2040 Background: Ixabepilone is a potent tubulin-targeting agent. The first epothilone analog, ixabepilone, has been developed to optimize the characteristics of the naturally occurring epothilone B.
METHODS
This open-label, single-arm Phase I dose escalation study was designed to establish the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), safety and a recommended dose of ixabepilone when administered as a weekly infusion to patients (pts) with solid tumors who had failed standard therapy. Eligible pts were aged ≥18 years and had histologically/cytologically confirmed solid tumor disease and an ECOG status of 0-2. Ixabepilone was administered weekly as a 30-minute infusion on a 21-day schedule. Due to neurotoxicity, infusion time was increased to 1 hour with a 1-week break allowed. Dosing ranged from 1-30 mg/m2. Tumor evaluations were performed every 6 or 8 weeks (21-day or 28-day schedule, respectively). Toxicity was evaluated continuously.
RESULTS
34 pts were treated on the 21-day schedule (median age 55, range 30-73) and 52 on the 28-day schedule (median age 55, range 33-79). 88% of pts had received prior chemotherapy. Grade 3 fatigue was the DLT in 2 of the 4 pts treated with 30 mg/m2 ixabepilone. No DLTs were seen at doses ≤25 mg/m2 on the 21-day schedule, or at doses of 15, 20 or 25 mg/m2 on the 28-day schedule. The MTD was 25 mg/m2 for the 21-day schedule. Of 12 pts who received this dose and schedule, 7 (58%) experienced Grade 1/2 neuropathy, 1 (8%) developed Grade 3 sensory neuropathy and 3 (25%) experienced Grade 3 fatigue. Of 52 pts who received 20 mg/m2 on the 28-day schedule, 2 (13%) had Grade 3 neutropenia, 1 (7%) had Grade 3/4 sensory neuropathy and 4 (27%) had Grade 3 fatigue. Five pts (two pts [21-day schedule], three pts [28-day schedule]) with breast, colon, ovary, head and neck tumors achieved objective partial responses.
CONCLUSIONS
The recommended doses of ixabepilone from this study are 25 mg/m2 (30-minute weekly infusion, 21-day schedule) and 20 mg/m2 (1-hour weekly infusion, 28-day schedule). Ixabepilone demonstrated efficacy and an acceptable safety profile in pts with a broad range of tumor types, several of whom had failed a taxane. [Table: see text].