• Safety profile and optimal dose of cediranib during chemoradiotherapy [ Designated as safety issue: Yes ]
• Progression-free survival [ Designated as safety issue: No ]

• MRI parameters [ Designated as safety issue: No ]
• Blood biomarkers [ Designated as safety issue: No ]
• Tumor biomarkers [ Designated as safety issue: No ]

RATIONALE: Cediranib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high-energy x-rays to kill tumor cells. Giving cediranib together with temozolomide and radiation therapy may kill more tumor cells.

PURPOSE: This phase I/II trial is studying the side effects and best dose of cediranib to see how well it works when given together with temozolomide and radiation therapy in treating patients with newly diagnosed glioblastoma.

OBJECTIVES:

Primary

• To determine the safety profile and optimal dose of cediranib (15 mg or 20 mg or 30 mg) when given in combination with temozolomide and radiotherapy in patients with newly diagnosed glioblastoma. (Phase I)
• To determine median progression-free survival of patients with newly diagnosed glioblastoma treated with this regimen. (Phase II)

Secondary

• To determine the radiographic response proportion in patients with measurable disease treated with this regimen. (Phase II)
• To determine the median overall survival of patients treated with this regimen. (Phase II)
• To determine the "vascular normalization" window in these patients by the application of serial, non-invasive, MRI parameters. (Phase II)
• To measure the glucose metabolism changes in a subset of patients by performing fludeoxyglucose F 18 positron emission tomography (FDG-PET) studies. (Phase II)
• To measure circulating endothelial and progenitor cells and plasma levels of VEGF-A; VEGF-B; VEGF-C; VEGF-D; sVEGFR1, sVEGFR2, bFGF, PlGF, PDGF-AA; PDGF-AB; PDGF-BB; SDF1α; tumstatin; thrombospondin-1; interleukin-8; collagen IV sICAM1, and sVCAM1 as markers for response to cediranib in these patients. (Phase II)
• To correlate treatment outcomes with pre-cediranib tumor specimens (with respect to cell proliferation, apoptosis, and microvascular density [MVD], basement membrane and pericyte coverage, and angiopoietin-1 and -2 expression) to determine whether these immunohistochemical analyses can be predictive of the response to cediranib. (Phase II)

OUTLINE: This is a phase I, dose-escalation study of cediranib followed by a phase II study. Patients begin study treatment within 21-42 days after craniotomy or 14-21 days after sterotactic biopsy.

• Phase Ib:

  • Chemoradiotherapy: Patients receive oral cediranib once daily and oral temozolomide once daily for 6 weeks. Within 2-6 hours of dosing, patients undergo concurrent intensity-modulated radiotherapy (IMRT) once daily, 5 days a week for 6 weeks.
  • Cediranib monotherapy: Patients receive oral cediranib once daily for 4 weeks (weeks 7-10).
  • Cediranib and temozolomide monthly therapy: Patients receive oral cediranib once daily for 24 weeks (weeks 11-34) and temozolomide once daily, 5 days a week in weeks 11, 15, 19, 23, 27, and 31.
  • Cediranib monotherapy: Patients receive a fixed-dose of cediranib once daily for 24 weeks (weeks 35-58).

• Phase II:

  • Chemoradiotherapy: Patients receive oral cediranib at the recommended phase II dose determined in phase Ib, oral temozolomide, and undergo concurrent IMRT as in phase Ib (weeks 1-6).
  • Cediranib monotherapy: Patients receive oral cediranib (at the recommended phase II dose determined in phase Ib) once daily for 4 weeks (weeks 7-10).
  • Cediranib and temozolomide monthly therapy: Patients receive oral cediranib (at the recommended phase II dose determined in phase Ib) once daily for 24 weeks (weeks 11-34) and temozolomide once daily, 5 days a week in weeks 11, 15, 19, 23, 27, and 31.
  • Cediranib monotherapy: Patients receive a fixed-dose of cediranib once daily for 24 weeks (weeks 35-58).

Patients undergo blood and urine sample collection at baseline and periodically during study. Blood samples are measured for tumstatin, as well as other well established biomarkers, including VEGF-A, -D, sVEGFR1, sVEGFR2, sICAM1, sVCAM1, PlGF, PDGF-AA, PDGF-AB, PDGF-BB, thrombospondin-1, and IL-8 by electrochemiluminescence detection. Circulating endothelial cell (CEC) assays are evaluated to assess the kinetics of CECs and progenitor cells prior to and during antiangiogenic therapy with cediranib and chemoradiotherapy. Urine samples are collected for proteomic analyses to evaluate serial change of growth factors such as VEGF and PlGF and of matrix metalloproteinases in response to treatment with cediranib. Archival tumor tissue is collected for analysis of tumor microvascular density, basement membrane and pericyte coverage, angiopoietin-1 and -2 expression, tumor cell proliferation, and apoptosis by immunostaining methods and immunoenzyme techniques.

Patients also undergo dynamic contrast enhanced (DCE)-MRI and T2-weighted or perfusion-weighted MRI at baseline and periodically during study to monitor antiangiogenic effect on tumor vasculature through parameters reflecting both tumor perfusion and permeability; and diffusion tensor imaging to measure degree of water diffusion and fractional anisotrophy. A subset of patients undergo fludeoxyglucose F 18 positron emission tomography (FDG-PET) periodically to monitor antiangiogenic effects on glucose utilization.

After completion of study treatment, patients are followed periodically for 1 year.

• Drug: cediranib maleate
• Drug: temozolomide
• Genetic: proteomic profiling
• Other: immunoenzyme technique
• Other: immunohistochemistry staining method
• Other: laboratory biomarker analysis
• Procedure: adjuvant therapy
• Procedure: diffusion tensor imaging
• Procedure: diffusion-weighted magnetic resonance imaging
• Procedure: dynamic contrast-enhanced magnetic resonance imaging
• Radiation: fludeoxyglucose F 18
• Radiation: intensity-modulated radiation therapy

DISEASE CHARACTERISTICS:

• Histologically confirmed glioblastoma

  • Newly diagnosed disease
• Scheduled to receive standard post-surgical (i.e., biopsy or resection) temozolomide and radiotherapy
• Must have residual, contrast-enhancing tumor (≥ 1 centimeter in ≥ 1 dimension)
• Patients must be maintained on a stable corticosteroid regimen for 5 days prior to their baseline scan and for 5 days prior to their first vascular MRI; the dose of steroids should remain the same during the baseline vascular MRIs
• Archival tumor tissue available for molecular analysis
• No intratumoral hemorrhage or peritumoral hemorrhage by MRI

PATIENT CHARACTERISTICS:

• Karnofsky performance status 60-100%
• Leukocytes ≥ 3,000/mcl
• Absolute neutrophil count ≥ 1,500/mcL
• Platelet count ≥ 100,000/mcL
• Hemoglobin ≥ 8 g/dL
• Total bilirubin normal
• AST/ALT ≤ 2.5 times upper limit of normal
• Creatinine normal OR creatinine clearance ≥ 60 mL/min
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• Proteinuria ≤ 1+ on two consecutive dipsticks ≥ 7 days apart
• Mini-mental status examination score ≥ 15

• Must be able to tolerate MRI and must consent to participate in additional Vascular Imaging Procedures per protocol

  • CT scans cannot be substituted for MRI
• Mean QTc ≤ 500 msec (with Bazett's correction) by electrocardiogram

• No concurrent malignancy except curatively treated basal cell or squamous cell carcinoma skin cancer or carcinoma in situ of the cervix or breast

  • Patients with prior malignancies must be disease-free for ≥ 5 years
• No history of familial long QT syndrome or other significant ECG abnormality
• No history of allergic reactions attributed to compounds of similar chemical or biologic composition to cediranib

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

  • Hypertension (e.g., blood pressure > 140/90 mm Hg)
  • Ongoing or active infection
  • Symptomatic congestive heart failure
  • Unstable angina pectoris
  • Cardiac arrhythmia
  • Psychiatric illness/social situations that would preclude study compliance
• No known coagulopathy that increases risk of bleeding
• No history of clinically significant hemorrhages in the past
• No New York Heart Association class III-IV heart disease
• No condition requiring concurrent drugs or biologics with proarrhythmic potential

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• No prior chemotherapy, radiotherapy, or any experimental therapy for this disease
• No prior IV bevacizumab for any other medical condition
• No prior carmustine implant (Gliadel Wafer)
• No prior brachytherapy or radiosurgery for this disease
• More than 30 days since prior and no other concurrent investigational agents or participation in an investigational therapeutic trial

• At least 2 weeks since prior and no concurrent enzyme-inducing anti-epileptic drugs (EIAEDs)

  • Concurrent non-EIAEDs allowed
• No concurrent CYP450-inducing anticonvulsants

• No concurrent anticoagulants (e.g., dalteparin, warfarin, or low-molecular weight heparin)

  • If patients require warfarin or other anticoagulants (e.g., low-molecular weight heparin) while on study, then patient may continue treatment
• No concurrent combination antiretroviral therapy for HIV-positive patients
• No concurrent VEGF inhibitors
• No concurrent pentamidine
• No concurrent herbal or nontraditional medications
• No other concurrent chemotherapy agents, investigational agents, or biologic therapy