Phase I dose escalation study of weekly ixabepilone, an epothilone analog, in patients with advanced solid tumors who have failed standard therapy |
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Authors: | Ahmad Awada Martine J Piccart Suzanne F Jones Ronald A Peck Thierry Gil David Lebwohl Chi-Yuan Wu Howard A Burris III |
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Affiliation: | (1) Institut Jules Bordet, Medical Oncology Clinic, 121 Blvd de Waterloo, Brussels, 1000, Belgium;(2) The Sarah Cannon Research Institute, 250 25th Avenue North, Suite 110, Nashville, TN 37203, USA;(3) Bristol-Myers Squibb, Princeton, NJ, USA |
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Abstract: | Purpose To establish the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), safety and recommended Phase II dose of ixabepilone,
administered weekly as an intravenous (IV) infusion to patients with solid tumors who have failed standard therapy.
Method This was an open-label, single-arm, Phase I, dose-escalation study.
Results The MTD of ixabepilone 30-min, weekly IV infusion on a 21-day schedule (N = 33)] was established at 25 mg/m2. Grade 3 fatigue was the DLT in 2/4 patients treated at 30 mg/m2. Ixabepilone was well tolerated at the MTD. Myelosuppression was rare, with no Grade 3/4 neutropenia. Due to the potential
for cumulative neurotoxicity, the protocol was amended to a 1-h infusion, weekly for 3 weeks with a 1-week break. No DLT occurred
at starting doses of 15, 20 and 25 mg/m2 on this modified schedule (N = 51), although overall toxicity was less at 15 and 20 mg/m2 than 25 mg/m2. Five patients (2 on the 30-min/21-day schedule and 3 on the 60-min/28-day schedule) achieved durable objective partial responses
across a variety of tumor types.
Conclusions Ixabepilone had an acceptable safety profile at the MTD of 25 mg/m2 (as a 30-min weekly infusion on a continuous 21-day schedule) and at 20 mg/m2 (as a 1-h weekly infusion on a modified 28-day schedule). The clinical activity and acceptable tolerability profile warrant
further single- or combination-agent evaluation. |
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Keywords: | Ixabepilone Dose-finding Solid tumors Weekly schedule |
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