Enzastaurin and Carboplatin in Treating Patients With Recurrent or Refractory Primary Brain Tumors

OBJECTIVES:

Primary

- Determine the maximum tolerated dose of enzastaurin hydrochloride when administered
with carboplatin in patients with recurrent or refractory primary brain tumors.

- Determine the pharmacokinetics of this regimen in these patients.

Secondary

- Correlate clinical outcome with GSK3-b activation in peripheral blood mononuclear cells
of patients treated with this regimen.

- Determine, preliminarily, the antitumor activity of this regimen in these patients.

OUTLINE: This is a dose-escalation study of enzastaurin hydrochloride. Patients are
stratified according to concurrent enzyme-inducing anti-epileptic drugs (EIAEDs) (yes vs
no).

Patients receive oral enzastaurin hydrochloride once daily on days 1-35 and carboplatin IV
over 30 minutes on day 8 of course 1. Patients receive oral enzastaurin hydrochloride once
daily on days 1-28 and carboplatin IV over 30 minutes on day 1 in all subsequent courses.
Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Cohorts of 4-12 patients receive escalating doses of enzastaurin hydrochloride until the
maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at
which 3 of 4 or 5 of 12 patients experience dose-limiting toxicity.

Patients undergo blood collection on days 7 and 8 and between weeks 4-5 of course 1 for
pharmacokinetic studies. Blood is also collected at baseline and on days 7 and 28 of each
course for analysis of biological markers (PI-3 kinase, GSK3-b, and mTOR) by western blot
and other assays.

PROJECTED ACCRUAL: A total of 96 patients will be accrued for this study.