Concurrent Bevacizumab With or Without Radiation Therapy in Treating Patients With Recurrent Glioblastoma

Conditions:Brain Cancer, Brain Cancer
Therapuetic Areas:Oncology
Age Range:18 - Any
Start Date:December 2012

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Randomized Phase II Trial of Concurrent Bevacizumab and Re-irradiation Versus Bevacizumab Alone as Treatment for Recurrent Glioblastoma

This randomized phase II trial studies how well bevacizumab with or without radiation
therapy works in treating patients with glioblastoma that has returned after a period of
improvement. Monoclonal antibodies, such as bevacizumab, may block tumor growth by targeting
certain cells. Specialized radiation therapy that delivers a high dose of radiation directly
to the tumor may kill more tumor cells and cause less damage to normal tissue. It is not yet
known whether bevacizumab is more effective with or without radiation therapy in treating
patients with recurrent glioblastoma.


I. To establish an improvement in overall survival in recurrent glioblastoma multiforme
(GBM) patients receiving bevacizumab and re-irradiation compared with patients receiving
bevacizumab alone.


I. To estimate and compare the rate of objective response in patients with measurable

II. To estimate and compare the 6-month progression-free survival rate. III. To estimate and
compare progression-free survival. IV. To estimate and compare the rate of treatment adverse
events. V. To estimate and compare the rate of >= grade 3 acute or delayed central nervous
system (CNS) toxicity.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive bevacizumab intravenously (IV) over 30-90 minutes every 2 weeks.

ARM II: Patients receive bevacizumab as in Arm I and undergo radiation therapy using
intensity-modulated radiation therapy (IMRT), 3-dimensional conformal radiation therapy
(3D-CRT), or proton beam radiation therapy (RT) 5 days a week for 2 weeks.

In both arms, courses with bevacizumab repeat every 2 weeks in the absence of disease
progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 2 months for 1 year,
every 6 months for 1 year and then annually thereafter.

Inclusion Criteria:

- Histopathologically proven diagnosis of glioblastoma or variants (gliosarcoma, giant
cell glioblastoma etc); patients will be eligible if the original histology was
lower-grade glioma and a subsequent diagnosis of glioblastoma or gliosarcoma is made

- Patients who did not have recent surgery for their glioblastoma must have shown
unequivocal radiographic evidence for tumor progression by contrast-enhanced MRI
scan (or CT scan for patients with non-compatible devices) within 21 days prior
to registration; Note: patients who did have surgery with a post-operative
contrast-enhanced scan falling outside the 5-week window prior to registration,
per definition of recent surgery, must have a repeat magnetic resonance imaging
(MRI) scan (or computed tomography [CT] scan for patients with non-compatible
devices) within 21 days prior to registration

- Patients must have passed an interval of 6 months or greater between completion
of prior radiotherapy and registration; if patients have not passed an interval
of at least 6 months, they may still be eligible if they meet one or more of the
following criteria:

- New areas of tumor outside the original radiotherapy fields as determined
by the investigator, or

- Histologic confirmation of tumor through biopsy or resection, or

- Nuclear medicine imaging, magnetic resonance (MR) spectroscopy, or MR
perfusion imaging consistent with true progressive disease, rather than
radiation necrosis obtained within 28 days of registration AND an interval
of at least 90 days between completion of radiotherapy and registration

- Patients unable to undergo MR imaging because of non-compatible devices can be
enrolled provided CT scans are obtained and are of sufficient quality; patients
without non-compatible devices may not use CT scans performed to meet this

- Prior history of standard dose CNS radiation of 60 Gy in 30 fractions or 59.4 Gy in
1.8 Gy fractions, or equivalent or lower doses

- Patients who have received prior treatment with non-standard radiation therapy
(RT) dose and fractionation, interstitial brachytherapy, stereotactic
radiosurgery, etc. are eligible as long as the criterion is met or approved by a
principal investigator

- Patients must have recovered from the toxic effects of prior therapy, and there must
be a minimum time of 28 days prior to registration from the administration of any
investigational agent or prior cytotoxic therapy with the following exceptions:

- 14 days from administration of vincristine

- 42 days from administration of nitrosoureas

- 21 days from administration of procarbazine

- Patients having undergone recent resection of their glioblastoma (within 5 weeks
prior to registration) must have recovered from the effects of surgery; for CNS
related core or needle biopsies, a minimum of 7 days must have elapsed prior to

- Residual disease following resection of recurrent glioblastoma is not mandated
for eligibility into the study; to best assess the extent of residual disease
post-operatively, a post-operative or intra-operative MRI scan (or CT scan for
patients with non-compatible devices) must be performed prior to registration
and should be within 96 hours post surgery (although 24 hours would be optimum)

- History/physical examination, including neurologic examination, within 14 days prior
to registration

- Karnofsky performance status >= 60 within 14 days prior to registration

- Complete blood count (CBC)/differential obtained within 14 days prior to
registration, with adequate bone marrow function

- Absolute neutrophil count (ANC) >= 1,500 cells/mm^3

- Platelets >= 75,000 cells/mm^3

- Hemoglobin >= 9.0 g/dl (Note: the use of transfusion or other intervention to achieve
hemoglobin [Hgb] >= 9.0 g/dl is acceptable)

- Total bilirubin =< 2.0 mg/dL

- Serum glutamic oxaloacetic transaminase (SGOT) or aspartate aminotransferase (AST) =<
2.5 times the upper limit of normal

- Serum creatinine =< 1.8 mg/dL

- Urine protein: creatinine (UPC) ratio < 1.0 within 14 days prior to registration OR
urine dipstick for proteinuria =< 2 positive (+) (patients discovered to have > 2+
proteinuria on dipstick urinalysis at baseline must have a UPC ratio done that is <
1.0 to be eligible; if the UPC ratio is >= 1.0 then the patients should undergo a
24-hour urine collection and must demonstrate =< 1g of protein in 24 hours to be

- Note: UPC ratio of spot urine is an estimation of the 24-hour urine protein
excretion; a UPC ratio of 1 is roughly equivalent to a 24-hour urine protein of
1 gm

- Patients must not be pregnant (positive pregnancy test) or breast feeding; pregnancy
test must be done within 7 days prior to registration; effective contraception (men
and women) must be used in patients of child-bearing potential while on study
treatment and for 6 months after

- Patients on full-dose anticoagulants (e.g., warfarin or low molecular weight [LMW]
heparin) must meet both of the following criteria:

- No active bleeding or pathological condition that carries a high risk of
bleeding (e.g., tumor involving major vessels or known varices)

- In-range international normalized ratio (INR) (usually between 2 and 3) on a
stable dose of oral anticoagulant or on a stable dose of low molecular weight
heparin, within 14 days prior to registration

- Patient must be able to provide study-specific informed consent prior to study entry

Exclusion Criteria:

- More than three relapses

- Infratentorial, or leptomeningeal evidence of recurrent disease

- Recurrent or persistent tumor greater than 6 cm in maximum diameter

- Prior therapy with an inhibitor of vascular endothelial growth factor (VEGF) or VEGF
receptor (VEGFR) (including bevacizumab)

- Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free
for a minimum of 1 year (for example, carcinoma in situ of the breast, oral cavity,
or cervix are all permissible)

- Severe, active co-morbidity, defined as follows:

- Unstable angina and/or congestive heart failure requiring hospitalization within
the last 6 months prior to registration

- Transmural myocardial infarction within the last 6 months prior to registration

- History of stroke or transient ischemic attack within 6 months prior to

- Significant vascular disease (e.g., aortic aneurysm, history of aortic
dissection) or clinically significant peripheral vascular disease

- Acute bacterial or fungal infection requiring intravenous antibiotics at the
time of registration

- Chronic obstructive pulmonary disease exacerbation or other respiratory illness
requiring hospitalization or precluding study therapy at the time of

- Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects;
note, however, that laboratory tests for liver function other than screening
panel and coagulation parameters are not required for entry into this protocol

- Acquired immune deficiency syndrome (AIDS) based upon current Centers for
Disease Control and Prevention (CDC) definition; note, however, that human
immunodeficiency virus (HIV) testing is not required for entry into this
protocol; the need to exclude patients with AIDS from this protocol is necessary
because the treatments involved in this protocol may be significantly
immunosuppressive; protocol specific requirements may also exclude
immuno-compromised patients

- Pregnancy or women of childbearing potential and men who are sexually active and not
willing/able to use medically acceptable forms of contraception

- Prior allergic reaction to the study drug (bevacizumab)

- Prior history of hypertensive crisis or hypertensive encephalopathy

- History of a non-healing wound, ulcer, or bone fracture within 90 days (3 months)
prior to registration

- Gastrointestinal bleeding or any other hemorrhage/bleeding event Common Terminology
Criteria for adverse Events (CTCAE), v. 4 grade 3 or greater within 30 days prior to

- Major surgical procedure, open biopsy, or significant traumatic injury within 28 days
prior to registration (with the exception of craniotomy)
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