Corticosteroids With or Without Bevacizumab in Improving Symptoms in Patients With Radionecrosis After Radiation Surgery for Brain Metastasis

PRIMARY OBJECTIVES:

I. To investigate whether the addition of bevacizumab to standard corticosteroid therapy
results in greater improvement in symptoms (clinical and patient-reported symptom
improvement associated with radionecrosis and less radionecrosis treatment-induced symptoms)
compared with standard corticosteroid therapy.

SECONDARY OBJECTIVES:

I. To evaluate the toxicity profile associated with bevacizumab and corticosteroid therapy.

II. To compare self-reported health related quality of life (HRQOL) using linear analogue
self-assessment (LASA), dexamethasone symptoms questionnaire-chronic (DSQ-C), and M.D.
Anderson Symptom Inventory-Brain Tumor Module (MDASI-BT) symptom and interference score
between treatment arms.

III. To compare intracranial progression-free survival and time to maximum radiographic
response between treatment arms.

IV. To compare the dose and duration of corticosteroids required between treatment arms and
correlate steroid requirement with DSQ-C and MDASI-BT scores.

TERTIARY OBJECTIVES:

I. To explore serum/urine biomarkers that predict for treatment response. II. To explore
early imaging biomarkers that predict for treatment response.

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

ARM I: Patients receive bevacizumab intravenously (IV) over 30-90 minutes on days 1 and 15.
Patients also receive dexamethasone or prednisone (corticosteroids) orally (PO) once daily
(QD) or twice daily (BID) on days 1-28. Treatment repeats every 28 days for 4 courses in the
absence of disease progression or unacceptable toxicity.

ARM II: Patients also receive placebo IV over 30-90 minutes on days 1 and 15. Patients
receive dexamethasone or prednisone (corticosteroids) PO QD or BID on days 1-28. Treatment
repeats every 28 days for 4 courses in the absence of disease progression or unacceptable
toxicity. After 4 courses of treatment, patients with clinical progression may cross-over to
Arm I. .

After completion of study treatment, all patients are followed up for 1 year.

Inclusion Criteria:

- PRE-REGISTRATION ELIGIBILITY CRITERIA:

- Patients who present with symptomatic brain radionecrosis after they have received
radiosurgery for brain metastases from primary solid tumor including but not limited
to lung, breast, colorectal cancer but excluding melanoma, choriocarcinoma, renal
cell carcinoma or gliomas (due to high risk of intratumoral hemorrhage)

- Imaging review is mandatory prior to registration/randomization to confirm
eligibility; it should be initiated as soon as possible after pre-registration
magnetic resonance imaging (MRI) is obtained; turnaround time for this review will be
=< 72 business hours after receipt of images by the Imaging and Radiation Oncology
Core (IROC)

- A diagnosis of radionecrosis will be based on a clinical onset of symptoms and
radiological findings of radionecrosis at 3-24 months following radiosurgery, with or
without pathological confirmation

- Symptomatic brain radionecrosis to at least one lesion following radiosurgery
treatment for brain metastases where symptomatic is defined as:

- New or increasing headache associated with mass effect, sensory or motor
abnormality, cognitive changes, speech difficulty, balance or coordination
difficulty, cranial nerve deficits

- Symptoms are persistent or worsening despite administration of at least
dexamethasone 4 mg daily for 1 week

- Clinical eligibility supported by central imaging real-time review

- The presence of at least the following conventional magnetic resonance (MR)
image characteristic:

- Conventional MR

- Lesion quotient of < 0.3, where lesion quotient is defined as the
proportional value of the maximum axial cross-sectional area of the
transverse relaxation time (T2)-weighted defined lesion over the
maximum axial cross-sectional area of the contrast-enhancing lesion on
the longitudinal relaxation time (T1)-weighted post-gadolinium
sequence on a comparable axial slice

- If the conventional MR findings are not seen, the following dynamic
susceptibility-contrast (DSC) MR characteristics may be used to meet eligibility for
this study:

- DSC MR

- The cut-offs below will be based on gradient echo type echo planar imaging
(GRE- EPI) DSC perfusion images, acquired without using a gadolinium
pre-load:

- Relative cerebral blood volume (rCBV) < 1.5 in the enhancing-lesion
relative to normal-appearing white matter (NAWM)

- Percentage of signal recovery (PSR) >= 76%, where PSR is determined by
comparing the lower signal intensity during passage of the contrast
bolus with the post-contrast signal intensity on the signal
intensity-time curve

- Centers that standardly use positron emission tomography (PET) or magnetic resonance
spectroscopy (MRS) to determine a diagnosis of radionecrosis are permitted to use
these modalities to assist in their patient selection; however the criteria described
for conventional MR and/or DSC should also be met for study eligibility; both PET and
MRS are not mandatory for study eligibility

- PRIOR TO START OF TREATMENT:

- Must have been taking a stable dose of corticosteroids for symptom management for at
least 1 week before baseline MRI

- No systemic therapy within 2 weeks prior to registration or plan for systemic therapy
within the first 8 weeks after study registration

- No bevacizumab =< 3 months of study registration

- Central imaging real-time review (72 hour turn around) to confirm eligibility

- Not pregnant and not nursing; for women of childbearing potential only, a negative
urine or serum pregnancy test done =< 14 days prior to registration and confirmation
they are not nursing is required

- Karnofsky performance status >= 60%

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

- Platelet count >= 100,000/mm^3

- Hemoglobin >= 10 g/dL (allowing transfusion or other intervention to achieve this
minimum hemoglobin)

- Blood urea nitrogen measurement (BUN) < 30 mg/dL

- Creatinine < 1.7 mg/dL

- Bilirubin =< 2.0 mg/dL

- Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) =< 3.0 x upper
limits of normal (ULN)

- International normalized ratio (INR) < 1.5 x ULN unless patients are receiving
anti-coagulation therapy; patients receiving anti-coagulation therapy with an agent
such as warfarin or heparin are allowed to participate if INR =< 3.0

- Urine protein to creatinine (UPC) ratio < 0.5 or if >= 0.5, 24-hour urine protein
must be < 1000 mg

- Able to participate in patient-report outcomes (MDASI-BT, DSQ-C, LASA)
questionnaires; assistance by research personnel is acceptable if participant has
disabilities that make reading or writing difficult

- No evidence of recent hemorrhage at pre-registration MRI of the brain, however the
following are permitted: presence of hemosiderin, resolving hemorrhagic changes
related to surgery, and presence of punctate hemorrhage in the tumor

- No excess risk of bleeding (any of the following):

- Bleeding diathesis or coagulopathy

- Thrombocytopenia

- Major surgical procedure, open biopsy, or significant traumatic injury within
the past 28 days or anticipation of need for major surgical procedure during the
course of the study

- Minor surgical procedures, stereotactic biopsy, fine need aspiration, or core
biopsy within the past 7 days

- No uncontrolled hypertension (systolic blood pressure =< 160 millimeters of mercury
[mmHg] or diastolic =< 100 mmHg); patients with hypertension must be adequately
controlled with appropriate anti-hypertensive therapy or diet

- No history of arterial thrombotic events within the past 6 months, including:

- Transient ischemic attack (TIA)

- Cerebrovascular accident (CVA)

- Peripheral arterial thrombus

- Unstable angina or angina requiring surgical or medial intervention

- Myocardial infarction (MI)

- Significant peripheral artery disease (i.e., claudication on less than one
block)

- Significant vascular disease (i.e., aortic aneurysm, history of aortic
dissection)

- Patients who have had a deep vein thrombosis or pulmonary embolus within the past 6
months are eligible if they are on stable therapeutic anticoagulation

- No current New York Heart Association classification II, III, or IV congestive heart
failure

- No history of bowel obstruction, abdominal fistula, gastrointestinal perforation, or
intra-abdominal abscess within past 12 months

- No central lung metastases with excessive active bleeding

- No uncontrolled intercurrent illness including, but not limited to any of the
following: ongoing or active infection requiring IV antibiotics, cardiac arrhythmia,
or psychiatric illness and/or social situations that would limit compliance with
study requirements

- No history of serious non-healing wound, ulcer, or bone fractures