Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Trial Contact Information
Registry Information

Alternate Title

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

Basic Trial Information

Objectives

Primary

1. To determine whether the addition of bevacizumab to temozolomide and radiotherapy improves efficacy, as measured by progression-free (PFS) and/or overall survival (OS), in patients with newly diagnosed glioblastoma. (Gliosarcoma closed to accrual as of 07/13/10).
2. To assess the association between overall survival and K^trans change from T1 to T2.
3. To assess the association between OS and spin echo CBV change from T1 to T2.

Secondary

1. To determine whether the tumor molecular profile conferring a mesenchymal/angiogenic phenotype is associated with a selective increase in benefit from the addition of bevacizumab to temozolomide and radiotherapy, as measured by OS or PFS, in these patients.
2. To compare the toxicities of chemoradiotherapy with bevacizumab vs conventional chemoradiotherapy in these patients.
3. To assess the association between PFS and K^trans change from T1 to T2.
4. To assess the association between PFS and spin echo CBV change from T1 to T2.
5. To assess the association between values of K^trans and spin echo CBV measured separately at T0 and at T1, and OS and PFS.
6. To assess the association between OS and K^trans changes from T0 to T1 and from T2 to T3.
7. To assess the association between OS and spin echo CBV changes from T0 to T1 and from T2 to T3.
8. To assess the association between OS and apparent diffusion coefficient (ADC) change from T0 to T1.
9. To assess the association between OS and ADC change from T1 to T2.
10. To assess the association between PFS and ADC change from T0 to T1.
11. To assess the association between PFS and ADC change from T1 to T2.
12. To assess the association between T1 values of ADC and OS and PFS.
13. To assess the association between change in lesion size between T1 and T3, as measured by advanced MRI, and OS and PFS.

Tertiary

1. To determine the differential acute effects associated with the addition of bevacizumab to temozolomide and radiation, as compared to the conventional arm, on measures of neurocognitive function (NCF), health-related quality of life (HR-QOL), and symptoms during radiation and across the longitudinal progression-free interval.
2. To determine the relationship of NCF, HR-QOL, and symptoms, with PFS and OS.
3. To determine the association between tumor molecular profile (i.e., mesenchymal/angiogenic phenotype and proneural phenotype) and NCF, HR-QOL, and symptoms.
4. To describe the association between HR-QOL as measured by the EORTC-QL30/BCM20 and mean symptom severity as measured by the MDASI-BT in patients enrolled in this study.
5. To evaluate the relationship between self-reported NCF and objectively measured tests of NCF.
6. To assess the association between measures of change in enhancing tumor size at week 22 and OS in patients treated with chemoradiotherapy with and without bevacizumab.
7. To assess the association between measures of change in T2-based tumor size at week 22 and OS in patients treated with these regimens.
8. To assess the association between changes in ADC values and OS in patients treated with these regimens.
9. To assess the association between measures of change in enhancing tumor size at week 22 and OS in patients with glioma receiving chemoradiotherapy with and without bevacizumab.
10. To assess the association between measures of change in T2-based tumor size at week 22 and OS in patients with glioma receiving chemoradiotherapy with and without bevacizumab.
11. To assess the association between changes in ADC values and OS in patients with glioma receiving chemoradiotherapy with and without bevacizumab.

Entry Criteria

Disease Characteristics:

• Histologically confirmed glioblastoma (gliosarcoma closed to accrual as of 07-13-10)
  • WHO grade IV disease
  • Tumor must have a supratentorial component

• Has undergone partial or complete surgical resection of tumor within the past 3-5 weeks
  • Diagnosis must be made by surgical excision (not by stereotactic biopsy)
  • No significant postoperative hemorrhage, defined as > 1 cm diameter of blood in the tumor cavity by MRI or CT scan

• Has ≥ 1 block of tumor tissue of sufficient size available for analysis of MGMT status and determination of molecular profile
  • At least 1 cm³ of tissue composed primarily of tumor must be present
  • No CUSA (Cavitron ultrasonic aspirator)-derived material

• No recurrent or multifocal malignant glioma

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

Prior/Concurrent Therapy:

• Recovered from prior surgery
• No prior chemotherapy or radiosensitizers for cancer of the head and neck region
  • Prior chemotherapy for a different cancer is allowed
• No prior temozolomide or bevacizumab
• No prior Gliadel wafers or any other intratumoral or intracavitary treatment
• No prior radiotherapy to the head and neck (except for T1 glottic cancer) resulting in overlap of radiotherapy fields
• 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 another therapeutic clinical trial
• No concurrent growth factors to induce elevations in neutrophil count for the purposes of administration of temozolomide on the scheduled dosing interval; to allow treatment with temozolomide at a higher dose; or to avoid interruption of the treatment during concurrent radiotherapy
• No concurrent erythropoietin
• No concurrent tumor debulking surgery, other chemotherapy, immunotherapy, biologic therapy, or additional stereotactic boost radiotherapy
• No other concurrent investigational drugs during the "blinded phase” of the study
• 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 (between 2 and 3) on a stable dose of oral anticoagulant or on a stable dose of low molecular weight heparin

Patient Characteristics:

• Karnofsky performance status 70-100%
• Absolute neutrophil count ≥ 1,800/mm³
• Platelet count ≥ 100,000/mm³
• Hemoglobin ≥ 10.0 g/dL (transfusion or other intervention allowed)
• ALT and AST ≤ 3 times normal
• Bilirubin ≤ 2.0 mg/dL
• PT/INR < 1.4 (for patients not on warfarin)
• Creatinine ≤ 1.7 mg/dL
• Urine protein:creatinine ratio < 0.5 OR 24-hour urine protein < 1,000 mg
• BUN ≤ 30 mg/dL
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for ≥ 6 months after completion of study treatment
• Systolic blood pressure (BP) ≤ 160 mm Hg or diastolic BP ≤ 90 mm Hg
• No evidence of acute cardiac ischemia by electrocardiogram
• No other invasive malignancy within the past 3 years, except for nonmelanomatous skin cancer or carcinoma in situ of the breast, oral cavity, or cervix
• No severe, active comorbidity, including any of the following:
  • Unstable angina and/or congestive heart failure within the past 6 months
  • Transmural myocardial infarction within the past 6 months
  • Evidence of recent myocardial infarction or ischemia as indicated by ST elevations of ≥ 2 mm by EKG
  • New York Heart Association 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, inadequately controlled cardiac arrhythmia
  • Significant vascular disease (e.g., aortic aneurysm or 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
  • AIDS based on current CDC definition
  • Active connective tissue disorders (e.g., lupus or scleroderma) that, in the opinion of the treating physician, may place the patient at high risk for radiation toxicity
  • Any other major medical illness or psychiatric impairment that, in the opinion of the investigator, would preclude study drug administration or completion of study therapy

Expected Enrollment

Outcomes

Overall survival
Progression-free survival

Treatment-related toxicity as assessed by NCI CTCAE v4.0

Outline

This is a multicenter study. Patients are stratified according to MGMT methylation status (methylated vs unmethylated vs invalid) and tumor molecular profile metagene score (favorable vs unfavorable vs undetermined). Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients undergo radiotherapy (intensity-modulated radiotherapy or 3-dimensional conformal radiotherapy) once daily 5 days a week for 6 weeks and receive concurrent oral temozolomide once daily for up to 7 weeks. Beginning 4 weeks after completion of chemoradiotherapy, patients receive adjuvant oral temozolomide once daily on days 1-5. Treatment with adjuvant temozolomide repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. Patients also receive placebo IV over 30-90 minutes once every 2 weeks beginning in week 4 of chemoradiotherapy and continuing until the completion of adjuvant temozolomide.

• Arm II: Patients undergo chemoradiotherapy and receive adjuvant temozolomide as in arm I. Patients also receive bevacizumab IV over 30-90 minutes once every 2 weeks beginning in week 4 of chemoradiotherapy and continuing until the completion of adjuvant temozolomide.

Some patients may undergo Dynamic Susceptibility-Contrast MRI (DSC-MRI) and Dynamic Contrast-Enhanced (DCE-MRI) imaging at baseline, periodically during the study, and after completion of treatment.

After completion of study treatment, patients are followed every 3 months for 1 year, every 4 months for 1 year, and then every 6 months thereafter.

Trial Contact Information

Trial Lead Organizations

Radiation Therapy Oncology Group

Mark Gilbert, MD, Protocol chair		Ph: 713-792-4008; 800-392-1611 Email: mrgilbert@mdanderson.org

Registry Information
Official Title		Phase III Double-Blind Placebo-Controlled Trial of Conventional Concurrent Chemoradiation and Adjuvant Temozolomide Plus Bevacizumab Versus Conventional Concurrent Chemoradiation and Adjuvant Temozolomide in Patients with Newly Diagnosed Glioblastoma
Trial Start Date		2009-04-03
Trial Completion Date		2010-04-01 (estimated)
Registered in ClinicalTrials.gov		NCT00884741
Date Submitted to PDQ		2009-04-08
Information Last Verified		2011-05-10
NCI Grant/Contract Number		CA21661

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