Oral Tarceva Study for Recurrent/Residual Glioblastoma Multiforme and Anaplastic Astrocytoma

The high-grade malignant brain tumors, glioblastoma multiforme (GBM) and anaplastic
astrocytoma (AA), comprise the majority of all primary brain tumors in adults. This group of
tumors also exhibits the most aggressive behavior, resulting in median overall survival
durations of only 9-12 months for GBM, and 3-4 years for AA, from initial diagnosis, despite
multimodal treatment approaches. Initial therapy consists of either surgical resection,
external beam radiation or both. The role of adjuvant or concomitant chemotherapy in the
initial therapy of GBM and AA has not, as yet, been clearly defined. Since most of these
patients experience a recurrence after first-line therapy, improvements in both first-line
and salvage therapy are critical to enhancing quality-of-life and prolonging survival. In
August 2003, the U.S. Food and Drug Administration (FDA) granted orphan drug status for
Erlotinib in patients with malignant glioma. Erlotinib (OSI-774) has been shown to be active
in a range of tumors including GBM, AA and non small cell lung cancer. Because of the
promising results in preliminary studies of Erlotinib and because of significant experience
with the safety of the dosages proposed in this study, this study will offer a safe adjuvant
treatment for patients with relapsing recurring glioblastoma or anaplastic astrocytoma.
Therefore, this phase I/II clinical research trial will test the hypothesis that Erlotinib
can be safely used up to a dose of 150 mg bid for 12 cycles to ultimately enhance survival
of patients with relapsed/refractory GBM/AA with particular genetic alterations including
EGFRvIII amplification and PTEN loss.

Inclusion Criteria:

- Male or female patients of ≥ 18 years of age.

- Patients with a documented histologic diagnosis of relapsed or refractory
glioblastoma multiforme (GBM), anaplastic astrocytoma (AA) or anaplastic mixed
oligoastrocytoma (AOA). All patients will have samples of their tissue evaluated for
EGFRvIII overexpression and PTEN loss.

- Patients with a histologically confirmed low grade brain tumor who relapse with an
enhancing tumor on magnetic resonance imaging (MRI) can be evaluated for toxicity
only.

- Patients must have at least one confirmed and evaluable tumor site.*

*A confirmed tumor site is one which is biopsy-proven. NOTE: Radiographic procedures
(e.g., Gd-enhanced MRI or computed tomography [CT] scans) documenting existing
lesions must have been performed within three weeks of treatment on this research
study.

- Patients must have a Karnofsky performance status ≥ 60% (or the equivalent Eastern
Cooperative Oncology Group [ECOG] level of 0-2) and an expected survival of ≥ three
months.

- No chemotherapy for six weeks prior to treatment under this research protocol and no
external beam radiation for eight weeks prior to treatment under this research
protocol.

- Patients must have adequate hematologic reserve with WBC ≥ 3000/mm3, absolute
neutrophils ≥ 1500/mm3 and platelets ≥ 100,000/mm3. Patients who are on Coumadin must
have a platelet count of ≥ 150,000/mm3

- Pre-enrollment chemistry parameters must show: bilirubin < 1.5X the institutional
upper limit of normal (IUNL); AST or ALT < 2.5X IUNL and creatinine < 1.5X IUNL.

- Pre-enrollment coagulation parameters (PT and PTT) must be ≤ 1.5X the IUNL.

- Concomitant Medications:

- Growth factor(s): Must not have received within 1 week of entry onto this study.

- Steroids: Systemic corticosteroid therapy is permissible in patients with
centrail nervous system (CNS) tumors for treatment of increased intracranial
pressure or symptomatic tumor edema. Patients with CNS tumors who are receiving
dexamethasone must be on a stable or decreasing dose for at least 1 week prior
to study entry.

- Study Specific: Patients on enzyme-inducing anticonvulsants will be changed to
non-enzyme inducing anticonvulsants or will not be allowed on this study.
Patients receiving proton pump inhibitor or H2 blockers will not be allowed on
study. Patients taking antacids will be allowed on study although they should
not take the antacid for two hours before or two hours after taking erlotinib.

- Patients must agree to use a medically effective method of contraception during and
for a period of three months after the treatment period. A pregnancy test will be
performed on each premenopausal female of childbearing potential immediately prior to
entry into the research study.

- Patients should not have received a CYP3A4 inhibitor within 1 week of study entry and
should not have received a CYP3A4 inducer within 4 weeks of study entry.

- Patients should not have received proton-pump inhibitors within 5 days of study entry
or H2 blockers within 2 days of study entry.

- Patients on steroids must receive prophylaxis for Pneumocystis carinii pneumonia
(PCP) with Bactrim, unless they have a history of allergy to sulfa drugs.

- Patients must be able to understand and give written informed consent. Informed
consent must be obtained at the time of patient screening.

Exclusion Criteria:

- Previous treatment with Tarceva®.

- Women who are pregnant or lactating.

- Women of childbearing potential and fertile men will be informed as to the potential
risk of procreation while participating in this research trial and will be advised
that they must use effective contraception during and for a period of three months
after the treatment period.

- Patients with significant intercurrent medical or psychiatric conditions that would
place them at increased risk or affect their ability to receive or comply with
treatment or post-treatment clinical monitoring.