Phase II Study of the Novel Epothilone Sagopilone (ZK-EPO) in Patients with Progressive Metastatic Breast Cancer.

Abstract

Abstract Background: Sagopilone, a microtubule-stabilizing agent, is a novel, fully synthetic epothilone undergoing clinical development in a variety of tumor types. Proof-of-concept has been demonstrated in Phase II trials of platinum-resistant and -sensitive ovarian cancer, prostate cancer, and melanoma. Sagopilone has shown significant preclinical activity in taxane-resistant breast cancer cell lines, and preliminary clinical activity in patients (pts) with taxane-sensitive and -resistant disease in Phase I. This Phase II study assessed the efficacy, safety, and tolerability of sagopilone in metastatic breast cancer (MBC).Methods: Pts with progressive MBC who received a maximum of 2 previous chemotherapies not containing taxanes or vinca alkaloids were randomized to either i.v. sagopilone 12, 16, or 22 mg/m2 over 3 h or 22 mg/m2 over 0.5 h, every 21 days, for up to 6 cycles. The primary endpoint was the proportion of pts with a complete response (CR) or partial response (PR) as best overall response. A Simon's 2-stage design was used: 15 pts were to be initially accrued per arm; a further 12 pts were recruited per arm if ≥5/15 pts showed a response. The study was to be considered successful if an objective response (CR or PR) was observed in ≥10/27 pts.Results: Eighty-two female pts (median age 59 years) were randomized to treatment. The median number of treatment cycles was 3 (range 1-9). Of 77 pts evaluable for best response (per protocol set), 11 (14%) had PR, 32 (42%) stable disease (SD), 30 (39%) progressive disease (PD), and 4 (5%) unknown (Table 1).Table 1. Number of pts (%) with best overall responseSagopilone12 mg/m² 3 h16 mg/m² 3 h22 mg/m² 3 h22 mg/m² 0.5 hTotalNo. of pts14 (100.0)26 (100.0)16 (100.0)21 (100.0)77 (100.0)PR0 (0.0)3 (11.5)3 (18.8)5 (23.8)11 (14.3)SD5 (35.7)10 (38.5)8 (50.0)9 (42.9)32 (41.6)PD9 (64.3)11 (42.3)4 (25.0)6 (28.6)30 (39.0)Unknown0 (0.0)2 (7.7)1 (6.3)1 (4.8)4 (5.2) The study outcome was not considered successful for any of the 4 regimens tested. All 82 pts were evaluable for safety. Thirty-six pts discontinued the study prior to cycle 6: 35 due to adverse events (AEs) and 1 due to consent withdrawal. Treatment-related AEs documented in ≥20% pts were: sensory neuropathy 60% (18% grade 3, 1% grade 4); asthenia 26% (6% grade 3); alopecia 23%, myalgia 20% (2% grade 3); fatigue 20%; and nausea 20% (1% grade 3).Conclusions: Sagopilone did not meet the primary endpoint in this pt population with progressive MBC. Treatment-related AEs appeared to be considerable but manageable at all dose levels. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6107.