Options for the treatment of patients who have progressed after an anthracycline and a taxane are limited. Capecitabine currently has a role in this setting, yet as many as 80% of patients do not respond to this treatment and those who respond eventually develop clinical resistance.

The antitumour activity of vinflunine has been demonstrated in patients with breast cancer after exposure to anthracycline and to taxane.

Vinflunine plus capecitabine has been shown to be a feasible combination for patients previously treated with an anthracycline and a taxane. Each drug in combination can be administered at efficacious doses.

This population has few therapeutic options with established clinical benefit. The development of a new regimen and potential new standard of care for this group is important.

• Primary objective:

  • to compare in patients with advanced breast cancer pretreated with anthracycline and taxane the efficacy of the combination of vinflunine and capecitabine with capecitabine alone, in terms of progression-free survival.

• Secondary objectives:

  • to evaluate the response rate, the time to response and the duration of response in both arms
  • to compare the disease control rate between arms
  • to evaluate the duration of disease control in both arms
  • to evaluate the overall survival in both arms
  • to evaluate safety

Methodology This multicentre, open-label, randomised, Phase III study will enrol a total of 334 patients with advanced breast cancer who have previously been treated with an anthracycline and a taxane. Patients will be randomised in a 1:1 ratio to receive VFL plus capecitabine (Arm A) or capecitabine alone (Arm B).

RECIST 1.1 will be used for tumor assessment CTC - CAE version 3.0 will be used for safety assessment

INCLUSION CRITERIA:

1. Written informed consent
2. Histologically or cytologically confirmed Her-2 negative carcinoma of the breast
3. Documented locally recurrent or metastatic disease not amenable to curative surgery or radiotherapy
4. One, two or three prior chemotherapy regimens including those administered in the neoadjuvant or adjuvant setting. At least one of the regimens must have been given for the treatment of advanced disease.
5. Prior treatment must have included both an anthracycline and a taxane. minimum cumulative dose of 180 mg/m² of doxorubicin or of 300 mg/m² of epirubicin
6. Documented progression on or within 12 months of the most recent chemotherapy.
7. Prior hormone therapy is allowed
8. Prior radiation therapy is allowed to less than 30% of the bone marrow
9. LMeasurable or non measurable disease defined according to RECIST V1.1
10. Adequate recovery from recent surgery
11. Estimated life expectancy superior or equal of 12 weeks
12. KPS equal or superior to 70%
13. Age equal or superior to 21 years and < 80 years
14. ANC) equal or superior to 1.5 x 109/L, platelet count equal or superior to 100 x109/L and haemoglobin > 10 g/dL.
15. Bilirubin inferior or equal to 1.5 x upper limit of normal (ULN), AST and ALT inferior or equal to 2.5 x ULN or inferior or equal to 5 x ULN in the case of liver metastases, alkaline phosphatase inferior or equal to 5 x ULN.
16. Calculated creatinine clearance superior or equal to 50 mL/min
17. Normal ECG
18. Patients on coumadin or warfarin must be on stable doses and INR inferior or equal to 3
19. Women of childbearing potential must be using a medically accepted method of contraception. Women of childbearing potential must have a negative serum or urine pregnancy test within 72 hours prior to first treatment administration.
20. Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be assessed with the patient before registration in the trial.

EXCLUSION CRITERIA

1. Known or with clinical evidence of brain metastasis or leptomeningeal involvement.
2. Pulmonary lymphangitis or symptomatic pleural effusion (grade > 2) that results in pulmonary dysfunction requiring active treatment.
3. Patients having received any other experimental drug or chemotherapy within 30 days
4. History of second primary malignancy, except: bilateral breast carcinoma, in situ carcinoma of the cervix, adequately treated non melanomatous carcinoma of the skin, and other malignancy treated at least 5 years previously with no evidence of recurrence
5. Pre-existing motor/sensory peripheral neuropathy of CTCAE version 3.0 grade >1
6. Patients having received > 3 regimens of chemotherapy
7. Prior therapy with capecitabine and/or vinca-alkaloids
8. History of severe hypersensitivity to vinca alkaloids and/or to fluoropyrimidine or any contra indication to any of the study drugs
9. Known or suspected DPD
10. Pregnant or lactating; With positive pregnancy test at inclusion
11. Female of childbearing potential who is unwilling or unable to use a medically accepted method to avoid pregnancy during the 2 months preceding the start of study treatment, throughout the study period and at least 3 months following the last dose of study treatment
12. Known history of HIV infection
13. Inability to take and/or absorb oral medication
14. Any serious, concurrent uncontrolled medical disorder especially uncontrolled hypercalcaemia, congestive heart failure, uncontrolled high-risk hypertension, arrhythmia, angina pectoris or previous history of myocardial infarction within 6 months prior to randomisation.
15. Prior BMT or autologous stem cell infusion following high-dose chemotherapy.