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Phase I trial of the oral
farnesyl protein transferase inhibitor lonafarnib (SCH66336): A Pediatric Brain
Tumor Consortium (PBTC) study
M. W. Kieran, R. Packer, J. Boyett, M. Sugrue, L. Kun, Pediatric Brain Tumor
Consortium (PBTC)
Dana-Farber Cancer Institute, Boston, MA; Schering-Plough, Warren, NJ
Background.
Children with recurrent or progressive central nervous system
(CNS) tumors after optimal up-front therapy have a poor prognosis.
Ras mutations or over-expression have been identified in both adult and
pediatric brain tumors.
Pre-clinical studies have demonstrated that both ras mutant and non-mutated
tumors that signal through this pathway can be effectively inhibited by farnesyl
transferase inhibitors.
We now report the results of the first phase I dose escalation trial of
lonafarnib (Sarasar) administered orally twice daily to children with recurrent
or progressive, poor prognosis CNS tumors.
Methods.
The primary objective of this study was to assess the
dose-limiting toxicities (DLTs) and maximally tolerated dose (MTD) of
Sarasar.
Additionally, the multiple dose pharmacokinetics of Sarasar was evaluated in
patients both receiving or not receiving steroids.
A preliminary assessment of activity was also performed.
The dose of Sarasar has ranged from 70 mg/m2 (dose level 0) to 90,
115, 150 and is currently at 200 mg/m2/dose BID given by mouth
without planned interruption. Evaluation for DLT was performed during the first
4 wks of therapy.
Results.
Thirty-nine children have been evaluated for this study to date
(22 male/17 female), median age 13.4 years (range 3.9-19.5), with the following
tumor types: high-grade glioma (17), brain stem glioma (6), medulloblastoma (3),
PNET (4), ependymoma (2), low-grade glioma (3), meningioma (3), and gliomatosis
cerebri (1).
Therapy has been well tolerated and dose escalation continues.
To date, the multiple dose PK have been determined in 9 patients.
Sarasar is absorbed and eliminated slowly after oral administration with
food.
Median Tmax was 4 hr and there was minimal fluctuation in plasma
concentrations.
Pre-dose steady state concentrations were 26 to 100% of Cmax values.
Conclusions.
This dose escalation of oral Sarasar in children with CNS
tumors continues to accrue patients at the 200mg/m2/dose given BID by
oral administration.
Full details of the dose-limiting and maximally-tolerated dose, pharmacokinetics
and preliminary discussion of activity will be presented.
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_19-003716,00.asp
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