EGFR Inhibition Using Weekly Erlotinib for Recurrent Malignant Gliomas

Amplification of the EGFR gene locus occurs also in approximately 40% of glioblastomas
(GBM). Activating EGFR mutations, such as EGFRvIII (Sugawa et al., 1990) occur in
approximately 50% of these GBMs (20% overall), leading to constitutive receptor activation
and oncogenic signaling. The high frequency of EGFR signaling abnormalities in GBM led to
initial enthusiasm for clinical trials of the EGFR TKIs erlotinib and gefitinib. However,
responses were rare.

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 NOS (Not otherwise specified).

- 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 VEGF/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.