Erlotinib in Treating Patients With Progressive Glioblastoma Multiforme

Brain and Central Nervous System Tumors Clinical Trial

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT00227032
• Other study ID #: LCCC 0424
• Secondary ID: CDR0000550155
• Status: Terminated
• Phase: Phase 1
• First received: September 23, 2005
• Last updated: March 5, 2012
• Start date: September 2005
• Est. completion date: March 2008

Study information

• Verified date: March 2012
• Source: UNC Lineberger Comprehensive Cancer Center
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Federal GovernmentUnited States: Institutional Review Board
• Study type: Interventional

Clinical Trial Summary

RATIONALE: Erlotinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

PURPOSE: This phase I trial is studying the side effects and best dose of erlotinib in treating patients with progressive glioblastoma multiforme.

Description:

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 10
• Est. completion date: March 2008
• Est. primary completion date: February 2008
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Study Design

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

Related Conditions & MeSH terms

• Brain and Central Nervous System Tumors
• Central Nervous System Neoplasms
• Glioblastoma
• Nervous System Neoplasms

Intervention

Drug:
• erlotinib hydrochloride
300 mg, per day for subjects taking EIAEDs 150 mg, per day for those NOT taking EIAEDs

Locations

Country	Name	City	State
United States	Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill	Chapel Hill	North Carolina

Sponsors (2)

Lead Sponsor	Collaborator
UNC Lineberger Comprehensive Cancer Center	National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression-free survival	Progression -free survival will be measured by radographic response using RECIST critera.	12 months	No
Primary	Correlation between presence of the EGFRvIII mutation with treatment outcomes		6 months	No