Phase II clinical trial of ixabepilone (BMS-247550), an epothilone B analog, in metastatic and locally advanced breast cancer

被引:169
作者
Low, JA
Wedam, SB
Lee, JJ
Berman, AW
Brufsky, A
Yang, SX
Poruchynsky, MS
Steinberg, SM
Mannan, N
Fojo, T
Swain, SM
机构
[1] Natl Canc Inst, Canc Res Ctr, Canc Therapeut Branch, NIH,Med Oncol Clin Res Unit, Bethesda, MD 20889 USA
[2] Natl Canc Inst, Canc Res Ctr, Canc Therapeut Branch, NIH,Biostat & Data Management Sect, Bethesda, MD 20889 USA
[3] Univ Pittsburgh, Magee Womens Hosp, Inst Canc, Pittsburgh, PA 15213 USA
关键词
D O I
10.1200/JCO.2005.10.024
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Purpose (BMS-247550) is an epothilone B analog that stabilizes microtubules and has antitumor activity in taxane-refractory patients in phase I studies. In a phase II trial, we evaluated the efficacy and safety of ixabepilone in women with metastatic and locally advanced breast cancer. Patients and Methods Breast cancer patients with measurable disease who had paclitaxel and/or docetaxel as prior neoadjuvant, adjuvant, or metastatic therapy were treated with ixabepilone at 6 mg/m(2)/d intravenously on days 1 through 5 every 3 weeks. Levels of glutamate (glu)-terminated and acetylated alpha-tubulin, markers of microtubule stabilization, were detected by Western blot and by immunohistochemistry in a subset of matched pre- and post-treatment tumor biopsies. Results Thirty-seven patients received 153 cycles of ixabepilone. The best responses were a complete response in one patient (3%), partial responses in seven patients (19%), and stable disease in 13 patients (35%). Grade 3 and 4 toxicities included neutropenia (35%), febrile neutropenia (14%), fatigue (14%), diarrhea (11%), nausea/vomiting (5%), myalgia/arthralgia (3%), and sensory neuropathy (3%). Two patients were removed from study because of prolonged grade 2 or 3 neurotoxicity, and three patients were removed from study for other grade 3 and 4 nonhematologic toxicities. Compared with baseline levels, levels of both glu-terminated and acetylated alpha-tubulin were increased in tumor biopsies performed after ixabepilone therapy. Conclusion An objective response was seen in 22% of the patients in a population who had been previously treated with a taxane. Sensory neuropathy was mild with grade 3 neurotoxicity rarely seen. Microtubule stabilization occurred in tumor biopsies after treatment with ixabepilone.
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收藏
页码:2726 / 2734
页数:9
相关论文
共 26 条
[1]   Phase I trial and pharmacokinetic study of BMS-247550, an epothilone B analog, administered intravenously on a daily schedule for five days [J].
Abraham, J ;
Agrawal, M ;
Bakke, S ;
Rutt, A ;
Edgerly, M ;
Balis, FM ;
Widemann, B ;
Davis, L ;
Damle, B ;
Sonnichsen, D ;
Lebwohl, D ;
Bates, S ;
Kotz, H ;
Fojo, T .
JOURNAL OF CLINICAL ONCOLOGY, 2003, 21 (09) :1866-1873
[2]   Epothilone B and its Analogs - A New Family of Anticancer Agents [J].
Altmann, Karl-Heinz .
MINI-REVIEWS IN MEDICINAL CHEMISTRY, 2003, 3 (02) :149-158
[3]   Microtubule-stabilizing agents: a growing class of important anticancer drugs [J].
Altmann, KH .
CURRENT OPINION IN CHEMICAL BIOLOGY, 2001, 5 (04) :424-431
[4]   Use and abuse of taxanes in the management of metastatic breast cancer [J].
Bernard-Marty, C ;
Cardoso, F ;
Piccart, MJ .
EUROPEAN JOURNAL OF CANCER, 2003, 39 (14) :1978-1989
[5]  
BOLLAG DM, 1995, CANCER RES, V55, P2325
[6]  
Chen T, 2004, J CLIN ONCOL, V22, p155S
[7]  
Hussain M, 2004, J CLIN ONCOL, V22, p384S
[8]  
Infante AS, 2000, J CELL SCI, V113, P3907
[9]  
Kelly WK, 2004, J CLIN ONCOL, V22, p384S
[10]  
Lee FYF, 2001, CLIN CANCER RES, V7, P1429