Cediranib Maleate and Cilengitide in Treating Patients With Progressive or Recurrent Glioblastoma

OBJECTIVES:

Primary

- To determine the safety profile of cediranib maleate in combination with cilengitide in
patients with progressive or recurrent glioblastoma.

Secondary

- To estimate the overall survival of patients treated with this regimen.

- To estimate the proportion of radiographic responses in patients with measurable
disease treated with this regimen.

- To estimate the overall and progression-free survival rate at 6 months in patients
treated with cediranib maleate (administered at the safe dose determined in the
dose-finding portion of the study) in combination with cilengitide.

- To explore potential imaging techniques and biomarkers to capture the disease process
through treatment.

OUTLINE: This is a two-part, multicenter study. Patients are initially enrolled in the
dose-finding portion of the study (part A). Once the safe dose of cediranib maleate is
determined, additional patients are enrolled in the dose-expansion portion of the study
(part B).

- Part A (dose finding): Patients receive oral cediranib maleate once daily on days 1-28
and cilengitide IV over 1 hour on days 1, 4, 8, 11, 15, 18, 22, and 25. Treatment
repeats every 28 days in the absence of disease progression or unacceptable toxicity.

- Part B (dose expansion): Patients are assigned to 1 of 2 groups according to prior
anti-VEGF therapy (yes vs no). Patients in both groups receive cediranib maleate
(administered at the safe dose determined in part A) and cilengitide as in part A.

Patients enrolled in part B undergo blood sample collection at baseline and periodically
during study to measure collagen IV, tumastatin, and other angiogenic biomarkers (e.g.,
VEGF-A, VEGF-D, sVEGFR1, sVEGFR2, sICAM1, sVCAM1, PlGF, PDGF-AA, PDGF-AB, PDGF-BB,
thrombospondin-1, Ang1, bFGF, IL-6, and IL-8) by ELISA assays and circulating endothelial
cell levels by immunostaining and flow cytometry. Some patients in part B also undergo MRIs
at baseline and periodically during study for correlative imaging studies.

After completion of study therapy, patients are followed up every 2 months.

DISEASE CHARACTERISTICS:

- Histologically confirmed glioblastoma

- Progressive or recurrent disease after prior radiotherapy (with or without
chemotherapy)

- Low-grade glioma that progressed after radiotherapy (with or without
chemotherapy) allowed provided there is subsequent histologic confirmation of
glioblastoma

- Must have measurable contrast-enhancing disease by MRI within the past 2 weeks

- Must be maintained on a stable corticosteroid regimen (i.e., no increase for 5 days)
before the start of study treatment

- No more than 2 recurrences/relapses of the tumor

- No significant intratumoral or peritumoral hemorrhage by MRI

- Last prior treatment regimen must have included anti-VEGF therapy (for patients
enrolled in group 1 of the dose-expansion portion of the study)

- Able to start study treatment 21-28 days after the last short-acting anti-VEGF
treatment (≥ 28 days after the last bevacizumab treatment)

PATIENT CHARACTERISTICS:

- Karnofsky performance status 60-100%

- WBC ≥ 3,000/mm^3

- ANC ≥ 1,500/mm^3

- Platelet count ≥ 100,000/mm^3

- Hemoglobin ≥ 8 g/dL

- Total bilirubin normal

- AST and/or ALT ≤ 3 times upper limit of normal

- Creatinine normal OR creatinine clearance ≥ 60 mL/min

- Proteinuria ≤ +1 on two consecutive dipsticks taken ≥ 7 days apart

- If the first urinalysis shows no protein, a repeat test is not required

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

- Able to tolerate MRI

- Mini-Mental Exam score ≥ 15

- No QTc > 500 msec (with Bazett's correction) by screening ECG

- No history of familial long QT syndrome

- No other significant ECG abnormality within the past 14 days

- No NYHA class III-IV cardiac disease

- No concurrent uncontrolled illness including, but not limited to, the following:

- Hypertension (BP > 140/90 mm Hg)

- Ongoing or active infection

- Symptomatic congestive heart failure

- Unstable angina pectoris

- Cardiac arrhythmia

- Psychiatric illness and/or social situation that would preclude compliance with
study requirements

- No known coagulopathy that increases the risk of bleeding

- No history of clinically significant hemorrhage

- No concurrent serious infection or medical illness that would preclude the ability of
the patient to receive study treatment with reasonable safety

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

- No other 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, breast, or
bladder

PRIOR CONCURRENT THERAPY:

- See Disease Characteristics

- Recovered from prior therapy

- At least 3 months since prior radiotherapy

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

- No more than 2 prior chemotherapy regimens

- No prior cediranib maleate or cilengitide for glioblastoma

- No prior anti-VEGF therapy (for patients enrolled in group 2 of the dose-expansion
portion of the study)

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

- Concurrent non-EIAEDs allowed

- No concurrent anti-coagulants (e.g., dalteparin or warfarin), except low prophylactic
doses of low molecular weight heparin

- No concurrent combination antiretroviral therapy for HIV-positive patients

- No concurrent VEGF inhibitors

- No concurrent drugs or biologics with proarrhythmic potential

- No concurrent herbal or non-traditional medications

- No concurrent prophylactic G-CSF or GM-CSF

- No other concurrent investigational drugs

- No other concurrent anticancer therapy