SipuleucelT

1
Sipuleucel-T BLA 125197 FDA Clinical Review and
Findings Ke Liu, MD, PhD Clinical
Reviewer Division of Clinical Evaluation,
Pharmacology and Toxicology (DCEPT), OCTGT,
CBER, FDA March 29, 2007 Cellular, Tissue and
Gene Therapies Advisory Committee Meeting

1
2
Outline of Presentation

• Efficacy findings
• Study design
• Results
• Safety findings
• Deaths, Serious Adverse Events (SAEs), Adverse
  Events (AEs)
• Cerebrovascular Accidents (CVAs) --- Sponsors
  updated information

2
3
Terminology of Presentation

• Study Names
• Study 1 D9901
• Study 2 D9902A
• Study agents
• Sipuleucel-T APC8015
• Placebo APC-Placebo
• APC8015F Frozen and thawed PBMC as source
  material, then prepared similarly as Sipuleucel T

3
4
Basis for BLA submissionOverall Survival

• Proposed Indication
• Treatment of men with asymptomatic metastatic
  androgen independent prostate cancer (AIPC)
• Basis of claim
• D9901 a 4.5-month overall survival difference
• D9902A a 3.3-month overall survival difference
  (not significant)

4
5
D9901 and D9902A

• Similarly designed randomized, double-blind,
  placebo-controlled trials in men with
  asymptomatic metastatic androgen independent
  prostate cancer.
• Primary Endpoint Time To Disease Progression
• D9901 enrolled 127 subjects, 82 in Sipuleucel-T
  arm, 45 in Placebo
• D9902A planned 120 subjects, but terminated
  early 65 in Sipuleucel-T arm, 33 in Placebo
• Study Period
• D9901, 01/00-09/04
• D9902A, 05/00-09/04

5
6
Key Eligibility Criteria

• Histologically documented adenocarcinoma of the
  prostate
• Metastatic disease as evidenced by soft tissue
  and/or bony metastases.
• PSA 5 ng/mL.
• Tumor or PSA progression after hormonal therapy.
• Castrate levels of testosterone (lt50 ng/dl)
• No cancer-related pain

6
7
Treatment Schema
P R O G R E S S I O N
R A N D O M I Z E 21
Sipuleucel-T Q 2 wks x 3 (N 82)

Follow-up
Asymptomatic Metastatic AIPC (N 127)
(Optional use of APC8015F Q 2 wks x 3) Follow-up
Placebo Q 2wks x 3 (N 45)

Post progression chemotherapy /- other options
allowed
7
8
Treatment Regimen

• Apheresis to harvest PBMCs, 2 to 3 days
• prior to the infusion date
• Sipuleucel-T or Placebo 3 doses, q 2 wks, i.v.
• The cell counts in each individual dose varied
• depending on the apheresis yield.
• Minimum for each dose of Sipuleucel-T was
• approximately 3 X 106 CD54 cells.
• The dose for Placebo was 1/3 of the
• total cells harvested from the apheresis.
• Bisphosphonate allowed
• Continued hormonal treatment

8
9
Primary Endpoint

• Time to disease progression, as defined by
  time from randomization to the first observation
  of disease progression
• Radiological Progression (Bone Scan q 8 wks,
  CT/MRI q 8 wks if baseline )
• New Cancer Related Pain (X-ray correlation
  required)
• Clinical Events
• Pathological Fracture, Cord or Nerve Root
  Compression
• Other Clinically-significant disease-specific
  events

9
10
Secondary Endpoints

• Overall time from randomization to the
  development of disease-related pain
• Overall time from randomization to earliest
  evidence of clinical progression
• Rate of objective response
• Duration of response
• Time to treatment failure

10
11
Statistical Assumptions

• Median Time to Progression
• Based on the sponsors past experience and a
  review of the literature
• Placebo 16 weeks Sipuleucel-T 31 weeks
  (HR 1.92)
• Alpha 5 two-sided 80 power
• 21 Randomization

11
12
D9901 Efficacy Results
12
13
D9901 Patient Demographic and Baseline
Characteristics
Sipuleucel-T
Placebo (n 82)
(n 45) Median age (range) 73
yrs (4785) 71 yrs (5086) Ethnicity Caucasian
73 (89) 42 (93.3) African-American
8 (9.8) 1
(2.2) Hispanic
1 (1.2) 1 (2.2)
Unknown 0
1 (2.2) ECOG PS
0 62 (75.6) 37 (82.2)
1 20 (24.4) 8 (17.8)
13
14
D9901 Patient Demographic and Baseline
Characteristics (continued)
Sipuleucel-T
Placebo (n 82)
(n 45) Gleason Score 6 n () 22
(26.8) 7 (15.6) 7
n () 28 (34.1) 18 (40) 8 n
() 32 (39) 20 (44.4) Disease
location Bone only 34 (42.0)
10 (23.8) Soft tissue only 5 (6.2)
3 (7.1) Bone and soft
tissue 42 (51.9) 29 (69) No. of bone
metastases/subject 0 5
(6.1) 4 (8.9) 1-5
31 (37.8) 17
(37.8) 6-10 12 (14.6)
12 (26.7) gt 10 34
(41.5) 12 (26.7)
14
15
D9901 Primary Endpoint ---Time to Progression

• 127 subjects randomized
• 114 had progression event
• 0 deaths prior to progression event
• Progression documented by
• Imaging 97
• Clinical event 10
• Onset of disease related pain correlated with
  imaging 7

15
16
D9901 Time to Disease Progression

• No statistical difference by Log-rank test p
  0.085, HR 1.39, 95 CI 0.95, 2.03
• Median TTP
• Sipuleucel-T 11.1 weeks (range 2.1 to 57.4)
• Placebo 9.1 weeks (range 3.9 to 52.1)

16
17
Discussion --- D9901 Primary Endpoint (TTP)
Result

• After unblinding, the 1st analysis showed a log
  rank p-value for time to progression 0.085
• Changed from 0.085 to 0.052
• Unblinded audit of clinical data
• Primarily driven by two subjects

17
18
Discussion continued ---D9901 Primary Endpoint
(TTP) Result

• Difficulties in interpretation of TTP results
• Overestimation of TTP
• Assumption 16 weeks for placebo and 31 weeks for
  Sipuleucel-T
• Actual observation 9-11 weeks for both arms
• Median progression prior to scheduled second
  assessment for progression
• Lack of scans to detect soft tissue progressions
  in some bone only subjects according to the study
  design
• Un-interpretable progression dates in some
  subjects due to protocol violations

18
19
Conclusion --- D9901 Primary Endpoint (TTP)

• FDA considers the p-value of 0.085 by log-rank
  test to be the result from the primary analysis
  specified in the protocol and the p-value of
  0.052 to be derived from an exploratory analysis.
• The study failed to show a Sipuleucel-T treatment
  effect on the primary endpoint, TTP.

19
20
D9901 Secondary Endpoints

• No difference observed between two arms for any
  of the following
• Overall time to the development of
  disease-related pain
• Overall time to earliest evidence of clinical
  progression
• Rate of objective response
• Duration of response
• Time to treatment failure

20
21
D9901 Overall Survival
21
22
D9901 Overall Survival
All subjects were followed for 36 months or
until death From available data
22
23
Therapy After Progression D9901

• Chemotherapy

• Placebo subjects cross-over to
• APC8015F 34/45 (75.6)

23
24
Potential Chemotherapy Confounding Effects on
Overall Survival

• Analysis of the time from randomization to 1st
  chemotherapy use did not suggest an earlier
  initiation of chemotherapy in Sipuleucel-T
  subjects
• The dose and cycles of chemotherapy were not
  collected
• Potential chemotherapy confounding effects on
  overall survival are unlikely, but cannot be
  ruled out

24
25
D9901 Efficacy Summary

• N 127, randomized 21 to Sipuleucel-T
  (Sipuleucel-T) Placebo
• A small sample size
• No difference between two arms in the
  pre-specified efficacy endpoints
• Overall Survival
• 4.5-month difference in median survival in
  Sipuleucel-T arm (p 0.010, HR 1.7)

25
26
CD54 Upregulation and Survival
Above the mean
Below the mean
26
27
Interpretation of CD54 Results

• Intrinsic property of individual patients
• Intrinsic property of individual products
• after manufacturing process. (Placebo did not
  undergo the same process as Sipuleucel-T)
• Other factors?

27
28
Immunological Analyses --- T cell Stimulation
Index
28
29
Interpretation of Stimulation Assays

• Proliferation assay not a direct assay for T cell
  response
• Assays performed only in a small subset of
  patients
• No response to human PAP

29
30
D9902A Efficacy Results
30
31
Study D9902

• Same design as D9901
• Planned 120 subjects
• Time To Disease Progression
• as 10 endpoint

Terminated (3/2003) Because
of D9901 overall negative efficacy
Renamed D9902A 98 subjects already enrolled

• D9902A
• Insufficient sample size
• Not powered to see a difference
• in TTP or overall survival

31
32
D9902A Patient Demographic and Baseline
Characteristics
Sipuleucel-T
Placebo (n 65)
(n 33) Median age (range) 70.0 yrs
(5184) 71.0 yrs (5787) Ethnicity Caucasian
59 (90.8) 31(93.9) African-American
2 (3.1) 2
(6.1) Hispanic
1 (1.5) 0 Other
3 (4.6)
0 ECOG PS 0 51 (78.5) 23
(69.7) 1 14 (21.5) 10
(30.3)
32
33
D9902A Patient Demographic and Baseline
Characteristics (continued)
Sipuleucel-T
Placebo (n 65)
(n 33) Gleason Score 6 n () 15
(23.4) 9 (27.3) 7
n () 29 (45.3) 8 (24.2) 8 n
() 20 (31.3) 16 (48.5) Disease
location Bone only 31 (47.7)
10 (30.3) Soft tissue only 7
(10.8) 7 (21.2) Bone and soft tissue 27
(41.5) 16 (48.5) No. of bone
metastases/subject N 61
N 32 0 5 (8.2)
4 (8.9) 1-5 19
(31.1) 11 (34.4) 6-10
6 (9.8) 2 (6.3) gt
10 31 (50.8) 12
(37.5)
33
34
D9902A Time to Disease Progression

• The estimated median TTP
• 10.9 weeks in the Sipuleucel-T arm (Range 3.4
  to 106.6 wks)
• 9.9 weeks in the APC placebo arm (Range 1.7
  to 130.1 wks)

34
35
D9902A Overall Survival
Median survival time (MST) Estimates
Sipuleucel-T 19.0 months (13.6, 31.9) Placebo
15.7 months (12.8, 25.4)
35
36
D9902A Efficacy Summary

• N 98, randomized 21 to Sipuleucel-T Placebo
• Similar trial design and execution as D9901
• Stopped early. Insufficient sample size to detect
  a difference in TTP or overall survival
• No statistical difference in time to progression,
  overall survival between treatment arms

36
37
Safety Evaluation

• Main analyses from D9901and D9902A database
• 146 subjects received Sipuleucel-T
• 76 subjects received Placebo
• Cerebrovascular accidents (CVA) events from an
  updated database including other phase 3 trials,
  D9902B and P-11
• Complete safety database update was submitted
  last week to include a total of 461 subjects who
  received Sipuleucel T and 231 subjects who
  received Placebo

37
38
Infusion Exposure (D9901 and D9902A)
38
39
Death (D9901 and D9902A)
Included one death from each of the following
in Sipuleucel-T arm Cardiac Arrest Dementia
Glioblastoma Met. Esophageal Ca Orthopedic
Complication Renal Failure Sepsis and ARDS
UTI one death from Small Cell Carcinoma In
Placebo
39
40
SAEs ( 2, D9901 and D9902A)
Other than Death
40
41
Common Adverse Events in D9901 and D9902A
gt10 in Sipuleucel T subjects Adverse
events that occurred more often in Sipuleucel-T
subjects _at_ Subjects who had at least one
leukapheresis
41
42
Trials Subjects for CVA Analyses
42
43
CVA Events
43
44
Safety Conclusions

• Almost all Sipuleucel-T treated subjects
  developed Adverse Events (98.6 Sipuleucel-T
  versus 96.1 placebo).
• Most AEs were grade 1 to 2 and resolved within 48
  hours.
• 24 Sipuleucel-T subjects developed SAEs, not
  different from 23 of Placebo treated subjects.
• Although the differences did not reach
  statistical significance, the increased CVA
  events observed in Sipuleucel-T subjects is a
  potential safety signal.

44
45
Conclusions --- Efficacy

• Neither study met pre-specified efficacy endpoint
  
• Survival analyses
• D9901 a 4.5-month overall survival difference.
  Statistically significant by log-rank test
• D9902A a 3.3-month overall survival difference
  --- Not statistically significant

45
46
Discussion --- Overall Survival in Cancer
Clinical Trials

• The most reliable cancer endpoint
• Usually the preferred endpoint when studies can
  be conducted to adequately assess it.
• An improvement in survival is a clinical benefit.
  
• The endpoint is precise and easy to measure,
  documented by the date of death.  Bias is not a
  factor in endpoint measurement.
• Demonstration of a statistically significant
  improvement in overall survival has supported new
  drug approvals

46
47
Discussion --- Overall Survival Difference in
D9901

• 4.5 month median survival difference is
  Clinically meaningful
• Limitations of survival result
• Post hoc analyses
• Survival not the pre-specified endpoint
• Primary method for survival analysis not
  pre-specified
• One study with a small sample size
• Difference could be due to chance

47