Super-selective Blood Brain Barrier Disruption and Intra-arterial - - PowerPoint PPT Presentation

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

• f Bevacizumab

DISCLOSURES

• eVisio Medical Systems
• Reach Bionics
• New York Presbyterian Hospital / Helmsley

Charitable Trust (MINT Program)

• Tomorrow Foundation
• Charles Maddock Foundation

2

3

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

• f 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)
• Secondary (from lower grade)

6

Treatment consists of surgery, radiation and Temozolamide (Temodar, an alkylating agent)

7

Precursor cell GBM

Low-Grade Astrocytoma Anaplastic Astrocytoma Low-Grade Oligodendroglioma Anaplastic Oligodendroglioma p53 mut./17p loss PDGF/R Amp. 22q loss Rb mut. P14/p16 loss CDK4 amp. 9p/19q/11p loss 1p/19q loss P14/p16/9p loss MGMT methylation

• Chrom. 10 loss

PTEN mut. CDK4 amp. MDM2 amp. PDGF/R amp

• Chrom. 10 loss

EGFR Amp(<10%)

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

• ver 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

Norden et al, Neurology 2008

10 Before Treatment 1 month 5 months 7 months

11

VEGFR-2

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

12

“Antiangiogenic drugs arrest brain tumor growth, by disrupting a vascular niche microenvironment .” Calabrese et al. Cancer Cell, 2007

13

14

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?

15

Cancer Stem Cell

Non-Stem Tumor Cell

Mannitol Tight Junction

Mannitol

Endothelial Cell

Angiogenesis Microcatheter

VEGF/VEGFR2 Complex

• 1. Selective BBB disruption

16

Cancer Stem Cell

Non-Stem Tumor Cell

VEGF/bevacizumab Complex

Bevacizumab

• 2. Selective bevacizumab delivery

17

Cancer Stem Cell

Non-Stem Tumor Cell

After

• 3. Selective inhibition of CSC signaling and angiogenesis

18

Stanley Rapoport

What is the Rationale for: The Use of Mannitol to Open the Blood Brain Barrier

19

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,

1986

Why Intra-arterial vs. Intravenous?

20

• J. Nuc Med, 1986

Intra-arterial chemotherapy gives a higher tumor dose than Intravenous administration

21

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

Phase 1 Trial: Super-Selective Intraarteial Cerebral Infusion

• f 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

29

a. b. c. 3 weeks Post Pre

30

Presentation Title Goes Here 31

• a. Selective Angiogram
• b. Pre
• c. Post

24 hours

32

Pre-Mannitol/Avastin Post-Mannitol/Avastin Selective angiography through left MCA

33

• a. Selective Angiogram

34

35

36

Flair

Pre Avastin Post Avastin

Brainstem Glioma

37

38

24 Hours

39

Metabolic responses of tumor to treatment: PET CT

40

41

Area Volume MR Perfusion

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
• f 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

47

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

49

50

Median progression free survival : 10 months

51

Phase II trial of Repeated IA Avastin alone

Primary Endpoints: Progression free survival and overall survival

52

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)

Summary and Conclusions

• We have a better understanding of the cancer

stem cell hypothesis and the perivascular niche

• Antiangiogenic drugs arrest brain tumor

growth, by disrupting a vascular niche microenvironment that is critical for the maintenance of cancers stem cells

• Bevacizumab delivery to the perivascular

niche may be important in targeting brain tumor stem cells in human GBM

• SIACI Mannitol and Bevacizumab is safe up to

a dose of 15 mg/kg

• SIACI Mannitol and Bevacizumab shows a

meaninful reduction in area, volume, perfusion and T2 signal intensity

• Determine if SIACI Mannitol/Bevacizumab

alone helps improve progression free survival and overall survival in patients with GBM

53

Acknowledgements

• John A. Boockvar, M.D.
• Director Brain Tumor,

Pituitary and Acoustic Neuroma Centers,Lennox Hill Hospital

• Investigator, Laboratory for

Brain Tumor Biology and Therapy, Feinstein Institute for Medical Research

• Professor of Neurosurgery

Hofstra-NSLIJ School of Medicine

54

Divider Slide Headline

Presentation Title Goes Here 55