Randomized, Phase II, Double-Blind, Placebo-Controlled Trial of Conventional Chemoradiation and Adjuvant Temozolomide Plus Cediranib Versus Conventional Chemoradiation and Adjuvant Temozolomide Plus Placebo in Patients With Newly Diagnosed Glioblastoma

Inclusion Criteria:

- Histologically confirmed glioblastoma or gliosarcoma (WHO grade IV)

- Diagnosis must have been made by partial or complete surgical excision within
the past 3-5 weeks

- Cavitron ultrasonic aspirator-derived material or stereotactic biopsy not
allowed

- Tumor must have a supratentorial component

- Must have ≥ 1 block of tumor tissue available for analysis of MGMT status

- Tumor tissue must be of sufficient size for analysis of MGMT status, as
determined by central pathology review

- No recurrent or multifocal malignant gliomas

- No metastases detected below the tentorium or beyond the cranial vault

- Karnofsky performance status 70-100%

- ANC ≥ 1,800/mm^3

- Platelet count ≥ 100,000/mm^3

- Hemoglobin ≥ 10.0 g/dL (transfusion or other intervention allowed)

- BUN ≤ 30 mg/dL

- Creatinine ≤ 1.7 mg/dL

- Urine protein:creatinine ratio ≤ 0.5 by urinalysis OR urine protein < 1,000 mg by
24-hour urine collection

- Bilirubin ≤ 2.0 mg/dL

- ALT and AST ≤ 3 times normal

- PT/INR < 1.4 (unless on full-dose anticoagulation)

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

- Able to undergo MRI or PET scan (i.e., no pacemaker or weight limitation) (for
advanced imaging substudy)

- Able to tolerate 2 IV lines, 1 in each arm (for advanced imaging substudy)

- Systolic BP ≤ 150 mm Hg or diastolic BP ≤ 90 mm Hg within the past 14 days (in the
presence or absence of a stable regimen of anti-hypertensive therapy)

- Mean QTc ≤ 500 msec (with Bazett's correction) on screening EKG

- No familial long QT syndrome or other significant ECG abnormality within the past 14
days

- No severe, active co-morbidity including, but not limited to, any of the following:

- Unstable angina and/or congestive heart failure requiring hospitalization

- Transmural myocardial infarction within the past 6 months

- Recent myocardial infarction or ischemia as evidenced by S-T elevations of ≥ 2
mm on EKG within the past 14 days

- NYHA class II-IV congestive heart failure requiring hospitalization within the
past 12 months

- Stroke, cerebral vascular accident, or transient ischemic attack within the past
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

- Abdominal fistula, gastrointestinal perforation, intra-abdominal abscess, or
significant traumatic injury within the past 28 days

- Acute bacterial or fungal infection requiring IV antibiotics

- Chronic obstructive pulmonary disease exacerbation or other respiratory illness
requiring hospitalization or precluding study therapy

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

- Laboratory tests for liver function and coagulation parameters not required

- AIDS based upon current CDC definition

- HIV testing not required

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

- Any other major medical illness or psychiatric impairment that, in the
investigator's opinion, would prevent administration or completion of study
therapy

- No other invasive malignancy within the past 3 years except adequately treated
nonmelanomatous skin cancer or curatively treated carcinoma in situ of the breast,
oral cavity, or cervix

- No prior allergic reaction to temozolomide

- No prior allergic reactions attributed to compounds of similar chemical or biologic
composition to cediranib maleate

- No prior allergic reactions attributed to compounds of similar chemical or biological
composition to gadolinium or [18F]FLT contrast agents (for advanced imaging substudy)

- See Disease Characteristics

- Must have recovered from prior surgery, post-operative infection, and other
complications

- More than 28 days since prior major surgical procedure or open biopsy (other than
craniotomy for tumor resection)

- More than 30 days since prior and no concurrent treatment on other therapeutic
clinical trials

- At least 14 days since prior and no concurrent enzyme-inducing anti-epileptic drugs
(EIAEDs)

- Concurrent non-EIAEDs allowed

- No prior chemotherapy or radiosensitizers for cancer of the head and neck region

- Prior chemotherapy for a different cancer allowed

- No prior temozolomide or cediranib maleate

- No prior Gliadel wafers or any other intratumoral or intracavitary treatment

- No prior radiotherapy to the head or neck (except for T1 glottic cancer) resulting in
overlap of radiotherapy fields

- No other concurrent VEGF inhibitors

- Concurrent full-dose anticoagulants (e.g., warfarin or low molecular weight heparin)
allowed provided both of the following criteria are met:

- 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) and patient is on a stable dose of oral
anticoagulant or low molecular weight heparin