Phase II Avastin + Bortezomib for Patients With Recurrent Malignant Glioma

Primary Objective To estimate 6-month progression free survival probability of patients with recurrent glioblastoma multiforme treated with bortezomib plus Avastin. This efficacy assessment will be made separately among patients on enzyme-inducing anti-epileptic drugs and non enzyme-inducing anti-epileptic drugs.

Secondary Objectives To evaluate safety \& tolerability of bortezomib plus Avastin among patients with recurrent malignant glioma.

To evaluate radiographic response, progression free survival \& overall survival of patients with recurrent malignant glioma treated with bortezomib plus Avastin

This is an open-label, 2-arm Phase II study assessing safety \& efficacy of bortezomib in combination with Avastin for patients with recurrent glioblastoma multiforme (gbm). 56 total patients with recurrent WHO grade IV malignant gliomas have been enrolled on study. Avastin was administered intravenously at a dose of 15 mg/kg every 3 weeks. Bortezomib was administered on days 1, 4, 8, 11, 22, 25, 29, \& 32 of a 42-day cycle. The dose of bortezomib was 1.7 mg/m2 for non-EIAED patients \& 2.5 mg/m2 for EIAED patients. Treatment continued until either evidence of progressive disease, unacceptable toxicity, non-compliance with study follow-up / withdrawal of consent. Brain MRIs were obtained after every cycle.

Bortezomib administration is associated with mild toxicity in most patients, such as fatigue, diarrhea \& nausea, constipation \& peripheral neuropathy. Less common, bortezomib administration leads to more significant hematologic toxicities \& peripheral neuropathies. Most significant toxicities associated with Avastin in recently completed phase II clinical trial at Duke were thrombotic complications \& grade 2 proteinuria. "Unacceptable" toxicities rates of 15 percent or less were considered desirable, while rates of 40 percent or greater were considered undesirable. The statistical hypothesis that needed testing differentiated between 15% \& 40% rate of unacceptable toxicity.

Eligibility Criteria:
Inclusion Criteria:

Patients have histologically confirmed diagnosis of recurrent/progressive WHO grade IV malignant glioma (MG)

* Age \>18 yrs
* No prior treatment with bortezomib, \& no Avastin in last 3 months, not allowed to have progressed to Avastin regimen. No history of \> or equal to grade 2 CNS hemorrhage or grade 3 or higher toxicities while on Avastin
* At least 6 weeks from surgical resection, 4 weeks from end of radiotherapy \& enrollment in this study
* Karnofsky Performance Status (KPS) \> or equal to 70%
* Hemoglobin (Hgb) \> or = to 9 g/deciliter (dL), absolute neutrophil count (ANC) \> or = to 1,500 cells/microliter, platelets \> or = to 125,000 cells/microliter;
* Serum creatinine \<1.5 mg/dL, serum glutamic oxalocetic transaminase (SGOT) \& bilirubin \<1.5 x upper limit of normal
* Signed informed consent approved by IRB;
* If sexually active, patients must agree to take contraceptive measures for duration of treatments
* May have had up to 3 biological therapies (such as tyrosine kinase inhibitors, topoisomerase I or II inhibitors, or rapamycin)

Exclusion Criteria:

* Gr 2 or greater peripheral neuropathy at time of study enrollment
* No prior taxanes, as it predisposes to sensory neuropathy
* Co-medication that may interfere with study results, e.g. immuno-suppressive agents other than corticosteroids
* Greater than 3 prior recurrences
* Evidence of CNS hemorrhage on baseline MRI on CT scan (except for grade 1 hemorrhage that has been stable for at least 3 months)
* History of thrombotic or hemorrhagic stroke or myocardial infarction within 6 months
* Requires therapeutic anti-coagulation
* At least 4 weeks from Day 0 of prior monthly chemotherapy (at least 6 weeks if a nitrosourea). At least 1 week from last dose of daily chemotherapy (such as metronomic temozolomide, cytoxan) or targeted therapies administered daily (such as gleevec, tarceva)
* Pregnancy or breast feeding
* Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection requiring IV antibiotics \& psychiatric illness/social situations that would limit compliance with study requirements, or disorders associated with significant immunocompromised state
* Patients with another primary malignancy that has required treatment within past year.

Avastin-Specific Concerns:

* Any prior history of hypertensive crisis or hypertensive encephalopathy
* Systolic blood pressure (BP) \> 150 mmHg or diastolic BP \> 100 mmHg
* Unstable angina
* New York Heart Association Gr II or \> congestive heart failure
* History of myocardial infarction within 6 months
* History of stroke within 6 months
* Clinically significant peripheral vascular disease
* Evidence of bleeding diathesis, coagulopathy as documented by an elevated prothrombin time (PT), partial thromboplastin time (PTT)/bleeding time
* Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to Day 0, anticipation of need for major surgical procedure during course of study
* Minor surgical procedures, fine needle aspirations or core biopsies within 7 days prior to Day 0
* Urine protein: creatinine ratio \> or = to 1.0 at screening
* History of abdominal fistula, GI perforation, or intra-abdominal abscess within 6 months prior to Day 0
* Serious, non-healing wound, ulcer, or bone fracture
* Known hypersensitivity to any component of Avastin
* Inability to comply with study and/or follow-up procedures