A phase I study of oral ixabepilone in patients with advanced solid tumors
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Abstract
Background
Intravenous infusion of ixabepilone is Food and Drug Administration-approved for treatment of patients with metastatic breast cancer. The aim of this study was to establish the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), safety, and pharmacokinetics (PK) of a novel oral formulation of ixabepilone in patients with advanced solid tumors.
Patients and methods
Forty-four patients received one of six daily doses of oral ixabepilone (5, 10, 15, 20, 25, or 30 mg) on days 1–5 of a 21-day cycle. PK parameters were evaluated in cycle 1 for all treated patients and in cycle 1 and cycle 2 for patients participating in assessments of food and gastric pH effects.
Results
The most common DLTs (reported in at least one patient) were neutropenia, neutropenic fever, diarrhea, ileus, and hypokalemia. The MTD of oral ixabepilone was 25 mg. Plasma concentrations of ixabepilone showed high variability; coefficients of variation for the area under the curve and the peak plasma concentration ranged from 61 to 131 % and from 17 to 172 %, respectively. The mean half-life of ixabepilone calculated after day 5 of cycle 1 ranged from 24 to 47 h. Ixabepilone exposure was higher when administered with a low-fat meal compared with the fasted state, and when administered 2 h after the histamine H2 receptor antagonist famotidine.
Conclusions
The MTD of oral ixabepilone when administered once daily for five consecutive days every 21 days was 25 mg. Ixabepilone exposure was highly variable; therefore, safety and efficacy of this novel oral formulation might not be reliably predicted.
Keywords
Ixabepilone Oral Pharmacokinetics Advanced solid tumorsNotes
Acknowledgments
The authors would like to thank the patients and their families for participation in this study. They would also like to thank research coordinator, Ion Cotarla, as well as Marion Hartley for her assistance in preparation of the manuscript. The authors take full responsibility for the content of this publication and confirm that it reflects their viewpoint and scientific expertise. They wish to acknowledge StemScientific for providing writing and editorial support, funded by Bristol-Myers Squibb.
Conflict of interest
Christoph Ahlers, Pamela Clemens, Susan Parker, and Lisa Iacono are employees of Bristol-Myers Squibb.
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