A Study of Bevacizumab (Avastin®) in Combination With Temozolomide and Radiotherapy in Participants With Newly Diagnosed Glioblastoma

Study Overview
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Brief Summary
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This 2 arm study investigated the efficacy and safety of the addition of bevacizumab to the current standard of care (multimodality therapy of concurrent radiotherapy plus temozolomide followed by adjuvant temozolomide) as compared to the current standard of care alone. Participants were randomly assigned to either the bevacizumab (10 milligrams per kilogram (mg/kg) intravenously [IV] once every 2 week [q2w]) or the placebo arm, in combination with radiation therapy (total dose 60 Gray [Gy], administered as 2 Gy fractions, 5 days/week) plus temozolomide (75 milligrams per meter squared [mg/m^2] oral administration [po] daily) for 6 weeks. After a 4 week treatment break, participants continued to receive bevacizumab (10 mg/kg IV q2w) or placebo, plus temozolomide (150-200 mg/m^2 po daily on days 1-5 of each 4 week cycle) for 6 cycles of maintenance treatment or until disease progression or unacceptable toxicity, whichever occured first. Following the maintenance phase, bevacizumab (15 mg/kg iv every 3 weeks [q3w]) or placebo monotherapy continued. The time on study treatment was until disease progression.

Official Title
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A Randomized, Double-Blind, Placebo-Controlled, Multicenter Phase III Trial of Bevacizumab, Temozolomide and Radiotherapy, Followed by Bevacizumab and Temozolomide Versus Placebo, Temozolomide and Radiotherapy Followed by Placebo and Temozolomide in Patients With Newly Diagnosed Glioblastoma

Conditions
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Glioblastoma

Intervention / Treatment
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* Drug: Bevacizumab
* Drug: Temozolomide
* Radiation: Radiation therapy
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: newly diagnosed glioblastoma World Health Organization (WHO) performance status less than or equal to (<=2) stable or decreasing corticosteroid dose within 5 days prior to randomization Key Exclusion Criteria: evidence of recent hemorrhage on postoperative magnetic resonance imaging (MRI) of brain any prior chemotherapy or immunotherapy for glioblastomas and low grade astrocytomas any prior radiotherapy to brain clinically significant cardiovascular disease history of greater than or equal to (>=) grade 2 hemoptysis within 1 month prior to randomization previous centralized screening for Methylguanine-DNA methyltransferase (MGMT) status for enrollment into a clinical trial

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Bevacizumab + RT + Temozolomide<br>In the Concurrent Phase participants will receive radiotherapy (RT) in daily fractions of 2 Gy to be given 5 days per week for 6 weeks and temozolomide 75 mg/m^2 daily from the first day to the last day of radiotherapy (it may continue for a maximum of 49 days in case of delay to the end of radiation therapy) and bevacizumab 10 mg/kg IV every 2 weeks for 6 weeks. There will be a 4 week treatment break. Participants will then enter the Maintenance Phase where they receive six 28-day cycle of bevacizumab 10 mg/kg IV q2w and temozolomide 150 to 200 mg/m^2 daily in the first 5 days of each cycle. The participants will then enter the Monotherapy Phase where they will receive bevacizumab 15 mg/kg IV q3w until disease progression/unacceptable toxicity. | Drug: Bevacizumab<br>* 10 mg/kg intravenously q2w in the Concurrent and Maintenance Phases. 15 mg/kg intravenously q3w in the Monotherapy Phase.<br>* Other names: Avastin;Drug: Temozolomide<br>* 75 mg/m^2 once daily for 6 weeks, followed by 150-200 mg/m^2 once daily on days 1-5 of six 4 week cycles.<br>Radiation: Radiation therapy<br>* 30 fractions of 2 Gy delivered on days 1-5 per week for 6 weeks.<br>|
| Placebo Comparator: Placebo + RT + Temozolomide<br>In the Concurrent Phase participants will receive radiotherapy in daily fractions of 2 Gy to be given 5 days per week for 6 weeks and temozolomide 75 mg/m^2 daily from the first day to the last day of radiotherapy (it may continue for a maximum of 49 days in case of delay to the end of radiation therapy) and placebo IV every 2 weeks for 6 weeks. There will be a 4 week treatment break. Participants will then enter the Maintenance Phase where they will receive six 28-day cycle of placebo IV q2w and temozolomide 150 to 200 mg/m^2 daily in the first 5 days of each cycle. The participants will then enter the Monotherapy Phase where they will receive placebo IV q3w until disease progression/unacceptable toxicity. | Drug: Temozolomide<br>* 75 mg/m^2 once daily for 6 weeks, followed by 150-200 mg/m^2 once daily on days 1-5 of six 4 week cycles.<br>Radiation: Radiation therapy<br>* 30 fractions of 2 Gy delivered on days 1-5 per week for 6 weeks.<br>Drug: Placebo<br>* Intravenously q2w in the Concurrent and Maintenance Phases and q3w in the Monotherapy Phase.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Co-Primary: Progression-free Survival (PFS) as Assessed by Investigator | PFS is defined as time from randomization to disease progression (PD) or death. PD was assessed using adapted Macdonald response criteria (modified World Health Organization [WHO] criteria) based on 3 components: radiological tumor assessments using Magnetic Resonance Imaging [MRI] scans,neurological assessment and changes in corticosteroid use. PD is assessed as greater than or equal to(>=) 25% increase in sum of products of the longest diameters of all index lesions (enhancing,measurable) compared with the smallest recorded sum (nadir); or unequivocal PD of existing non-index lesions (non-enhancing and enhancing,non-measurable); or unequivocal appearance of new lesions); or neurological worsening (if corticosteroid dose is stable or increased) compared to neurological evaluation at previous disease assessment with no need for a confirmatory scan. Participants without a PFS event were censored at last disease assessment. | Randomization until PFS Event [Until data cutoff= 31 March 2012 (up to 31.4 months) | 
| Co-Primary: Overall Survival (OS) | Overall Survival was defined as the time from randomization to death due to any cause. | Randomization until OS Event (Until data cutoff= 28 February 2013 [up to 42.2 months]) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PFS as Assessed by an Independent Review Facility | An Independent Review Facility reviewed the MRI scans used by investigator to evaluate radiological tumor response. PFS is defined as time from randomization to PD or death. PD was assessed using adapted Macdonald response (modified WHO) criteria based on 3 components: radiological tumor assessments using MRI scans, neurological assessment and changes in corticosteroid use. PD is assessed as >=25% increase in sum of products of the longest diameters of all index lesions (enhancing, measurable) compared with the smallest recorded sum (nadir); or unequivocal PD of existing non-index lesions (non-enhancing and enhancing, non-measurable); or unequivocal appearance of new lesions); or neurological worsening (if corticosteroid dose is stable or increased) compared to neurological evaluation at previous disease assessment with no need for a confirmatory scan. Participants without a PFS event were censored at last disease assessment. | Randomization until PFS Event (Until data cutoff= 31 March 2012 [up to 29.5 months]) | 
| Kaplan-Meier (KM) Estimate of One Year Overall Survival | KM estimate of one year overall survival (probability to survive for at least 1 year) was reported. Corresponding 95% confidence interval (CI) was calculated using Greenwood's formula. | Randomization until Overall Survival Event (Until data cutoff= 28 February 2013 [up to 42.2 months]) | 
| Kaplan-Meier (KM) Estimate of Two Year Overall Survival | KM estimate of two year overall survival was reported (probability to survive for at least 2 years). Corresponding 95% CI was calculated using Greenwood's formula. | Randomization until Overall Survival Event (Until data cutoff= 28 February 2013 [up to 42.2 months]) | 
| PFS in Participants With Stable/Improved Health Related Quality of Life (HRQoL) Based on European Organization for Research & Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) Core 30 (C30)(EORTC QLQ-C30) & EORTC QLQ Brain Neoplasm 20 (BN20) | EORTC QLQ-C30: 30 items; 5 functional scales; 9 symptom scales; & global health status. Most questions used 4-point scale (1:Not at all, 4:Very much), 2 questions used 7-point scale (1:very poor, 7:Excellent). EORTC QLQ-BN20: 20 items rated on a 4 point scale (1:not at all, 4:very much). EORTC QLQ-C30 and BN20 scores were transformed to a 0-100 scale, higher score=better functioning/global health (C30) or more severe symptoms (BN20). Stable HRQoL: change from baseline (BL) within 10 points. Improved HRQoL: an increase from BL >/=10 points for functioning/global health status, & decrease of >/=10 points for symptoms. PFS is reported for participants with Stable/Improved global health; physical, social functioning (C30); motor dysfunction & communication deficit (BN20). PFS: randomization to PD or death. PD: >=25% increase in sum of products of longest diameters of index lesions; or progression of existing non-index lesions; or appearance of new lesions; or neurological worsening. | Randomization until PFS Event [Until data cutoff= 31 March 2012 (up to 31.4 months) | 
| Number of Participants With Non-Serious Adverse Events, Serious Adverse Events and Death | An adverse event (AE) was considered any unfavorable and unintended sign, symptom, or disease associated with the use of the study drug, whether or not considered related to the study drug. Preexisting conditions that worsened during the study were reported as AE.A serious adverse event (SAE) is any experience that suggests a significant hazard,contraindication, side effect or precaution that: results in death, is life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or is medically significant. Non-serious adverse events (Non-SAEs) included all AEs except SAEs (non-SAEs = all AEs - SAEs). Nine participants randomized to the Placebo+RT+Temozolomide arm incorrectly received at least 1 dose of bevacizumab and were added to the Bevacizumab+RT+Temozolomide arm for Safety. | Randomization until study completion (Until data cutoff= 09 Sep 2015 [up to 64 months]) |