Bevacizumab With or Without Trebananib in Treating Patients With Recurrent Brain Tumors

PRIMARY OBJECTIVES:

I. To assess the safety and tolerability of AMG 386 (trebananib) 15 mg/kg weekly in
combination with bevacizumab 10 mg/kg every 2 weeks (Cohort 1). (closed to accrual 10/2/12)
II. To assess the efficacy of AMG 386 in combination with bevacizumab 10 mg/kg every 2 weeks
compared to bevacizumab monotherapy in bevacizumab-naive patients, as measured by 6-month
progression-free survival (PFS6) (Cohort 2).

SECONDARY OBJECTIVES:

I. To further assess the toxicity profile (Cohorts 1 and 2). II. To assess feasibility of AMG
386 15 mg/kg weekly in combination with bevacizumab 10 mg/kg every 2 weeks (Cohort 1 [closed
to accrual 10/2/12]), as measured by the percentage of patients requiring dose
reduction/interruption or discontinuation in the first 2 and subsequent cycles.

III. To determine the radiographic response rate (RR), median progression-free survival
(PFS), and overall survival (OS) in bevacizumab-naive patients (Cohort 2).

IV. To assess the efficacy of AMG 386 15 mg/kg weekly in combination with bevacizumab 10
mg/kg every 2 weeks in patients who have progressed while on bevacizumab, as measured by
overall survival (OS) (cross-over from placebo arm of Cohort 2).

V. To correlate outcome to treatment with tumor genotype, expression profile, and circulating
angiogenesis biomarkers in tumor specimens (Cohort 2).

VI. To determine the RR, PFS6, and PFS in patients who have progressed while on bevacizumab
therapy and receive AMG 386 in combination with bevacizumab (cross-over from placebo arm of
Cohort 2).

VII. To determine the serum pharmacokinetics of AMG 386 in patients receiving bevacizumab
(Cohort 1 and cross-over from placebo arm of Cohort 2).

OUTLINE: This is a safety study (cohort 1 [closed to accrual 10/2/12]) followed by a
randomized study (cohort 2).

Cohort 1: Patients receive bevacizumab intravenously (IV) over 30-90 minutes on days 1 and 15
and trebananib IV over 30-60 minutes on days 1, 8, 15, and 22. Courses repeat every 28 days
in the absence of disease progression or unacceptable toxicity. (closed to accrual 10/2/12)

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

ARM I: Patients receive bevacizumab and trebananib as in Cohort 1.

ARM II: Patients receive bevacizumab as in Arm I and placebo IV over 30-60 minutes on days 1,
8, 15, and 22. Courses repeat every 28 days in the absence of disease progression or
unacceptable toxicity. Patients with disease progression may cross over to Arm I.

After completion of study treatment, patients are followed up at 30 days, every 2 months for
1 year, every 6 months for 1 year, and then annually thereafter.

Inclusion Criteria:

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

- The tumor must be supratentorial; patients with infratentorial disease, spinal cord
disease, and/or leptomeningeal disease are excluded

- Patients must have shown unequivocal evidence for tumor progression on the previous
treatment regimen (prior to enrollment on this study) by magnetic resonance imaging
(MRI) scan of the brain with and without contrast within 14 days prior to
registration; the dose of steroids must be stable or decreasing for at least 5 days
prior to the scan; patients with tumor progression who then undergo surgical resection
prior to enrollment on study may be eligible as long as pathology confirms progressive
or recurrent glioblastoma multiforme (GBM) (or variants); for patients who undergo
surgical resection, registration on study may not occur any sooner than 28 days from
surgery; an MRI scan of the brain with and without contrast is still required within
14 days prior to registration on study but is not required to demonstrate measurable
disease or tumor progression after surgery

- Patients unable to undergo MRI because of non-compatible devices can be enrolled,
provided computed tomography (CT) scans are obtained and are of sufficient quality;
patients without non-compatible devices may not have CT scans performed to meet this
requirement

- History/physical examination within 14 days prior to registration

- Karnofsky performance scale >= 70 within 14 days prior to registration

- Patients who have received prior treatment with interstitial brachytherapy,
stereotactic radiosurgery, or implanted chemotherapy sources, such as wafers of
polifeprosan 20 with carmustine, must have confirmation of progressive disease within
14 days prior to registration based upon nuclear imaging, magnetic resonance (MR)
spectroscopy, perfusion imaging, or histopathology

- Leukocytes > 3,000/mm^3 (within 14 days prior to registration)

- Absolute neutrophil count (ANC) >= 1,500 cells/mm^3 (within 14 days prior to
registration)

- Hemoglobin >= 10.0 g/dL (note: the use of transfusion or other intervention to achieve
hemoglobin [Hgb] >= 10.0 g/dL is acceptable) (within 14 days prior to registration)

- Platelets >= 100,000 cells/mm^3 (within 14 days prior to registration)

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
< 2.5 X institutional upper limit of normal (within 14 days prior to registration)

- Bilirubin =< 2.0 mg/dL (within 14 days prior to registration)

- Creatinine within normal upper institutional limits or creatinine clearance > 60
mL/min/1.73 m^2 (per 24 hour urine collection or calculated according to the
Cockcroft-Gault formula) for subjects with creatinine levels above the institutional
normal (within 14 days prior to registration)

- Patients with creatinine levels below normal institutional limits are eligible

- Prothrombin time (PT)/international normalized ratio (INR) =< 1.5 (within 14 days
prior to registration)

- Urinary protein =< 30 mg/dL in urinalysis or =< 1+ on dipstick (within 14 days prior
to registration)

- Generally well-controlled blood pressure with systolic blood pressure =< 140 mm Hg AND
diastolic blood pressure =< 90 mm Hg within 5 days prior to registration; the use of
anti-hypertensive medications to control hypertension is permitted

- Women of childbearing potential must have a negative serum beta-human chorionic
gonadotropin (HCG) pregnancy test within 14 days prior to registration

- Women of childbearing potential and male patients who are sexually active must
practice adequate contraception during therapy and for 180 days (6 months) afterwards

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

Exclusion Criteria:

- Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free
for a minimum of 3 years (for example, carcinoma in situ of the breast, oral cavity,
or cervix are all permissible)

- Prior systemic cytotoxic chemotherapy within (i.e., =<) 28 days (42 days for
nitrosoureas or mitomycin C) prior to registration, or patients who have not returned
to baseline or =< Common Terminology Criteria for Adverse Events (CTCAE) version 4 (v.
4) grade 2 from adverse events (excluding alopecia) due to agents administered more
than 28 days prior to registration

- Patients who received non-cytotoxic drug therapy must be off treatment for at least 14
days prior to registration; prior treatment with anti-vascular endothelial growth
factor (VEGF) targeted agents; AMG 386 therapy; or other molecules that inhibit
angiopoietins or TEK tyrosine kinase, endothelial (Tie2) receptor including, but not
limited to, XL-820, XL-184 (cabozantinib-s-malate), and CVX-060/PF-4856884 is not
allowed regardless of time frame

- Patients who have not yet completed at least 21 days (30 days for prior monoclonal
antibody therapy) since ending other investigational device or drug trials, or who are
currently receiving other investigational treatments

- Treatment within 30 days prior to enrollment with strong immune modulators, including
but not limited to systemic cyclosporine, tacrolimus, sirolimus, mycophenolate
mofetil, methotrexate, azathioprine, rapamycin, thalidomide, lenalidomide, and
targeted immune modulators such as abatacept (CTLA-4-Ig), adalimumab, alefacept,
anakinra, belatacept (LEA29Y), efalizumab, etanercept, infliximab, or rituximab

- Prior radiotherapy within 90 days (3 months) prior to registration unless there is
either: a) histopathologic confirmation of recurrent tumor; or b) new enhancement on
MRI outside of the radiation treatment field

- Major surgical procedure (including craniotomy and open brain biopsy) or significant
traumatic injury within 28 days prior to registration or those patients who receive a
non-central nervous system (CNS) minor surgical procedures (e.g. core biopsy or fine
needle aspiration) within 3 days prior to registration; there is no waiting period for
central line placement; there is a 7-day window for recovery prior to registration for
patients who underwent stereotactic biopsy of the brain

- Prior therapy with anti-VEGF targeted agents (e.g. bevacizumab, cediranib, vandetanib,
aflibercept, sunitinib, sorafenib, etc.); prior therapy with thalidomide and
lenalidomide is allowed as long as treatment has not occurred within 30 days prior to
enrollment

- More than 2 relapses

- Therapeutic anticoagulation with warfarin < 7 days prior to registration; (therapeutic
or prophylactic therapy with aspirin, a low-molecular weight heparin, or a Factor Xa
inhibitor is acceptable)

- Intratumoral hemorrhage or peritumoral hemorrhage, demonstrated by MRI or CT scan,
CTCAE, v. 4 grade 2 or greater or evidence of significant hemorrhage (regardless of
CTCAE, v. 4 grade) defined as > 1 cm diameter of blood (including postoperative
hemorrhage)

- Gastrointestinal bleeding or any other hemorrhage/bleeding event CTCAE, v. 4 grade 3
or greater within 30 days prior to study entry

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

- Unstable angina and/or congestive heart failure requiring hospitalization within
180 days (6 months) prior to registration

- Transmural myocardial infarction within 180 days (6 months) prior to registration

- History of stroke, cerebral vascular accident (CVA), or transient ischemic attack
within 180 days (6 months) prior to registration

- 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 registration

- Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects

- 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

- Known coagulopathy that increases risk of bleeding or a history of clinically
significant hemorrhages in the past

- History of non-healing wounds or ulcers, or bone fractures within 90 days (3
months) prior to registration

- History of venous or arterial thromboembolism within 12 months prior to
registration

- Prior allergic reaction to the study drugs involved in this study