Avastin in Combination With Temozolomide for Unresectable or Multifocal GBMs and Gliosarcomas

Study Overview
=================
Brief Summary
-----------------
Primary objective- To determine efficacy of Avastin, 10 mg/kg every other week, in combination with standard 5-day temozolomide in terms of response rate. Secondary objective- To determine safety of Avastin & Temozolomide in unresectable glioblastoma patients

Detailed Description
-----------------
Subjects have histologically confirmed WHO gr IV primary malignant glioma that is unresectable/multifocal. This is Phase II study where up to 41 subjects will receive up to 4 cycles of Avastin & Temozolomide. Avastin administered at 10 mg/kg every 14 days beginning a minimum of 7 days after biopsy/28 days after craniotomy. Temozolomide dosed at 200 mg/m2 daily for 5 days in 28-day cycle. Patients will receive up to 4 cycles of Avastin & Temozolomide, then proceed with standard XRT. Study will use 2-stage minimax study design in which 21 subjects are accrued during 1st stage, with possibility that additional 20 patients accrued during 2nd stage. In initial Phase I & II trials, 4 potential Avastin-associated safety signals were identified: hypertension, proteinuria, thromboembolic events, & hemorrhage. Avastin-associated adverse events in Phase III trials include congestive heart failure, GI perforations, wound healing complications, & arterial thromboembolic events. Most common toxicity associated with Temozolomide has been mild myelosuppression.

Official Title
-----------------
Avastin in Combination With Temozolomide for Unresectable or Multifocal Glioblastoma Multiformes and Gliosarcomas

Conditions
-----------------
Glioblastoma, Gliosarcoma

Intervention / Treatment
-----------------
* Drug: Avastin and Temozolomide


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients have histologically confirmed diagnosis of WHO gr IV primary malignant glioma. Patients will be unresectable or have multifocal disease. Age ≥ 18years & life expectancy of >12 weeks Evidence of measurable primary CNS neoplasm on contrast enhanced MRI. Interval of <1 week between prior biopsy/4 weeks from surgical resection & enrollment on protocol Karnofsky ≥60% Hemoglobin ≥9g/dl, ANC ≥1,500 cells/microliter, platelets ≥125,000 cells/microliter Serum creatinine ≤1.5 mg/dl, serum SGOT & bilirubin ≤1.5 x ULN For patients on corticosteroids, they must have been on stable dose for 1 week prior to entry, if clinically possible, & dose should not be escalated over entry dose level Signed informed consent approved by IRB prior to patient entry No evidence of > grade 1 CNS hemorrhage on baseline MRI/CT scan If sexually active, patients will take contraceptive measures for duration of treatments Exclusion Criteria: Pregnancy/breast feeding Co-medication that may interfere with study results Active infection requiring IV antibiotics Prior or current Treatment w XRT/chemo for brain tumor, irrespective of grade of tumor Evidence of > grade 1 CNS hemorrhage on baseline MRI or CT scan Avastin-Specific Concerns: Inadequately controlled hypertension Any prior history of hypertensive crisis/hypertensive encephalopathy New York Heart Association Grade II or > congestive heart failure History of myocardial infarction/unstable angina < 6 months prior to study enrollment History of stroke/transient ischemic attack < 6 months prior to study enrollment Significant vascular disease Symptomatic peripheral vascular disease Evidence of bleeding diathesis/coagulopathy Major surgical procedure, open biopsy,/significant traumatic injury within 28 days prior to study enrollment/anticipation of need for major surgical procedure during course of study Core biopsy/other minor surgical procedure, excluding placement of vascular access device, <7 days prior to study enrollment History of abdominal fistula, GI perforation, /intra-abdominal abscess <6 months prior to study enrollment Serious, non-healing wound, ulcer, or bone fracture Proteinuria at screening as demonstrated by either UPC ratio ≥1.0 at screening OR Urine dipstick for proteinuria ≥2+ Known hypersensitivity to any component of Avastin Pregnant/lactating. Use of effective means of contraception in subjects of child-bearing potential Current, ongoing treatment with full-dose warfarin or its equivalent

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Avastin and Temozolomide<br>Avastin administered at 10 mg/kg every 2 weeks beginning a minimum of 7 days after biopsy or 28 days after craniotomy. Temozolomide dosed at 200 mg/m2 daily for 5 days in a 28-day cycle. | Drug: Avastin and Temozolomide<br>* This is Phase II study with the combination of Avastin & Temozolomide for unresectable or multifocal WHO grade IV malignant glioma patients. Patients will receive up to 4 cycles of Avastin & Temozolomide . Avastin administered at 10 mg/kg every 14 days beginning minimum of 7 days after biopsy or 28 days after craniotomy. Temozolomide will be dosed at 200 mg/m2 daily x 5 days in 28-day cycle. Patients will have baseline MRI & repeat MRI every 4 weeks. If there is no evidence of disease progression after each cycle, or unacceptable toxicity, or as determined by investigators, patient non-compliance or patient withdraws consent to continue therapy & requests discontinuation, patients will receive up to 4 cycles of Avastin & Temozolomide, then proceed with standard XRT therapy, & future therapy after 4 cycles will be at discretion of patient & treating physicians.<br>* Other names: Temozolomide - Temodar;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Rate | The proportion of subjects with complete or partial response as determined by a modification of the RANO (Response Assessment in Neuro-Oncology) criteria. A confirmation of response was not required. Complete Response was defined as complete disappearance on MR/CT of all enhancing tumor and mass effect, off all corticosteroids (or receiving only adrenal replacement doses), accompanied by a stable or improving neurologic examination, and maintained for at least 4 weeks. Partial Response was defined as greater than or equal to 50% reduction in tumor size on MR/CT by bi-dimensional measurement, on a stable or decreasing dose of corticosteroids, accompanied by a stable or improving neurologic examination, and maintained for at least 4 weeks. | 4 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Glioma, Temozolomide, Temodar, Avastin, Bevacizumab, GBM, Gliosarcoma, Multifocal GBM, Brain tumor, Unresectable GBM, Glioblastoma multiforme