The increasing use of anthracyclines and taxanes in the adjuvant, neoadjuvant and first-line metastatic settings, led to a raise of patients presenting with metastatic breast cancer after treatment with these agents. Options for the treatment of patients who have progressed after an anthracycline and a taxane are limited. The high level of in-vitro synergy of vinflunine combined with 5-fluorouracil (5-FU) together with the good tolerance and the encouraging response rate observed while combining IV vinflunine to oral capecitabine make it a promising combination to investigate further in a phase III trial. This phase III trial will evaluate the effectiveness and the safety profile of such combination for the treatment of patient with advanced breast cancer previously treated with or resistant to anthracycline and taxane resistant.

This multicentre, open-label, randomised, Phase III study will enrol 764 patients with advanced breast cancer who have previously been treated with or are resistant to an anthracycline and who are taxane resistant. Patients will be randomised in a 1:1 ratio to receive vinflunine plus capecitabine (Arm A) or capecitabine alone (Arm B).

Randomisation will be stratified according to a minimization procedure:

1. Resistance to anthracyclines ("yes" versus "no"), Relapse ≤ 12 months in the adjuvant or neoadjuvant setting or progression ≤ 4 months in the metastatic setting,
2. Karnofsky performance status ("90-100" versus "70-80"),
3. Measurable disease ("yes" versus "no"),
4. The number of prior lines of chemotherapy in the metastatic setting ("0" versus "1" versus "> 1") and,
5. Study site.

Patients randomised in Arm A will receive:

• Vinflunine at the dose of 280 mg/m² on day 1 of each cycle every 3 weeks, over a 20-minute i.v. infusion and,
• Capecitabine which will be self-administered by the patient in an outpatient setting. Patients will take 825 mg/m² twice daily per os for 14 consecutive days beginning on day 1 of each cycle followed by 1 week of rest. A cycle of therapy is defined as 3 weeks.

For patients randomised in Arm B, capecitabine will be self administered by the patient in an outpatient setting. Patients will take 1250 mg/m² twice daily per os for 14 consecutive days beginning on day 1 of each cycle followed by 1 week of rest. A cycle of therapy is defined as 3 weeks.

The doses and timing of treatment will be modified based on toxicities experienced by the patient.

Patients will be assessed for toxicity, tumour response and progression at regular intervals during treatment. Patients will be evaluated for safety if they received any study drug. Laboratory values, adverse events and other symptoms will be graded.

Tumour response, progression-free survival and duration of response will be evaluated for all randomised patients. Tumour assessment is to be performed every 6 weeks (+/- 3 working days) from randomisation (regardless of the timing of treatment cycles) until disease progression is documented. Patients who discontinue protocol treatment for reasons other than disease progression will have tumour assessments every 6 weeks until documented disease progression. Patients may continue to receive additional cycles of therapy until progressive disease or intolerable toxicity.

Quality of Life assessment, will be measured by EORTC QLQ-C30 and QLQ-BR23 questionnaires, which will be completed by patients.

The primary endpoint for the trial is progression free survival calculated from the date of randomization until the date of progression or the date of death whatever the reason of death. The analysis of Progression-Free Survival is planned to take place when 615 progressions or deaths have been observed. One interim safety analysis is planned and will take place when 50 patients of each arm have completed at least one cycle of study treatment. It is anticipated that up to 170 active study centres will participate, and that accrual will be completed in approximately 30 months.

Inclusion Criteria:

• female patients
• 21 years of age or older
• histologically/cytologically confirmed carcinoma of the breast
• documented locally recurrent or metastatic disease not amenable to curative surgery or radiotherapy
• either one, two or three prior chemotherapy regimens
• prior treatments including both an anthracycline and a taxane and patient no longer candidate for these drugs
• measurable or non-measurable disease according to RECIST 1.1
• Karnofsky performance score of at least 70 %
• adequate haematological, hepatic and renal functions
• ECG without clinically relevant abnormality

Exclusion Criteria:

• known or clinical evidence of brain metastasis or leptomeningeal involvement
• pulmonary lymphangitis or symptomatic pleural effusion
• any serious, concurrent uncontrolled medical disorder
• history of second primary malignancy
• preexisting motor/sensory peripheral neuropathy
• known history of HIV infection
• prior therapy with capecitabine and/or vinca-alkaloids
• history of severe hypersensitivity to vinca alkaloids and/or to fluoropyrimidine or contra indication to any of these drugs
• known or suspected dihydropyrimidine dehydrogenase (DPD) deficiency
• pregnancy or breast feeding