Cediranib, Temozolomide, and Radiation Therapy in Treating Patients With Newly Diagnosed Glioblastoma

Study Overview
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Brief Summary
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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. 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.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine the safety profile and optimal dose of AZD2171 (cediranib) (15mg or 20mg or 30mg) in combination with temozolomide and radiation in patients with newly diagnosed glioblastoma (Phase Ib) II. To determine median progression-free survival of patients with newly diagnosed glioblastoma treated with AZD2171 in combination with temozolomide and radiation (Phase II) SECONDARY OBJECTIVES: I. To determine the radiographic response proportion in newly diagnosed glioblastoma patients with measurable disease. (Phase II) II. To determine the median overall survival. (Phase II) III. To determine the vascular normalization window in newly diagnosed glioblastoma patients by the application of serial, non-invasive, MRI parameters. (Phase II) IV. To measure the glucose metabolism changes in a subset of newly diagnosed glioblastoma patients by performing FDG PET studies. (Phase II) V. Measurement of 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, sVCAM1 as markers for response to AZD2171 in newly diagnosed glioblastoma patients. (Phase II) VI. Correlation of treatment outcomes with pre-AZD2171 tumor specimens with respect to cell proliferation, apoptosis, microvascular density (MVD), basement membrane and pericyte coverage, angiopoietin-1 and -2 expression to determine whether these immunohistochemical analyses can be predictive of the response to AZD2171. (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 stereotactic biopsy. PHASE Ib: CHEMORADIOTHERAPY: Patients receive cediranib orally (PO) 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 cediranib PO once daily for 4 weeks (weeks 7-10). Cediranib and temozolomide monthly therapy: Patients receive cediranib PO 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 cediranib PO at the recommended phase II dose determined in phase Ib, temozolomide PO, and undergo concurrent IMRT as in phase Ib (weeks 1-6). Cediranib monotherapy: Patients receive cediranib PO (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 cediranib PO (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 anisotropy. 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.

Official Title
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A Phase Ib/II Study of AZD2171 in Combination With Daily Temozolomide and Radiation in Patients With Newly Diagnosed Glioblastoma Not Taking Enzyme-Inducing Anti-epileptic Drugs

Conditions
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Adult Giant Cell Glioblastoma, Adult Glioblastoma, Adult Gliosarcoma

Intervention / Treatment
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* Drug: Cediranib Maleate
* Procedure: Diffusion Tensor Imaging
* Procedure: Diffusion Weighted Imaging
* Procedure: Dynamic Contrast-Enhanced Magnetic Resonance Imaging
* Radiation: Fludeoxyglucose F-18
* Radiation: Intensity-Modulated Radiation Therapy
* Other: Laboratory Biomarker Analysis
* Procedure: Perfusion Magnetic Resonance Imaging
* Procedure: Positron Emission Tomography
* Drug: Temozolomide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 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 No other concurrent chemotherapy agents, investigational agents, or biologic therapy 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (enzyme inhibitor therapy, chemotherapy, IMRT)<br>See Detailed Description | Drug: Cediranib Maleate<br>* Given PO<br>* Other names: Recentin;Procedure: Diffusion Tensor Imaging<br>* Undergo DTI<br>* Other names: DTI;Procedure: Diffusion Weighted Imaging<br>* Undergo T1 weighted DCE-MRI<br>* Other names: MR Diffusion-Weighted Imaging;Procedure: Dynamic Contrast-Enhanced Magnetic Resonance Imaging<br>* Undergo DCE-MRI<br>* Other names: DYNAMIC CONTRAST ENHANCED MRI;Radiation: Fludeoxyglucose F-18<br>* Undergo 18 FDG PET<br>* Other names: Fluorodeoxyglucose F18;Radiation: Intensity-Modulated Radiation Therapy<br>* Undergo IMRT<br>* Other names: Intensity-Modulated Radiotherapy;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Procedure: Perfusion Magnetic Resonance Imaging<br>* Undergo PWI<br>* Other names: magnetic resonance perfusion imaging;Procedure: Positron Emission Tomography<br>* Undergo 18 F FDG-PET<br>* Other names: proton magnetic resonance spectroscopic imaging;Drug: Temozolomide<br>* Given PO<br>* Other names: Temomedac;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival (Phase II) | The fraction of patients alive and free of disease progression after the MRI scan scheduled. This fraction will be compared, using a one sample, two-sided exact binomial test, to 50% progression-free survival (PFS). For safety assessment, the study will be powered to ensure at least 85% chance of observing a serious adverse event, if the probability of such an event on treatment were >=5%. | At day 218 | 
| Safety profile and optimal dose of cediranib during chemoradiotherapy (Phase I) | A dose-limiting toxicity of cediranib is defined as a clinically significant adverse event or abnormal laboratory value assessed as unrelated to disease progression, intercurrent illness, or concomitant medications/temozolomide and occurs following the first dose of cediranib in the chemoradiation. | Up to 30 days after the last dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Blood biomarkers (Phase II) | Log-transformation is expected to yield approximately homogenous and symmetric standard errors, both for Poisson events and quantities obtained by assays with successive dilutions. We will plot the median levels and quartiles over time. First, we will compare on-study values to baseline, than we will test for an association between treatment time and markers, using a linear mixed effects model with log-transformed data and a spline function of time. The two-sided, paired t-test test will be powered to detect an effect-size of 0.5. | Up to 1 year | 
| MRI parameters (Phase II) | The comparisons of all MRI measurements will be against their day -1 values (baseline), using a 2-sided, paired Wilcoxon test (Hollander and Wolfe 1973). | Up to 48 weeks | 
| Tumor biomarkers (Phase II) | Exploratory analyses will be performed to determine if there is any correlation between the molecular/vascular phenotype of the tumor or quantitative measurements, we will use for this purpose ANOVA on log-transformed marker measurements. We will analyze changes in the measurements, and correlate biomarkers with clinical and radiographic response, similarly as for blood and urine biomarkers. | At baseline |