Trial Information

Phase I Study of Erlotinib Administered Every 72 Hours in Patients With Glioblastoma Multiforme With Pharmacokinetic/Pharmacodynamic Correlates

OBJECTIVES:

Primary

- Determine the maximum tolerated dose of erlotinib hydrochloride when administered in
escalating doses every 72 hours in patients with progressive glioblastoma multiforme.

Secondary

- Determine the relationship between plasma and cerebrospinal fluid (CSF) concentrations
of erlotinib hydrochloride in these patients.

- Determine the relationship between plasma and CSF concentrations of erlotinib
hydrochloride in patients not receiving concurrent enzyme-inducing antiepileptic drugs
(EIAEDs) vs those receiving concurrent EIAEDs.

- Correlate CYP3A4 activity, as measured by midazolam hydrochloride clearance, with
plasma clearance of erlotinib hydrochloride in these patients.

- Correlate CYP1A2 activity, as measured by the 4-hour paraxanthine (17X)/caffeine (137X)
plasma ratio, with plasma clearance of erlotinib hydrochloride in these patients.

- Determine, preliminarily, objective response and disease progression in patients
treated with erlotinib hydrochloride.

- Correlate the presence of EGFRvIII mutation with objective response and disease
progression in patients treated with erlotinib hydrochloride.

OUTLINE: This is an open-label, dose-escalation study. Patients are stratified according to
use of concurrent enzyme-inducing antiepileptic drugs (EIAEDs) (yes vs no).

Patients receive oral erlotinib hydrochloride once every 72 hours for 28 days. Courses
repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses* of erlotinib hydrochloride until the
maximum tolerated dose (MTD) is determined or preliminary results show no direct
relationship between plasma and cerebrospinal fluid concentrations. The MTD is defined as
the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting
toxicity.

NOTE: *Interim enrollment of patients is allowed; these patients receive the current
approved dose of erlotinib hydrochloride.

Patients undergo blood sample collection periodically on day 13 for pharmacokinetic studies.
The pharmacokinetic study comprises midazolam hydrochloride and caffeine clearance
assessment and correlation of these assessments with CYP3A4 activity and CYP1A2 activity.

Paraffin-embedded and frozen tumor tissue is obtained from patients who underwent prior
surgical resection for analysis of wild-type EGFR and EGFRvIII mutation by
immunohistochemistry.

Quality of life is assessed at baseline and then at 1 month and 6 months.

After completion of study therapy, patients are followed periodically.