Trial Information

A Phase I/II Trial Of STI571 In Children With Newly Diagnosed Poor Prognosis Brainstem Gliomas And Recurrent Intracranial Malignant Gliomas

PRIMARY OBJECTIVES:

I. Determine the maximum tolerated dose (MTD) of imatinib mesylate after completion of
radiation in children with newly diagnosed poor prognosis brainstem gliomas. (Phase I,
strata I closed to accrual as of 5/28/04.) II. Determine the maximum tolerated dose (MTD) of
imatinib mesylate in children with recurrent high-grade intracranial glioma stratified
according to the use of enzyme-inducing anticonvulsant drugs (EIACDs). (Phase I, strata IIA
and IIB closed to accrual as of 8/15/03 and 8/15/04, respectively) III. Determine the safety
and efficacy of this drug in patients with newly diagnosed diffuse intrinsic brainstem
gliomas. (Phase II)

SECONDARY OBJECTIVES:

I. Explore neuroimaging and biological correlatives of therapeutic activity of this regimen
in these patients. (Phase I, all strata closed to accrual as of 8/15/04) II. Determine the
pharmacokinetics of these regimens in these patients overall and by enzyme-inducing
anticonvulsant drugs (EIACDs) (Phase I, all strata closed to accrual as of 8/15/04.) III.
Estimate the progression-free survival (PFS) and overall survival (OS) of newly diagnosed
diffuse intrinsic brainstem gliomas treated with this drug. (Phase I and II)

OUTLINE: This is a phase I dose-escalation, multicenter study followed by a phase II.
Patients are stratified according to tumor type (newly diagnosed intrinsic brainstem glioma
vs recurrent/refractory intracranial high-grade glioma). Patients in stratum II (phase I
only) are further stratified according to concurrent use of enzyme-inducing anticonvulsant
drugs (EIACDs) (yes vs no). Patients are assigned to one of three strata in the phase I
study.

- Phase I

- Stratum I (newly diagnosed brainstem glioma): Patients undergo radiotherapy once
daily five days a week for 6 weeks. Beginning 1-3 weeks after completion of
radiotherapy, patients without evidence of intratumoral bleed receive oral
imatinib mesylate twice daily. Imatinib mesylate treatment repeats every 4 weeks
for up to 13 courses in the absence of disease progression or unacceptable
toxicity. (Closed to accrual as of 5/28/04.)

- Stratum II A (recurrent or refractory high-grade intracranial gliomas/no
concurrent EIACDs): Patients receive imatinib mesylate as in stratum I. (Closed to
accrual as of 8/15/03.)

- Stratum II B (recurrent or refractory high-grade intracranial gliomas and
concurrent EIACDs): Patients receive imatinib mesylate as in stratum I. (Closed to
accrual as of 8/15/04.)

Cohorts of 2-3 patients receive escalating doses of imatinib mesylate until the maximum
tolerated dose (MTD) is determined. The MTD is defined as the dose at which it is estimated
that 20% of patients will experience dose-limiting toxicity. MTDs are independently
estimated in each strata. For stratum I, newly diagnosed brain stem gliomas, the dose level
which at least 5 of 6 patients experience no dose-limiting toxicity will be the dose used in
the efficacy and safety phase (phase II).

- Phase II: (Open to accrual as of 5/28/04.)

- Stratum I only: Patients undergo radiotherapy as in phase I. Patients receive
imatinib mesylate at the MTD established in phase I.

Patients enrolled in the phase I portion and not treated at the MTD are to be followed for
the shortest of 1) three months after the last protocol based treatment or 2) the date other
therapy is initiated. Stratum I patients treated at the MTD in the phase I portion and all
patients in the phase II portion of the study are to be followed until death or withdrawal
from the study

PROJECTED ACCRUAL: Approximately 140 patients will be accrued for this study within 2 years.