NDA 21-801 Satraplatin Proposed Indication

1
NDA 21-801 Satraplatin Proposed Indication

• Satraplatin is indicated for the treatment of
  patients with androgen independent (hormone
  refractory) prostate cancer who have failed
  prior chemotherapy

2
Study Population

• Hormone refractory metastatic prostate
• cancer
• Failed one prior chemotherapy regimen
• No prior platinum drug
• ECOG PS lt 2
• Stable analgesic regimen

3
Study Design

• Double-blind, randomized trial - satraplatin plus
  prednisone versus placebo plus prednisone
• Satraplatin 80 mg/m2 daily x 5 every 35 days
• Prednisone 5 mg bid daily
• 21 randomization
• Stratification PS, PPI score, Type of
  Progression (Tumor Size vs PSA)
• At progression no crossover to satraplatin

4
Study Endpoints

• Primary
• - PFS
• - OS
• Secondary
• - Time to Pain Progression

5
PFS

• Composite Endpoint
• - Radiologic progression
• - Pain progression
• - ECOG P.S. (2 units)
• - Weight loss (gt10)
• - Skeletal related events
• - Clinical events
• - Death

6
Partial Regulatory HistoryPFS Endpoint

• Oct. 2002-EOP2 - ? Appropriateness of PFS
  endpoint.
• May 2003-EOP2 - No agreement on PFS definition
• June 2005-pre-NDA No experience with composite
  PFS endpoint
• March 2006 - PFS endpoint will be a review issue

7

• ODAC Question
• Is the composite PFS endpoint, as defined, an
  acceptable endpoint for treatment evaluation in
  hormone refractory prostate cancer?

8
Sample Size Considerations
Date Endpoint HR Power Pts Events
5/03 OS 1.3 80 792
7/03 PFS/OS 1.3 85 912 637 PFS 602 OS
4/04 OS 1.3 85 912 602 OS
6/05 PFS/OS 1.3 90 694 PFS 700 OS
2/07 PFS/OS 950 802 PFS 463 (6/06)
9
Participant Countries
Country No. Pts Country No. Pts
U.S.A 258 Russia 28
France 141 Croatia 24
Argentina 98 Italy 23
U.K. 85 Peru 23
Poland 71 Hungary 22
Germany 61 Israel 14
Belgium 46 Netherlands 11
Spain 42 Canada 3
10
Demographics
Characteristic Total n950
Age (median (min-max) 70 (42-95) yrs
Race Caucasian 89
ECOG 0-1 89
Current bisphosphonates 30
PPI 0 36
Average analgesic score 0 41
Prior docetaxel 51
11
Progression Free Survival
12
Interim Overall Survival66 Events
13
ODAC Question

• Should the FDA wait for the final survival
  analysis before deciding whether this application
  is approvable?

14
PFS Events
Satraplatin n528 Prednisone n274 Total n802
Radiologic 36 37 36
Pain 35 43 37
Death 9 5 8
PS/Weight 6 6 6
Other 15 10 13
15
Radiologic ProgressionIndependent Radiology
Review

• Independent blinded review of all radiology
  studies by 2 radiologists
• If the two radiologists disagree as to the
  occurrence of progression or response or if they
  differ on the date of progression or response a
  third radiologist (adjudicator) reviews the
  studies and agrees with either radiologist 1 or
  radiologist 2

16
Adjudicated Radiology Progression
Radiologic No. Number Adjudicated Percent Adjudicated
Progression 290 116 40
Not Progression 660 220 33
Total 950 336 35
17
ODAC Question

• As 336 of 950 study patients (35) required
  adjudication to determine progression what does
  this indicate about the reliability of radiologic
  progression assessment?

18
Radiologic ProgressionImaging Methods
Imaging Method Total N290
Bone scan only 66
Bone scan other 16
19
Radiologic Progression
20
Time to Pain Progression
21
Pain Progression Assessment

• Based on average weekly Present Pain Intensity
  (PPI) and Analgesic Scores (AS) recorded by
  patients on pain diaries
• Pain progression
• PPI Increase gt 1 point from baseline or
  gt 2 points from nadir observed for gt 2
  consecutive weeks
• Increase in average AS of gt25 (narcotics only)
  observed for gt 2 consecutive weeks
• Independent blind review
• 
  

22
Baseline PPI
Pain Score Number of patients ()
0 (None) 327 (35.9)
1 (Mild) 258 (28.3)
2 (Discomforting) 212 (23.3)
3 (Distressing) 97 (10.6)
4 (Horrible) 14 (1.5)
5 (Excruciating) 3 (0.1)
23
Baseline PPI 0, 1 or 2 Narcotic Use
PPI No. of patients No. analgesic score 0 analgesic score 0
0 327 301 92
1 258 160 62
2 212 69 33
24
Pain and/or Analgesic Progression
25
Analgesic Score Progression of Pain Progression
26
ODAC Question

• Was pain progression reliably assessed in this
  trial?

27
Objective Response Rate
Satraplatin N274 Placebo N134
CR PR 8 0.7
Number of patients with soft tissue lesions Number of patients with soft tissue lesions Number of patients with soft tissue lesions
28
Drug Exposure
Satraplatin Pred Placebo Pred
Number of treatment cycles Median (range) 4 (1-32) 2 (1-19)
of patients with Dose reduction lt 70 mg/m2 Dose delay gt 7 days Dose increase gt 90 mg/m2 21 44 8 0.3 11 10
29
Cycle 1 Hematologic Toxicity
Satraplatin Pred n629 Placebo Pred n313
Hemoglobin All Grades Grade 3-4 96 9 90 3
Platelets All Grades Grade 3-4 87 22 20 1
Neutrophils All Grades Grade 3-4 67 21 5 1
30
Grade 3/4 Non-Hematologic TEAEs
Satraplatin Pred n629 Placebo Pred n313
Any TEAE 55 30
GI Disorders 8 2
Infections 5 1
31

• ODAC Discussion Issues
• - Is PFS, as defined, an acceptable endpoint for
  treatment evaluation in HRPC?
• Was radiologic progression reliably assessed?
• Was pain progression reliably assessed?
• Should FDA should wait for the final survival
  analysis before deciding whether this application
  is approvable? That analysis should be available
  by the end of 2007