Phase I study of the novel epothilone analog ixabepilone (BMS-247550) in patients with advanced solid tumors and lymphomas Journal Article
| Authors: | Aghajanian, C.; Burris, H. A. 3rd; Jones, S.; Spriggs, D. R.; Cohen, M. B.; Peck, R.; Sabbatini, P.; Hensley, M. L.; Greco, F. A.; Dupont, J.; O'Connor, O. A. |
| Article Title: | Phase I study of the novel epothilone analog ixabepilone (BMS-247550) in patients with advanced solid tumors and lymphomas |
| Abstract: | 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. © 2007 by American Society of Clinical Oncology. |
| Keywords: | survival; adult; controlled study; treatment outcome; aged; middle aged; survival analysis; treatment failure; unclassified drug; major clinical study; clinical trial; drug tolerability; mortality; neutropenia; drug efficacy; recommended drug dose; solid tumor; antineoplastic agents; united states; cancer staging; antineoplastic agent; neoplasm staging; neoplasm; neoplasms; controlled clinical trial; cohort studies; bleeding; stomatitis; thrombocytopenia; myalgia; peripheral neuropathy; drug administration schedule; cohort analysis; practice guideline; continuous infusion; pathology; time; time factors; arthralgia; drug dose escalation; drug hypersensitivity; febrile neutropenia; loading drug dose; nonhodgkin lymphoma; lymphoma, non-hodgkin; multicenter study; chemically induced disorder; drug response; lymphoma; cancer relapse; drug blood level; maximum tolerated dose; phase 1 clinical trial; drug administration; infusions, intravenous; peripheral nervous system diseases; intravenous drug administration; ixabepilone; epothilones; epothilone derivative; tubulin modulator; tubulin modulators; pharyngitis; practice guidelines; bms 249798; bms 326412; oxazine derivative |
| Journal Title: | Journal of Clinical Oncology |
| Volume: | 25 |
| Issue: | 9 |
| ISSN: | 0732-183X |
| Publisher: | American Society of Clinical Oncology |
| Date Published: | 2007-03-20 |
| Start Page: | 1082 |
| End Page: | 1088 |
| Language: | English |
| DOI: | 10.1200/jco.2006.08.7304 |
| PUBMED: | 17261851 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 56" - "Export Date: 17 November 2011" - "CODEN: JCOND" - "Source: Scopus" |
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