AMG 595 First-in-Human in Recurrent Gliomas

This study of AMG 595 will be conducted in two parts: Part 1 (dose exploration) and Part 2
(dose expansion). Part 1 of the study is in subjects with recurrent glioblastoma multiforme
(GBM) and/or anaplastic astrocytomas (AA), and Part 2 is examining the MTD in subjects with
recurrent GBM. Approximately 30-40 subjects may be enrolled in Part 1, and up to 36 subjects
may be enrolled in Part 2. The dose of AMG 595 utilized in Part 2 will be dependent upon
data obtained in Part 1 of the study.

Inclusion Criteria:

- Karnofsky performance score > or = 70%

- Must have pathologically documented, and definitively diagnosed recurrent WHO Grade
IV advanced malignant glioblastoma multiforme (Part 1 and Part 2) and/or WHO Grade
III anaplastic astrocytoma (Part 1 only).

- GBM and/or AA tumors expressing EGFRvIII as assessed on archived tissue by IHC
staining of sections containing a minimum of 100 evaluable tumor cells.

- Archived tumor tissue from the initial diagnosis or subsequent relapse(s) of Grade IV
advanced malignant glioblastoma multiforme or Grade III anaplastic astrocytoma
available for submission to central review.

- Subjects with recurrent disease (confirmed by MRI and evaluable by Macdonald
criteria) at the time of first or second recurrence or progression following initial
definitive therapy(s)

- QTcF ≤ 470 msec

- Hematological function, as follows: Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L,
Platelet count ≥ 100 x 10^9/L, Hemoglobin > 9 g/dL

- Renal function, as follows: Estimated glomerular filtration rate using the Modified
Diet in Renal Disease (MDRD) equation > 45 mL/min/1.73m^2, Urinary protein
quantitative value of < 30 mg/dL in urinalysis or ≤ 1+ on dipstick, unless
quantitative protein is < 500 mg in a 24 hr urine sample

Exclusion Criteria:

- History of central nervous system bleeding as defined by stroke or intraocular bleed
(including embolic stroke) within 6 months before enrollment.

- Evidence of acute intracranial / intratumoral hemorrhage, except for subjects with
stable grade 1 hemorrhage.

- Peripheral sensory neuropathy > Grade 2.

- Clinically significant ECG changes which obscure the ability to assess the PR, QT,
and QRS interval; congenital long QT syndrome.

- Recent infection requiring intravenous anti-infective treatment that was completed ≤
14 days before enrollment.

- Received radiation therapy within 12 weeks before enrollment or has not recovered
from the toxic effects of such therapy.

- For Part 1 (dose escalation): Treatment with bevacizumab or antiangiogenic therapy
within 4 weeks before enrollment, or for Part 2 (dose expansion): any prior treatment
with bevacizumab or antiangiogenic therapy.