AMG 102 and Avastin for Recurrent Malignant Glioma
Condition: Glioblastoma Multiforme; Gliosarcoma
MeSH terms: Glioblastoma; Glioma; Gliosarcoma
Intervention: AMG 102; Avastin
Intervention description: AMG 102 will be administered as a continuous intravenous infusion by an infusion pump at 20 mg/kg every 2 weeks over 60 or 30 minutes.; Avastin will be administered as a continuous intravenous infusion at 10 mg/kg every 2 weeks (6-week study cycle) over 60 or 30 minutes. Avastin will be given prior to AMG 102.
Intervention MeSH terms: Bevacizumab; Rilotumumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 36.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: glioblastoma multiforme; gliosarcoma; malignant glioma; glioma; Avastin; bevacizumab; AMG 102; rilotumumab; recurrent; Duke; Pro00022491

Summary:

      The primary purpose of the study is to assess the response rate of AMG 102 and Avastin
      treatment in subjects with advanced malignant glioma. Secondary objectives are to estimate
      overall survival and 6-month progression-free survival rates in this population and to assess
      the safety of this combination in this population.

      Patients must have recurrent histologically confirmed diagnosis of World Health Organization
      (WHO) grade IV malignant glioma (glioblastoma multiforme or gliosarcoma) with no more than 3
      prior progressions. Subjects will receive Avastin and AMG 102 every two weeks. Avastin will
      be administered prior to AMG 102. Up to 36 adult subjects will take part in this study at
      Duke.

      In initial Phase I and II clinical trials, four potential Avastin-associated safety issues
      were identified: hypertension, proteinuria, thromboembolic events, and hemorrhage. The most
      common side effect for AMG 102 have been nausea and fatigue.
    

Eligibility criteria:

        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.