GLIADEL ® Wafer development was based on the concept that a biodegradable polymer capable of sustained local delivery of a drug might circumvent the restrictions imposed by the blood-brain barrier and allow for more effective direct treatment of brain tumor. To accomplish this, the ideal polymer would have the following physical characteristics: - a water-soluble matrix rather than one that could be enzymatically degraded (patient’s enzyme levels vary, which could affect the release of drug) - hydrophobic monomers that permit surface erosion while limiting penetration of water through the polymer matrix surface - anhydride bonds to provide the appropriate instability necessary for the successful employment of degradable hydrophobic monomers.
This analysis represents the primary endpoint in the Brem trial; it is an analysis of all patients, i.e., the ITT group. The important information here, which will be repeated in each analysis presented, is a reduction of 33% in the risk of death in those patients who received GLIADEL . This is a significant reduction in risk, both clinically and statistically. Note that the hazard ratio (which is simply another way of expressing risk reduction) has been adjusted for prognostic factors. This simply means that a statistical method has been applied which takes into account the prognostic factors in each group and “teases” out the true or independent effect of GLIADEL. The risk reduction or survival benefit seen here can truly be attributed to GLIADEL and does not result from chance imbalances in prognostic factors between the groups.
This analysis looks at the subgroup of patients with GBM in the Brem trial. It is a comparison of 6-month survival between the groups; patients in the GLIADEL group had approximately a 50% increase in 6-month survival as compared to those in the placebo group, a statistically significant difference with a p-value of 0.02.
The median survival for GLIADEL ® treated patients was 13.9 months (95% CI: 12.1 to 15.1 months) while the median survival time for the placebo treated patients was 11.6 months (95% CI: 10.2 to 12.7 months) The estimated hazard ratio for GLIADEL ® treatment is 0.73 (95% CI: 0.56 to 0.95, p=0.018). When only patients with glioblastoma were included in the analysis, the hazard ratio with GLIADEL ® Wafer treatment was 0.78 (95% CI: 0.59-1.03, p=0.08, log-rank test) This trended towards, but did not reach statistical significance, likely a result of an inadequate sample size (n=207/240). Note that all p-values refer to an unstratified log-rank analysis of the Kaplan-Meier which is the gold standard statistical test for such a study.
These data are derived directly form the ITT Kaplan-Meier curve. 13 patients survived greater than 3 years, 11 in the GLIADEL ® Wafer treated group and 2 in the placebo group. There were 3 GBM patients surviving greater than 3 years and all three were in the GLIADEL ® Wafer treated group.
Gliadel-treated patients saw the benefit of both a reduction in the risk of death as well as a longer time to deterioration in Karnofsky Performance Score. This suggests that patients lived longer and better when compared to those receiving placebo wafers.
The adverse events above were of significant concern in the recurrent surgery trial. As such, they were a focus of data collection in the large Phase III Westphal trial. The Valtonen study was small and, thus, does not contribute significantly to the safety database for GLIADEL.
This difference did reach statistical significance. Potential explanations for these differences include the fact that all patients in this trial had prior surgery, radiation, and steroid therapy which may have contributed to a propensity for poor wound healing. Additionally, CSF leaks in patients implanted with GLIADEL ® Wafer might be expected to contain carmustine (BCNU), a cytotoxic agent which may contribute to poor wound healing through its effects on rapidly dividing cells. A watertight dural closure is, therefore, essential in helping to prevent this complication.
In general, there were no statistically significant differences in the various healing abnormalities studied. However, a trend toward an increase in CSF leaks was seen in the GLIADEL ® Wafer group. While this did not result in an increase in infections, it is important to achieve a water-tight dural closure.
The rate of intracranial infections in both the Brem and Westphal trials was very low. In fact, the literature available regarding the “expected” rates in patients undergoing craniotomy suggests these rates are well within what might otherwise be expected. Two pertinent articles are summarized below: An study by Kourinek, et.al., published in Neurosurgery in 1997, looked at 2944 patients undergoing craniotomy followed prospectively over 15 months. Infections were defined as deep (meningitis/empyema/abscess) or superficial (scalp infections/osteitis of the bone flap). Deep infections were seen in 2.5% of the patients, well within the range of what was seen in this trial. Additionally, CSF leak was found to be a risk factor for infection. Applying this information to these trial results, it is important to note that, in spite of slightly more leaks in the GLIADEL group, the incidence of infection was not different between the groups. In a study published by Tenney, et.al., in J Neurosurgery (1985), 936 patients undergoing craniotomy were followed prospectively over 30 months. Deep infections were defined in this study as involving the subgaleal space/bone/meninges/or brain parenchyma; superficial infections were defined as being limited to the scalp/skin/subcutaneous tissue. Deep wound infections occurred in 4.3% of the patients. Among craniotomies, procedures for removal of brain tumors had the highest deep wound infection rate (6%); those with gliomas had a rate of 9%. Antibiotic prophylaxis was used in less than 1% of the patients.
The safety results across the trials consistently demonstrate the tolerability of GLIADEL.
Newer management techniques for glioblastoma
Local Therapies for Brain Tumors Zvi Ram Department of Neurosurgery Tel Aviv Medical Center, ISRAEL
What is a Local Therapy? <ul><li>Direct administration of a therapeutic measure into the brain tumor, or its surroundings, to produce an anti-tumor response </li></ul>
Prerequisites for Local Therapies <ul><li>Specificity (No collateral damage) </li></ul><ul><li>Efficacy </li></ul><ul><li>Mode of delivery – How to get your therapy to the target </li></ul><ul><li>Predictability of effect and toxicity </li></ul>
Does Local Therapy for Brain Tumors Make Sense? <ul><li>NO </li></ul><ul><li>Malignant brain tumors are in fact a “systemic infiltrative disease” </li></ul><ul><li>Always recur </li></ul><ul><li>Hemispherectomy fails (contralateral tumor progression will cause death) </li></ul>
Does Local Therapy for Brain Tumors Make Sense? <ul><li>Yes </li></ul><ul><li>90% of GBM recur within 2 cm from the original resection site. </li></ul><ul><li>Gross total resection of tumors prolongs life. </li></ul><ul><li>May replace more aggressive measures (surgery) </li></ul><ul><li>May enable treatment of surgically- inaccessible tumors. </li></ul><ul><li>Local interaction may produce additional effects (Immune enhancement?) </li></ul>
Examples of Local Therapies <ul><li>In Situ Cytotoxic drugs </li></ul><ul><li>In Situ Toxins </li></ul><ul><li>Gene transfer into tissue </li></ul><ul><li>Ablative procedures (Brachytherapy, radiofrequency ablation, Focused ultrasound, laser ablation, etc.) </li></ul><ul><li>Local Immune enhancers </li></ul><ul><li>Stereotaxic Radiosurgery </li></ul>
GLIADEL ® Wafer Mechanism of BCNU Release <ul><li>Released via surface erosion </li></ul><ul><li>Hydrophobic monomers permit surface erosion for slow release & protect active agent from hydrolysis </li></ul><ul><li>70% release of BCNU by 3-4 weeks </li></ul>Time Surface Erosion Brem H, Langer R: Polymer-Based Drug Delivery to the Brain. Science & Medicine . 1996;3(4):2-11.
THE LANCET Placebo-controlled Trial of Safety and Efficacy of Intraoperative Controlled Delivery by Biodegradable Polymers of Chemotherapy for Recurrent Gliomas Henry Brem, Steven Piantadosi, Peter C Burger, Michael Walker, Robert Selker, Nicholas A Vick, Keith Black, Michael Sisti, Steven Brem, Gerard Mohr, Paul Muller, Richard Morawetz, S Clifford Schold, for the Polymer-Brain Tumor Treatment Group Lancet 345:1008-12, 1995
Simo Valtonen , M.D., Ulla Timonen, M.D., Petri Toivanen, M.SC., Hannu Kalimo, M.D., Leena Kivipelto, M.D., Olli Heiskanen, M.D. Prof., Geirmund Unsgaard, M.D.Prof., Timo Kuurne, M.D. Interstitial Chemotherapy with Carmustine-loaded Polymers for High-grade Gliomas: a Randomized Double-blind Study Department of Neurosurgery (SV) and Pathology (HK), Turku University Central Hospital, Turku, Finland; Department of Neurosurgery (LK, OH), Helsinki University Central Hospital, Helsinki, Finland; Department of Neurosurgery (TK), Tampere University Hospital, Tampere, Finland; Department of Neurosurgery (GU), University Hospital of Trondheim, Trondheim, Norway; and Orion Pharma (UT, PT), Espoo, Finland Neurosurgery 41:44-8; 1997
European Study of BCNU- Polyanhydride Polymer as the Initial Treatment of Malignant Glioma 100% 75% 50% 25% 0% 0 25 50 75 100 Weeks Survival Placebo (n = 16) GLIADEL (n = 16) Placebo-Polymer BCNU-Polymer S. Valtonen et al. 1997
31% of patients are alive versus 6% of patients with placebo polymers are alive Two Years After Implantation
Overall Survival ITT Group GLIADEL ® Wafer Package Insert . 100 90 80 70 60 50 40 30 20 10 0 0 4 8 12 16 20 24 28 32 36 40 44 48 52 Months From Implant Surgery Survival % HR = 0.73 Median Survival G: 13.9 mos P: 11.6 mos (p<0.05 log-rank) GLIADEL Placebo Long term
Long-Term Survival Data on file, Guilford Pharmaceuticals GLIADEL ® (N=120) N (%) Placebo (N=120) N (%) Survival>1 year 71 (59.2) 59 (49.2) Survival>2 years 19 (15.8) 10 (8.3) Survival>3 years 11 (9.2) 2 (1.7)
Karnofsky Performance Score Decline All Patients (ITT) 0 6 4 2 8 14 12 10 16 22 20 18 24 26 Months from Date of Randomization 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Proportion without Decline GLIADEL ® Placebo Hazard Ratio = 0.74 Risk Reduction = 26% p = 0.05 Median Time to Decline GLIADEL ® 11.9 months Placebo 10.4 months Westphal M, Hilt DC, Bortey E, et al. NeuroOncology . 2003;5(2).
Gliadel as the Initial Treatment of Malignant Brain Tumors <ul><li>Gliadel : 60 weeks </li></ul><ul><li>Placebo: 50 weeks </li></ul><ul><li>n = 240 </li></ul><ul><li>p = 0.03 </li></ul>European Association of Neurological Surgeons, November, 2000
Gliadel ® demonstrates proof of principle that controlled release with polymers directly to the brain is safe and improves outcome
Transient edema and “ abscess-like” Appearance. Resolution with steroids over time
Healing Abnormalities <ul><li>Recurrent Trial </li></ul><ul><ul><li>14% of GLIADEL ® Wafer and 5% of placebo patients </li></ul></ul><ul><ul><li>Classified as: </li></ul></ul><ul><ul><ul><li>CSF leaks </li></ul></ul></ul><ul><ul><ul><li>Subdural collections </li></ul></ul></ul><ul><ul><ul><li>Wound dehiscence or poor healing </li></ul></ul></ul><ul><ul><ul><li>Subgaleal or wound effusions </li></ul></ul></ul>
Healing Abnormalities Primary Setting Placebo (N=120) 6 (5.0) GLIADEL ® Wafer (N=120) 5 (4.2) Fluid, CSF, or subdural collections N (%) N (%) CSF leaks 6 (5.0) 1 (0.8) Wound dehiscence or poor healing 6 (5.0) 6 (5.0) Subgaleal or wound effusion 4 (3.3) 5 (4.2) No difference in overall healing abnormalities among the two groups
Intracranial Infections <ul><li>Recurrent Trial </li></ul><ul><ul><li>GLIADEL ® Wafer group 3.6% </li></ul></ul><ul><ul><li>Placebo group 1.0% </li></ul></ul><ul><li>Primary Trial </li></ul><ul><ul><li>GLIADEL ® Wafer group 6.0% </li></ul></ul><ul><ul><li>Placebo group 5.0% </li></ul></ul>
Summary of Safety Results from Randomized Controlled Trials <ul><li>Seizures </li></ul><ul><ul><li>No difference in frequency of seizures </li></ul></ul><ul><ul><li>Earlier onset of seizures in recurrent setting </li></ul></ul><ul><li>Healing Abnormalities </li></ul><ul><ul><li>Greater frequency in recurrent setting NOT seen in initial surgery setting </li></ul></ul><ul><ul><li>Slightly greater risk of CSF leak in GLIADEL ® group in initial surgery setting but NO increased risk of infection </li></ul></ul>
Conclusion <ul><li>The benefit to risk ratio in patients undergoing either initial or recurrent surgery for malignant glioma favors GLIADEL ® Wafer </li></ul>
NEW TREATMENTS HIGHER DOSE GLIADEL RX FOR METASTASIS TAXOL 5FU, EPIRUBICIN TEMODAR DRUG RESISTANCE MODIFIERS ANTI-ANGIOGENSIS FUTURE: VACCINES MICROCHIPS MOLECULAR TARGETS STEM CELLS INDIVIDUALIZED THERAPY
TAXOL CLINICAL TRIALS Oncogel = 6.0mg paclitaxel/ml of ReGel, Protherics, Inc Phase I: lymphoma, melanoma, lung, head and neck, laryngeal, thyroid and breast carcinoma (16 pts) Phase I: Recurrent Gliomas: PI: MACIEJ LESNIAK University of Chicago, University of North Carolina, Vanderbilt, Hopkins
<ul><li>In patients with complete resection, overall survival was </li></ul><ul><ul><li>15.2 months for those receiving 5-FU microspheres followed by radiotherapy </li></ul></ul><ul><ul><li>12.3 months for those receiving radiotherapy alone </li></ul></ul><ul><li>These differences were not significant. Safety was acceptable with prophylactic high doses of corticosteroids </li></ul><ul><li>The implantation of 5-fluorouracil microspheres in the wall of the cavity resection did increase overall survival , however, this study was not designed and sufficiently powered to demonstrate statistical significance </li></ul>Randomized, Multicenter Phase II Trial in Patients with Gross Total Resection of High-Grade Glioma
Hazard Ratio = 0.75 Stupp, R. et al. N Engl J Med 2005;352:987-996 TMZ Overall Survival
Gliadel Implantable BCNU Wafers: Similar Survival to Temozolomide GLIADEL Overall Survival 0 10 20 30 40 50 60 70 80 90 100 0 3 6 9 12 15 18 21 24 28 32 36 40 44 Survival Rate (%) Months from Implant Surgery Hazard Ratio = 0.75 Median OS, mo: 10.9 13.1 p=0.031 2-yr survival: 6% 33% HR [95% C.I.]: 0.75 [0.58-0.98] p=0.034 GLIADEL Placebo Meldorf M et al. AANS, 2003 (Abstract 1492). Stupp et al, ASCO, 2004 (www.asco.org). TMZ Overall Survival Placebo GLIADEL
PHASE II: SURGERY, RT, GLIADEL AND TMZ La Roca RV, Hodes J, Villaneuva TW, Vitaz TW, Morassutti, Doyle MJ, Glisson S, Cervera A, Stribinskiene L, New P, Litofsky, NS Median Survival 18.6 months SNO 2007 Stupp et al: 14.6 without Gliadel
Conclusions: Survival rates for newly diagnosed patients were better than those reported in previous phase III trials. The combination of Gliadel and radiochemotherapy with TMZ was well tolerated and appeared to increase survival without increasing adverse events. Ann Surg Oncol. 2010.
Is there a way to overcome the resistance to BCNU?
Phase II trial of Gliadel plus O6-benzylguanine in adults with recurrent glioblastoma multiforme <ul><li>Quinn JA, Jiang SX, Carter J, Reardon DA, Desjardins A, Vredenburgh JJ, Rich JN, Gururangan S, Friedman AH, Bigner DD, Sampson JH, McLendon RE, Herndon JE, Threatt S, Friedman HS </li></ul><ul><li>52 patients </li></ul><ul><li>6 month OS = 82% </li></ul><ul><li>Median OS = 50.3 weeks </li></ul><ul><li>1 and 2 yr survival: 47% and 10% </li></ul><ul><li>Toxicities: Hydrocephalus (9.6%), CSF leak (19.2%), Infection (13.4%) </li></ul><ul><li>Clin Cancer Res. 15, 1064-8, 2009 </li></ul>
CED The Concept of Convection-Enhanced Delivery for Brain Tumor Therapy
Convection Gd-saline infusion, 100 min Moseley, Stanford University, 2000
Variables Acting in Convection <ul><li>Anatomy </li></ul><ul><li>Physical barriers (scar tissue, gliosis, sulci, etc.) </li></ul><ul><li>Drugs </li></ul><ul><li>Toxicity </li></ul><ul><li>Chemical and physical characteristics </li></ul><ul><li>Local degradation by enzymes </li></ul><ul><li>Clearance from the brain parenchyma </li></ul>
Drugs <ul><li>Choosing the right drugs for CED </li></ul><ul><ul><li>Efficacy </li></ul></ul><ul><ul><li>Toxicity to normal brain </li></ul></ul><ul><ul><li>Stability in situ </li></ul></ul><ul><ul><li>Individual DISTRIBUTION characteristics (Infusate!) </li></ul></ul>
The Concept of Backflow <ul><li>Backflow reduces efficacy of distribution </li></ul><ul><li>Backflow increases toxicity (spillage of the drug into the subarachnoid space and CSF where it can affect the entire brain surface) </li></ul>
Infusion-induced edema is significant Under infusion- or tumor-induced edema, dramatic increases in conductivity in white matter occur Sampson, Duke University, 2004 IL13PE peri- Tumoral infusion
Deformation due to edema Sampson, Duke University, 2003 Intra-Tumoral Transmid Infusion
Convection-Enhanced Delivery of Taxol in Recurrent Malignant Gliomas CED of Cytotoxic Drugs
Baseline MRI 2 Weeks post taxol Large Tumors Effect
Failures <ul><li>Mechanical/Physical issues </li></ul><ul><ul><li>Placement in cystic/necrotic cavities </li></ul></ul><ul><ul><li>Penetration into ventricles/cysts/necrosis </li></ul></ul><ul><li>Backflow (Associated with CSF distribution and toxicity) </li></ul><ul><li>Anatomical/structural boundaries (glial scars, tissue conductivity, etc) </li></ul>
Penetration into the Ventricular System Multifocal GBM Necrotic Tumor
Diffusion 19 hours post infusion Diffusion allows slow spread of drug molecules not metabolized or degraded Moseley, Stanford University, 2000
Convection Effect Diffusion Effect Effect of Diffusion on Covective Volume
1 day post Taxol 7 days post Taxol Diffusion Effect
Histology <ul><li>Tissue obtained from treated tumors by Biopsy (1 patient) or resection (3 patients) </li></ul>
Imaging T1 +CM Baseline Day 28 during CED T1 +CM FET-PET Diffusion weighted MRI FET-PET Time points: MRI baseline, d3, d6, d28, w6, w12, w18, w24, w30 … PET baseline d28 w12 w24 … Mardor (2001)
Convection Studies <ul><li>Taxol </li></ul><ul><li>Toxins </li></ul><ul><ul><li>Pseudomonas toxin linked to IL-13 </li></ul></ul><ul><ul><li>Diphtheria toxin linked to transferrin </li></ul></ul><ul><ul><li>Pseudomonas toxin linked to IL4 </li></ul></ul><ul><ul><li>Chemotherapeutic drugs (Temozolomide) </li></ul></ul><ul><li>Other Studies </li></ul><ul><ul><li>Antisense Pharma </li></ul></ul><ul><ul><li>Oncolytic viruses (Crusade) </li></ul></ul><ul><ul><li>CED for Parkinson’s disease </li></ul></ul>
CED of Pseudomonas Exotoxin (NeoPharm) IL13 receptor expressed only on tumor cells Post resection – Peri-tumoral CED
CED of Intra-Tumoral TransMid (Diphtheria Toxin/Transferrin) (KS Biomedix, Xenova) Tf Receptor expressed only on tumor cells Intra-Tumoral CED
Research Goals to Improve CED <ul><li>Optimizing convection: </li></ul><ul><li>Better distribution = Better response </li></ul><ul><li>(Optimal infusate) </li></ul><ul><li>Imaging the convective process </li></ul><ul><li>Simulation of convection (Pre-treatment) </li></ul>
How Can We Enhance Drug Convectibility? <ul><li>Several parameters were evaluated: </li></ul><ul><ul><li>Capillarity </li></ul></ul><ul><ul><li>Polarity (considered by some) </li></ul></ul><ul><ul><li>Density </li></ul></ul><ul><ul><li>Molecular Wt (considered to have a limit) </li></ul></ul><ul><ul><li>Viscosity </li></ul></ul><ul><ul><li>Membrane interaction (?) </li></ul></ul><ul><ul><li>LogP/LogD (partitioning coefficient, distribution coefficient) </li></ul></ul><ul><ul><li>Diffusibility </li></ul></ul>
Viscosity <ul><li>Linear correlation found between viscosity, volume of convection, and the incidence of backflow. </li></ul>Low Intermediate High
Volume of convection for various drugs as a function of their viscosity <ul><li>Viscosity can be readily increased by simple measures </li></ul><ul><li>(added sugars, albumin, etc.) </li></ul>
Imaging Convection <ul><li>Efficacy and safety guidelines </li></ul><ul><li>Convection volume can be reliably predicted by mixture of Gd (1:70 concentration) in the infusate </li></ul>Infusate mixed with Evans Blue/ Blue bovine serum Albumin (40Kd) R 2 =0.95, p<0.0001
CED of Nano Particles (Iron Oxide) <ul><li>Use of particles that can be imaged by MRI (i.e., Ferromagnetic particles coated with drugs). </li></ul>Collaboration – S. Margol Bar Ilan University
Prediction of cytotoxicity <ul><li>Cytotoxic drugs – correlation between early DWMRI changes and later observed changes (anti-tumor, local toxicity) on T1 MRI </li></ul><ul><li>Toxic complications – early prediction </li></ul>T1 DWMRI T1 2 Weeks post treatment 6 Weeks post treatment
Simulation of CED <ul><li>Measurement of multiple imaging variables before treatment. </li></ul><ul><li>Simulate the convective process for individual patients as a function of location of catheters, flow rates, etc. </li></ul><ul><li>Simulate and predict potential toxicity (mostly from backflow) </li></ul>
Simulation result displayed as green overlay over an anatomical T1 scan. Simulation result overlaid over segmented gadolinium infusion.
Future Studies <ul><li>Mandatory to use tracers mixed with the convected infusate </li></ul><ul><li>Verfication of the simulation models </li></ul><ul><li>Enhancing predictive value </li></ul><ul><li>Integrating advanced imaging modalities </li></ul><ul><li>Upcoming CED study of Temozolomide </li></ul>
Possible Applications of CED <ul><li>Neoplastic diseases </li></ul><ul><li>Degenerative brain diseases </li></ul><ul><ul><li>Parkinson’s disease </li></ul></ul><ul><ul><li>Alzheimer </li></ul></ul><ul><li>Metabolic and genetic disorders </li></ul><ul><li>Extracranial indications </li></ul>
Acknowledgements <ul><li>Collaborative work of Neurosurgery (Tel Aviv Medical Center) and Advanced Technology Center, Sheba Medical Center (Yael Mardor). </li></ul><ul><li>BrainLAB </li></ul><ul><li>Therataxis (Raghu Raghavan) </li></ul><ul><li>Clinical Collaborators (Munich) </li></ul><ul><li>Pharma Companies </li></ul>