Inclusion Criteria:
1. Signed Informed Consent Form. 2. Age >/= 18 years. 3. Histologically confirmed glioblastoma in first, second or third relapse. A pathology
report constitutes adequate documentation of histology for study inclusion. Subjects
with an initial diagnosis of a lower grade glioma are eligible if a subsequent
biopsy is determined to be glioblastoma. The amount of prior systemic therapy for
this population is, nevertheless, restricted to three regimens, with one including
temozolomide.
4. Radiographic demonstration of disease progression following prior therapy. 5. Bi-dimensionally measurable disease with a minimum measurement of 1 cm (10 mm) in
one diameter on MRI performed within 14 days prior to registration (Day 1). Baseline
MRIs for subjects who underwent salvage surgery after first or second relapse must
be obtained >/= 4 weeks after the procedure. If receiving corticosteroids, subjects
must be on a stable or decreasing dose of corticosteroids for >/= 5 days prior to
baseline MRI.
6. Patients having undergone recent resection of recurrent or progressive tumor will be
eligible as long as all of the following conditions apply: 1) They have recovered
from the effects of surgery. 2) Evaluable or measurable disease following resection
of recurrent tumor is not mandated for eligibility into the study. 3) To best assess
the extent of residual measurable disease post-operatively, a MRI should be done no
later than 96 hours in the immediate post-operative period or 4-6 weeks
post-operatively. .
7. An interval of >/= 4 weeks since surgical resection is required prior to starting
protocol therapy.
8. Prior standard radiation for glioblastoma. 9. Prior chemotherapy: All first-relapse subjects must have received temozolomide. All
second- and third-relapse subjects must have received temozolomide. Patients may not
have received prior nitrosoureas.
10. Recovery from the effects of prior therapy, including the following: Four weeks from
cytotoxic agents (3 weeks from procarbazine, 2 weeks from vincristine); Four weeks
from any investigational agent; One week from non-cytotoxic agents(eg accutane,
thalidomide); Eight weeks from radiotherapy to minimize the potential for MRI
changes related to radiation necrosis that might be misdiagnosed as progression of
disease, or 4 weeks if a new lesion, relative to the pre-radiation MRI, develops
that is outside the primary radiation field; Patients may have had gliadel wafers
during their original surgery but they must be >/= 9 months post their original
surgery date.
11. Prior therapy with gamma knife or other focal high-dose radiation is allowed, but
the subject must have subsequent histologic documentation of recurrence or positron
emission tomography (PET) or MR Spectroscopic documentation of tumor, unless the
recurrence is a new lesion outside the irradiated field. 12. Patients must have adequate bone marrow function (WBC >/= 3,000/µl, absolute
neutrophil count (ANC) >/= 1,500/mm^3, platelet count of >/= 100,000/mm^3, and
hemoglobin >/= 10 gm/dl), adequate liver function (SGPT < 3 times normal and
alkaline phosphatase < 2 times normal, bilirubin <1.5 mg/dl), adequate renal
function (creatinine /= 60 cc/min/1.73 m^2)
and a urine protein:creatinine ratio of Exclusion Criteria:
1. Prior treatment with anti-angiogenesis (eg bevacizumab, sorafenib, sunitinib) agent
or nitrosurea (eg. lomustine, carmustine, nimustine).
2. Prior treatment with polifeprosan 20 with carmustine wafer except for the patients
with gliadel wafers >/= 9 months post their original surgery date.
3. Patients must not have received any investigational agents within 28 days prior to
commencing study treatment.
4. Prior intracerebral agents. 5. Need for urgent palliative intervention for primary disease (e.g., impending
herniation)
6. Evidence of recent hemorrhage on baseline MRI of the brain with the following
exceptions:
- (1) Presence of hemosiderin (2) Resolving hemorrhagic changes related to
surgery (3) Presence of punctate hemorrhage in the tumor.
7. Blood pressure of > 140 mmHg systolic and > 90 mmHg diastolic. 8. History of hypertensive encephalopathy. 9. New York Heart Association (NYHA) Grade II or greater chronic heart failure(CHF)
10. History of myocardial infarction or unstable angina within 6 months prior to Day 1. 11. History of stroke or transient ischemic attack within 6 months prior to study
enrollment. 12. Significant vascular disease (e.g., aortic aneurysm, aortic dissection) or recent
peripheral arterial thrombosis within 6 months prior to Day 1. 13. Evidence of bleeding diathesis or coagulopathy or INR >1.5 unless on a stable dose
of anticoagulation therapy. History of significant bleeding disorder unrelated to
cancer, including:
- (1) Diagnosed congenital bleeding disorders (e.g., von
Willebrand's disease) (2) Diagnosed acquired bleeding disorder within one year
(e.g., acquired anti-factor VIII antibodies) (3) Ongoing or recent (
14. History of abdominal fistula, gastrointestinal perforation, or intra-abdominal
abscess within 6 months prior to Day 1. 15. History of intracerebral abscess within 6 months prior to Day 1. 16. Major surgical procedure, open biopsy, or significant traumatic injury within 28
days prior to Day 1, anticipation of need for major surgical procedure during the
course of the study. 17. Minor surgical procedures (excluding placement of a vascular access device),
stereotactic biopsy, fine needle aspirations, or core biopsies within 7 days prior
to Day 1. 18. Serious non-healing wound, ulcer, or bone fracture. 19. Pregnancy (positive pregnancy test) or lactation. 20. Known hypersensitivity to any component of bevacizumab. 21. History of any other malignancy (except non-melanoma skin cancer or carcinoma in
situ of the cervix), unless in complete remission and off of all therapy for that
disease for a minimum of 3 years are ineligible. 22. Pregnant or nursing females. 23. Unstable systemic disease, including active infection, uncontrolled hypertension, or
serious cardiac arrhythmia requiring medication. 24. Subjects unable to undergo an MRI with contrast. 25. Patients with a known allergy to bevacizumab, or a known allergy to nitrosoureas
(eg. lomustine, carmustine, nimustine) will be excluded. 26. Patient must be able to tolerate the procedures required in this study including
periodic blood sampling, study related assessments, and management at the treating
institution for the duration of the study. Inability to comply with protocol or
study procedures (for example, an inability to swallow tablets) will be an exclusion
criteria.
