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

Study Overview
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Brief Summary
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This randomized phase II trial studies temozolomide, radiation therapy, and cediranib maleate to see how well they work compared with temozolomide, radiation therapy, and a placebo in treating patients with newly diagnosed glioblastoma (a type of brain 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. Cediranib maleate 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. It is not yet known whether temozolomide and radiation therapy are more effective when given with or without cediranib maleate in treating glioblastoma.

Detailed Description
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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.

Official Title
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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

Conditions
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Adult Glioblastoma, Adult Gliosarcoma

Intervention / Treatment
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* Radiation: 3-Dimensional Conformal Radiation Therapy
* Drug: Cediranib Maleate
* Radiation: Intensity-Modulated Radiation Therapy
* Other: Laboratory Biomarker Analysis
* Other: Placebo Administration
* Drug: Temozolomide


Participation Criteria
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Eligibility Criteria
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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

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cediranib, TMZ, and RT<br>Cediranib (3 days) followed by radiation therapy (RT) + daily temozolomide (TMZ) + cediranib followed by cediranib monotherapy (4 weeks) followed by TMZ + cediranib for 12 cycle maximum. | Radiation: 3-Dimensional Conformal Radiation Therapy<br>* Undergo 3-dimensional conformal radiotherapy<br>* Other names: Radiation, 3D Conformal;Drug: Cediranib Maleate<br>* Given PO<br>* Other names: Recentin;Radiation: Intensity-Modulated Radiation Therapy<br>* Undergo intensity-modulated radiation therapy<br>* Other names: Radiation, Intensity-Modulated Radiotherapy;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Temozolomide<br>* Given PO<br>* Other names: TMZ;|
| Active Comparator: Placebo, TMZ, and RT<br>Placebo (3 days) followed by radiation therapy (RT) + daily temozolomide (TMZ) + placebo followed by placebo monotherapy (4 weeks) followed by TMZ + placebo for 12 cycle maximum. | Radiation: 3-Dimensional Conformal Radiation Therapy<br>* Undergo 3-dimensional conformal radiotherapy<br>* Other names: Radiation, 3D Conformal;Radiation: Intensity-Modulated Radiation Therapy<br>* Undergo intensity-modulated radiation therapy<br>* Other names: Radiation, Intensity-Modulated Radiotherapy;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Placebo Administration<br>* Given PO<br>Drug: Temozolomide<br>* Given PO<br>* Other names: TMZ;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 6-month Progression-free Survival Rate | Six-month progression-free survival is the rate of patients who have NOT progressed at six months, where progressive disease is defined as any of the following: ≥ 25% increase in sum of the products of perpendicular diameters of enhancing lesions; any new lesion; or clinical deterioration. Progression will be determined by central review of MRI exams, assessed using MacDonald criteria for progression versus response on 2D T1 and T2 weighted images. | From randomization to 6 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | OS will be estimated using the Kaplan-Meier method and differences between treatment arms will be tested using the log rank test. Multivariate analyses with the Cox proportional hazard model for OS will be performed with the stratification variables as fixed variables to assess the treatment effect adjusting patient-specific risk factors. | From randomization to time of death due to any cause. Patients are followed until death. Analysis occurs after all patients have been potentially followed for six months. | 
| Progression-free Survival (PFS) | Progression-free survival time is defined as time from randomization to date of first progression or death from any cause and is estimated by the Kaplan-Meier method. Patients last known to be alive without progression are censored at the date of last contact. Progression is defined as any of the following: ≥ 25% increase in sum of the products of perpendicular diameters of enhancing lesions; any new lesion; or clinical deterioration. | From randomization to time of first progression or death due to any cause. Patients are followed until death. Analysis occurs after all patients have been potentially followed for six months. | 
| Incidence of Grade 3+ Toxicities | The number of patients with reported grade 3 and higher treatment-related toxicities as assessed by Common Terminology Criteria for Adverse Events version 4.0 | From randomization to six months. |