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A phase I/II trial of BMS-247550 for patients with recurrent high-grade gliomas.

Al Musella's Comments: (This is his personal views and are not necessarily the views of the Musella Foundation!)


Posted on: 06/08/2004

A phase I/II trial of BMS-247550 for patients with recurrent high-grade gliomas.

ASCO Abstract No: 1546

Author(s): D. Peereboom, K. Carson, D. Lawson, G. Lesser, J. Supko, S. Grossman, The New Approaches to Brain Tumor Therapy (NABTT) Consortium; Cleveland Clinic Brain Tumor Institute, Cleveland, OH; Johns Hopkins Oncology Center, Baltimore, MD; Emory University, Atlanta, GA; Wake Forest University, Winston-Salem, NC; MGH Cancer Center, Boston, MA

Abstract: Background: BMS-247550 is a semi-synthetic analog of epothilone B, a novel non-taxane microtubule-stablizing agent. A phase I/II trial of this agent in patients with recurrent high-grade glioma is in progress.

Methods: Patients (pts) receive BMS-247550 on a 1-hour infusion, daily x 5 every 3 weeks. In the phase I portion, cohorts of 3 pts are treated at each dose level starting at 5 mg/m2/day. Pts are stratified into groups A and B according to the use or non-use, respectively, of cytochrome P450 enzyme-inducing anticonvulsants. Dose escalation for each group occurs separately using the continual reassessment method (CRM) to calculate each dose level. The MTD is reached when the CRM assigns two consecutive dose levels within 10% of the previous level. Pharmacokinetic sampling (PKs) occurs on days 1-5 of cycle 1. The phase II portion of the study combines group A and B pts at their respective MTDs in a standard 2-stage design.

Results: Ten pts have entered the study, all on the phase I portion: median age 55 (range 41-71); 3 male; 3 in group A. All had received radiation and 9 had received prior chemotherapy. Group A completed dose level 1 (5 mg/m2) with no dose-limiting toxicities (DLT). Group B pts have received drug on 3 dose-levels: 5 mg/m2 (3 pts), 7.5 (1) and 6 (3) with 1 treatment-related death (sepsis/typhlitis) at 7.5 mg/m2 necessitating a dose de-escalation to 6 mg/m2. No other DLTs have occurred. Grade 2-5 treatment-related toxicities: Group A - 0 pts; Group B - 1 pt had G2 fatigue and 1 pt had G3 abdominal pain/cramps, G4 neutropenia, and G5 sepsis. All 8 pts evaluable for response have progressed. PKs are being assessed.

Conclusions: To date, BMS-247550 has not shown new toxicities in glioma pts with the possible exception of typhlitis for which BMS-247550 could not be excluded as the cause. The most severe toxicity has been hematological. Dose escalation in group B is near completion, and the MTD will be close to that (6 mg/m2) established in non-CNS pts. Because BMS 247550 is a substrate for the P450 system, pharmacodynamic differences between the groups A and B may emerge with further accrual to the study.

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