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Phase II Trial of Avastin Plus Bortezomib for Patients With Recurrent Malignant Glioma

Phase 2
18 Years
Open (Enrolling)
Glioblastoma, Gliosarcoma

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Trial Information

Phase II Trial of Avastin Plus Bortezomib for Patients With Recurrent Malignant Glioma

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 will be enrolled in study. Avastin
administered intravenously at dose 15 mg/kg every 3 weeks. Bortezomib administered on day 1,
4, 8, 11, 22, 25, 29, & 32 of 42-day cycle. Dose of bortezomib will be 1.7 mg/m2 for
non-EIAED patients & 2.5 mg/m2 for EIAED patients. Treatment will continue until either
evidence of progressive disease, unacceptable toxicity, non-compliance with study follow-up
/ withdrawal of consent. Brain MRIs will be 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 < are considered desirable, while rates of 40 percent or > are
considered as undesirable. Statistical hypothesis that needs testing differentiates between
15% & 40% rate of unacceptable toxicity.

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

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

- 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

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

6 month progression-free survival among patients receiving EIAED and patients not receiving EIAED.

Outcome Time Frame:

6 - 9 months

Safety Issue:


Principal Investigator

Katherine B Peters, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Duke University Health System


United States: Institutional Review Board

Study ID:




Start Date:

May 2008

Completion Date:

August 2014

Related Keywords:

  • Glioblastoma
  • Gliosarcoma
  • Glioblastoma
  • Gliosarcoma
  • Glioblastoma multiforme
  • Recurrent malignant glioma
  • GBM
  • Recurrent GBM
  • Malignant glioma
  • Brain tumor
  • Avastin
  • Bevacizumab
  • Bortezomib
  • Velcade
  • Glioblastoma
  • Glioma
  • Gliosarcoma



Duke University Health System Durham, North Carolina  27705