AZD2171 in Treating Patients With Recurrent Glioblastoma Multiforme

PRIMARY OBJECTIVE:

I. Determine the proportion of patients with recurrent glioblastoma multiforme (GM) who are
alive and progression free 6 months after starting AZD2171 therapy.

SECONDARY OBJECTIVES:

I. Assess the biological effect of AZD2171 by using the following MRI techniques: dynamic
contrast-enhanced imaging; arterial spin-labeling imaging; perfusion-weighted imaging; and
diffusion- tensor imaging at serial time points.

II. Measure circulating endothelial and progenitor cells and plasma levels of tumstatin,
(vascular endothelial growth factor (VEGF)-A and -D, sVEGF receptors, P1GF, platelet-derived
growth factor (PDGF)-AA, PDGF-AB, PDGF-BB, Ang1, thrombospondin-1, and interleukin-8 as
markers for response to antiangiogenic therapy in recurrent GM.

III. Correlate treatment outcomes with pre-AZD2171 tumor specimens with respect to
microvascular density, basement membrane and pericyte coverage, and angiopoietin-1 and -2
expression to determine whether these immunohistochemical analyses can be predictive of the
response to AZD2171.

IV. Measure polymorphisms of kdr/flk-1 gene and genetic analysis of HIF1-alpha, TP53, and
endothelial nitric oxide synthase genes in the archival tumor specimens.

V. Determine the overall survival of patients with recurrent GM treated with AZD2171.

VI. Determine the radiographic response rate in patients with recurrent GM treated with
AZD2171.

VII. Determine the safety of AZD2171 in this patient population.

OUTLINE: This is a multicenter study.

Patients receive oral AZD2171 once daily on days 1-28. Courses repeat every 28 days in the
absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed periodically for up to 12 months.

Criteria:

- AST/ALT =< 2.5 times upper limit of normal

- Creatinine normal OR creatinine clearance >= 60 mL/min

- Measurable contrast-enhancing tumor >= 1 cm in longest diameter by baseline MRI or CT
scan:

- Patient must have been on no steroids OR a stable dose of steroids for >= 5 days
prior to baseline MRI or CT scan

- Patients who are on steroids must be maintained on a stable corticosteroid
regimen from baseline scan until the start of study treatment

- No intratumoral or peritumoral hemorrhage by MRI

- Karnofsky performance status >= 60%

- No other concurrent malignancy within the past 5 years except curatively treated
basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix
or breast

- Mini-mental status examination score >= 15

- Histologically confirmed glioblastoma multiforme

- Platelet count >= 100,000/mm3

- Hemoglobin >= 8 g/dL

- Bilirubin normal

- No history of allergic reactions attributed to compounds of similar chemical or
biologic composition to AZD2171

- Mean QTc =< 470 msec (with Bazett's correction) on screening electrocardiogram

- No history of familial long QT syndrome

- No greater than +1 proteinuria on 2 consecutive dipsticks taken >= 1 week apart
unless first urinalysis shows no protein

- No uncontrolled intercurrent illness, including, but not limited to, any of the
following:

Hypertension; Ongoing or active infection; Symptomatic congestive heart failure; Unstable
angina pectoris; Cardiac arrhythmia; Psychiatric illness/social situations that would
limit compliance with study requirements

- No known coagulopathy that increases the risk of bleeding

- No history of clinically significant hemorrhages

- Recovered from toxicity of prior therapy

- At least 3 months since prior radiation therapy, including cranial radiation therapy

- At least 3 weeks since prior chemotherapy (6 weeks for nitrosoureas)

- At least 3 weeks since prior molecularly-targeted agents

- At least 4 weeks since prior major surgery

- No more than 2 prior chemotherapy regimens or antineoplastic drugs

- More than 30 days since prior participation in an investigational trial

- At least 2 weeks since prior enzyme-inducing antiepileptic drugs (EIAEDs)

- No concurrent EIAEDs; Concurrent non-EIAEDs allowed

- No concurrent combination antiretroviral therapy for HIV-positive patients

- No other concurrent investigational agents

- No concurrent vascular endothelial growth factor inhibitors:

Prior thalidomide or lenolidomide allowed

- No concurrent anticoagulants (e.g., warfarin) or antiplatelet agents including
aspirin

- No other concurrent anticancer agents or therapies

- No concurrent grapefruit juice

- WBC >= 3,000/mm3

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

- Absolute neutrophil count >= 1,500/mm3