Erlotinib in Treating Patients With Progressive Glioblastoma Multiforme

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

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.

Study Overview

• Status: Terminated
• Conditions: Brain and Central Nervous System Tumors
• Intervention / Treatment: Drug: erlotinib hydrochloride

Detailed 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.

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599-7295
      • Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Subjects receiving EIAEDs; Patients will be stratified according to concurrent use of enzyme inducing anti-epileptic drugs (EIAED)	Drug: erlotinib hydrochloride; 300 mg, per day for subjects taking EIAEDs 150 mg, per day for those NOT taking EIAEDs
Experimental: Subjects NOT taking EIAEDs; Patients will be stratified according to concurrent use of enzyme inducing anti-epileptic drugs (EIAED)	Drug: erlotinib hydrochloride; 300 mg, per day for subjects taking EIAEDs 150 mg, per day for those NOT taking EIAEDs

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free survival	Progression -free survival will be measured by radographic response using RECIST critera.	12 months
Correlation between presence of the EGFRvIII mutation with treatment outcomes		6 months

Collaborators and Investigators

• Sponsor: UNC Lineberger Comprehensive Cancer Center
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Celeste Lindley, PharmD, UNC Lineberger Comprehensive Cancer Center; Principal Investigator: Frances A. Collichio, MD, UNC Lineberger Comprehensive Cancer Center

Study record dates

Study Major Dates

• Study Start: September 1, 2005
• Primary Completion (Actual): February 1, 2008
• Study Completion (Actual): March 1, 2008

Study Registration Dates

• First Submitted: September 23, 2005
• First Submitted That Met QC Criteria: September 23, 2005
• First Posted (Estimate): September 27, 2005

Study Record Updates

• Last Update Posted (Estimate): March 6, 2012
• Last Update Submitted That Met QC Criteria: March 5, 2012
• Last Verified: March 1, 2012

More Information

Terms related to this study

• Keywords: adult glioblastoma; adult giant cell glioblastoma; adult gliosarcoma; recurrent adult brain tumor
• Additional Relevant MeSH Terms: Nervous System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioblastoma; Nervous System Neoplasms; Central Nervous System Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Erlotinib Hydrochloride
• Other Study ID Numbers: LCCC 0424; CDR0000550155 (Other Identifier: PDQ number)