In metastatic breast cancer (MBC) patients who have already received anthracyclines, taxanes, antimetabolites and vinca-alkaloids and have developed drug resistance to these drugs, therapeutic options are very limited. Alkylating agents showed a modest activity in pretreated metastatic breast cancer. This phase III trial will compare the effectiveness and the safety profile of vinflunine to an alkylating agent of physician choice in MBC patients who have exhausted anthracyclines, taxanes, antimetabolites and vinca-alkaloids.

Breast cancer is the most frequently diagnosed cancer in women worldwide and the second leading cause of cancer-related deaths in women.

Patients with metastatic breast cancer (MBC) remains incurable, and current goals of therapy are to ameliorate symptoms, delay disease progression, improve or at least maintain quality of life (QoL), and prolong overall survival (OS).There are a number of agents with established single-agent activity, with the anthracyclines and taxanes considered generally the most active. In addition, several drugs with different mechanisms of action such as antimetabolites and vinca-alkaloids have also demonstrated substantial activity in the metastatic setting as single-agents or in combination.

In patients who progress after having received anthracyclines, taxanes, antimetabolites and vinca- alkaloids, therapeutic options are scarce. In this heavily pretreated population for whom overall survival is not expected to exceed 6 to 7 months, there is a clear need for novel therapies.

Vinflunine (VFL) is a microtubule inhibitor obtained by semi-synthesis, interacts with tubulin at the vinca-binding domain and inhibits tubulin assembly by perturbing microtubule dynamics and mitotic spindles without affecting assembled microtubules. VFL antitumour activity was fully demonstrated against a large and varied panel of murine and xenograft models.

The main haematological toxicity reported was the neutropenia Grade 3-4 (40-50%). The incidence of its complications (febrile neutropenia and neutropenic infection) was less than 8%. The main non-haematological toxicity Grade 3-4 (with an incidence more than 10%) reported were constipation and fatigue.

This was a prospective multicentre, open-label, randomised (1:1), phase III study comparing OS in patients treated with vinflunine versus those treated with an alkylating agent of physician's choice as third line treatment or more for patients with locally recurrent and/or metastatic breast cancer previously treated with and no longer candidate to anthracyclines, antimetabolites, taxanes and vinca- alkaloids..

The primary endpoint for the trial was OS. Patients were assessed for toxicity, tumour response and progression and status (alive-dead) at regular intervals during the study treatment and the follow-up period. Patients were treated until disease progression, unacceptable toxicity, patient or investigator's decision. After the study treatment discontinuation, patients were followed until death.

The VFL dose of 280 mg/m² was the selected dose for this phase III study in patients with heavily pre- treated MBC. Indeed, VFL dose was reduced from 320 to 280 mg/m² in advanced transitional cell carcinoma of urothelial tract patients with performance status (PS) of 1 or with PS of 0 and having received prior pelvic irradiation. This dose was more regularly tolerable in patients with advanced disease stage who were heavily pre-treated.

Inclusion Criteria:(main conditions)

• Female patients 18 to 75 years of age with metastatic breast cancer histologically/cytologically confirmed not amenable to curative surgery or radiotherapy and who have received at least two prior chemotherapy regimens including anthracyclines,taxanes,antimetabolite and vinca-alkaloid and are no longer candidate for these drugs,
• Karnofsky performance score of at least 70 %, adequate haematological, hepatic and renal functions and ECG without clinically relevant abnormality.

Exclusion Criteria:

• Concurrent serious uncontrolled medical disorder,
• known or clinical evidence of brain metastases or leptomeningeal involvement,
• pulmonary lymphangitis or symptomatic pleural effusion or symptomatic ascites,
• history of second primary malignancy,
• HIV infection, preexisting neuropathy,
• pregnancy or breast feeding.