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  • Malignant gliomas are the most common primary brain tumor, accounting for slightly more than half of the estimated 35,000 primary benign and malignant brain tumors diagnosed in 2000. More than 80% of malignant gliomas are WHO Grade III (anaplastic astrocytoma) and Grade IV (glioblastoma multiforme) tumors. The majority of the 13,000 deaths annually attributed to primary malignant brain tumors are due to malignant gliomas.
  • The National Comprehensive Cancer Network Guidelines (2000) recommend maximal surgical resection followed by radiotherapy with or without chemotherapy as the current standard of care. The most widely studied agent is carmustine (BCNU).
  • The treatment for this disease has evolved over time. A great advance in median survival was made with the addition of radiotherapy to surgical resection. The addition of intravenous BCNU, unfortunately, added less than a month to the median survival. BCNU has been shown to have activity against these tumors in vitro; several reasons exist to explain why use of systemic BCNU has not resulted in greater gains.
  • The treatment for this disease has evolved over time. A great advance in median survival was made with the addition of radiotherapy to surgical resection. The addition of intravenous BCNU, unfortunately, added less than a month to the median survival. BCNU has been shown to have activity against these tumors in vitro; several reasons exist to explain why use of systemic BCNU has not resulted in greater gains.
  • Although BCNU has been shown to have activity against malignant gliomas in vitro, the survival benefit seen is, at most, one month. The reasons for this are varied but are certainly related to the limitations of providing a systemic therapy for a predominantly local disease. BCNU is rapidly cleared, thereby limiting tumor cell exposure to a cytotoxic agent. Additionally, the levels needed systemically to allow adequate levels in the CNS are prohibitive, resulting in more significant myelosuppression, the primary toxicity of BCNU.
    These limitations led to development of a local drug delivery system incorporating BCNU, the GLIADEL® Wafer.
  • The GLIADEL® Wafer is a copolymer comprised of carboxyphenoxypropane and sebacic acid in a 20:80 ratio. The polyanhydride bonds break down in an aqueous environment allowing controlled release of BCNU over a 2-3 week period. Each wafer contains 7.7 mg of BCNU; up to 8 wafers are implanted into the resection cavity for a total dose of 61.6 mg of BCNU.
    Local delivery of BCNU avoids the systemic toxicity associated with BCNU while delivering high BCNU doses to the tumor cavity. GLIADEL ® Wafer has been shown to be safe and effective in the setting of resection for recurrent glioblastoma multiforme.
  • In the same trial, the 6-month survival benefit in the GBM subgroup was significant. The product was well-tolerated in this trial and, based upon these data, the product was approved for use in the recurrent setting in 1996.
  • Given that malignant gliomas are a relatively uncommon disease, the clinical experience with GLIADEL® Wafer to date is significant. Unlike other chemotherapeutic agents sometimes used in this disease, the clinical benefit of GLIADEL® Wafer is supported by more than one randomized, double-blind, placebo-controlled trial.. In the more than 6000 patients who have been treated with the wafer to date, and with attention to specific issues in the peri-operative period, adverse events are uncommon.
  • Even though the Valtonen trial was a small study, the results of this 32 patient trial strongly suggested a survival benefit in patients undergoing initial surgical resection. In order to confirm these results, and to respond to a request by the FDA, a larger trial was initiated. This also provided an opportunity for the following: 1) to fully define the safety profile of the GLIADEL® Wafer, particularly as it relates to the use of external beam radiotherapy following implantation of the wafer; 2) to establish whether a survival benefit was accompanied by a slower deterioration in patients’ functional status as measured by KPS and neuroperformance measures; and 3) to determine time-to-progression.
  • ppt

    1. 1. 1 GLIADEL® WAFER sNDA 20-637s Guilford Pharmaceuticals Inc. Baltimore, Maryland
    2. 2. 2 GLIADEL® Wafer Indication GLIADEL® is indicated for use as an adjunct to surgery to prolong survival in patients with recurrent glioblastoma multiforme for whom surgical resection is indicated.
    3. 3. 3 Clinical Trials: Recurrent Malignant Glioma 632TOTAL Treatment Protocol349Study 9501 Multicenter, randomized, double-blind, placebo-controlled Phase III 222Study 8802 Multicenter, open-label Phase III40Study 9115 Multicenter, open-label, dose escalation Phase I/II 21Study 8701 Type of Study Patients Enrolled
    4. 4. 4 Clinical Trials: Newly Diagnosed Malignant Glioma 294TOTAL Multicenter, randomized, double-blind, placebo-controlled Phase III 240Study T-301 Multicenter, randomized, double-blind, placebo-controlled Phase III 32Study 0190 Multicenter, open-label Phase I/II22Study 9003 Type of Study Patients Enrolled
    5. 5. 5 GLIADEL® Approvals (1996-2000) Newly Diagnosed and Recurrent: Canada Recurrent: France Argentina Austria Brazil Chile Columbia Germany Greece Hong Kong Israel Ireland Luxembourg Malaysia The Netherlands New Zealand Peru Portugal Singapore South Africa South Korea Spain United Kingdom Uruguay
    6. 6. 6 Phase III Multicenter Trials of GLIADEL® Wafer in Newly-diagnosed Malignant Glioma 0190 Trial: Interstitial Chemotherapy for Malignant Glioma: A Phase III Placebo-controlled Study to Examine the Safety and Efficacy of GLIADEL® Placed at the Time of First Surgery T-301 Trial: A Phase III, Multicenter, Randomized Double-Blind, Placebo-Controlled Trial of Polifeprosan 20 with Carmustine 3.85% Implant in Patients Undergoing Initial Surgery for Newly- Diagnosed Malignant Glioma
    7. 7. 7 GLIADEL® Wafer Proposed Indication GLIADEL® Wafer is indicated for use as a treatment to significantly prolong survival and maintain overall function (as measured by preservation of Karnofsky Performance Status) and neurological function in patients with malignant glioma undergoing primary and/or recurrent surgical resection.
    8. 8. 8 Agenda Introductions Louise Peltier, Senior Director, Regulatory Affairs, Guilford Pharmaceuticals Inc. Overview of Primary Malignant Glioma: Clinical Features and Treatment Allan Hamilton, M.D., Professor and Chairman, Department of Neurosurgery, University of Arizona School of Medicine Phase III Trials (T-301and 0190) Dana Hilt, M.D., Vice President of Clinical Research, Guilford Pharmaceuticals Inc. Statistical Analytic Methods Steven Piantadosi, M.D., Ph.D., Professor and Director, Oncology Biostatistics, Johns Hopkins University School of Medicine Phase III Trial (T-301) Efficacy and Safety Results Dana Hilt, M.D., Vice President of Clinical Research, Guilford Pharmaceuticals Inc.
    9. 9. 9 Guilford Invited Guests Henry Brem, M.D. Harvey Cushing Professor of Neurosurgery and Oncology Chairman, Department of Neurosurgery Johns Hopkins School of Medicine Henry Friedman, M.D. Professor and Director, Neuro-oncology Duke University School of Medicine Janet Wittes, Ph.D. President Statistics Collaborative
    10. 10. 10 Allan Hamilton, M.D. Professor and Chairman, Department of Neurosurgery, University of Arizona School of Medicine Overview of Primary Malignant Glioma: Clinical Features and Treatment
    11. 11. 11 Primary Malignant Glioma Incidence Approximately 16,500 new cases annually Glioblastoma multiforme accounts for approximately 75% of patients More than 13,000 deaths annually Central Brain Tumor Registry US Statistical Report 1992-1997
    12. 12. 12 Primary Malignant Glioma Presentation: headache, seizure or new neurological deficit. Average age at onset 55 – 60 years. Imaging (CT or MRI) is key in provisional diagnosis. During surgical resection a provisional or tentative diagnosis is made based on intra-operative pathology. Final pathologic diagnosis requires fixed tissue examination.
    13. 13. 13 Primary Malignant Glioma Treatment Maximal surgical resection followed by radiation therapy +/- chemotherapy1 Complete surgical resection of high grade tumor difficult Majority of tumors recur within 2 cm of original resection site2 Carmustine (BCNU) is the most widely studied chemotherapeutic agent 1 Nat’l Comprehensive Cancer Network Guidelines 2000 (NCCN) 2 Hochberg FH, et.al. Assumptions in the radiotherapy of glioblastoma. Neurology 1980;30:907-11
    14. 14. 14 McDonald JD, Rosenblum ML: In: Rengachary SS, Wilkins RH, eds. Principles of Neurosurgery. St Louis, MO: Mosby-Wolfe; 1994: chap 26. 0 2 4 6 8 10 12 Surgery Only Surgery + Radiotherapy Surgery + Radiotherapy + Chemotherapy 9.25 4 10 MedianSurvival(Months) Glioblastoma: Treatment Outcome
    15. 15. 15 Natural History of High Grade Glioma: Effects of PCV Chemotherapy Randomized, prospective study of surgical resection and radiotherapy (RT) vs. surgical resection, radiotherapy, and PCV chemotherapy (RT-PCV) in high grade glioma patients MRC, 15 centers in the UK 674 patients enrolled -RT (n=339) -RT-PCV (n=335) GBM Histology – 76% * MRC Brain Tumour Working Party: J Clin Oncol 19(2): 509-518 (2001).
    16. 16. 16 Natural History of High Grade Glioma: Effects of PCV Chemotherapy 0 2 4 6 8 10 12 MedianSurvival(Months) Surgery + Radiotherapy 9.5 Surgery + Radiotherapy + PCV Chemotherapy 10 MRC Brain Tumour Working Party: J Clin Oncol 19(2): 509-518 (2001). p = 0.50
    17. 17. 17 Prognostic Factors: Primary Malignant Glioma Prognostic Factors shown to influence survival Age (>60 years) Karnofsky Performance Score (<70) Tumor histology Proposed Prognostic Factors Size of tumor Extent of resection Burger PC, et al., Cancer 59:1617-1625, 1987 Ammirati M, et al., Neurosurgery 21:201-206, 1987
    18. 18. 18 Limitations of Systemic BCNU Rapidly cleared with t½ ~ 15 minutes1 Limits exposure of tumor cells to BCNU High doses required for adequate CNS levels Achievable dose limited by systemic toxicity 1 Wang CH, et.al. The delivery of BCNU to brain tumors. J Control Release 1999;61:21-41
    19. 19. 19 The GLIADEL® Wafer Biodegradable polyanhydride copolymer containing 7.7 mg BCNU/wafer Circumvents limitations of systemic BCNU Local delivery of BCNU over 2-3 weeks at high tissue levels No detectable systemic BCNU levels No systemic BCNU toxicity No additional surgical intervention required
    20. 20. 20 Phase III Trial of GLIADEL® Wafer in Newly Diagnosed Malignant Glioma
    21. 21. 21 Brem H, Plantations S, Burger PC, et al. Placebo-controlled trial of safety and efficacy of intraoperative controlled delivery by biodegradable polymers of chemotherapy for recurrent gliomas. Lancet. 1995;345:1008-1012. 6 Month Survival Recurrent GBM (8802) 90 80 70 60 50 40 30 20 10 0 0 1 2 3 4 5 6 Months From Implant Surgery SurvivalRate(%) GLIADEL® 100 Placebo Hazard Ratio: .57 95% CI: 0.36 – 0.89 Risk Reduction: 43% P = 0.02
    22. 22. 22 Overall Survival (ITT) Primary Malignant Glioma (0190) 0 10 20 30 40 50 60 70 80 90 100 0 3 6 9 12 15 18 21 24 Months from Implant Surgery SurvivalRate(%) GLIADEL® Placebo Median Survival (months) Gliadel® 13.4 Placebo 9.2 Hazard Ratio: 0.37 95% CI: 0.17– 0.82 Risk Reduction: 63% P = 0.01
    23. 23. 23 Clinical Experience To Date More than 6000 patients have been treated with GLIADEL® Wafer to date Well tolerated with attention to: Post-operative management of cerebral edema Water tight dural closure Post-operative anticonvulsant medication
    24. 24. 24 Rationale for Phase III Study T-301 Confirm safety & efficacy results of 0190 Study Fully define safety profile in primary surgery Determine extent of clinical benefit on: Survival Maintenance of KPS status and neuroperformance Time-to-progression
    25. 25. 25 Phase III Multicenter Trials of GLIADEL® Wafer in Newly-Diagnosed Malignant Glioma Dana C. Hilt, M.D. Vice President of Clinical Research, Guilford Pharmaceuticals Inc.
    26. 26. 26 Phase III Multicenter Trials of GLIADEL® Wafer in Newly-diagnosed Malignant Glioma 0190 Trial: Interstitial Chemotherapy for Malignant Glioma: A Phase III Placebo-controlled Study to Examine the Safety and Efficacy of GLIADEL® Placed at the Time of First Surgery T-301 Trial: A Phase III, Multicenter, Randomized Double-Blind, Placebo-Controlled Trial of Polifeprosan 20 with Carmustine 3.85% Implant in Patients Undergoing Initial Surgery for Newly- Diagnosed Malignant Glioma
    27. 27. 27 Study 0190: Trial Design Primary malignant glioma patients Surgery Placebo or Gliadel® Wafers Radiotherapy Study was conducted at four centers in Finland and Norway Primary efficacy endpoints 12-Month survival
    28. 28. 28 Study 0190: Baseline Patient Characteristics Characteristic Median age (years) Median Mini Mental score Median Karnofsky Performance score Median No. of wafers GBM tumor histology GLIADEL® Wafers (n=16) 56 24.5 75 8 11 Placebo Wafers (n=16) 54 24.5 90 8 16
    29. 29. 29 Overall Survival (ITT) Primary Malignant Glioma (0190) 0 10 20 30 40 50 60 70 80 90 100 0 3 6 9 12 15 18 21 24 Months from Implant Surgery SurvivalRate(%) GLIADEL® Placebo Median Survival (months) Gliadel® 13.4 Placebo 9.2 Hazard Ratio: 0.37 95% CI: 0.17– 0.82 Risk Reduction: 63% P = 0.01
    30. 30. 30 Study 0190: Overall Survival Adjusted for Prognostic Factors - GBM Patients1 Hazard Ratio 95% CI P- Value GLIADEL® vs. Placebo 0. 27 0.10 - 0.71 0.008 KPS 0.96 0.93 – 0.99 0.02 Age 1.08 1.01 - 1.14 0.02 1 Valtonen et al., Neurosurgery 41(1): 44-49, 1997
    31. 31. 31 Study 0190: Efficacy Conclusions1 GLIADEL® , in conjunction with surgery and radiotherapy, decreases the risk of death by 63% in patients with newly diagnosed malignant glioma Trial was positive in overall (ITT) population Trial was positive in GBM patients when accounting for all major prognostic factors 1 Valtonen et al., Neurosurgery 41(1): 44-49, 1997
    32. 32. 32 Study T-301: Objectives To determine the efficacy and safety of (GLIADEL® Wafer) implants plus surgery and limited field radiation therapy compared to placebo implants plus surgery and limited field radiation in patients undergoing initial surgery for newly-diagnosed malignant glioma.
    33. 33. 33 Study T-301: Trial Design Randomized, double-blind, placebo- controlled study Primary Efficacy Endpoint Overall Survival - All Patients Randomized (ITT) by the Kaplan-Meier method 12 months after final patient was enrolled FDA fully informed prospectively of study design and analysis
    34. 34. 34 Study T-301: Trial Design Secondary Efficacy Endpoints Overall Survival - GBM Patients Karnofsky Performance Decline, Neuroperformance Decline, Progression-Free Survival, and Quality of Life Evaluation
    35. 35. 35 A total of 42 sites in 14 countries participated in the study Australia: 3 sites Italy: 3 sites Austria: 1 site The Netherlands: 2 sites Belgium: 2 sites New Zealand: 1 site France: 7 sites Spain: 3 sites Germany: 5 sites Switzerland: 2 sites Greece: 1 site United Kingdom: 4 sites Israel: 3 sites United States: 5 sites Study T-301: Clinical Sites
    36. 36. 36 Study T-301: Inclusion Criteria 1. Male or female, aged between 18 and 65 years; 2. Radiographic evidence on cranial MRI of a single contrast enhancing unilateral supratentorial cerebral‑ tumor; 3. Surgical treatment within two weeks of the baseline MRI scan indicated; 4. Karnofsky Performance Score of 60 or higher; 5. No previous treatment for suspected primary malignant glioma
    37. 37. 37 Study T-301: Baseline Characteristics CHARACTERISTIC Age (years) Mean Range Sex Male Female Tumor Type Anaplastic astrocytoma Anaplastic oligodendroglioma Anaplastic oligoastrocytoma Glioblastoma multiforme Metastasis/Brain Metastasis Other 53.6 30-67 84 36 1 4 3 106 1 5 52.6 21-72 76 44 1 5 7 101 2 4 GLIADEL ® WAFER ( n = 120) (n = 120) PLACEBO WAFER
    38. 38. 38 Study T-301: Baseline Characteristics PLACEBO WAFER (n=120) GLIADEL® WAFER (n=120) KARNOFSKY Performance Status 60 70 80 85 90 95 100 16 21 25 2 31 0 25 16 17 24 0 40 1 22 Karnofsky Score
    39. 39. 39 Study T-301: Tumor Size* 34.060.0Median (cm3 ) 50.866.8Mean (cm3 ) 7683Number reported Placebo Wafer (n=120) GLIADEL® Wafer (n=120) * Comparability at baseline; p-value < 0.05
    40. 40. 40 Statistical Methodology Steven Piantadosi, M.D., Ph.D. Professor and Director, Oncology Biostatistics Johns Hopkins University School of Medicine
    41. 41. 41 Outline Key design features to reduce bias Pre-specification of analysis Use of stratification Control of prognostic factors All the analyses are pre-specified per protocol
    42. 42. 42 Features to Eliminate Bias in T-301 Study Placebo-controlled, double-masked Stratified blocked randomization within center Study also blocked by country because center is nested within country Study not blocked by histological type, age, or Karnofsky Performance Score (FDA review Page 37) Pre-specified analyses
    43. 43. 43 Key Pre-specified Features in SAP Overall Survival estimated by Kaplan-Meier method Treatment differences assessed by logrank test and proportional hazards model Pre-specified covariates: Age Karnofsky performance score Tumor type Country of treatment
    44. 44. 44 Approach to Analysis All analyses were performed by Steven Piantadosi, M.D., Ph.D. Review of protocol and SAP before acquiring the data from the sponsor No contact with sponsor before discussion of study results Initial analysis used stratified (by country) log rank test and countries with small numbers of patients were pooled together No post-hoc analyses conducted
    45. 45. 45 Stratified Analysis The T-301 study was conducted using stratified blocked randomization by clinical center, as is typical with such trials. This explicitly acknowledges center as a source of variation, and requires the use of a statistical test that accounts for the stratification, i.e, the stratified logrank test.
    46. 46. 46 Stratification of Clinical Trials Treating known sources of variability as unknown sources of noise is to be avoided Simon R (1980), Cancer Treat Rep 64: 405-410 Fleiss JL (1986), Controlled Clinical Trials 7:267-275 Localio AR (2001), Ann Int Med 135:112-123 Over stratification in the extreme becomes equivalent to no stratification at all Simon R (1980), Cancer Treat Rep 64: 405-410 Simon R (1982), Br J Clin Pharm 14:473-482 Limited stratification is generally desirable to increase the sensitivity of the trial, over-stratification can be detrimental to a trial Simon R (1982), Br J Clin Pharm 14:473-482
    47. 47. 47 Stratification by Center vs. Country Stratified randomization within center also creates stratification by country Treatment practices are likely to vary more between countries than within centers within a country The protocol and SAP pre-defined country as an effect that might need to be controlled (covariate or stratification factor) Stratification by 38 centers is almost equivalent to not controlling for center or country, because the sizes of the strata are too small Stratification by country (pooling countries with a small number of patients) appropriately controls this extraneous variation
    48. 48. 48 Effect of Country-of-Treatment on Survival: Placebo-Group (T-301)
    49. 49. Overall Survival T-301 8802 0190
    50. 50. 50 Assessing the Influence of Prognostic Factors on Survival A priori identification of prognostic factors Univariate regression was first used to identify the important prognostic factors (defined as p-value ≤ 0.05) In order to account for the effects of these significant prognostic factors on survival, a backward elimination method (stepdown method) of multiple regression using the proportional hazard model was used FDA analysis on Page 39 is misleading
    51. 51. 51 Univariable Prognostic Factors1 Prognostic Factor Karnofsky Score <70 vs. KPS >70 Age >60 vs. <60 Number of Wafers implanted 8 vs. <8 GBM Patients vs. Non-GBM Patients Hazard Ratio 1.9 1.6 1.4 1.8 95% CI 1.4 – 2.6 1.2 – 2.2 1.0 – 1.9 1.1 – 2.9 P-value <0.0001 0.03 0.02 0.02 1 Cox Model stratified by country with single covariates
    52. 52. 52 Multivariable Proportional Hazards Analysis (ITT) 95% CIPrognostic Factor Hazard Ratio1 Lower Upper P-Value GLIADEL® vs. Placebo 0.72 0.53 0.98 0.03 1.93 1.37 2.72 0.0002 1.73 1.24 2.42 0.001 1.44 0.84 2.47 0.18 1 Proportional Hazard Model stratified by country Karnofsky Score <70 vs. KPS >70 Age >60 vs. <60 GBM Patients vs Non-GBM Patients
    53. 53. 53 Summary of Statistical Methodology T-301 provides, by design, unbiased, precise estimates of treatment effect. It is adequate and well controlled All of the analyses presented are rigorously prespecified The use of stratification by the sponsor is correct and consistent with standard statistical practice The GLIADEL® treatment effect (risk reduction of 30%) is clinically significant and convincingly independent of prognostic factors
    54. 54. 54 Phase III Multicenter Trials of GLIADEL® Wafer in Newly-Diagnosed Malignant Glioma Dana C. Hilt, M.D. Vice President of Clinical Research, Guilford Pharmaceuticals Inc.
    55. 55. 55 Study T-301: Overall Survival Analysis (ITT) Hazard Ratio: 0.71 95% CI: 0.52 – 0.96 Risk Reduction: 29% P = 0.031 Months from Implant Surgery Placebo GLIADEL® SurvivalRate 100 90 80 70 60 50 40 30 20 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 10 Median Survival (months) Gliadel® 13.9 Placebo 11.6 1 Stratified by country
    56. 56. 56 Overall Survival – Adjusted for Prognostic Factors1 – (ITT) Hazard Ratio 95% CI P-Value2 GLIADEL® vs. Placebo 0.72 0.53 - 0.98 0.03 KPS <70 vs. KPS >70 1.93 1.37 - 2.72 0.0002 Age >60 vs. <60 1.73 1.24 - 2.42 0.001 1 Adjusted for age, tumor type, and Karnofsky Score 2 Stratified by country
    57. 57. 57 Study T-301: Conclusion GLIADEL® Wafer administration produces a clinically significant increase in survival (risk reduction = 29%) in malignant glioma patients undergoing primary surgery. Treatment effect is maintained after accounting for the effect of prognostic factors (risk reduction = 28%)
    58. 58. 58 Study T-301: Reoperation for Disease Progression A higher percentage of patients had reoperation for disease progression than originally projected. Reoperation may have confounded the primary endpoint of survival. A prespecified sensitivity analysis was performed to account for the results of this event by censoring patients alive at the time of reoperation.
    59. 59. 59 Study T-301: Overall Survival Analysis - Reoperation for Disease Progression (ITT) Months from Implant Surgery SurvivalRate GLIADEL® Placebo 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 10 20 30 40 50 60 70 80 100 90 Median Survival (months) Gliadel® 14.8 Placebo 11.4 Hazard Ratio: 0.64 95% CI: 0.45 – 0.92 Risk Reduction: 36% P = 0.011 1 Stratified by country
    60. 60. 60 Study T-301: Secondary Efficacy Endpoints Secondary Efficacy Endpoints Overall Survival - GBM patients Karnofsky Performance Decline, Neuroperformance Decline, Progression-Free Survival, and Quality of Life Evaluation
    61. 61. 61 Study T-301: Overall Survival (GBM Patients) GLIADEL® Placebo 100 90 80 70 60 50 40 30 20 10 0 0 642 8 141210 16 222018 24 SurvivalRate Months from Implant Surgery Median Survival (months) Gliadel® 13.5 Placebo 11.4 Hazard Ratio: 0.76 95% CI: 0.55 – 1.05 Risk Reduction: 24% P = 0.101 1 Stratified by country
    62. 62. 62 Study T-301: Overall Survival Adjusted for Prognostic Factors1 (GBM Patients) 1 Adjusted for age and Karnofsky Score 2 Cox Proportional Hazard model stratified by country and number of wafers (<8,8) implanted Hazard Ratio 95% CI P-Value2 GLIADEL® vs. Placebo 0.69 0.49 - 0.97 0.04 KPS <70 vs. KPS >70 2.04 1.38 - 3.01 <0.001
    63. 63. 63 Study T-301: Karnofsky Performance Decline (ITT) 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 642 8 141210 16 222018 24 26 Months from Implant Surgery Proportion GLIADEL® Placebo Median Deterioration (months) Gliadel® 11.9 Placebo 10.4 Hazard Ratio: 0.74 95% CI: 0.55 – 1.0 Risk Reduction: 26% P = 0.051 1 Stratified by country
    64. 64. 64 Study T-301: Neuroperformance Decline (ITT) Neuroperformance Measure Median Time without Deterioration (weeks) P Value1 Vital Signs Level of Consciousness Personality Speech Visual Status Fundus Cranial Nerves III, IV, VI Cranial Nerves, Other Motor Status Sensory Status Cerebellar Status 54.9 52.1 51.7 49.6 44.0 55.1 54.9 54.3 45.4 51.6 54.1 49.1 45.4 40.0 36.7 42.4 46.3 49.1 46.3 31.4 44.1 46.7 0.01 0.02 0.008 0.003 0.09 0.007 0.02 0.003 0.01 0.02 0.01 GLIADEL® Wafer(n=120) Placebo Wafer(n=120) 1 Stratified by Country
    65. 65. 65 Study T-301: Neuroperformance Decline in Speech (ITT) ProportionWithoutDecline 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Time to Deterioration (weeks) 0 10 20 30 40 50 60 70 80 90 100 110 120 GLIADEL® Placebo Median Deterioration (weeks) Gliadel® 49.6 Placebo 36.7 Hazard Ratio: 0.64 95% CI: 0.48 – 0.86 Risk Reduction: 36% P = 0.0031 1 Stratified by country
    66. 66. 66 Study T-301: Neuroperformance Decline in Cranial Nerves III, IV, VI (ITT) 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Time to Deterioration (weeks) 0 10 20 30 40 50 60 70 80 90 100 110 120 GLIADEL® Placebo Median Deterioration (weeks) Gliadel® 54.9 Placebo 49.1 Hazard Ratio: 0.68 95% CI: 0.50 – 0.93 Risk Reduction: 32% P = 0.021 ProportionWithoutDecline 1 Stratified by country
    67. 67. 67 Study T-301: Neuroperformance Decline in Motor Status (ITT) 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Time to Deterioration (weeks) 0 10 20 30 40 50 60 70 80 90 100 110 120 GLIADEL® Placebo Median Deterioration (weeks) Gliadel® 45.4 Placebo 31.4 Hazard Ratio: 0.69 95% CI: 0.51 – 0.92 Risk Reduction: 31% P = 0.011 ProportionWithoutDecline 1 Stratified by country
    68. 68. 68 Study T-301: Neuroperformance Decline in Cerebellar Status (ITT) 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Time to Deterioration (weeks) 0 10 20 30 40 50 60 70 80 90 100 110 120 GLIADEL® Placebo Median Deterioration (weeks) Gliadel® 54.1 Placebo 46.7 Hazard Ratio: 0.67 95% CI: 0.49 – 0.91 Risk Reduction: 33% P = 0.011 ProportionWithoutDecline 1 Stratified by country
    69. 69. 69 GLIADEL® Wafer Safety Review of safety in newly diagnosed malignant glioma
    70. 70. 70 Safety Summary GLIADEL® Wafer in Primary Surgery Intracranial hypertension 9.2% vs. 1.7%. However, no difference in brain edema. Intracranial hypertension was typically observed late, at the time of tumor recurrence, and was not likely associated with GLIADEL® use. CSF leak (5% vs. 0.8%) was more common in GLIADEL® - treated patients. However, intracranial infections and other healing abnormalities were not increased. Convulsions are not more common in GLIADEL® -treated vs. placebo-treated patients.
    71. 71. 71 Safety Summary GLIADEL® Wafer in Primary Surgery Careful monitoring of GLIADEL® -treated patients for cerebral edema/intracranial hypertension with consequent steroid use is warranted. CSF leak, though uncommon, may be more frequent in GLIADEL® -treated patients. Attention to a water tight dural closure and local wound care is indicated. The safety profile of GLIADEL® appears more benign in the primary surgery setting vs. recurrent disease.
    72. 72. 72 Study T-301: Neurologic Adverse Events Occurring in >5% of Patients Abnormal gait Amnesia Anxiety Aphasia Ataxia Brain edema Coma Confusion Convulsion Depression Dizziness Facial paralysis Grand mal convulsion Hallucinations 6 (5.0) 11 (9.2) 8 (6.7) 21 (17.5) 7 (5.8) 27 (22.5) 5 (4.2) 28 (23.3) 40 (33.3) 19 (15.8) 6 (5.0) 8 (6.7) 6 (5.0) 6 (5.0) 6 (5.0) 12 (10.0) 5 (4.2) 22 (18.3) 5 (4.2) 23 (19.2) 6 (5.0) 25 (20.8) 45 (37.5) 12 (10.0) 11 (9.2) 5 (4.2) 5 (4.2) 4 (3.3) Adverse Event PLACEBO Wafer (n=120) n (%) GLIADEL® Wafer (n=120) n (%)
    73. 73. 73 Study T-301: Neurologic Adverse Events Occurring in >5% of Patients Hemiplegia Hypesthesia Hypokinesia Incoordination Insomnia Intracranial hypertension Neuropathy Paresthesia Personality disorder Somnolence Speech disorder Thinking abnormal Tremor 49 (40.8) 7 (5.8) 2 (1.7) 3 (2.5) 6 (5.0) 11 (9.2) 8 (6.7) 7 (5.8) 10 (8.3) 13 (10.8) 13 (10.8) 7 (5.8) 6 (5.0) 53 (44.2) 6 (5.0) 8 (6.7) 8 (6.7) 7 (5.8) 2 (1.7) 12 (10.0) 10 (8.3) 9 (7.5) 18 (15.0) 10 (8.3) 10 (8.3) 8 (6.7) Adverse Event PLACEBO Wafer (n=120) n (%) GLIADEL® Wafer (n=120) n (%)
    74. 74. 74 Convulsions (T-301) 5 (4.2)6 (5.0)Grand Mal convulsions 24 (20)14 (11.7)Convulsions – severe 45 (37.5)40 (33.3)Number of patients (%) Placebo Wafer (n=120) GLIADEL® Wafer (n=120) Time-to-First Seizure did not differ in the two treatment groups. 5 (4.2)3 (2.5)Convulsions (< 5 days)
    75. 75. 75 1-6812-60Range for duration (days) 1015Median duration (days) 6 (5.0)5 (4.2)Number of patients (%) Placebo Wafer (n=120) GLIADEL® Wafer (n=120) Healing Abnormality: Fluid, CSF or Subdural Collections (T-301)
    76. 76. 76 32-211Range for duration (days) 39Median duration (days) 1 (0.8)6 (5.0)Number of patients (%) Placebo Wafer (n=120) GLIADEL® Wafer (n=120) Healing Abnormality: CSF Leak (T-301)
    77. 77. 77 2-1722-281Range for duration (days) 610Median duration (days) 6 (5.0)6 (5.0)Number of patients (%) Placebo Wafer (n=120) GLIADEL® Wafer (n=120) Healing Abnormality: Wound Dehiscence, Breakdown or Poor Healing (T-301)
    78. 78. 78 2-263-30Range for duration (days) 103Median duration (days) 5 (4.2)4 (3.3)Number of patients (%) Placebo Wafer (n=120) GLIADEL® Wafer (n=120) Healing Abnormality: Subgaleal or Wound Effusion (T-301)
    79. 79. 79 Study T-301: Intracranial Infections GLIADEL® n (%) Placebo n (%) Abscess 4 (3) 5 (4) Meningitis 2 (2) 2 (2) Total 6 (5) 7 (6)
    80. 80. 80 Post-operative Surgical Complications: Comparison of T-301 to Published Series The frequency of post-operative seizures, infections and hemorrhage/stroke are similar in the GLIADEL® and placebo groups in the T- 301 study. Is the placebo wafer group a benign control as it involves the implantation of a placebo wafer?
    81. 81. 81 Comparison of Post-operative Surgical Infections Author/Study # of Patients Disease Infection Brell et al1 200 Glioma/ Metastasis 5.5% Sawaya et al2 327 Glioma 1.75% Kourinek et al3 2944 Craniotomy 4% Tenney et al4 251 Tumor 6% T-301- GLIADEL 120 Glioma 5% T-301- Placebo 120 Glioma 6% 1 Brell et al., (2000) Acta Neurochir (Wien) 142:739-50 2 Sawaya et al., (1998) Neurosurgery 42:1044-56 3 Kourinek et al., (1997) Neurosurgery 41:1073-81 4 Tenney et al, (1985) J Neurosurg 62:243-7
    82. 82. 82 Comparison of Post-operative Surgical Seizures Author/Study # of Patients Disease Seizures Cabantog et al1 207 GBM/AA 1% Brell et al2 200 Glioma/ Metastasis 4% Sawaya et al3 327 Glioma 2.5% Pace et al4 119 Glioma 36-83% Tandon et al5 200 Glioma 51% Moots et al6 65 Glioma 32% T-301- GLIADEL 120 Glioma 33% T-301- Placebo 120 Glioma 37% 1 Cabantog et al., (1994) Can J Neurol Sci 32:213-18 2 Brell et al., (2000) Arta Neurochir 142:739-50 3 Sawaya et al., (1998) Neurosurgery 42:1044-56 4 Pace et al., (1998) J Exp Clin Canc Rsh 17:479-82 5 Tandon et al., (2001) Neurology India 49:55-9 6 Moots et al., (1995) Arch Neurol 52:717-24
    83. 83. 83 Comparison of Post-operative Surgical Hemorrhage/Stroke Author/Study # of Patients Disease Hemorrhage/ Stroke Cabantog et al1 207 GBM/AA 1% Brell et al2 200 Glioma/ Metastasis 4.5% Sawaya et al3 327 Glioma 2.0% T-301- GLIADEL4 120 Glioma 7.5% T-301- Placebo4 120 Glioma 4.8% 1 Cabantog et al., (1994) Can J Neurol Sci 32:213-18 2 Brell et al., (2000) Acta Neurochir (Wien) 142:739-50 3 Sawaya et al., (1998) Neurosurgery 42:1044-56 4 Events reported within 30 days of surgery
    84. 84. 84 Post-Operative Surgical Complications: Conclusion The frequency of seizures, infections, and hemorrhage/ stroke after GLIADEL® Wafer implantation is similar to that observed after craniotomy for glioma
    85. 85. 85 GLIADEL® Wafer in Primary Malignant Glioma: Summary of Benefits and Risks No evidence of earlier onset of seizures or increased frequency of seizures in primary malignant glioma patients CSF Leak was more common with GLIADEL® treatment No evidence for increase in intracranial infections or other healing abnormalities
    86. 86. 86 GLIADEL® Wafer in Primary Malignant Glioma: Summary of Benefits and Risks Gliadel® Wafer studies expanded to newly diagnosed malignant glioma Statistically significant and clinically meaningful increase in survival compared to placebo wafers Delayed time to overall function (KPS) and neurological decline (10/11 measures) S
    87. 87. 87 Consistency of GLIADEL® Wafer Phase III Trial Results Consistent efficacy and safety profile between two prospective randomized, placebo-controlled, double-blind Phase III clinical studies in the primary surgery for malignant glioma
    88. 88. 88 Summary of Efficacy Results from Randomized Controlled Trials of GLIADEL® Wafer (ITT) Study 8802 T-301 0190 Hazard Ratio 0.69 0.71 0.37 95% CI 0.47-1.02 0.52-0.96 0.17-0.82 P-value 0.06 0.031 0.01 1 Stratified by country
    89. 89. 89 Summary of Efficacy Results from Randomized Controlled Trials of GLIADEL® Wafer (GBM) 1 Hazard ratio adjusted for prognostic factors. 2 Stratified by country Study 8802 T-301 0190 Hazard Ratio1 0.57 0.72 0.21 95% CI 0.36-0.89 0.53-0.98 0.08-0.60 P-value 0.02 0.032 <0.01
    90. 90. 90 Summary of Benefits and Risks The benefit to risk ratio for GLIADEL® in patients with primary malignant glioma is favorable
    91. 91. 91 GLIADEL® Wafer Proposed Indication GLIADEL® Wafer is indicated for use as a treatment to significantly prolong survival and maintain overall function (as measured by preservation of Karnofsky Performance Status) and neurological function in patients with malignant glioma undergoing primary and/or recurrent surgical resection.

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