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


Phase 1
18 Years
N/A
Not Enrolling
Both
Brain and Central Nervous System Tumors

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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.

Inclusion Criteria


DISEASE CHARACTERISTICS:

- Histologically confirmed glioblastoma multiforme (or high-grade glioma that is
behaving clinically and/or radiographically like glioblastoma multiforme)

- Progressed after first-line therapy (e.g., surgery, chemotherapy, or radiotherapy)

PATIENT CHARACTERISTICS:

- Karnofsky performance status 60-100%

- ANC > 1,500/mm³

- Platelet count > 100,000/mm³

- Hemoglobin > 8.5 g/dL

- ALT and AST < 2 times upper limit of normal (ULN)

- Alkaline phosphatase < 2 times ULN

- Bilirubin < 1.5 mg/dL

- Creatinine < 1.5 mg/dL OR creatinine clearance > 50 mL/min

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

- No diagnosis or history of significant renal or hepatic disease

- No contraindication (e.g., mass effect, brain shift) to lumbar puncture procedure

- No active infection

- No diagnosis or history of corneal abnormalities

- No diagnosis or history of malabsorptive syndrome or other disorder affecting
gastrointestinal absorption

- No history of hypersensitivity reactions to midazolam hydrochloride (CYP3A4
biomarker)

PRIOR CONCURRENT THERAPY:

- See Disease Characteristics

Type of Study:

Interventional

Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Progression-free survival

Outcome Description:

Progression -free survival will be measured by radographic response using RECIST critera.

Outcome Time Frame:

12 months

Safety Issue:

No

Principal Investigator

Celeste Lindley, PharmD

Investigator Role:

Principal Investigator

Investigator Affiliation:

UNC Lineberger Comprehensive Cancer Center

Authority:

United States: Federal Government

Study ID:

LCCC 0424

NCT ID:

NCT00227032

Start Date:

September 2005

Completion Date:

March 2008

Related Keywords:

  • Brain and Central Nervous System Tumors
  • adult giant cell glioblastoma
  • adult gliosarcoma
  • adult glioblastoma
  • recurrent adult brain tumor
  • Glioblastoma
  • Nervous System Neoplasms
  • Central Nervous System Neoplasms

Name

Location

Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel HillChapel Hill, North Carolina  27599-7570