zk-219477 and Breast-Neoplasms

Treatments for women with recurrent brain metastases from breast cancer are limited. In this phase II study,we administered sagopilone to patients with breast cancer and brain metastases. We observed modest activity with a central nervous system objective response rate of 13.3%; however, median PFS was disappointing. Further studies should focus on other agents to treat this challenging clinical problem.. Patients with progressive metastatic breast cancer to the central nervous system (CNS) have limited treatment options.. We conducted a phase II study of sagopilone, an epothilone B analogue that crosses the blood-brain barrier, in patients with breast cancer brain metastases. Women were treated with 16 mg/m(2) or 22 mg/m(2) intravenously every 21 days. The primary endpoint was CNS objective response rate (ORR). Secondary endpoints included toxicity, progression-free survival (PFS), and overall survival (OS). Using modified, high-resolution magnetic resonance angiography (MRA), we also evaluated changes in vessel tortuosity with treatment.. Fifteen women were enrolled; all had progressive CNS disease despite whole-brain radiotherapy. Two patients achieved a partial response (ORR, 13.3%) and remained in the study for 6 cycles. Responses were not associated with normalization of tumor-associated vessels on correlative imaging studies. Median PFS and OS were 1.4 months and 5.3 months, respectively. The most common grade 3 toxicities were lymphopenia and fatigue. Enrollment was stopped prematurely because of limited observed activity and slow accrual.. Sagopilone was associated with modest CNS activity in patients with breast cancer; however median PFS was disappointing. Further studies should examine other potentially active agents and/or combinations for this challenging clinical problem.

Topics: Adult; Aged; Antineoplastic Agents; Benzothiazoles; Blood-Brain Barrier; Brain Neoplasms; Breast Neoplasms; Disease-Free Survival; Epothilones; Female; Humans; Infusions, Intravenous; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Treatment Outcome

Sagopilone is a novel, fully synthetic epothilone that has shown promising preclinical activity in a range of tumor models, including platinum-resistant ovarian cancer and metastatic breast cancer (MBC). This open-label, multicenter, Phase II study investigated the efficacy, safety, and tolerability of sagopilone administered to patients with MBC. Women with MBC whose previous chemotherapy regimen included a taxane and an anthracycline received sagopilone 16 or 22 mg/m(2) as a 3-h intravenous infusion every 21 days. Efficacy (using modified Response Evaluation Criteria in Solid Tumors), safety, and tolerability were assessed in this population. A total of 65 patients received sagopilone at either 16 mg/m(2) (N = 39) or 22 mg/m(2) (N = 26). Patients received a median of two cycles of sagopilone. Among the 65 patients who were evaluable for efficacy, there were three confirmed tumor responses over both treatment arms; however, the primary target of the study was not reached. The main treatment-related adverse events were sensory neuropathy (81.5%) and fatigue (44.6%). There were no deaths related to the study drug. Sagopilone was moderately tolerated in both treatment arms and showed limited activity in heavily pre-treated patients with MBC.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Benzothiazoles; Breast Neoplasms; Canada; Disease Progression; Disease-Free Survival; Drug Administration Schedule; Epothilones; Fatigue; Female; Germany; Humans; Infusions, Parenteral; Kaplan-Meier Estimate; Middle Aged; Nervous System Diseases; Prospective Studies; Time Factors; Treatment Failure; United States