Pilot Study of 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.