EGFR Inhibition Using High Dose Administration of Erlotinib Weekly for Recurrent Malignant Gliomas With EGFR Variant III Mutation
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 patients with other cancers (lung cancer or pancreatic cancer). It is considered investigational in brain tumors. Erlotinib blocks a messenger that tells cancer cells to grow. That messenger is called "epidermal growth factor receptor" which is abbreviated "EGFR." The tumor contains a form of EGFR called variant number 3 (abbreviated EGRR variant III or EGFRvIII for short) that is different from the normal form. Research suggests that erlotinib is particularly effective at stopping the 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:||Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: 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|
- Clinical Benefit Rate (either radiographic response or at least 6 months of progression-free survival) [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
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 EGFRvIII mutant, recurrent malignant gliomas will be explored by determination of radiographic response and 6 month progression-free survival (6mPFS rate).
- Cmax and AUC blood concentration levels of Erlotinib [ Time Frame: up to 3 years ] [ Designated as safety issue: No ]Pharmacokinetics will be measured, including intratumoral concentration of erlotinib and active metabolites. Blood samples will be drawn at indicated timepoints in order to assess the Cmax blood concentration levels of Erlotinib for subjects on treatment.
- Immunohistochemistry Score (4 point scale, 0 to 3) [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]Evaluation of the in vivo biological activity of protocol therapy will be explored by a within patient comparison of EGFR activation (measured by pEGFR), PI3K/AKT/mTOR/S6K signaling (measured by pS6K and pAKT and related molecules), RAS/RAF/MEK/ERK signaling (measured by pERK and related molecules) and cell proliferation (measured by Ki-67 immunostaining to estimate the proliferation index as the % of tumor cells staining per high power field) in pre-treatment archived tissue versus the tissue acquired during treatment for patients in cohort B. Slides analyzed by immunohistochemistry will be scored for staining on a 4 point scale (0-3)
|Study Start Date:||December 2010|
|Estimated Study Completion Date:||December 2014|
|Estimated Primary Completion Date:||December 2014 (Final data collection date for primary outcome measure)|
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.
For patients with no cytoreductive surgery planned. All doses of erlotinib will be self-administered in an open-label, unblinded manner. During the treatment period, patients will receive single-agent erlotinib at a starting dose of 2000 mg on days 1 of every 7 days. Patients who are unable to swallow tablets may dissolve the tablets in water for administration.
Other Name: 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.
For patients with cytoreductive surgery planned. All erlotinib doses except the immediate pre-operative dose will be self-administered in an open-label, unblinded manner. During the treatment period, 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. Resection will occur within approximately 3 hours after the pre-operative dose. Following recovering from surgery, treatment with erlotinib post-operatively should resume no sooner than the 8th post-operative day and no later than 28th post-operative day.
Other Name: Tarceva
|United States, New Jersey|
|Memorial Sloan-Kettering at Basking Ridge|
|Basking Ridge, New Jersey, United States, 07920|
|United States, New York|
|Memorial Sloan-Kettering Cancer Center at Commack|
|Commack, New York, United States, 11725|
|Memorial Sloan Kettering Cancer Center|
|New York, New York, United States, 10065|
|Columbia University Medical Center|
|New York, New York, United States, 10032|
|Principal Investigator:||Andrew Lassman, MD||Columbia University|