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

Inclusion Criteria:

• Patients must have a histologically confirmed intracranial malignant glioma of the following types:

Glioblastoma (GBM) Gliosarcoma (GS) is a subset of GBM and patients with GS are therefore eligible.

Anaplastic astrocytoma (AA) Anaplastic oligodendroglioma (AO) Anaplastic oligoastrocytoma (AOA, also called anaplastic mixed gliomas or AMG) High grade glioma NOS (Not otherwise specified) Patients will be eligible if the original histology was low-grade glioma and a subsequent histological diagnosis of a high grade (malignant) glioma is made.

• EGFRvIII mutation detected on pretreatment tissue from at least 1 prior surgery, preferably the most recent surgery in patients who have undergone more than 1 resection. EGFR gene amplification alone is insufficient. This MUST BE PERFORMED AT Columbia University Medical Center or Memorial Sloan-Kettering Cancer Center. Any questions should be addressed to the Sponsor.
• At least 15 unstained slides or at least 1 tissue blocks must be collected from at least one prior surgery. Frozen tissue is also requested if available.
• Before starting study treatment, patients must have recovered from toxic effects of prior therapies and at least 4 weeks must have elapsed since any prior anti-cancer therapy except: at least 6 weeks from nitrosoureas (e.g., BCNU, CCNU) and at least 3 months from prior brain radiotherapy to reduce the likelihood that patients enrolled have pseudoprogression rather than true disease progression.
• Patients must be able to undergo contrast enhanced MRI scans (or CT scans for patients unable to tolerate MRI).
• Patients must have shown unequivocal evidence for contrast enhancing tumor progression by MRI (or CT for patients who cannot tolerate MRI) in comparison to a prior scan. The same type of scan, i.e., MRI (or CT for patients who cannot undergo MRI) must be used throughout the period of protocol treatment for tumor measurement. Criteria in section 12 for progression on this study are not mandatory for eligibility if the disease progression is obvious in the opinion of the investigator and the PI or co-PI agrees. Any questions should be addressed to the Sponsor.
• Age > or = to 18 years.
• Karnofsky Performance Status > or = to 60%
• Life expectancy of greater than 8 weeks.
• Patients must have normal organ and marrow function (WBC > or = to 2,000/μl, ANC > or = to 1,500/mm3, platelet count of > or = to 100,000/mm3, and hemoglobin > 10 gm/dl), adequate liver function (SGOT, SGPT and bilirubin < 2 times ULN), and adequate renal function (creatinine < 1.5 mg/dL) before starting therapy. These tests must be performed within 14 days prior to registration. Eligibility level for hemoglobin may be reached by transfusion.
• Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation because the effects of erlotinib on the developing human fetus are unknown. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.
• Women of childbearing potential must have a negative B-HCG pregnancy test documented within 7 days prior to treatment.
• Women must agree not to breast feed.
• Patients must have the ability to understand and the willingness to sign a written informed consent document.

Cohort A (medical) specific inclusion criteria:

Patients must 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, progressive disease led to the surgery, and the histology of the most recent surgery documented recurrent/progressive/persistent malignant glioma.
• Patients must be on a stable or decreasing dose of corticosteroids for a minimum of 5 days before the baseline MRI/CT. If the corticosteroid dose is increased between the date of imaging and registration a new baseline MRI/CT is required. Definition of stable steroids includes patients on no steroids.
• The baseline brain MRI/CT must be performed on the 14th day or less prior to initiation of study treatment. Otherwise it must be repeated.

Cohort B (surgical) specific inclusion criteria:

• Patients must fulfill all of the General Inclusion Criteria.
• An MRI/CT scan showing progression is required. Stable corticosteroids are not required.

Exclusion Criteria:

• There is no limit on the number or type of prior chemotherapies except:
• Patients must not have received prior treatment with convection enhanced delivery, other catheter based intratumoral treatment, or carmustine (BCNU)/Gliadel wafers because of potential difficulty interpreting brain scans in such patients.
• Patients with prior therapy that included stereotactic radiosurgery (including gamma-knife or cyber-knife) 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. Imaging with MRSpectroscopy, MRPerfusion, PET, or other techniques is not adequate to exclude radiation necrosis for this study. (Clarke et al., 2008).
• Patients may not have received prior treatment with an EGFR inhibitor such as erlotinib,(Tarceva), gefitinib,(Iressa), lapatinib,(Tykerb), vandetanib,(Zactima), or cetuximab (Erbitux), PF299804, or therapy with an anti-EGFR vIII antibody. Any question about the definition of an EGFR inhibitor should be discussed with the Sponsor.
• Patients may not have received prior treatment with direct VEGF/VEGFR inhibitors such as bevacizumab (Avastin), aflibercept (VEGF-Trap), cediranib (AZD2171), or XL-184 (Cabozantinib) because evidence suggests the biology of gliomas following progression on such agents differs, and there is little to no historic control data presently available for such patients.
• Patients may not smoke or plan to smoke tobacco or marijuana during study therapy.
• Patients may not be receiving any other investigational agents concurrently with study treatment.
• Patients must not be taking Enzyme Inducing Anti-Epileptic Drug (EIAED) defined as:

EIAEDs:

Carbamazepine (Tegretol, Tegretol XR, Carbatrol) Oxcarbazepine (Trileptal) Phenytoin (Dilantin, Phenytek) Fosphenytoin (Cerebyx) Phenobarbital Primidone (Mysoline) If previously on an EIAED, the patient must be off of it for at least two weeks prior to study treatment.

• Patients must not have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to erlotinib.
• Patients must not have uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with erlotinib. In addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated. This applies only to patients who have a documented history of HIV and HIV testing is not otherwise required.
• Patients must not have other active concurrent malignancy. Any questions should be addressed to the Sponsor.