Bunnell Craig, Vahdat Linda, Schwartzberg Lee, Gralow Julie, Klimovsky Judith, Poulart Valerie, Peck Ronald, Thomas Eva
Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Clin Breast Cancer. 2008 Jun;8(3):234-41. doi: 10.3816/CBC.2008.n.026.
The aim of this study was to determine the safety, maximum tolerated dose (MTD), recommended phase II dose, and efficacy of the epothilone B analogue ixabepilone plus capecitabine in anthracycline-pretreated/ resistant and taxane-resistant metastatic breast cancer (MBC).
A total of 106 patients were enrolled. The study consisted of a dose-escalation phase (phase I) and a tumor response rate evaluation phase (phase II). Seventy-four patients were treated in phase I with schedule A (ixabepilone 40 mg/m2 intravenously on day 1 plus capecitabine 1650-2000 mg/m2 on days 1-14 of a 21-day cycle) or schedule B (ixabepilone 8-10 mg/m2 on days 1-3 plus capecitabine 1650 mg/m2 on days 1-14 of a 21- day cycle).
No dose-limiting toxicities (DLTs) were observed in the 8/1650 mg/m2 and 10/1650 mg/m2 cohorts; 1 of 30 patients in the 40/1650 mg/m2 cohort and 2 of 30 patients in the 40/2000 mg/m2 cohort had a DLT consisting of grade 3 plantar-palmar erythrodysesthesia (PPE). The 40/2000 mg/m2 dose was defined as the MTD for schedule A, and a total of 62 patients were treated for the phase II portion of the trial, which examined tumor response. The objective response rate was 30%, median time-to-response was 6 weeks, median duration of response was 6.9 months, and median progression-free survival was 3.8 months. Grade 3/4 treatment-related events in phase II included fatigue (34%), PPE (34%), myalgia (23%), nausea (16%), peripheral neuropathy (19%), and diarrhea/vomiting (10%). Grades 3/4 neutropenia (69%) and leukopenia (55%) were managed primarily by dose reduction/treatment interruption.
Ixabepilone plus capecitabine demonstrated clinical activity and an acceptable safety profile in patients with anthracycline-pretreated/resistant and taxane-resistant MBC. Ixabepilone was recently approved in the United States for the treatment of resistant/refractory locally advanced or MBC.
本研究旨在确定埃坡霉素B类似物伊沙匹隆联合卡培他滨在蒽环类药物预处理/耐药及紫杉烷耐药的转移性乳腺癌（MBC）患者中的安全性、最大耐受剂量（MTD）、推荐的II期剂量及疗效。
共纳入106例患者。本研究包括剂量递增阶段（I期）和肿瘤缓解率评估阶段（II期）。74例患者在I期接受A方案（第1天静脉注射伊沙匹隆40 mg/m²，联合21天周期中第1 - 14天卡培他滨1650 - 2000 mg/m²）或B方案（第1 - 3天伊沙匹隆8 - 10 mg/m²，联合21天周期中第1 - 14天卡培他滨1650 mg/m²）治疗。
在8/1650 mg/m²和10/1650 mg/m²队列中未观察到剂量限制性毒性（DLT）；40/1650 mg/m²队列的30例患者中有1例、40/2000 mg/m²队列的30例患者中有2例出现DLT，表现为3级手足红斑感觉异常（PPE）。40/2000 mg/m²剂量被定义为A方案的MTD，共有62例患者接受了试验II期部分的治疗，该部分研究了肿瘤缓解情况。客观缓解率为30%，中位缓解时间为6周，中位缓解持续时间为6.9个月，中位无进展生存期为3.8个月。II期3/4级治疗相关事件包括疲劳（34%）、PPE（34%）、肌痛（23%）、恶心（16%）、周围神经病变（19%）以及腹泻/呕吐（10%）。3/4级中性粒细胞减少（69%）和白细胞减少（55%）主要通过剂量降低/治疗中断来处理。
伊沙匹隆联合卡培他滨在蒽环类药物预处理/耐药及紫杉烷耐药的MBC患者中显示出临床活性和可接受的安全性。伊沙匹隆最近在美国被批准用于治疗耐药/难治性局部晚期或MBC。
