AMG 102 and Avastin for Recurrent Malignant Glioma

Inclusion criteria

• Patients must have recurrent histologically confirmed diagnosis of WHO grade IV malignant glioma (glioblastoma multiforme or gliosarcoma) with no more than 3 prior progressions.
• 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 possible.
• 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.

Exclusion criteria

• 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 hemorrhage.
• 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 kinase inhibitors.
• Treated with thalidomide or tamoxifen within 1 week before enrollment unless the patient has recovered from the toxic effects of such therapy.
• Treated with immunotherapeutic agents, vaccines, or MAb therapy within 4 weeks before enrollment unless the patient has recovered from the toxic effects of such therapy.
• Treated with alkylating agents within 4 weeks before enrollment or if the patient has been treated with daily or metronomic chemotherapy unless the patient has recovered from the toxic effects of such therapy.
• Treated with chemotherapy (non-alkylating agents) within 2 weeks before enrollment unless the patient has recovered from the toxic effects of such therapy.
• Less than 4 weeks after surgical resection of the brain tumor or less than 2 weeks after stereotactic biopsy before enrollment unless the patient has 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 therapeutic anticoagulation)
• 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.