A Study of Avastin (Bevacizumab) and Irinotecan Versus Temozolomide Radiochemistry in Patients With Glioblastoma

Study Overview
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Brief Summary
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This 2 arm study will compare the effect of Avastin + irinotecan versus temozolomide, in combination with conventional involved field radiotherapy, in patients with newly diagnosed glioblastoma and a non-methylated MGMT promoter. Patients will be randomized 3:1 to receive Avastin 10mg/kg iv every 2 weeks + irinotecan 125mg/m2 iv every 2 weeks, or temozolomide 75mg/m2 po daily during radiotherapy followed by 6 cycles of temozolomide 150-200mg/m2 po daily on days 1-5 of each 4 week cycle. The anticipated time on study treatment is until disease progression, and the target sample size is 100-500 individuals.

Conditions
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Glioblastoma Multiforme

Intervention / Treatment
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* Drug: bevacizumab [Avastin]
* Drug: irinotecan
* Drug: temozolomide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: adult patients, 18-70 years of age; glioblastoma, confirmed histologically; no previous chemotherapy or radiotherapy for glioblastoma; non-methylated MGMT promoter in the tumor. Exclusion Criteria: prior systemic treatment for glioblastoma multiforme; prior treatment with Avastin; significant cardiovascular disease; other active malignant disease.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br> | Drug: bevacizumab [Avastin]<br>* 10mg/kg iv every 2 weeks<br>Drug: irinotecan<br>* 125mg/m2 iv every 2 weeks<br>|
| Active Comparator: 2<br> | Drug: temozolomide<br>* 75mg/m2 po daily during radiotherapy, followed by 150-200mg/m2/day po on days 1-5 of each 6x4 week cycle of adjuvant therapy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving Progression-Free Survival (PFS) Without Disease Progression or Death at 6 Months | Progression-free survival was defined as the time from randomization to objective tumor progression or death from any cause, whichever came first. Progression was defined as 25 percent (%) increase in size of enhancing tumor or any new tumor on gadolinium contrast agent magnetic resonance imaging (Gd-MRI) scans, or neurologically worse, and steroids stable or increased. Percentage of participants achieving PFS without disease progression or death was reported. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) | Progression-free survival was defined as the time from randomization to objective tumor progression or death from any cause, whichever came first. Progression was defined as 25% increase in size of enhancing tumor or any new tumor on Gd-MRI scans, or neurologically worse, and steroids stable or increased. PFS was estimated using Kaplan-Meier method. | From baseline to the end of the study (up to 4.5 years) | 
| Overall Survival (OS) | Overall survival was defined as the time from randomization to death from any cause. OS was estimated using Kaplan-Meier method. | From baseline until death (up to 4.5 years) | 
| Percentage of Participants Who Discontinued | Discontinuation was defined as the percentage of participants who permanently discontinued treatment in either treatment arm. Percentage of participant with individual discontinuation reason are reported. CNS: central nervous system; CTCAE: Common Terminology Criteria for Adverse Events . Other reason refers to any other reason than the specified ones. | From baseline until death (up to 4.5 years) | 
| Number of Participants With A Best Overall Response (BOR) of Complete Response (CR) and With A BOR of CR or Partial Response (PR) | BOR was defined as the best response observed for a participant during assessment. Number of participants who had BOR as CR and number of participants who had BOR as CR or PR were reported. Complete response was defined as disappearance of all enhancing tumor on consecutive Gd-MRI scans at least 1 month apart, off steroids, and neurologically stable or improved. Partial response was defined as 50% reduction in size of enhancing tumor on consecutive Gd-MRI scans at least 1 month apart, steroids stable or reduced, and neurologically stable or improved. | 4 week after radiotherapy (RT) (up to Week 4), >4 Week after RT (up to Week 8) and Month 6 | 
| Percentage of Participants With Response on FLAIR Imaging | FLAIR lesions were determined as stable, progressive or decreased. FLAIR lesions was determined as progressive only if they were not be attributed to causes apart from tumor infiltration (sequelae of radiation therapy, demyelination, ischemia, infection, seizures, or other treatment effects). Percentage of participants are based on ITT population. Dis.=Discontinuation. | At screening, Baseline, Month 6 and Therapy Discontinuation (Up to 4.5 years) | 
| Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ - C30) at Baseline, Post-Baseline (up to Month 30) | The EORTC QLQ-C30 incorporates: 5 functional scales (physical, role, cognitive, emotional, and social); 9 symptom scales (fatigue, pain, nausea and vomiting, dyspnea, insomnia, appetite loss, constipation, diarrhea and financial difficulties); and a global health and quality-of-life scale. Most questions used 4 point scale (1 'Not at all' to 4 'Very much'; 2 questions used 7-point scale (1 'very poor' to 7 'Excellent'). Scores were averaged and transformed to 0-100 scale; higher score for Global Qol/functional scales=better level of functioning or a higher score for symptom scale=greater degree of symptoms. The change in global health status was determined to be the difference in values at baseline and each specific visit. The term ''baseline'' refers to the time of randomization to the maintenance phase. | Baseline, Post-Baseline (up to Month 30) | 
| Change From Baseline for EORTC QLQ Brain Neoplasm 20 (BN20) at Baseline, Post-Baseline (up to Month 30) | EORTC QLQ-BN20 consisted of 20 items assessing visual disorders, motor dysfunction, communication deficit, various disease symptoms (e.g. headaches and seizures), treatment toxicities (e.g. hair loss) and future uncertainty. All of the 20 items are rated on a 4 point Likert scale from 1=not at all, 2=a little, 3=quite a bit and 4=very much, and were linearly transformed to a 0-100 scale, with higher scores indicating more severe symptoms. | Baseline, Post-Baseline (up to Month 30) | 
| Change From Baseline for Mini-Mental Status Examination (MMSE) at Baseline, Post-Baseline (up to Month 30) | The MMSE briefly measures orientation to time and place, immediate recall, short-term verbal memory, calculation, language and construct ability. Each area tested had a designated point value, the total score can range from 0 to 30, with a higher score indicating better function. | Baseline, Post-Baseline (up to Month 30) | 
| Change From Baseline for Karnofsky Performance Status (KPS) Score at Baseline, Post-Baseline (up to Month 30) | KPS is an 11-level score (0, 10, 20, 30, 40, 50, 60, 70, 80, 90, and 100) which ranges between 0 (death) to 100 (complete healthy status); a higher score represents a higher ability to perform daily tasks. Deterioration in KPS was defined as decrease of 20 or more points in KPS score. | Baseline, Post-Baseline (up to Month 30) | 
| Percentage of Participants Who Received Corticosteroid for Glioblastoma | Participants used corticosteroids for the glioblastoma condition. Corticosteroids included dexamethasone, methylprednisone, fortecortin, hydrocortisone, urbason, and prednisolone. | From baseline to Month 6 | 
| Time to Treatment Failure |  | From baseline until end of study (up to 4.5 years) |