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Phase II Double-Blinded Placebo-Controlled Study of Bevacizumab With or Without AMG 386 in Patients With Recurrent Glioblastoma or Gliosarcoma

Phase 2
18 Years
Open (Enrolling)
Adult Anaplastic Oligodendroglioma, Adult Giant Cell Glioblastoma, Adult Glioblastoma, Adult Gliosarcoma, Adult Oligodendroglioma, Recurrent Adult Brain Tumor

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Trial Information

Phase II Double-Blinded Placebo-Controlled Study of Bevacizumab With or Without AMG 386 in Patients With Recurrent Glioblastoma or Gliosarcoma


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-naïve patients, as measured by 6-month
progression-free survival (PFS6) (Cohort 2).


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 OS in bevacizumab-naïve 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.

OUTLINE: This is a safety study (cohort 1 [closed to accrual 10/2/12]) followed by a
randomized study (cohort 2). Patients are stratified according to age in years (< 50 vs >=
50), Karnofsky performance status (70-80% vs 90-100%), and recent resection (yes vs no).

Cohort 1: Patients receive bevacizumab 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 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

- 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 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

- 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, MR spectroscopy, perfusion
imaging, or histopathology

- No more than 2 relapses

- No intratumoral hemorrhage or peritumoral hemorrhage, demonstrated by MRI or CT scan,
Common Terminology Criteria for Adverse Events (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)

- Karnofsky performance scale >= 70%

- Leukocytes > 3,000/mm^3

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

- Hemoglobin (Hgb) >= 10.0 g/dL (Note: The use of transfusion or other intervention to
achieve Hgb >= 10.0 g/dL is acceptable)

- Platelets >= 100,000/mm^3

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvate transaminase [SGPT])
< 2.5 times institutional upper limit of normal

- Bilirubin =< 2.0 mg/dL

- Creatinine within normal institutional limits OR creatinine clearance > 60 mL/min
(per 24-hour urine collection or calculated according to the Cockcroft-Gault formula)

- Prothrombin time (PT)/international normalized ratio (INR) =< 1.5

- Urinary protein =< 30 mg/dL in urinalysis or =< 1+ on dipstick

- 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 (β)-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

- No prior invasive malignancy (except non-melanomatous skin cancer) unless
disease-free for a minimum of 1095 days (3 years); (for example, carcinoma in situ of
the breast, oral cavity, or cervix are all permissible)

- No gastrointestinal bleeding or any other hemorrhage/bleeding event CTCAE, v. 4 grade
3 or greater within 30 days prior to study entry

- No 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

- 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 (COPD) 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

- Known acquired immune-deficiency syndrome (AIDS) based upon current 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

- No prior allergic reaction to the study drugs involved in this study

- No prior systemic cytotoxic chemotherapy within 28 days (42 days for nitrosoureas or
mitomycin C) prior to registration, or patients who have not returned to baseline or
=< CTCAE 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 Tie2
receptor including, but not limited to, XL-820, XL-184, and CVX-060/PF-4856884
is not allowed regardless of time frame

- No 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

- No 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

- No 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

- No major surgical procedure (including craniotomy) 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

- 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

- Prior therapy with thalidomide and lenalidomide is allowed as long as treatment has
not occurred within 30 days prior to enrollment

- No 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

- No history of venous or arterial thromboembolism within 12 months prior to

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Outcome Measure:

Dose-limiting toxicity (DLT) (Cohort 1)

Outcome Description:

Defined as a clinically significant adverse event or abnormal laboratory value assessed as unrelated to disease progression, intercurrent illness, or concomitant medications and meets any of the criteria below.

Outcome Time Frame:

28 days

Safety Issue:


Principal Investigator

Eudocia Lee

Investigator Role:

Principal Investigator

Investigator Affiliation:

Radiation Therapy Oncology Group


United States: Food and Drug Administration

Study ID:




Start Date:

June 2012

Completion Date:

Related Keywords:

  • Adult Anaplastic Oligodendroglioma
  • Adult Giant Cell Glioblastoma
  • Adult Glioblastoma
  • Adult Gliosarcoma
  • Adult Oligodendroglioma
  • Recurrent Adult Brain Tumor
  • Brain Neoplasms
  • Glioblastoma
  • Oligodendroglioma
  • Gliosarcoma



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