Phase II Study to Evaluate the Efficacy and Safety of AMG 102 and Avastin in Subjects With Recurrent Malignant Glioma
- Patients must have recurrent histologically confirmed diagnosis of WHO grade IV
malignant glioma (glioblastoma multiforme or gliosarcoma) with no more than 3 prior
- Age ≥ 18 years.
- Karnofsky ≥ 60%.
- An interval of at least 4 weeks between either prior tumor biopsy or prior major
surgical procedure and study enrollment.
- Bi-dimensionally measurable disease as assessed by magnetic resonance imaging.
- Hemoglobin ≥9.0 g/dl, ANC ≥1500 cells/µl, Platelets ≥125,000 cells/µl (without
transfusion within 14 days before enrollment).
- Serum creatinine < 1.5 mg/dl, bilirubin < 1.5 times upper limit of normal, and serum
SGOT (AST) and SGPT (ALT) < 2.5 times upper limit of normal.
- For patients on corticosteroids, they must be on a stable dose for 1 week prior to
entry, and the dose should not be escalated over entry dose level, if clinically
- Signed informed consent approved by the Institutional Review Board.
- No evidence of active CNS hemorrhage on the baseline MRI or CT scan.
- If sexually active, patients will take contraceptive measures for the duration of
treatment as stated in the informed consent.
- Pregnancy or breast-feeding.
- Baseline ECG with QTc > 0.45 second
- Co-medication that may interfere with study results; e.g. immuno-suppressive agents
other than corticosteroids.
- Thrombosis or vascular ischemic events within the last twelve months, such as deep
venous thrombosis, pulmonary embolism, transient ischemic attack, cerebral
infarction, or myocardial infarction.
- Active infection requiring IV antibiotics 7 days before enrollment.
- History of central nervous system bleeding as defined by stroke or intraocular bleed
(including embolic stroke) within 6 months before enrollment.
- Evidence of acute intracranial hemorrhage; except for subjects with stable grade 1
- Less than 12 weeks from radiation therapy, unless progressive disease outside of the
radiation field or 2 consecutive scans or histopathologic confirmation.
- Treated previously with any c-Met or HGF targeted therapy.
- Treated previously with VEGF or VEGFR therapies, including antibodies and tyrosine
- Treated with thalidomide or tamoxifen within 1 week before enrollment or has not
recovered from the toxic effects of such cancer therapy.
- Treated with immunotherapeutic agents, vaccines, or MAb therapy within 4 weeks before
enrollment or have not recovered from the toxic effects of such cancer therapy.
- Treated with alkylating agents within 4 weeks before enrollment or has not recovered
from the toxic effects of such cancer therapy.
- Treated with chemotherapy (non-alkylating agents) within 2 weeks before enrollment or
has not recovered from the toxic effects of such cancer therapy.
- Less than 4 weeks after surgical resection of the brain tumor or less than 2 weeks
after biopsy before enrollment or have not recovered from acute side effects of such
procedures except for neurological effects.
- Plans to receive surgery, radiation therapy or other elective surgeries during the
course of the study.
- Concurrent severe and/or uncontrolled medical disease (e.g. uncontrolled diabetes,
congestive cardiac failure, myocardial infarction within 6 months before enrollment)
that could compromise participation in the study.
- Concurrent or prior (within 7 days of enrollment) anticoagulation therapy, except:
Use of low dose coumadin-type anticoagulants (≤ 2 mg PO QD) low molecular weight
heparins (LMWH), e.g. Enoxaparin sodium (Lovenox) and unfractionated heparin for
prophylaxis against central venous catheter thrombosis is allowed.
- Grade 2 or greater peripheral edema or effusion (pleural, pericardial, or ascites).
- Inability to comply with study and/or follow-up procedure.
- Current, recent (within 4 weeks of the first infusion of this study), or planned
participation in an experimental drug study.
Avastin-Specific Exclusion Criteria
Subjects meeting any of the following criteria are ineligible for study entry:
- Inadequately controlled hypertension (defined as systolic blood pressure >150 mmHg
and/or diastolic blood pressure > 100 mmHg)
- Prior history of hypertensive crisis or hypertensive encephalopathy
- New York Heart Association (NYHA) Grade II or greater congestive heart failure
- History of myocardial infarction or unstable angina within 6 months prior to Day 1,
the day protocol therapy starts.
- History of stroke or transient ischemic attack within 6 months prior to Day 1
- Significant vascular disease (e.g. aortic aneurysm, requiring surgical repair or
recent peripheral arterial thrombosis) (within 6 months prior to Day 1).
- History of hemoptysis (≥ 1/2 teaspoon of bright red blood per episode) within 28 days
prior to Day 1
- Evidence of bleeding diathesis or significant coagulopathy (in the absence of
- Major surgical procedure, open biopsy, or significant traumatic injury within 28 days
prior to Day 1
- Core biopsy or other minor surgical procedure, excluding placement of a vascular
access device, within 7 days prior to Day 1
- Serious, non-healing wound, active ulcer or untreated bone fracture
- Proteinuria as defined by ≥ +1 on urinalysis dipstick
- Known hypersensitivity to any component of Avastin
- Pregnant (positive pregnancy test) or lactation.