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A phase I/II trial of
BMS-247550 for patients with recurrent high-grade gliomas
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.
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.
Copyright 2004 American Society of
Clinical Oncology All rights reserved worldwide.
Source: http://www.asco.org/ac/1,1003,_12-002636-00_18-0026-00_19-002725,00.asp
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