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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.

Transcript

  • 1. GLIADEL ® WAFER sNDA 20-637s Guilford Pharmaceuticals Inc. Baltimore, Maryland
  • 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. Clinical Trials: Recurrent Malignant Glioma 632 TOTAL Treatment Protocol 349 Study 9501 Multicenter, randomized, double-blind, placebo-controlled Phase III 222 Study 8802 Multicenter, open-label Phase III 40 Study 9115 Multicenter, open-label, dose escalation Phase I/II 21 Study 8701 Type of Study Patients Enrolled
  • 4. Clinical Trials: Newly Diagnosed Malignant Glioma 294 TOTAL Multicenter, randomized, double-blind, placebo-controlled Phase III 240 Study T-301 Multicenter, randomized, double-blind, placebo-controlled Phase III 32 Study 0190 Multicenter, open-label Phase I/II 22 Study 9003 Type of Study Patients Enrolled
  • 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. 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. 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. 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. 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. 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. 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. 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. Primary Malignant Glioma
    • Treatment
      • Maximal surgical resection followed by radiation therapy +/- chemotherapy 1
        • Complete surgical resection of high grade tumor difficult
        • Majority of tumors recur within 2 cm of original resection site 2
      • 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. Glioblastoma: Treatment Outcome 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 Median Survival (Months)
  • 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. Natural History of High Grade Glioma: Effects of PCV Chemotherapy MRC Brain Tumour Working Party: J Clin Oncol 19(2): 509-518 (2001). p = 0.50 0 2 4 6 8 10 12 Median Survival (Months) Surgery + Radiotherapy 9.5 Surgery + Radiotherapy + PCV Chemotherapy 10
  • 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. Limitations of Systemic BCNU
    • Rapidly cleared with t ½ ~ 15 minutes 1
      • 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. 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
      • N o additional surgical intervention required
  • 20. Phase III Trial of GLIADEL ® Wafer in Newly Diagnosed Malignant Glioma
  • 21. 6 Month Survival Recurrent GBM (8802) 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. 90 80 70 60 50 40 30 20 10 0 0 1 2 3 4 5 6 Months From Implant Surgery Survival Rate (%) GLIADEL ® 100 Placebo Hazard Ratio: .57 95% CI: 0.36 – 0.89 Risk Reduction: 43% P = 0.02
  • 22. Overall Survival (ITT) Primary Malignant Glioma (0190) Hazard Ratio: 0.37 95% CI: 0.17– 0.82 Risk Reduction: 63% P = 0.01 0 10 20 30 40 50 60 70 80 90 100 0 3 6 9 12 15 18 21 24 Months from Implant Surgery Survival Rate (%) GLIADEL ® Placebo Median Survival (months) Gliadel ® 13.4 Placebo 9.2
  • 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. 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. 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. 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. 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
      • 24-Month survival
  • 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. Overall Survival (ITT) Primary Malignant Glioma (0190) Hazard Ratio: 0.37 95% CI: 0.17– 0.82 Risk Reduction: 63% P = 0.01 0 10 20 30 40 50 60 70 80 90 100 0 3 6 9 12 15 18 21 24 Months from Implant Surgery Survival Rate (%) GLIADEL ® Placebo Median Survival (months) Gliadel ® 13.4 Placebo 9.2
  • 30. Study 0190: Overall Survival Adjusted for Prognostic Factors - GBM Patients 1 1 Valtonen et al., Neurosurgery 41(1): 44-49, 1997 0.02 0.93 – 0.99 0.96 KPS 1.08 0. 27 Hazard Ratio 1.01 - 1.14 0.10 - 0.71 95% CI 0.02 0.008 P-Value Age GLIADEL ® vs. Placebo
  • 31. Study 0190: Efficacy Conclusions 1
    • 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. 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. 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. 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. Study T-301: Clinical Sites 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
  • 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. Study T-301: Baseline Characteristics C HARACTERISTIC 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. 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. Study T-301: Tumor Size* * Comparability at baseline; p-value < 0.05 34.0 60.0 Median (cm 3 ) 50.8 66.8 Mean (cm 3 ) 76 83 Number reported Placebo Wafer (n=120) GLIADEL ® Wafer (n=120)
  • 40. Statistical Methodology
    • Steven Piantadosi, M.D., Ph.D.
    • Professor and Director, Oncology Biostatistics
    • Johns Hopkins University School of Medicine
  • 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. 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. 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. 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. 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. 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. 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. Effect of Country-of-Treatment on Survival: Placebo-Group (T-301)
  • 49. Overall Survival T-301 8802 0190
  • 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. Univariable Prognostic Factors 1 1 Cox Model stratified by country with single covariates 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
  • 52. Multivariable Proportional Hazards Analysis (ITT) 95% CI Prognostic Factor Hazard Ratio 1 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. 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. 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. Study T-301: Overall Survival Analysis (ITT) Hazard Ratio: 0.71 95% CI: 0.52 – 0.96 Risk Reduction: 29% P = 0.03 1 1 Stratified by country Months from Implant Surgery Placebo GLIADEL ® Survival Rate (%) 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
  • 56. Overall Survival – Adjusted for Prognostic Factors 1 – (ITT) 1 Adjusted for age, tumor type, and Karnofsky Score 2 Stratified by country 0.0002 1.37 - 2.72 1.93 KPS < 70 vs. KPS >70 1.73 0.72 Hazard Ratio 1.24 - 2.42 0.53 - 0.98 95% CI 0.001 0.03 P-Value 2 Age > 60 vs. <60 GLIADEL ® vs. Placebo
  • 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. 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. Study T-301: Overall Survival Analysis - Reoperation for Disease Progression (ITT) 1 Stratified by country Months from Implant Surgery Survival Rate (%) 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 = 0.01 1
  • 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. Study T-301: Overall Survival (GBM Patients) 1 Stratified by country GLIADEL ® Placebo 100 90 80 70 60 50 40 30 20 10 0 0 6 4 2 8 14 12 10 16 22 20 18 24 Survival Rate (%) 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 = 0.10 1
  • 62. Study T-301: Overall Survival Adjusted for Prognostic Factors 1 (GBM Patients) 1 Adjusted for age and Karnofsky Score 2 Cox Proportional Hazard model stratified by country and number of wafers (<8,8) implanted <0.001 1.38 - 3.01 2.04 KPS < 70 vs. KPS >70 0.69 Hazard Ratio 0.49 - 0.97 95% CI 0.04 P-Value 2 GLIADEL ® vs. Placebo
  • 63. Study T-301: Karnofsky Performance Decline (ITT) 1.0 1 Stratified by country 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 6 4 2 8 14 12 10 16 22 20 18 24 26 Months from Implant Surgery Proportion without Decline 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 = 0.05 1
  • 64. Study T-301: Neuroperformance Decline (ITT) 1 Stratified by Country Neuroperformance Measure Median Time without Deterioration (weeks) P Value 1 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)
  • 65. Study T-301: Neuroperformance Decline in Speech (ITT) 1 Stratified by country Proportion Without Decline 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 = 0.003 1
  • 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 = 0.02 1 Proportion Without Decline 1 Stratified by country
  • 67. Study T-301: Neuroperformance Decline in Motor Status (ITT) 1 Stratified by country 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 = 0.01 1 Proportion Without Decline
  • 68. Study T-301: Neuroperformance Decline in Cerebellar Status (ITT) 1 Stratified by country 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 = 0.01 1 Proportion Without Decline
  • 69. GLIADEL ® Wafer Safety
    • Review of safety in newly diagnosed malignant glioma
  • 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. 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. 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 Adverse Event 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) PLACEBO Wafer (n=120) n (%) GLIADEL ® Wafer (n=120) n (%)
  • 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. 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. Healing Abnormality: Fluid, CSF or Subdural Collections (T-301) 1-68 12-60 Range for duration (days) 10 15 Median duration (days) 6 (5.0) 5 (4.2) Number of patients (%) Placebo Wafer (n=120) GLIADEL ® Wafer (n=120)
  • 76. Healing Abnormality: CSF Leak (T-301) 3 2-211 Range for duration (days) 3 9 Median duration (days) 1 (0.8) 6 (5.0) Number of patients (%) Placebo Wafer (n=120) GLIADEL ® Wafer (n=120)
  • 77. Healing Abnormality: Wound Dehiscence, Breakdown or Poor Healing (T-301) 2-172 2-281 Range for duration (days) 6 10 Median duration (days) 6 (5.0) 6 (5.0) Number of patients (%) Placebo Wafer (n=120) GLIADEL ® Wafer (n=120)
  • 78. Healing Abnormality: Subgaleal or Wound Effusion (T-301) 2-26 3-30 Range for duration (days) 10 3 Median duration (days) 5 (4.2) 4 (3.3) Number of patients (%) Placebo Wafer (n=120) GLIADEL ® Wafer (n=120)
  • 79. Study T-301: Intracranial Infections 7 (6) 6 (5) Total 2 (2) 2 (2) Meningitis 5 (4) 4 (3) Abscess Placebo n (%) GLIADEL ® n (%)
  • 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. Comparison of Post-operative Surgical Infections 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 4% Craniotomy 2944 Kourinek et al 3 6% Tumor 251 Tenney et al 4 6% Glioma 120 T-301- Placebo 5% Glioma 120 T-301- GLIADEL 1.75% Glioma 327 Sawaya et al 2 5.5% Glioma/ Metastasis 200 Brell et al 1 Infection Disease # of Patients Author/Study
  • 82. Comparison of Post-operative Surgical Seizures 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 37% 33% 32% 51% 36-83% 2.5% 4% 1% Seizures Glioma 65 Moots et al 6 Glioma 119 Pace et al 4 Glioma 200 Tandon et al 5 Glioma 120 T-301- GLIADEL Glioma 120 T-301- Placebo Glioma 327 Sawaya et al 3 Glioma/ Metastasis 200 Brell et al 2 GBM/AA 207 Cabantog et al 1 Disease # of Patients Author/Study
  • 83. Comparison of Post-operative Surgical Hemorrhage/Stroke 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 7.5% Glioma 120 T-301- GLIADEL 4 4.8% Glioma 120 T-301- Placebo 4 2.0% Glioma 327 Sawaya et al 3 4.5% Glioma/ Metastasis 200 Brell et al 2 1% GBM/AA 207 Cabantog et al 1 Hemorrhage/Stroke Disease # of Patients Author/Study
  • 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. 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. 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. 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. 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 0.03 1 0.01 1 Stratified by country
  • 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 Ratio 1 0.57 0.72 0.21 95% CI 0.36-0.89 0.53-0.98 0.08-0.60 P-value 0.02 0.03 2 <0.01
  • 90. Summary of Benefits and Risks The benefit to risk ratio for GLIADEL ® in patients with primary malignant glioma is favorable
  • 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.