Corticosteroids + Bevacizumab vs. Corticosteroids + Placebo (BEST) for Radionecrosis After Radiosurgery for Brain Metastases

This is a randomized double-blinded phase II study of corticosteroids with bevacizumab vs.
corticosteroids with placebo for brain radionecrosis following radiosurgery for brain
metastases. This is a two-arm clinical trial with parallel group design for longitudinal
quality of life endpoint. Patients will be stratified according to age (≤ 65 years vs. > 65
years), pathological confirmation of necrosis (yes vs. no), MDASI-BT mean global score
(symptom + interference scores) ( < 4.0 vs. > 4.0) and prior whole brain radiotherapy (yes
vs. no). The primary and secondary objectives are detailed below.

Primary Objective:

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:

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

2. To compare self-reported health related quality of life (HRQOL) using LASA,
Dexamethasone Symptoms Questionnaire-Chronic (DSQ-C), and MDASI-BT symptom and
interference score between treatment arms.

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

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

Patient event monitoring will occur every 2 months after treatment up to 6 months. Then event
monitoring will occur up to one year.

Pre-Registration Eligibility Criteria:

1. 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

2. Patients at institutions that elect to utilize central imaging review to confirm
eligibility must be pre-registered prior to submission of these images; images should
be submitted as soon as possible after the 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)

3. Patients at institutions that elect to confirm eligibility locally may be
pre-registered at the same time as they are randomized

Registration/Randomization Eligibility Criteria:

1. 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.

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

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

1.1.2 Symptoms are persistent or worsening despite administration of at least
dexamethasone 4 mg (or equivalent corticosteroid) daily for 1 week

1.2 Clinical eligibility supported by central imaging real-time review. The presence
of at least the following conventional MR image characteristic:

1.2.1 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 T2-weighted
defined lesion over the maximum axial cross-sectional area of the contrast-enhancing
lesion on the 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.

1.2.2 DSC MR - The cut-offs below will be based on GRE EPI DSC perfusion images,
acquired without using a gadolinium pre-load:

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

1.2.2.2. 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

1.2.3 Centers that standardly use PET or 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.

2. Prior to start of treatment

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

2.2 No systemic therapy within 2 weeks prior to registration or plan for systemic
therapy within the first 8 weeks after study registration. The protocol provides a
list of 'approved systemic' therapies that are allowed for concurrent use with
bevacizumab.

2.3 No bevacizumab ≤ 3 months of study registration.

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

3. Not pregnant and not nursing, because this study involves an investigational agent
whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn
are unknown. Therefore, 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.

4. Age ≥ 18 years

5. Karnofsky Performance Status ≥ 60%

6. Required Initial Laboratory Values ≤14 days of registration:

6.1 Absolute Neutrophil Count (ANC) ≥ 1,500/mm^3

6.2 Platelet Count ≥ 100,000/mm3

6.3 Hemoglobin ≥ 10 g/dL*

6.3.1 allowing transfusion or other intervention to achieve this minimum hemoglobin

6.4 BUN < 30 mg/dL

6.5 Creatinine < 1.7 mg/dL

6.6 Bilirubin ≤ 2.0 mg/dL

6.7 ALT ≤ 3.0 x upper limits of normal (ULN)

6.8 AST ≤ 3.0 x ULN

6.9 INR <1.5 x ULN**

6.9.1 unless patients are receiving anti-coagulation therapy. Patients receiving
anti-coagulation therapy with an agent such warfarin or heparin are allowed to
participate if INR ≤ 3.0.**

6.10 UPC Ratio <0.5 or if ≥ 0.5

6.10.1 24-hour urine protein must be <1000 mg

7. 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.

8. 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.

9. No excess risk of bleeding (any of the following):

9.1 Bleeding diathesis or coagulopathy

9.2 Thrombocytopenia

9.3 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.

9.4 Minor surgical procedures, stereotactic biopsy, fine needle aspiration, or core
biopsy within the past 7 days.

10. No clinically significant cardiovascular disease.

10.1 No uncontrolled hypertension (systolic blood pressure ≤ 160 mm Hg or diastolic ≤
100 mm Hg). Patients with hypertension must be adequately controlled with appropriate
anti-hypertensive therapy or diet.

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

10.2.1 transient ischemic attack (TIA)

10.2.2 cerebrovascular accident (CVA)

10.2.3 peripheral arterial thrombus

10.2.4 unstable angina or angina requiring surgical or medial intervention

10.2.5 myocardial infarction (MI)

10.2.6 significant peripheral artery disease (i.e., claudication on less than one
block)

10.2.7 significant vascular disease (i.e., aortic aneurysm, history of aortic
dissection)

10.3 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.

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

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

12. No central lung metastases with excessive active bleeding.

13. 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.

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