HOWARD A. RIINA, MD PROFESSOR AND VICE CHAIRMAN RESIDENCY PROGRAM DIRECTOR DEPARTMENT OF NEUROSURGERY NEW YORK UNIVERSITY SCHOOL OF MEDICINE Super-selective Blood Brain Barrier Disruption and Intra-arterial Infusion of Bevacizumab
DISCLOSURES • eVisio Medical Systems • Reach Bionics • New York Presbyterian Hospital / Helmsley Charitable Trust (MINT Program) • Tomorrow Foundation • Charles Maddock Foundation 2
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Epidemiology • Estimated number of people living with a diagnosis of primary brain and central nervous system (CNS) tumor in the US in 2000: 359,000 • Total new cases of primary brain/CNS tumors (malignant and non-malignant) expected in 2005 in the US: 43,800 • Total estimated new cases of primary malignant brain /CNS tumors to be diagnosed in 2005 in the US: 18,500 • Estimated number of deaths attributable to primary malignant brain/CNS tumors in the US in 2005: 12,760 4
More Statistics • The leading cause of death from childhood cancers among persons up to 19 years • The second leading cause of cancer-related deaths in males ages 20-39 • The fifth leading cause of cancer-related deaths in women ages 20-39 • Lifetime Risk: • Males have a 0.66% lifetime risk of being diagnosed with a primary malignant brain tumor and a 0.50% chance of dying from a brain tumor • Females have a 0.54% lifetime risk of being diagnosed with a primary malignant brain tumor and a 0.41% chance of dying from a brain tumor. 5
Glioblastoma Multiforme • Gliomas are primary central nervous systems tumors whose cell of origin is unknown • Gliomas are graded 1-4 • GBM is grade IV with median survival 12 months; 2 year survival is 25% • Two types of GBM • Primary (de novo) Treatment consists of surgery, • Secondary (from lower grade) radiation and Temozolamide (Temodar, an alkylating agent) 6
Precursor p53 mut./17p loss cell 1p/19q loss PDGF/R Amp. 22q loss Low-Grade Low-Grade Oligodendroglioma Astrocytoma Rb mut. P14/p16 loss P14/p16/9p loss CDK4 amp. MGMT methylation 9p/19q/11p loss Anaplastic Anaplastic Oligodendroglioma Astrocytoma CDK4 amp. MDM2 amp. Chrom. 10 loss PDGF/R amp PTEN mut. Chrom. 10 loss GBM EGFR Amp(<10%) 7
Bevacizumab • Bevacizumab, a humanized monoclonal antibody to vascular endothelial growth factor (VEGF) • • IV Bevacizumab (at 10mg/kg) in the recurrent disease setting has demonstrated partial responses in 50% of treated patients who have had no previous exposure to the drug • • Studies have showed a 50% 6-month progression free survival (6MPFS), a dramatic improvement over historical controls 8
Treatment for Recurrent GBM • FDA approves Bevacizumab (Avastin) for GBM in May 2009 Phase II data shows 1. 50% radiographic response rate 2. 50% 6MPFS 9
Time to Response on IV Avastin Before 1 month 5 months 7 months Treatment Norden et al, Neurology 2008 10
Cancer stem cells (like endothelial cells) release high levels of VEGF ligand and have high levels of VEGFR-2 receptors and are responsive to Bevacizumab in vitro and in vivo VEGFR-2 Dirks et al, 2009 VEGFR-2 11
“ Antiangiogenic drugs arrest brain tumor growth, by disrupting a vascular niche microenvironment . ” Calabrese et al. Cancer Cell, 2007 12
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How can we improve treatment with antiangiogenic agents? • Dose intensification improve delivery methods? • Does it overcome the blood brain barrier? • Is a better target the cancer stem cell niche? 14
1. Selective BBB disruption VEGF/VEGFR2 Complex Mannitol Endothelial Cell Tight Junction Cancer Stem Cell Non-Stem Tumor Cell Microcatheter Mannitol 15 Angiogenesis
2. Selective bevacizumab delivery VEGF/bevacizumab Complex Cancer Stem Cell Non-Stem Tumor Cell Bevacizumab 16
3. Selective inhibition of CSC signaling and angiogenesis Cancer Stem Cell Non-Stem Tumor Cell After 17
What is the Rationale for: The Use of Mannitol to Open the Blood Brain Barrier Stanley Rapoport 18
Why Intra-arterial vs. Intravenous? Images obtained at 40 min after injection of [11C]BCNU by i.v. (A) and superselective intra-arterial (B) routes. IA injection achieves both high tumor concentrations (50-400 fold) of activity as well as very low activity in surrounding and contralateral brain J. Nuc Med, 19 1986
Intra-arterial chemotherapy gives a higher tumor dose than Intravenous administration J. Nuc Med, 1986 20
Hypothesis: Super-Selective Intraarterial Cerebral Infusion of Mannitol followed by Bevacizumab (Avastin) was safe and effective for patients with recurrent or relapsing malignant glioma FDA IND and IRB approval took one year 21
Phase 1 Trial: Super-Selective Intraarteial Cerebral Infusion of Mannitol followed by Bevacizumab (Avastin) for Recurrent Malignant Brain Tumors 22
Initial Study Design • Patients with recurrent glioblastoma multiforme (GBM) and anaplastic astrocytomas • Super-selective osmotic BBBD • mannitol (25% in 10cc over 60 seconds) • SIACI of bevacizumab • dose of 2 mg/kg (3 patients per cohort for a total of 5 cohorts) with dose escalation up to a dose of 10 mg/kg 23
Safety Trial Design • 3 x 3 design dose escalation study of IA bevacizumab • Dosage used 2,4, 6, 8, 10, 11, 12, 13, 14, 15 mg/kg body weight • 30 patients in the trial assuming no dose limiting toxicity • 28 day observation period for DLT and then patients start standard biweekly IV bevacizumab 24
Demographics 25
Phase I Trial • Dose limiting toxicity (DLT) was assessed over a four-week period in order to determine a maximum tolerated dose (MTD) of SIACI bevacizumab • • Treatment response was assessed on MR imaging using the WHO-based MacDonald criteria and volumetric analysis at four weeks 26
Phase I Trial • Following SCIACI patients received standard biweekly IV Bevacizumab (10mg/kg) protocol • Changes in intra-tumoral MR perfusion were included in the post infusion imaging assessment • Response to SIACI was correlated to previous exposure to IV Bevacizumab and to tumor expression levels of VEGF on immunohistochemistry 27
• Fifteen patients received a single dose of SIACI Mannitol followed by SIACI of Bevacizumab • • No DLT was observed during the 28-day observation period after using SIACI Bevacizumab up to a dose of 10mg/kg • • No patients discontinued treatment because of intra-tumoral hemorrhage, wound dehiscence, or bowel perforation 28
a. b. 3 weeks c. 29 Pre Post
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a. Selective Angiogram b. Pre c. Post 24 hours Presentation Title Goes Here 31
Selective angiography through left MCA Pre-Mannitol/Avastin Post-Mannitol/Avastin 32
a. Selective Angiogram 33
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Flair 36 Pre Avastin Post Avastin
Brainstem Glioma 37
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24 Hours 39
Metabolic responses of tumor to treatment: PET CT 40
Volume MR Perfusion Area 41
Results- One Month after a single infusion 42
Results • 10/15 patients (66.7%; 95% CI = 40.8%- 86.6%) had a reduction in Area (median reduction for these 10 patients = -24.7%). 8/15 patients (53.3%; 95% CI = 28.7%-76.8%) had a reduction in Volume (median reduction for these 8 patients = -44.7%). 8/9 patients (88.9%; 95% CI = 56.1%- 99.4%) had a reduction in MRP (median reduction for these 8 patients = - 38.8%). 43
Results • Post-infusion MRI at one month showed a mean tumor area reduction of 17.06% (SD 30.77%) and volume reduction of 20.74% (SD 42.98%). • MRI perfusion demonstrated that a single dose of SIACI Mannitol/Bevacizumab concurrently diminished loco- regional relative cerebral blood volume (rCBV) by 22.42% (SD 30.61%). • Prior IV Bevacizumab therapy correlated with diminished response to SIACI Mannitol/Bevacizumab treatment. 44
Results: Dose Limited Toxicity • We did not achieve a maximum tolerated dose (MTD) of IA Bevacizumab up to 15mg/kg body weight • There was no dose limiting toxicity associated with the combination of IA Mannitol and Bevacizumab • The study stopped at 15mg/kg which is the highest IV dose of Bevacizumab approved by the FDA 45
Serious Adverse Events •Seizures: 2 (days 4 and 12 both in patients with Seizure history) •Pulmonary Embolism: 1 (during intubation) •Rash •Stroke: 1 (balloon assisted rupture of vessel) 46
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Conclusions of the Safety Trial • SIACI of Mannitol followed by Bevacizumab for recurrent malignant glioma (up to10mg/kg) is safe and well tolerated • Radiographic responses suggest that this novel delivery method can act locally and after a single dose in patients with recurrent malignant glioma, even at doses well below the standard IV dose of 10mg/kg • Results support the testing of the efficacy of this treatment in a larger number of patients and using a multi-dose regimen in the recurrent setting of GBM 48
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Median progression free survival : 10 months 50
Phase II trial of Repeated IA Avastin alone 51 Primary Endpoints: Progression free survival and overall survival
IA Avastin alone - PFS after a single treatment Mean PFS : 122.53 days (86.72 - 158.3) Median PFS : 133 days (87.12 – 178.9) 52
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