A Pilot Dose Escalation Trial of a Densified Chemotherapy Association of Docetaxel and Epirubicin Driven by Mathematical Modeling in Metastatic Breast Cancer Patients: The MODEL1 Study

To determine the maximum tolerated dose of a densified regimen of the association of docetaxel (DTX) and epirubicin (EPI), supported by the concomitant administration of hematopoietic growth factors in patients with metastatic breast cancer in first-line, optimizing in each patient the administration schedule using a formal procedure based on mathematical models in order to manage the severity of induced neutropenia. The models used in this project allow: * an optimal administration schedule of the planned total dose per cycle (number of infusions and calculating their rates and durations) * an individualization of the administration schedule from the second cycle (based on observations from the first cycle), and * an assessment of the risk of a dose-limiting toxicity event combining several severe non-hematological toxicities (conditioning the decision for dose escalation). Using formal mathematical models the investigators expect controlling the hematological and non-hematological toxicities in order to realize the full series of six cycles of densified DTX+EPI chemotherapy (2 weeks per cycle) for each patient. For each patient, chemotherapy is considered feasible if it is possible, in the absence of tumor progression, to consider 6 cycles of treatment without observing any serious adverse events and without: * patient death that may be related to the treatments; * decision of the patient to interrupt treatment for physical or psychological tolerance reasons; * decision of the investigator to discontinue treatment, in the absence of disease progression.

Sex

Female

Minimum age

18 Years

Inclusion Criteria:

* Age ≥ 18 years,
* ECOG performance status ≤ 2
* Diagnosed with metastatic HER2-negative hormone-resistant chemotherapy-naive breast cancers, previous adjuvant chemotherapy treatment are allowed.
* Histologically or cytologically proven breast cancer metastases or associated with CA 15-3 levels 50% above the normal value
* Hormone resistance defined by the presence of negative hormone receptors or disease progression within 6 months of the initiation of hormone therapy.
* Adequate renal and liver function (ASAT and ALAT \< twice the upper limit normal value (ULN) if no liver metastases, or \< 4×ULN if liver metastases; total bilirubin \< 2×ULN),
* Adequate cardiac function (left ventricular ejection fraction (LVEF) \> 50%),
* Neutrophils ≥ 1200/mm3
* Platelets ≥ 105/mm3

Exclusion Criteria:

* Cerebral metastases and meningeal involvement,
* Other malignant diseases,
* Significant comorbidities,
* Previous chemotherapy for metastatic disease, or previous chemotherapy with a total cumulative dose greater than 600 mg/m² for EPI or greater than 450 mg/m² for DTX