Ixabepilone is a semisynthetic analogue of epothilone B, in which the lactone oxygen of epothilone B is replaced by nitrogen to increase drug stability. In vitro studies have shown that ixabepilone is active in cancer cells with upregulated bIII-tubulin expression, which is actually linked with resistance to taxanes and vinca alkaloids. Furthermore, in preclinical models the drug was found to be a poor substrate for multidrug resistance and does not strongly induce P-glycoprotein expression. Its low susceptibility to multiple mechanisms of drug resistance and the lack of cross-resistance with commonly used agents, such as taxanes, make ixabepilone an attractive potential candidate for the treatment of breast cancer previously exposed to taxanes and 
anthracyclines. In support of this notion, a phase III trial clearly demonstrated that the combination of ixabepilone and capecitabine was more efficacious than capecitabine monotherapy in patients with MBC resistant to anthracyclines and taxanes. Currently, ixabepilone is the only epothilone to receive approval by the United States Food and Drug Administration and other Regulatory Agencies for the treatment of MBC. Ixabepilone has been extensively studied in MBC, both in chemotherapy-naive and in heavily pretreated patients. In most phase II or randomized Tubeimoside-I trials, reported so far, ixabepilone was administered at a dose of 40 mg/m2 as a 3hour infusion every 3 weeks. In an attempt to repeat the success story of weekly paclitaxel in the treatment of MBC, as demonstrated in large phase III trials, investigators are currently evaluating the efficacy and safety profile of weekly ixabepilone. To further explore the clinical profile of weekly administration of ixabepilone, the Hellenic Cooperative Oncology Group designed a randomized non-comparative phase II trial in patients with MBC, previously treated with adjuvant chemotherapy, evaluating the approved dose of ixabepilone monotherapy and that of 20 mg/m2 on days 1, 8 and 15 of a 4-week cycle, as first line chemotherapy. The primary objective of the study was overall response rate. Secondary objectives were safety profile, progression-free survival, duration of overall response, time to treatment failure, time to tumor progression and survival. We report here the final analysis of this study. Results of a pre-planned collateral translational research study exploring the predictive/prognostic role of certain biological markers are also reported. Premedication with corticosteroids was not routinely administered. However, oral corticosteroids were required 12 hours prior to the ixabepilone infusion for all patients who had experienced a hypersensitivity reaction in any previous cycle. Antiemetics were not routinely administered but were added to the regimen in patients who experienced severe nausea or vomiting. Granulocyte-colony stimulating factor was not given initially during cycle 1, but could be added to subsequent treatment cycles in patients with febrile neutropenia or delayed neutrophil recovery requiring a dose delay. Treatment was continued until disease progression, intolerable toxicity or consent 3,4,5-Trimethoxyphenylacetic acid withdrawal by the patient. Dose adjustments for adverse reactions are shown as supporting information. In case toxicities recurred after the initial dose reduction, an additional 20% dose reduction was recommended. If toxicities recurred after the second dose reduction, administration of ixabepilone was discontinued permanently. In case bisphophonates had to be given concurrently with the ixabepilone treatment, they were administered sequentially following the infusion of the drug.