Gliadel Wafer sNDA 20-637s: Guilford Pharmaceuticals Inc. Baltimore, Maryland

GLIADEL WAFER
sNDA 20-637s
Guilford Pharmaceuticals Inc.
Baltimore, Maryland
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.
Clinical Trials: Recurrent

Malignant Glioma
Patients
Enrolled
Type of Study
Study 8701
21
Multicenter, open-label, dose escalation

Phase I/II
Study 9115
40
Multicenter, open-label Phase III
Study 8802
222
Multicenter, randomized, double-blind,

placebo-controlled Phase III
Study 9501
349
Treatment Protocol
TOTAL
632
Clinical Trials: Newly Diagnosed

Malignant Glioma
Patients Enrolled
Type of Study
Study 9003
22
Multicenter, open-label Phase I/II
Study 0190
32

Study T-301
240
TOTAL
294

GLIADEL Approvals (1996-2000)

Newly Diagnosed and Recurrent:
Canada
Recurrent:
France
Chile
Hong Kong
Malaysia
Portugal
Spain
Argentina
Austria
Columbia
Germany
Israel
Ireland
The Netherlands New Zealand
Singapore
South Africa
United Kingdom Uruguay
Brazil
Greece
Luxembourg
Peru
South Korea
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 NewlyDiagnosed Malignant Glioma
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.
Agenda
Introductions
Overview of Primary Malignant Glioma: Clinical Features and

Treatment
Dana Hilt, M.D., Vice President of Clinical Research, Guilford

Pharmaceuticals Inc.
Statistical Analytic Methods
Allan Hamilton, M.D., Professor and Chairman, Department of

Neurosurgery, University of Arizona School of Medicine
Phase III Trials (T-301and 0190)
Louise Peltier, Senior Director, Regulatory Affairs, Guilford

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

8
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
9
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
10
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
11
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.
12
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
Natl Comprehensive Cancer Network Guidelines 2000 (NCCN)
Hochberg FH, et.al. Assumptions in the radiotherapy of glioblastoma. Neurology 1980;30:907-11
13
Glioblastoma: Treatment Outcome

Median Survival (Months)
12
10
9.25
10
8
6
4
2
0
Surgery Only
Surgery +
Radiotherapy
Surgery +
Radiotherapy +
Chemotherapy
McDonald JD, Rosenblum ML: In: Rengachary SS, Wilkins RH, eds. Principles of Neurosurgery.
St Louis, MO: Mosby-Wolfe; 1994: chap 26.
14
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).
15
Natural History of High Grade

Glioma: Effects of PCV Chemotherapy
12
Median Survival (Months)
10
9.5
10
8
6
4
2
p = 0.50
0
Surgery +
Surgery +
Radiotherapy
Radiotherapy +
PCV Chemotherapy
MRC Brain Tumour Working Party: J Clin Oncol 19(2): 509-518 (2001).
16
Prognostic Factors:
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
17
Limitations of Systemic BCNU
Rapidly cleared with t ~ 15 minutes1
Limits exposure of tumor cells to BCNU
High doses required for adequate CNS levels
Achievable dose limited by systemic toxicity
Wang CH, et.al. The delivery of BCNU to brain tumors. J Control Release 1999;61:21-41
18
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
19
Phase III Trial of GLIADEL Wafer in

Newly Diagnosed Malignant Glioma
20
6 Month Survival
Recurrent GBM (8802)
100
Survival Rate (%)
90
80
70
GLIADEL
60
50
40
Hazard Ratio:
30
95% CI:
20
.57
Placebo
0.36 0.89
Risk Reduction: 43%
10
P = 0.02
0
0
Months From Implant Surgery

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.
21
Overall Survival (ITT)

Primary Malignant Glioma (0190)
100
Hazard Ratio:
Survival Rate (%)
90
95% CI:
80
0.37
0.17 0.82
Risk Reduction: 63%
70
P = 0.01
60
50
40
GLIADEL
30
20
Median Survival (months)
10
Gliadel
Placebo
13.4
9.2
Placebo
0
0
12
15
18
21
24
Months from Implant Surgery

22
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
23
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
24

Wafer in Newly-Diagnosed Malignant Glioma
Dana C. Hilt, M.D.

Vice President of Clinical
Research, Guilford
25

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 NewlyDiagnosed Malignant Glioma
26
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
27
Study 0190: Baseline

Patient Characteristics
Characteristic
Median age (years)
GLIADEL Placebo
Wafers Wafers
(n=16)
(n=16)
56
54
24.5
24.5
Median Karnofsky Performance score
75
90
Median No. of wafers
GBM tumor histology
11
16
Median Mini Mental score
28
Overall Survival (ITT)

Primary Malignant Glioma (0190)
100
Hazard Ratio:
Survival Rate (%)
90
95% CI:
80
0.37
0.17 0.82
Risk Reduction: 63%
70
P = 0.01
60
50
40
GLIADEL
30
20
10
Gliadel
Placebo
13.4
9.2
Placebo
0
0
12
15
18
21
24

29
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
Valtonen et al., Neurosurgery 41(1): 44-49, 1997
30
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
Valtonen et al., Neurosurgery 41(1): 44-49, 1997
31
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.
32
Study T-301: Trial Design
Randomized, double-blind, placebocontrolled 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
33
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
34
Study T-301: Clinical Sites

A total of 42 sites in 14 countries participated in the study
Australia:
Austria:
Belgium:
France:
Germany:
Greece:
Israel:
3 sites
1 site
2 sites
7 sites
5 sites
1 site
3 sites
Italy:
The Netherlands:
New Zealand:
Spain:
Switzerland:
United Kingdom:
United States:
3 sites
2 sites
1 site
3 sites
2 sites
4 sites
5 sites
35
Study T-301: Inclusion Criteria

1. Male or female, aged between 18 and 65 years;
2. Radiographic evidence on cranial MRI of a single
contrastenhancing 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
36
Study T-301: Baseline Characteristics
GLIADEL
WAFER
( n = 120)
PLACEBO
WAFER
(n = 120)
52.6
21-72
53.6
30-67
Male
76
84
Female
44
36
CHARACTERISTIC
Age (years) Mean

Range
Sex
Tumor Type Anaplastic astrocytoma

1
Anaplastic oligodendroglioma
5
Anaplastic oligoastrocytoma
7
Glioblastoma multiforme
101
Metastasis/Brain Metastasis
2
Other
4
1
4
3
106
1
5
37
Study T-301: Baseline Characteristics

Karnofsky Score
KARNOFSKY
Performance
Status
GLIADEL
WAFER
(n=120)
PLACEBO
WAFER
(n=120)
60
16
16
70
21
17
80
25
24
85
90
31
40
95
100
25
22
38
Study T-301: Tumor Size*

GLIADEL Wafer Placebo Wafer
(n=120)
(n=120)
Number reported
83
76
Mean (cm3)
66.8
50.8
Median (cm3)
60.0
34.0
* Comparability at baseline; p-value < 0.05
39
Statistical Methodology
Steven Piantadosi, M.D., Ph.D.
Professor and Director, Oncology
Biostatistics
Johns Hopkins University School of
Medicine
40
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
41
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
42
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
43
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

44
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.
45
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

46
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
47
Effect of Country-of-Treatment on
Survival: Placebo-Group (T-301)
48
Overall Survival
T-301
8802
0190
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

50
Univariable
Prognostic Factors1
Prognostic
Factor
Hazard Ratio
95% CI
P-value
Karnofsky Score
<70 vs. KPS >70
1.9
1.4 2.6
<0.0001
Age >60 vs. <60
1.6
1.2 2.2
0.03
Number of Wafers implanted

8 vs. <8
1.4
1.0 1.9
0.02
GBM Patients vs.

Non-GBM Patients
1.8
1.1 2.9
0.02
Cox Model stratified by country with single covariates

51
Multivariable Proportional
Hazards Analysis (ITT)
Prognostic
Factor
Hazard
Ratio1
95% CI
Lower
Upper
P-Value
GLIADEL vs. Placebo
0.72
0.53
0.98
0.03
Karnofsky Score
<70 vs. KPS >70
1.93
1.37
2.72
0.0002
Age >60 vs. <60
1.73
1.24
2.42
0.001
GBM Patients vs
Non-GBM Patients
1.44
0.84
2.47
0.18
Proportional Hazard Model stratified by country
52
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
53

Wafer in Newly-Diagnosed Malignant Glioma
Dana C. Hilt, M.D.

Vice President of Clinical
Research, Guilford
54
Study T-301: Overall Survival

Analysis (ITT)
100
Hazard Ratio:
0.71
95% CI:
0.52 0.96
Risk Reduction:
29%
P = 0.031
Survival Rate (%)
90
80
70
60
50
40
30
GLIADEL
20
Gliadel
Placebo
10
13.9
11.6
Placebo
0
0
10
12
14
16
18
20
22
24
26

1
Stratified by country
55
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
Adjusted for age, tumor type, and Karnofsky Score
56
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%)
57
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.
58
Study T-301: Overall Survival Analysis Reoperation for Disease Progression (ITT)
100
Hazard Ratio:
0.64
95% CI:
0.45 0.92
Risk Reduction: 36%
P = 0.011
Survival Rate (%)
90
80
70
60
50
40
GLIADEL
30
20
10
Gliadel
Placebo
Placebo
14.8
11.4
0
0
10
12
14
16
18
20
22
24
26
59
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
60
Study T-301: Overall Survival

(GBM Patients)
100
Hazard Ratio:
0.76
95% CI:
0.55 1.05
Risk Reduction: 24%
P = 0.101
Survival Rate (%)
90
80
70
60
50
40
30
20
10
Gliadel
Placebo
GLIADEL
Placebo
13.5
11.4
0
0
10
12
14
16
18
20
22
24
61
Study T-301: Overall Survival Adjusted for

Prognostic Factors1 (GBM Patients)
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
Adjusted for age and Karnofsky Score
Cox Proportional Hazard model stratified by country and

number of wafers (<8,8) implanted
62
Study T-301: Karnofsky

Performance Decline (ITT)
Proportion without Decline
1.0
Hazard Ratio:
0.74
95% CI:
0.55 1.0
Risk Reduction: 26%
P = 0.051
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
Gliadel
Placebo
0.0
0
GLIADEL
Median Deterioration (months)
11.9
10.4
Placebo
8
10
12
14
16
18
20
22
24 26
63
Study T-301: Neuroperformance

Decline (ITT)
Neuroperformance
Measure
Vital Signs
Level of Consciousness
Personality
Speech
Visual Status
Fundus
Cranial Nerves III, IV, VI
Cranial Nerves, Other
Motor Status
Sensory Status
Cerebellar Status
1
Stratified by Country
Median Time without

Deterioration (weeks)
GLIADEL
Placebo
Wafer(n=120)
Wafer(n=120)
49.1
54.9
45.4
52.1
40.0
51.7
36.7
49.6
42.4
44.0
46.3
55.1
49.1
54.9
46.3
54.3
31.4
45.4
44.1
51.6
46.7
54.1
P Value1
0.01
0.02
0.008
0.003
0.09
0.007
0.02
0.003
0.01
0.02
0.01
64
Proportion Without Decline

Decline in Speech (ITT)
1.0
Hazard Ratio:
0.64
95% CI:
0.48 0.86
Risk Reduction: 36%
P = 0.0031
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
Median Deterioration (weeks)
0.1
Gliadel
Placebo
0.0
0
10
GLIADEL
49.6
36.7
20
Placebo
30
40
50
60
70
80
90
100
110
120
Time to Deterioration (weeks)

1
65
Study T-301: Neuroperformance Decline in

Cranial Nerves III, IV, VI (ITT)
1.0
Hazard Ratio:
0.68
95% CI:
0.50 0.93
Risk Reduction: 32%
P = 0.021
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
Gliadel
Placebo
0.0
0
10
GLIADEL
54.9
49.1
20
Placebo
30
40
50
60
70
80
90
100
110
120

1
66

Decline in Motor Status (ITT)
1.0
Hazard Ratio:
0.69
95% CI:
0.51 0.92
Risk Reduction: 31%
P = 0.011
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
Gliadel
Placebo
0.0
0
10
GLIADEL
45.4
31.4
20
Placebo
30
40
50
60
70
80
90
100
110
120

1
67
Study T-301: Neuroperformance Decline in

Cerebellar Status (ITT)
1.0
Hazard Ratio:
0.67
95% CI:
0.49 0.91
Risk Reduction: 33%
P = 0.011
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
Gliadel
Placebo
0.0
0
10
GLIADEL
54.1
46.7
20
Placebo
30
40
50
60
70
80
90
100
110
120

1
68
GLIADEL Wafer Safety
Review of safety in newly diagnosed

malignant glioma
69
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.
70
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.
71
Study T-301: Neurologic Adverse Events

Occurring in >5% of Patients
Adverse Event
Abnormal gait
Amnesia
Anxiety
Aphasia
Ataxia
Brain edema
Coma
Confusion
Convulsion
Depression
Dizziness
Facial paralysis
Grand mal convulsion
Hallucinations
GLIADEL Wafer
(n=120)
n (%)
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)
PLACEBO Wafer
(n=120)
n (%)
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)
72
Study T-301: Neurologic Adverse Events

Occurring in >5% of Patients
Adverse Event
GLIADEL Wafer
(n=120)
n (%)
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)
PLACEBO Wafer
(n=120)
n (%)
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)
73
Convulsions (T-301)
(n=120)
(n=120)
Number of patients (%)
40 (33.3)
45 (37.5)
Convulsions severe
14 (11.7)
24 (20)
Grand Mal convulsions
6 (5.0)
5 (4.2)
Convulsions (< 5 days)
3 (2.5)
5 (4.2)
Time-to-First Seizure did not differ in the two treatment groups.
74
Healing Abnormality:
Fluid, CSF or Subdural Collections (T-301)

(n=120)
(n=120)
5 (4.2)
6 (5.0)
Median duration (days)
15
10
12-60
1-68
Range for duration (days)
75
Healing Abnormality:
CSF Leak (T-301)
(n=120)
(n=120)
6 (5.0)
1 (0.8)
2-211
76
Healing Abnormality: Wound Dehiscence,

Breakdown or Poor Healing (T-301)
GLIADEL Wafer
Placebo Wafer
(n=120)
(n=120)
6 (5.0)
6 (5.0)
10
2-281
2-172
77
Healing Abnormality: Subgaleal or

Wound Effusion (T-301)
GLIADEL Wafer
(n=120)
Placebo Wafer
(n=120)
4 (3.3)
5 (4.2)
10
3-30
2-26
78
Study T-301:
Intracranial Infections
GLIADEL
n (%)
Placebo
n (%)
Abscess
4 (3)
5 (4)
Meningitis
2 (2)
2 (2)
Total
6 (5)
7 (6)
79
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?
80
Comparison of Post-operative Surgical

Infections
Author/Study
# of
Patients
Brell et al1
Disease
Infection
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%
Brell et al., (2000) Acta Neurochir (Wien) 142:739-50

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
1
2
81

Seizures
Author/Study
# of
Patients
Disease
Seizures
Cabantog et al1
207
GBM/AA
1%
Brell et al2
200
Glioma/
4%
Metastasis
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%
Cabantog et al., (1994) Can J Neurol Sci 32:213-18

Brell et al., (2000) Arta Neurochir 142:739-50
3
Pace et al., (1998) J Exp Clin Canc Rsh 17:479-82

Tandon et al., (2001) Neurology India 49:55-9
6
Moots et al., (1995) Arch Neurol 52:717-24
82

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%
Cabantog et al., (1994) Can J Neurol Sci 32:213-18

Brell et al., (2000) Acta Neurochir (Wien) 142:739-50
3
4
Events reported within 30 days of surgery
1
2
83
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
84
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
85
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
86
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
87
Summary of Efficacy Results from Randomized

Controlled Trials of GLIADEL Wafer (ITT)
Study
Hazard Ratio
95% CI
P-value
8802
0.69
0.47-1.02
0.06
T-301
0.71
0.52-0.96
0.031
0190
0.37
0.17-0.82
0.01
88
Summary of Efficacy Results from Randomized

Controlled Trials of GLIADEL Wafer (GBM)
Study Hazard Ratio1
95% CI
P-value
8802
0.57
0.36-0.89
0.02
T-301
0.72
0.53-0.98
0.032
0190
0.21
0.08-0.60
<0.01
1
2
Hazard ratio adjusted for prognostic factors.

89
Summary of Benefits and Risks

The benefit to risk ratio for
GLIADEL in patients with
primary malignant glioma
is favorable
90
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.
91

Gliadel Wafer sNDA 20-637s: Guilford Pharmaceuticals Inc. Baltimore, Maryland

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Gliadel Wafer sNDA 20-637s: Guilford Pharmaceuticals Inc. Baltimore, Maryland

Uploaded by

Copyright:

Available Formats

GLIADEL WAFER

Clinical Trials: Recurrent

Multicenter, open-label, dose escalation

Multicenter, open-label Phase III

Multicenter, randomized, double-blind,

Clinical Trials: Newly Diagnosed

Multicenter, open-label Phase I/II

Multicenter, randomized, double-blind,

Multicenter, randomized, double-blind,

GLIADEL Approvals (1996-2000)

Phase III Multicenter Trials of GLIADEL

0190 Trial: Interstitial Chemotherapy for Malignant

T-301 Trial: A Phase III, Multicenter, Randomized

Overview of Primary Malignant Glioma: Clinical Features and

Dana Hilt, M.D., Vice President of Clinical Research, Guilford

Statistical Analytic Methods

Allan Hamilton, M.D., Professor and Chairman, Department of

Phase III Trials (T-301and 0190)

Louise Peltier, Senior Director, Regulatory Affairs, Guilford

Steven Piantadosi, M.D., Ph.D., Professor and Director, Oncology

Phase III Trial (T-301) Efficacy and Safety Results

Dana Hilt, M.D., Vice President of Clinical Research, Guilford

Guilford Invited Guests

Henry Brem, M.D.

Overview of Primary Malignant Glioma:

Allan Hamilton, M.D.

Primary Malignant Glioma

Approximately 16,500 new cases annually

Glioblastoma multiforme accounts for

More than 13,000 deaths annually

Central Brain Tumor Registry US Statistical Report 1992-1997

Primary Malignant Glioma

Presentation: headache, seizure or new neurological

Imaging (CT or MRI) is key in provisional diagnosis.

During surgical resection a provisional or tentative

Final pathologic diagnosis requires fixed tissue

Primary Malignant Glioma

Maximal surgical resection followed by

Majority of tumors recur within 2 cm of original

Carmustine (BCNU) is the most widely studied

Natl Comprehensive Cancer Network Guidelines 2000 (NCCN)

Hochberg FH, et.al. Assumptions in the radiotherapy of glioblastoma. Neurology 1980;30:907-11

Glioblastoma: Treatment Outcome

Natural History of High Grade

Randomized, prospective study of surgical resection

MRC, 15 centers in the UK

674 patients enrolled

GBM Histology 76%

Natural History of High Grade

Median Survival (Months)

Prognostic Factors shown to influence

Age (>60 years)

Karnofsky Performance Score (<70)

Proposed Prognostic Factors

Burger PC, et al., Cancer 59:1617-1625, 1987

Limitations of Systemic BCNU

Rapidly cleared with t ~ 15 minutes1

Limits exposure of tumor cells to BCNU

High doses required for adequate CNS levels

Achievable dose limited by systemic toxicity

The GLIADEL Wafer

Biodegradable polyanhydride copolymer containing

Circumvents limitations of systemic BCNU