Temozolomide and Radiation Therapy With or Without Cediranib Maleate in Treating Patients With Newly Diagnosed Glioblastoma

PRIMARY OBJECTIVES:

I. To determine if the addition of cediranib (cediranib maleate) to chemoradiation treatment
enhances treatment efficacy as measured by the 6-month progression-free survival rate.

SECONDARY OBJECTIVES:

I. To determine if the addition of cediranib to chemoradiation treatment enhances treatment
efficacy as measured by overall survival.

II. To determine if the addition of cediranib to chemoradiation treatment enhances treatment
efficacy as measured by progression-free survival.

III. To determine if there is an association between tumor O6-methylguanine-deoxyribonucleic
acid (DNA) methyltransferase (MGMT) gene methylation status and treatment response and
outcome.

IV. To compare and record the toxicities of the cediranib + chemoradiation arm versus the
chemoradiation arm.

V. To evaluate whether 6-month progression-free survival is associated with overall survival.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive cediranib maleate orally (PO) once daily (QD) for 3 days. Patients
then undergo radiation therapy (intensity-modulated radiation therapy or 3-dimensional
conformal radiation therapy) QD, 5 days a week, for 6 weeks and receive temozolomide PO QD
and cediranib maleate PO QD for 6 weeks. Patients then receive temozolomide PO QD alone on
days 1-5. Treatment with temozolomide repeats every 28 days for up to 12 courses in the
absence of disease progression or unacceptable toxicity.

ARM II: Patients receive placebo PO QD for 3 days. Patients then undergo radiation therapy
(intensity-modulated radiation therapy or 3-dimensional conformal radiation therapy) QD, 5
days a week, for 6 weeks and receive temozolomide PO QD and placebo PO QD for 6 weeks.
Patients then receive temozolomide PO QD alone on days 1-5. Treatment with temozolomide
repeats every 28 days for up to 12 courses in the absence of disease progression or
unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 1 year,
every 4 months for 1 year, and then every 6 months thereafter.

Inclusion Criteria:

- Histologically proven diagnosis of glioblastoma or gliosarcoma (World Health
Organization [WHO] grade IV) confirmed by central review prior to step 2 registration

- Tumor tissue that is determined by central pathology review prior to step 2
registration to be of sufficient size for analysis of MGMT status

- Patients must have at least 1 block of tumor tissue; submission of 2 blocks is
strongly encouraged

- Cavitron ultrasonic aspirator (CUSA)-derived material is not allowed; fresh
frozen tumor tissue acquisition is encouraged

- Diagnosis must be made by surgical excision, either partial or complete;
stereotactic biopsy is not allowed because it will not provide sufficient tissue
for MGMT analysis

- The tumor tissue must be sent as soon as possible to maximize the likelihood of
eligibility; tumor tissue may not be submitted later than 28 days after the
surgical procedure, because tissue analysis will not be able to be performed in
time for treatment to commence by the mandatory 6-week post-surgery outer limit;
submission of tissue earlier than 28 days post-surgery is highly recommended

- The tumor must have a supratentorial component

- History/physical examination, including neurologic examination, within 14 days prior
to step 2 registration

- The patient must have recovered from the effects of surgery, post-operative infection,
and other complications before step 2 registration

- A diagnostic contrast-enhanced magnetic resonance imaging (MRI) of the brain must be
performed preoperatively and postoperatively prior to step 1 registration; the
postoperative scan must be performed within 28 days prior to step 1 registration

- Documentation of steroid doses/concurrent medications within 14 days prior to step 2
registration

- Karnofsky performance status >= 70 within 14 days prior to step 2 registration

- Complete blood count (CBC)/differential obtained within 14 days prior to step 2
registration on study, with adequate bone marrow function defined as follows:

- Absolute neutrophil count (ANC) >= 1,800 cells/mm^3

- Platelets >= 100,000 cells/mm^3

- Hemoglobin >=10.0 g/dl (Note: The use of transfusion or other intervention to achieve
hemoglobin (Hgb) >= 10.0 g/dl is acceptable)

- Adequate renal function, as defined below:

- Blood urea nitrogen (BUN) =< 30 mg/dl within 14 days prior to step 2 registration

- Creatinine =< 1.7 mg/dl within 14 days prior to step 2 registration

- Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) =< 3 x normal range
within 14 days prior to step 2 registration

- Systolic blood pressure =< 140 mm Hg AND diastolic pressure =< 90 mm Hg within 14 days
prior to step 2 registration in the presence or absence of a stable regimen of
anti-hypertensive therapy

- Prothrombin time/international normalized ratio (PT INR) < 1.4 for patients not on
warfarin confirmed by testing within 1 week of step 2 registration

- Patients on full-dose anticoagulants (e.g., warfarin or low molecular weight [LMW]
heparin) must meet both of the following criteria:

- No active bleeding or pathological condition that carries a high risk of bleeding
(e.g., tumor involving major vessels or known varices)

- In-range INR (usually between 2 and 3) on a stable dose of oral anticoagulant or
on a stable dose of low molecular weight heparin

- Patient must provide study specific informed consent prior to step 1 registration

- Women of childbearing potential and male participants must practice adequate
contraception

- For females of child-bearing potential, negative serum pregnancy test within 14 days
prior to step 2 registration

Exclusion Criteria:

- Prior invasive malignancy (except for non-melanomatous skin cancer) unless disease
free for >= 3 years; (for example, carcinoma in situ of the breast, oral cavity, and
cervix are all permissible)

- Recurrent or multifocal malignant gliomas

- Metastases detected below the tentorium or beyond the cranial vault

- Prior chemotherapy or radiosensitizers for cancers of the head and neck region; note
that prior chemotherapy for a different cancer is allowable (except temozolomide or
cediranib); prior use of Gliadel wafers or any other intratumoral or intracavitary
treatment are not permitted

- Prior radiotherapy to the head or neck (except for T1 glottic cancer), resulting in
overlap of radiation fields

- Severe, active co-morbidity, defined as follows:

- Unstable angina and/or congestive heart failure requiring hospitalization

- Transmural myocardial infarction within the last 6 months

- Evidence of recent myocardial infarction or ischemia by the findings of S-T
elevations of >= 2 mm using the analysis of an electrocardiogram (EKG) performed
within 14 days of step 2 registration

- New York Heart Association grade II or greater congestive heart failure requiring
hospitalization within 12 months prior to step 2 registration

- History of stroke, cerebral vascular accident (CVA) or transient ischemic attack
within 6 months

- Serious and inadequately controlled cardiac arrhythmia

- Significant vascular disease (e.g., aortic aneurysm, history of aortic
dissection) or clinically significant peripheral vascular disease

- Evidence of bleeding diathesis or coagulopathy

- Serious or non-healing wound, ulcer, or bone fracture or history of abdominal
fistula, gastrointestinal perforation, intra-abdominal abscess major surgical
procedure, open biopsy, or significant traumatic injury within 28 days prior to
step 2 registration, with the exception of the craniotomy for tumor resection

- Acute bacterial or fungal infection requiring intravenous antibiotics at the time
of step 2 registration

- Chronic obstructive pulmonary disease exacerbation or other respiratory illness
requiring hospitalization or precluding study therapy at the time of step 2
registration

- Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects

- Acquired immune deficiency syndrome (AIDS) based upon current Centers for Disease
Control (CDC) definition; note, however, that human immunodeficiency virus (HIV)
testing is not required for entry into this protocol

- Active connective tissue disorders, such as lupus or scleroderma, which in the
opinion of the treating physician may put the patient at high risk for radiation
toxicity

- Any other major medical illnesses or psychiatric impairments that in the
investigator's opinion will prevent administration or completion of protocol
therapy

- Pregnancy or women of childbearing potential and men who are sexually active and not
willing/able to use medically acceptable forms of contraception

- Pregnant or lactating women

- Prior allergic reaction to temozolomide

- Patients treated on any other therapeutic clinical protocols within 30 days prior to
step 1 registration or during participation in the study

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to cediranib

- Mean QTc >500 msec (with Bazett's correction) in screening electrocardiogram or
history of familial long QT syndrome or other significant ECG abnormality noted within
14 days of treatment

- Patients receiving concurrent vascular endothelial growth factor (VEGF) inhibitors are
prohibited from participating in this study

- Patients must not be on enzyme-inducing anti-epileptic drugs (EIAED); patients may be
on non-enzyme inducing anti-epileptic drugs (NEIAED) or may not be taking any
anti-epileptic drugs; in patients who have previously been on EIAED there must be at
least a 14 day period since the last dose of an EIAED before the first dose of
cediranib