Ph II Bev + Either Temozolomide/Etoposide for GBM Pts Who Have Failed Bev + Irinotecan

Study Overview
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Brief Summary
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Primary objective To estimate 6-month progression free survival probability of pts w recurrent GBM treated w bev + either daily temozolomide/etoposide following progression on bev + irinotecan Secondary Objectives To evaluate safety & tolerability of bev + either daily temozolomide/etoposide among pts w recurrent GBM who have progressed on bev + irinotecan To evaluate radiographic response, progression free survival & overall survival of pts w recurrent GBM treated w bev + either daily temozolomide/etoposide following progression on bev + irinotecan

Detailed Description
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This is exploratory, two-arm, phase II study designed to assess anti-tumor activity of bev + either daily temozolomide/etoposide among GBM pts w progressive disease following bev + irinotecan. About 48 participants w recurrent GBM will take part in this study. Approximately 24 participants will receive bev plus temozolomide & approximately 24 will receive bev + etoposide. Pts must have confirmed diagnosis of GBM & radiographic evidence of recurrence following prior therapy bev + irinotecan. 24 pts will be enrolled onto each arm of this single-stage study. If 4 or more of these 24 pts live 6/more months without disease progression, treatment regimen will be considered worthy of further investigation. Otherwise, treatment regimen will be determined not worthy of further investigation within pt population. Type I & II error rates associated w testing are 0.030 & 0.115 respectively. Management guidelines dose reduction/interruption for temo, etoposide, & bev.

Official Title
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Phase II Study of Bevacizumab Plus Either Temozolomide or Etoposide for (GBM) Patients Who Have Failed Bevacizumab Plus Irinotecan

Conditions
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Glioblastoma, Gliosarcoma

Intervention / Treatment
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* Drug: Temo + Avastin
* Drug: VP-16 + Avastin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Pts have confirmed diagnosis of GBM & radiographic evidence of recurrence following prior therapy w bev + irinotecan Age >18 yrs Interval of >4 wks between prior surgical resection/1 week from stereotactic biopsy Interval of >12 wks from end of prior external beam radiation therapy (XRT) unless there is new area of enhancement consistent w recurrent tumor outside of XRT field,/there are progressive changes on MRI on >2 consecutive MRI scans >4wks apart, /there is biopsy-proven tumor progression Interval of >4 wks from prior chemo / investigational agent unless pt has recovered from all anticipated toxicities associated w that therapy. Eastern Cooperative Oncology Group (ECOG) 0-1 Hematocrit >29percent, absolute neutrophil count (ANC)>1,000 cells/ml l, platelets > 100,000 cells/ml l Serum creatinine<1.5 mg/dl, serum glutamate oxaloacetate transaminase (SGOT) & bilirubin<1.5 times upper limit of normal (ULN) Signed informed consent approved by Institutional Review Board (IRB) prior to pt entry No evidence of hemorrhage on baseline MRI/CT scan other than those that are stable gr1 If sexually active, pts will take contraceptive measures for duration of treatments Exclusion Criteria: Co-medication that may interfere w study results Active infection requiring intravenous antibiotics Progression to daily etoposide/progression to daily temo Gr3/greater toxicity related to prior bev therapy,/prior temozolomide/etoposide Requires therapeutic anti-coagulation with warfarin. Inability to comply w study and/or follow-up procedures Current, recent,/planned participation in experimental drug study other than Genentech-sponsored bev cancer study Inadequately controlled hypertension Any prior history of hypertensive crisis/hypertensive encephalopathy New York Heart Association (NYHA) Gr II/greater congestive heart failure History of myocardial infarction (MI)/unstable angina within 6 mths prior to study enrollment History of stroke/transient ischemic attack within 6 mths prior to study enrollment Significant vascular disease Symptomatic peripheral vascular disease Evidence of bleeding diathesis or coagulopathy Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to study enrollment or anticipation of need for major surgical procedure during the course of the study Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to study enrollment History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to study enrollment Serious, non-healing wound, ulcer, or bone fracture Proteinuria at screening as demonstrated by either: urine protein:creatinine (UPC) ratio >1.0 at screening / Urine dipstick for proteinuria ≥ 2+ Known hypersensitivity to any component of bevacizumab Pregnant or lactating. Use of effective means of contraception in subjects of child-bearing potential

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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Temo + Avastin<br>Patients treated with bevacizumab + temozolomide | Drug: Temo + Avastin<br>* Patients have progressed/had gr3/> toxicity related to etoposide, with no had progression/gr 3/> toxicity related to temozolomide, will only be considered for bevacizumab and temozolomide. Bevacizumab intravenously at dose 10mg/kg every other wk. For patients on bevacizumab and temozolomide, temozolomide administered on continuous dosing schedule at 50mg/m2/day.<br>* Other names: bevacizumab;|
| Experimental: VP-16 + Avastin<br>Patients treated with bevacizumab and VP-16 (etoposide) | Drug: VP-16 + Avastin<br>* Patients have progressed/had gr3/> toxicity related to temozolomide, but have not progressed/gr3/> toxicity related to etoposide,considered only for bevacizumab and etoposide. Bevacizumab intravenously at dose 10mg/kg every other wk. Patients on bevacizumab and etoposide, etoposide once daily at 50mg/m2/day first 21 days of each 28-day cycle.<br>* Other names: avastin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Primary Outcome Measure is 6 Month Progression-free Survival. | Percentage of participants surviving six months from the start of study treatment without progression of disease. PFS was defined as the time from the date of study treatment initiation to the date of the first documented progression according to the Macdonald criteria, or to death due to any cause. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Radiographic Response | Percentage of participants with an objective response (complete response or partial response) based on modified Macdonald criteria. | 41 months | 
| Median Progression-free Survival (PFS) | Time in months from the start of study treatment to the date of first progression according to Macdonald criteria, or to death due to any cause. Patients alive who had not progressed as of the last follow-up had PFS censored at the last follow-up date. Median PFS was estimated using a Kaplan-Meier curve. | 41 months | 
| Median Overall Survival (OS) | Time in months from the start of study treatment to date of death due to any cause. Patients alive as of the last follow-up had OS censored at the last follow-up date. Median OS was estimated using a Kaplan-Meier curve. | 41 months | 
| Grade 3 or Greater, Treatment Related, Non-hematologic Toxicities. | Incidence of ≥Grade 3 treatment related, non-hematologic toxicity | 41 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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GBM, Glioblastoma, Gliosarcoma, Bevacizumab, Avastin, Etoposide, Brain tumor, Irinotecan, Glioblastoma multiforme, Temodar, Temozolomide, Etopophos, Toposar, VePesid, VP-16, Camptosar