Originally published as JCO Early Release 10.1200/JCO.2006.08.7304 on January 29 2007

This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Aghajanian, C. Articles by O'Connor, O. A. Search for Related Content PubMed PubMed Citation Articles by Aghajanian, C. Articles by O'Connor, O. A. Social Bookmarking                            What's this?

Phase I Study of the Novel Epothilone Analog Ixabepilone (BMS-247550) in Patients With Advanced Solid Tumors and Lymphomas

Carol Aghajanian, Howard A. Burris, III, Suzanne Jones, David R. Spriggs, Marvin B. Cohen, Ronald Peck, Paul Sabbatini, Martee L. Hensley, F. Anthony Greco, Jakob Dupont, Owen A. O'Connor

From the Developmental Chemotherapy Service, Memorial Sloan-Kettering Cancer Center, New York, NY; Sarah Cannon Cancer Center, Nashville, TN; Bristol-Myers Squibb, Princeton, NJ; and Bristol-Myers Squibb Oncology, Wallingford, CT

Address reprint requests to Carol Aghajanian, MD, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021; e-mail: aghajanc{at}mskcc.org

Purpose To establish the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), safety, pharmacokinetics, and pharmacodynamics of ixabepilone when administered as a 1-hour infusion every 3 weeks to patients with advanced solid tumors or relapsed/refractory non-Hodgkin's lymphoma. Dosing schedules of 40 mg/m² and 50 mg/m² over 3 hours were also evaluated.

Patients and Methods Sixty-one patients were enrolled using an initial accelerated dose-escalation phase followed by a standard dose-escalation phase, with doses of ixabepilone ranging from 7.4 to 65 mg/m². The pharmacokinetics of ixabepilone and two of its chemical degradation products were evaluated. Plasma pharmacodynamics were evaluated for both 1- and 3-hour infusions using an assay that measures the amount of endogenous tubulin in peripheral-blood mononuclear cells that exists in the polymerized versus the unpolymerized state. Response evaluation was performed every 6 weeks.

Results The most common DLTs were neutropenia, stomatitis/pharyngitis, myalgia, and arthralgia. The MTD of ixabepilone as a 1-hour infusion every 3 weeks was established as 50 mg/m². The maximum plasma concentration and area under the plasma concentration time curve appeared to increase less than proportionally to dose. Durable objective responses were seen in eight patients, including two complete responses. Five of the responders had experienced treatment failure with a taxane.

Conclusion The recommended dose of ixabepilone for the initiation of phase II studies on the basis of these results is 50 mg/m² over 1 hour every 3 weeks. The promising efficacy and tolerability results demonstrated by ixabepilone in this study warrant its continued development.

published online ahead of print at www.jco.org on January 29, 2007.

Supported by Bristol-Myers Squibb, Princeton, NJ.

Presented in part in poster format at the 42nd Annual Meeting of the American Society of Clinical Oncology, June 2-6, 2006, Atlanta, GA.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				P. Sabbatini and D. R. Spriggs Epothilones: Better or More of the Same? J. Clin. Oncol., July 1, 2009; 27(19): 3079 - 3081. [Full Text] [PDF]

				L. Boehnke Michaud The optimal therapeutic use of ixabepilone in patients with locally advanced or metastatic breast cancer Journal of Oncology Pharmacy Practice, June 1, 2009; 15(2): 95 - 106. [Abstract] [PDF]

				B. C. Widemann, W. Goodspeed, A. Goodwin, T. Fojo, F. M. Balis, and E. Fox Phase I Trial and Pharmacokinetic Study of Ixabepilone Administered Daily for 5 Days in Children and Adolescents With Refractory Solid Tumors J. Clin. Oncol., February 1, 2009; 27(4): 550 - 556. [Abstract] [Full Text] [PDF]

				R. Plummer, P. Woll, D. Fyfe, A. V. Boddy, M. Griffin, P. Hewitt, J. Carmichael, F. Namouni, M. Cohen, and M. Verrill A Phase I and Pharmacokinetic Study of Ixabepilone in Combination with Carboplatin in Patients with Advanced Solid Malignancies Clin. Cancer Res., December 15, 2008; 14(24): 8288 - 8294. [Abstract] [Full Text] [PDF]

				S. Goodin Ixabepilone: A novel microtubule-stabilizing agent for the treatment of metastatic breast cancer Am. J. Health Syst. Pharm., November 1, 2008; 65(21): 2017 - 2026. [Abstract] [Full Text] [PDF]

				S. Bhushan and C. M Walko Ixabepilone: A New Antimitotic for the Treatment of Metastatic Breast Cancer Ann. Pharmacother., September 1, 2008; 42(9): 1252 - 1261. [Abstract] [Full Text] [PDF]

				J. Hoffmann, I. Vitale, B. Buchmann, L. Galluzzi, W. Schwede, L. Senovilla, W. Skuballa, S. Vivet, R. B. Lichtner, J. M. Vicencio, et al. Improved Cellular Pharmacokinetics and Pharmacodynamics Underlie the Wide Anticancer Activity of Sagopilone Cancer Res., July 1, 2008; 68(13): 5301 - 5308. [Abstract] [Full Text] [PDF]

				S. Goel, M. Cohen, S. N. Comezoglu, L. Perrin, F. Andre, D. Jayabalan, L. Iacono, A. Comprelli, V. T. Ly, D. Zhang, et al. The Effect of Ketoconazole on the Pharmacokinetics and Pharmacodynamics of Ixabepilone: A First in Class Epothilone B Analogue in Late-Phase Clinical Development Clin. Cancer Res., May 1, 2008; 14(9): 2701 - 2709. [Abstract] [Full Text] [PDF]

				J. J. Lee and S. M. Swain The Epothilones: Translating from the Laboratory to the Clinic Clin. Cancer Res., March 15, 2008; 14(6): 1618 - 1624. [Abstract] [Full Text] [PDF]

				H. Roche, L. Yelle, F. Cognetti, L. Mauriac, C. Bunnell, J. Sparano, P. Kerbrat, J.-P. Delord, L. Vahdat, R. Peck, et al. Phase II Clinical Trial of Ixabepilone (BMS-247550), an Epothilone B Analog, As First-Line Therapy in Patients With Metastatic Breast Cancer Previously Treated With Anthracycline Chemotherapy J. Clin. Oncol., August 10, 2007; 25(23): 3415 - 3420. [Abstract] [Full Text] [PDF]