EGFR Inhibition Using Weekly Erlotinib for Recurrent Malignant Gliomas

Sponsor

Andrew B Lassman, MD (Other)

Overall Status

Completed

CT.gov ID

NCT01257594

Collaborator

Genentech, Inc. (Industry), OSI Pharmaceuticals (Industry)

Enrollment

Locations

Arms

95.8

Actual Duration (Months)

5.5

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to test the effectiveness of a drug called erlotinib in treating the tumor. This is a multi-center pilot study that explores efficacy and molecular effects of high dose weekly erlotinib for recurrent EGFR vIII mutant malignant gliomas, and correlate molecular profile of pre-treatment tissue with outcome.

Condition or Disease	Intervention/Treatment	Phase
Brain Cancer	Drug: erlotinib Procedure: Cytoreductive Surgery	Phase 1

Detailed Description

This is a pilot study of erlotinib for subjects who have a brain tumor called a glioblastoma or another malignant glioma, which has continued to grow after treatment. The purpose of this study is to test the effectiveness of a drug called erlotinib in treating the tumor. The study drug, erlotinib (also called Tarceva) is a pill (taken by mouth) that has been approved by the U.S. Food and Drug Administration (FDA) for the subjects with other cancers (lung cancer or pancreatic cancer). It is not approved for glioblastoma or another malignant glioma. Erlotinib blocks a messenger that tells cancer cells to grow. That messenger is called Epidermal Growth Factor Receptor (EGFR). This type of tumor contains a form of EGFR called variant number 3 (abbreviated EGFR variant III or EGFRvIII for short) that is different from the normal form.Research suggests that erlotinib is particularly effective at stopping EGFRvIII. Research also suggests that high doses of erlotinib taken once per week may be more effective than low doses of erlotinib taken once per day.

Study Design

Study Type:

Interventional

Actual Enrollment :

22 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Pilot Study of EGFR Inhibition Using High Dose Administration of Erlotinib Weekly for Recurrent Malignant Gliomas With EGFR Variant III Mutation

Actual Study Start Date :

Jan 7, 2011

Actual Primary Completion Date :

Nov 22, 2016

Actual Study Completion Date :

Dec 31, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: No cytoreductive surgery planned Patients who are not candidates for surgery as part of their routine care will enroll into the medical arm of the trial. They will initiate pulsatile erlotinib dosing and continue therapy until either disease progression or intolerable toxicity.	Drug: erlotinib For patients with no cytoreductive surgery planned, patients will receive single-agent erlotinib at a starting dose of 2000 mg on days 1 of every 7 days. For patients with cytoreductive surgery planned, patients will receive single-agent erlotinib at a starting dose of 2000 mg day 1 of every 7 days (+/- 2 days). One pre-operative dose of 2000 mg erlotinib will be administered in an open-label, unblinded manner, administered in the hospital "on call" to the operating room. Other Names: Tarceva
Experimental: Cytoreductive surgery planned Patients scheduled for "salvage" resection as part of their routine care will be considered for this cohort. They will receive 1 pre-operative dose of 2000 mg erlotinib. Resection will occur ≤ 3 hours after the pre-operative dose. After recovery from surgery, patients will resume pulsatile erlotinib dosing.	Drug: erlotinib For patients with no cytoreductive surgery planned, patients will receive single-agent erlotinib at a starting dose of 2000 mg on days 1 of every 7 days. For patients with cytoreductive surgery planned, patients will receive single-agent erlotinib at a starting dose of 2000 mg day 1 of every 7 days (+/- 2 days). One pre-operative dose of 2000 mg erlotinib will be administered in an open-label, unblinded manner, administered in the hospital "on call" to the operating room. Other Names: Tarceva Procedure: Cytoreductive Surgery Standard procedure

Arm

Intervention/Treatment

Experimental: No cytoreductive surgery planned

Patients who are not candidates for surgery as part of their routine care will enroll into the medical arm of the trial. They will initiate pulsatile erlotinib dosing and continue therapy until either disease progression or intolerable toxicity.

Drug: erlotinib

For patients with no cytoreductive surgery planned, patients will receive single-agent erlotinib at a starting dose of 2000 mg on days 1 of every 7 days. For patients with cytoreductive surgery planned, patients will receive single-agent erlotinib at a starting dose of 2000 mg day 1 of every 7 days (+/- 2 days). One pre-operative dose of 2000 mg erlotinib will be administered in an open-label, unblinded manner, administered in the hospital "on call" to the operating room.

Other Names:

Tarceva

Experimental: Cytoreductive surgery planned

Patients scheduled for "salvage" resection as part of their routine care will be considered for this cohort. They will receive 1 pre-operative dose of 2000 mg erlotinib. Resection will occur ≤ 3 hours after the pre-operative dose. After recovery from surgery, patients will resume pulsatile erlotinib dosing.

Drug: erlotinib

Other Names:

Tarceva

Procedure: Cytoreductive Surgery

Standard procedure

Outcome Measures

Primary Outcome Measures

Clinical Benefit Rate (either radiographic response or at least 6 months of progression-free survival) [Up to 3 years]
All patients will have their tumor measurements recorded at baseline and at the time of each MRI/CT scan. Clinical efficacy of pulsatile dosing with the EGFR Tyrosine Kinase Inhibitor erlotinib in patient with EGFR vIII mutant, recurrent malignant gliomas will be explored by determination of radiographic response and 6 month progression-free survival (6mPFS rate).

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Histologically confirmed intracranial malignant glioma of the following types: Glioblastoma (GBM), Gliosarcoma (GS), Anaplastic astrocytoma (AA), Anaplastic oligodendroglioma (AO), Anaplastic oligoastrocytoma (AOA, also called anaplastic mixed gliomas or AMG), High grade glioma not otherwise specified (NOS).
EGFRvIII mutation detected on pretreatment tissue from at least 1 prior surgery.
At least 15 unstained slides or at least 1 tissue blocks must be collected from at least one prior surgery.
Recovered from toxic effects of prior therapies.
Able to undergo contrast enhanced MRI scans (or CT scans for patients unable to tolerate MRI).
Shown unequivocal evidence for contrast enhancing tumor progression by MRI (or CT for patients who cannot tolerate MRI) in comparison to a prior scan.
Age > or = 18 years.
Karnofsky Performance Status > or = 60%.
Life expectancy of > 8 weeks.
Normal organ and marrow function, adequate liver function and adequate renal function before starting therapy.
Women of child-bearing potential and men must agree to use adequate contraception.
Women of childbearing potential must have a negative pregnancy test documented within 7 days prior to treatment.
Women must agree not to breast feed.
Ability to understand and the willingness to sign a written informed consent document.
Ability to swallow the tablets.

Cohort A (medical) specific inclusion criteria:

Fulfill all of the general inclusion criteria.
MRI/CT must demonstrate measurable enhancing tumor of at least 1cm2 in cross-sectional area to allow assessment of radiographic response, unless: measurable disease is not present because the patient underwent gross total resection as the most recent anti-tumor therapy.
At least 3 months have elapsed between any prior brain radiotherapy and initiation of study therapy.
MRI/CT must demonstrate measureable enhancing tumor at least 1cm by 1cm squared in cross-sectional area to allow assessment of radiographic response.
Stable or decreasing dose of corticosteroids for a minimum of 5 days before the baseline MRI/CT.
The baseline MRI/CT must be performed on the 14th day or less prior to initiation of study treatment.

Cohort B (surgical) specific inclusion criteria:

Fulfill all of the general inclusion criteria.
An MRI/CT scan showing progression is required.

Exclusion Criteria:

Received prior treatment with convection enhanced delivery, other catheter based intratumoral treatment, or carmustine (BCNU)/Gliadel wafers.
Prior therapy that included stereotactic radiosurgery during therapy for newly diagnosed or recurrent disease, or re-irradiation of any type, must have confirmation of true progressive disease rather than radiation necrosis based upon surgical documentation of recurrent/progressive disease.
Prior treatment with an EGFR inhibitor.
Received prior treatment with direct Vascular endothelial growth factor (VEGF)/Vascular Endothelial Growth Factor Receptors (VEGFR) inhibitors.
Smoking or plan to smoke tobacco or marijuana during study therapy.
Receiving any other investigational agents concurrently with study treatment.
Taking Enzyme Inducing Anti-Epileptic Drug (EIAED). If previously on an EIAED, the patient must be off of it for at least two weeks prior to study treatment.
History of allergic reactions attributed to compounds of similar chemical or biologic composition to erlotinib.
Uncontrolled intercurrent illness that would limit compliance with study requirements.
Have HIV and are receiving combination antiretroviral therapy.
Other active concurrent malignancy.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Memorial Sloan-Kettering at Basking Ridge	Basking Ridge	New Jersey	United States	07920
2	Memorial Sloan-Kettering Cancer Center at Commack	Commack	New York	United States	11725
3	Columbia University Medical Center	New York	New York	United States	10032
4	Memorial Sloan Kettering Cancer Center	New York	New York	United States	10065