Introduction: Ixabepilone (BMS-247550) is a novel, semi-synthetic analog of epothilone B that induces microtubule stabilization and is active in patients (pts) with breast cancer as well as other tumor types. Preclinical data suggests that a more prolonged infusion of ixabepilone, with the aim of minimizing Cmax but maintaining an efficacious threshold concentration, may result in reduced neurotoxicity with preserved efficacy. This study was designed to investigate the safety, tolerability, and pharmacokinetics of a Cremophor free formulation of ixabepilone given as a 24-h infusion in pts with advanced solid malignancies.
Methods: Eligible pts had normal renal and hepatic function and may have received up to three prior chemotherapy regimens. Cremophor free ixabepilone administered as a 24-h intravenous infusion every 21 days (cycle). A standard “3+3” dose escalation design with the maximum tolerated dose (MTD) of ixabepilone determined by evaluating dose limiting toxicities (DLTs) during cycle one. Ixabepilone pharmacokinetics were evaluated on Day 1 of the first cycle.
Results: Twenty-nine pts (mean age: 58.8, ranging 37-75; male/female: 18/11) have been enrolled on five cohorts with doses ranging from 10-40 mg/m2 receiving a total of 86 cycles of ixabepilone. Tumor types: lung (14 pts), gastrointestinal (7 pts), gynecologic (4 pts), breast (3 pts), and other (1 pt) cancers. First pt enrolled at 40 mg/m2 experienced the DLT of febrile neutropenia and died with hepato-renal syndrome due to liver metastasis. No additional DLTs were observed in the pts enrolled subsequently in the expanded dose level 30 mg/m2, 35 mg/m2 or the expanded dose level 40 mg/m2. The MTD has not yet been reached. Incidence of Grade 3/4 neutropenia, thrombocytopenia and febrile neutropenia occurred in 36, 16, and 8%, respectively. One Grade 3/4 event was reported for each of the following toxicities: deep vein thrombosis, fatigue, epistaxis, and pulmonary embolism. Most pts discontinued treatment due to disease progression. One pt discontinued ixabepilone after six cycles due to Grade 2 sensory neuropathy related to treatment. A total of twenty-one pts were evaluable for pharmacokinetic analysis. In the 40 mg/m2 group, the peak concentration of ixabepilone was about 1/4th of that observed in pts treated with 40 mg/m2 over 3 hours and geometric mean of the area under the concentration-time curve from time zero to infinity was similar. No responses were observed. One pt with non-small cell lung carcinoma (NSCLC), treated with 20 mg/m2 of ixabepilone had stable disease for 15 cycles. Two additional pts with NSCLC and breast cancer had stable disease for 8 cycles.
Conclusion: Ixabepilone administered over 24 hrs in a Cremophor free formulation was generally well tolerated. The MTD has not yet been reached.
- American Association for Cancer Research