death from any cause, whichever occurs first in participants with triple negative breast cancer only. | At 5 years | 
| Number of Disease-free Survival Events for ER+/PR-/HER2- Subgroup | DFS is defined as the interval between the date of randomization and the date of breast cancer relapse (local, regional or distant) or the date of invasive contralateral breast cancer or death from any cause, whichever occurs first in participants with ER+/PR-/HER2- breast cancer only. | At 5 years | 
| Number of Distant Metastasis-free Survival Events for the Whole Population | The distant metastases-free survival is the length of time during and after the treatment for cancer that a patient is still alive and the cancer has not spread to other parts of the body. | At 5 years | 
| Number of Event-free Survival | The Event-free Survival is defined as the interval between the date of randomization and the date of breast cancer relapse (local, regional or distant) or the date of invasive contralateral breast cancer or the date of second neoplasia, or the date of death from any cause, whichever occurs first. | At 5 years | 
| Overall Survival | The overall survival is the length of time from randomization that patients enrolled in the study are still alive. | At 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage II breast cancer, stage IIIA breast cancer, stage IIIB breast cancer, stage IIIC breast cancer