AMG 102 and Avastin for Recurrent Malignant Glioma

Study Overview
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Brief Summary
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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.

Official Title
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Phase II Study to Evaluate the Efficacy and Safety of AMG 102 and Avastin in Subjects With Recurrent Malignant Glioma

Conditions
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Glioblastoma Multiforme, Gliosarcoma

Intervention / Treatment
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* Drug: AMG 102
* Drug: Avastin


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AMG 102 with Avastin<br>Avastin will be administered as a continuous intravenous infusion at 10 mg/kg prior to AMG 102, which will be administered as a continuous intravenous infusion by an infusion pump at 20 mg/kg. Subjects will receive infusions every 2 weeks. | Drug: AMG 102<br>* 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.<br>* Other names: rilotumumab;Drug: Avastin<br>* 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.<br>* Other names: Bevacizumab;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Radiographic Response | The percentage of participants with a complete or partial response as determined by modified Response Assessment in Neuro-Oncology (RANO) criteria will be determined. Complete Response (CR) is defined as complete disappearance on MR/CT of all enhancing tumor and mass effect, off all corticosteroids (or receiving only adrenal replacement doses) and accompanied by a stable or improving neurologic examination. Partial Response (PR) is defined as greater than or equal to 50% reduction in tumor size on MR/CT by bi-dimensional measurement, on a stable or decreasing dose of corticosteroids and accompanied by a stable or improving neurologic examination. Tumor assessments are done at baseline and the end of every 6-week cycle thereafter. | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median Overall Survival (OS) | Overall survival is defined as the time in months from the start of protocol treatment until the date of death, or the date of last follow-up if alive. Kaplan-Meier methods will be used to estimate overall survival. | 2 years | 
| Six-month Progression-free Survival (PFS6) | The percentage of participants alive and progression-free at 6 months after the start of study treatment will be determined. PFS6 will be calculated from the date study treatment started until the date of progression or death, or the date of last follow-up if participants are alive without progression. Kaplan-Meier methods will be used to estimate survival. | 6 months | 
| Percentage of Participants Who Experience Treatment-related Grade 2 or Greater CNS Hemorrhage or Grade 4 or Greater Non-hematologic Toxicities | The percentage of participants who experience unacceptable toxicity, defined as any treatment-related grade 2 or greater CNS hemorrhage or grade 4 or greater non-hematologic toxicity, will be calculated. | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Duke, glioblastoma multiforme, gliosarcoma, malignant glioma, glioma, Avastin, bevacizumab, AMG 102, rilotumumab, recurrent, Pro00022491