The SPARC Trial: Satraplatin in Patients With Androgen Independent Prostate Cancer That Has Failed First-Line Chemotherapy

1
The SPARC TrialSatraplatin in Patients With
Androgen Independent Prostate Cancer That Has
Failed First-Line Chemotherapy

• Marcel Rozencweig, MD
• Chief Medical OfficerGPC Biotech, Inc.

2
Agenda

• I. SPARC overview
• II. Response to FDA Briefing Document

3
Trial DesignDouble-blind, Placebo-controlled
Study
Metastatic HRPC after 1 prior chemotherapy
R A N D O M I Z E
Satraplatin 80 mg/m2 d1-5 q 35d Granisetron 1 mg
BID d1-5 q 35d Prednisone 5 mg BID
Stratify
Placebo 80 mg/m2 d1-5 q 35d Placebo 1 mg BID d1-5
q 35d Prednisone 5 mg BID
ECOG PS 0 - 1 vs 2 PPI 0 - 1 vs 2 - 5 PSA vs
tumor progression
21
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Endpoints
Source
CE-40

• Primary endpoints
• Progression-free survival (accelerated approval)
  
• Overall survival (full approval)
• Secondary endpoint
• Time to pain progression
• Other pre-specified endpoints
• Pain response
• Tumor response (RECIST criteria)
• PSA response (Bubley criteria)

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Statistical Considerations
p 19 CE - DV
CE-41

• PFS and OS assessed by Kaplan-Meier estimates and
  compared using 2-sided stratified log-rank test
• Overall ? of 0.05 split between PFS and OS
• ITT population
• Target accrual of 912 patients consistent with
  observation of 700 PFS events to detect HR
  0.77 for PFS with 90 power and 2-sided ? 0.05
  
• 700 deaths also required to detect same HR for OS

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Composite PFS Endpoint(Excluded PSA)
pp 16-17 CO
CE-43

• Time from randomization to first occurrence of
  any of the following
• Radiographic progression (RECIST for soft tissue
  and visceral lesions, 2 new lesions on bone
  scan)
• Increased pain (PPI score/analgesic use)
• Altered ECOG PS (2 units)
• Weight loss (10)
• Skeletal-related events
• Intervention for disease-related obstruction
• Death from any cause

7
Disease-Related Pain Assessments
p 17 CO DV 5/8
CE-45

• Patient diaries to be completed daily
  continuously
• Average pain over 24 hoursa
• Present Pain Intensity (PPI) score based on
  McGill-Melzack questionnaireb
• 6 point scale
• 0 no pain
• 5 excruciating pain
• Analgesic use

a Tannock. J Clin Oncol. 1996141756 b
Melzack. Pain. 19751277.
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Pain Progression Assessment
SPARC NDA 19-297/S-014
PPI assessment Continuous One day q3wks
Confirmed ? 2 consecutive wks One day q3wks
Progression 2-point increase in PPI from nadir 1-point increase in PPI from nadir
1-point increase in PPI from baseline 1-point increase in PPI from baseline (FDA analysis)
Narcotics ?NSAIDs and/or narcotics
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Central Adjudication of Progression Events
Independent Review Committee (IRC)
p 17 CO- DV 5/8
CE-47

• Primary PFS endpoint determined by IRC
• Type of progression event and date of the
  earliest disease progression event assigned by
  IRC
• Independent blinded radiology review of ALL scans
  and x-rays
• Independent blinded medical oncology review of
  relevant clinical profile for ALL patients
• No access to blood counts, PSA valuesa, or
  investigator assessments of progression

a Except for the first 53 patients.
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Enrollment by Country (N 950)
Source
CE-51
n ()
United States 258 (27.2)
France 141 (14.8)
Argentina 98 (10.3)
United Kingdom Poland Germany Others (n 10) 85 (8.9) 71 (7.5) 61 (6.4) 236 (24.8)

• 170 centers from 16 countries participated
• 10 largest accruing centers accounted for 22 of
  total accrual

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Baseline Characteristics

• Patients in both arms were well balanced
• Age
• ECOG performance status
• Type of progression at entry
• Baseline PPI score
• Baseline analgesic score
• Prior therapy
• 51.3 received first-line docetaxel

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SPARC

• Efficacy

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Primary EndpointProgression-Free Survival (IRC
Adjudicated)
Page 53 of CE - DV
CE-11
HR 0.6795 CI 0.57, 0.77 Stratified log-rank
p lt 0.0001
30
17
16
7
Number at risk
Satraplatin 635 363 229 143 90 63 43 24 18 12
Placebo 315 140 63 37 24 11 5 5 1 0
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Distribution of IRC-Defined PFS Events
Source
CE-66
Satraplatin prednisonen 528() Placebo prednisonen 274 ()
Radiographic 35.8 36.9
Pain 34.3 42.7
Skeletal events 4.2 1.8
PS 2.8 2.9
Weight 2.8 2.6
Bladder/Ureteral 1.6 1.9
No progression until death 9.1 4.7
Death on study 0.9 1.8
Other 7.6 5.4
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Progression-Free SurvivalPrior Docetaxel (IRC)
efficacy odac.ppt s 12 Page 74 of SCE
EF-49
HR 0.6795 CI 0.54, 0.83 Stratified log-rank
p 0.0006
Number at risk
Satraplatin 327 167 107 69 39 28 19 13 9 5
Placebo 160 61 28 16 8 4 1 1 0 0
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PFS Hazard Ratios by Patient Subsets
SCE Fig 2 p 57 - DV
CE-17
HR (95 CI), log scale
Subgroup N HR
ITT 950 0.67
ECOG 0 - 1 848 0.66
ECOG 2 102 0.72
PPI 0 327 0.70
PPI 1 584 0.67
Tumor progression 522 0.62
PSA progression only 426 0.74
Age lt 65 273 0.74
Age 65 677 0.63
LDH lt 2 ULN 776 0.66
LDH 2 ULN 89 0.50
Hemoglobin lt 11 g/dL 204 0.54
Hemoglobin 11 g/dL 744 0.69
Alkaline phosphatase lt 1.5 ULN 562 0.68
Alkaline phosphatase 1.5 ULN 374 0.60
Prior docetaxel 487 0.67
No prior docetaxel 463 0.67
No bisphosphonate 669 0.62
Bisphosphonate 281 0.74
Caucasians 841 0.68
Non-Caucasians 109 0.60
North America 261 0.67
Outside North America 689 0.65
0.2
1.0
2.0
0.5
Favors satraplatin
Favors placebo
17
Time to Pain ProgressionPrespecified Secondary
Endpoint (IRC)
Page 60 of CE - DV
CE-25
HR (95 CI), log scale
Subgroup N HR
ITT 950 0.64
ECOG 0 - 1 848 0.63
ECOG 2 102 0.69
PPI 0 327 0.69
PPI 1 584 0.63
Tumor progression 529 0.51
PSA progression only 420 0.86
Age lt 65 273 0.69
Age 65 677 0.61
LDH lt 2 ULN 776 0.59
LDH 2 ULN 89 0.59
Hemoglobin lt 11 g/dL 204 0.52
Hemoglobin 11 g/dL 744 0.64
Alkaline phosphatase lt 1.5 ULN 562 0.71
Alkaline phosphatase 1.5 ULN 374 0.55
Prior docetaxel 487 0.66
No prior docetaxel 463 0.60
No bisphosphonate 600 0.59
Bisphosphonate 350 0.71
Caucasians 841 0.64
Non-Caucasians 109 0.67
North America 261 0.62
Outside North America 689 0.62
0.2
1.0
2.0
0.5
Favors satraplatin
Favors placebo
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Pain Responsea (Pre-specified Analysis)
p lt 0.005
n 351
n 181
a Decreased PPI by 2 points with no increase in
analgesic score for 5 weeks.
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Exploratory and Clinically Relevant Pain Analyses

• More patients in satraplatin arm became pain free
  for a minimum of 5 weeks
• Especially among patients with PPI 2 - 5 (p
  0.0076)
• More patients in satraplatin arm with reduction
  in narcotics by 50 for a minimum of 5 weeks
• Especially among patients with analgesic scorea
  gt 8 (p 0.005)

a 40 mg morphine po 8.
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Exploratory AnalysisWeekly Percentage of
Patients With 50 PPI Decrease
40
Odds ratioa 1.98 95 CI 1.81, 2.16 p lt 0.0001
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Satraplatin Placebo
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Cumulative of patients
10
0
0
10
20
30
40
50
60
Time, wk
Satraplatin n 432 287 161 90 55 37 21
Placebo n 222 132 46 27 12 7 4
a OR derived from a Repeated Measures Logistic
Regression model with baseline PPI as covariate.
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Pre-specified PSA and Tumor Response Rates
Bubley criteria
RECIST criteria
p lt 0.0001
p 0.002
n 476
n 225
n 274
n 134
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Interim Overall Survival

• 463 events
• Interim analysis favors satraplatin arm
• HR 0.90 (95 CI 0.74, 1.09)
• Final analysis pending pre-specified number of
  events (n 700)

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SPARC

• Safety

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Grade 3 - 4 Myelosuppression
p 21 SCS, Table 7 - DV
CE-61
Grade 3 - 4 Grade 3 - 4 Grade 4 Grade 4
Satraplatin prednisone() Placebo prednisone() Satraplatin prednisone() Placebo prednisone()
Neutropenia 21.1 0.6 4.1 0
Thrombocytopenia 21.8 1.3 0.3 0
Leukopenia 13.7 0.6 1.0 0
Anemia 9.4 3.2 1.7 0.6
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Nonhematologic Adverse Events With Higher
Incidence in Satraplatin Arm
Clin overview Tables 18, 19, 20
SA-3
All grades All grades Grade 3 - 4 Grade 3 - 4
Adverse event Satraplatin prednisone() Placebo prednisone() Satraplatin prednisone() Placebo prednisone() p value
Nausea 29.1 10.9 1.3 0.3 NS
Vomiting 16.5 8.9 1.6 0 0.036
Diarrhea 24.8 6.1 1.9 0 0.011
Constipation 22.9 10.9 1.9 1.0 NS
Fatigue/Asthenia (pooled) 31.6 19.8 4.9 2.9 NS
Infections 23.7 11.5 4.5 1.0 0.003
Fever (pooled) 10.2 5.8 0.6 0.3 NS
Bleeding/Bruising (pooled) 9.7 4.5 1.9 1.6 NS
Pulmonary (pooled) 8.1 4.2 1.3 1.0 NS
Thrombosis (pooled) 4.3 0 1.7 0 0.020
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SPARC

• Summary and Discussion

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SummarySatraplatin Efficacy
Source
CE-63

• Primary endpoint (PFS) achieved with very robust
  results
• 33 risk reduction of disease progression or
  death
• p lt 0.0001
• Clinical relevance
• Primarily driven by a delay in tumor progression
  and pain progression
• Consistency across sensitivity and subset
  analyses
• Prior or no prior docetaxel

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SummarySatraplatin Positive Outcomes
Source
CE-67

• Delay in pain progression
• Pain response
• PSA response
• Objective tumor response

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SummarySatraplatin Safety

• Safety well established
• Myelosuppression and GI manifestations most
  frequent adverse events
• Adverse events mostly mild to moderate

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Agenda

• I. SPARC overview
• II. Response to FDA Briefing Document

31
Topic 1Definition of Composite PFS Endpoint

• No FDA experience with components of composite
  PFS endpoint used together
• All PFS components have been used individually or
  in combination in prior trials
• Pain response predicts survival TAX 327
• Review issue
• All PFS components of clinical relevance
• Statistically persuasive and consistent findings

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Topic 2 Independent Radiology Review

• Current state of the art
• Low pre-specified threshold for sending cases for
  adjudication
• Acceptable rate of adjudication
• 3,000 time-points
• 7,000 radiographic assessments

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Topic 2 38.6 Adjudication by Third Reader
Patients N 950n () Patients N 950n ()
Potential impact on PFS 201 (21.2)
No impact on PFS 166 (17.5)
Earlier non-radiographic PFS event 116
Disagreement on RECIST response 31
lt 7 days disagreement 19
Total adjudications 367 (38.6)
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Topic 2Worst-Case PFS Analysis Favors
Satraplatin

• PFS for worst-case scenario
• Earliest date for satraplatin
• Latest date for control

HR HR (95 CI), log scale
Intent to treat 0.67
Worst case 0.79
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Topic 3 Assessments of Pain Progression Aligned
With Draft FDA Guidance

• FDA standards changed after SPARC begana
• SPARC pain assessments
• Consistent with current psychometric standards
  (validity, reliability, sensitivity)
• Able to measure clinically meaningful differences
  
• Potential influence of language and culture on
  patient response is minimal

a FDA Draft Guidance for Industry on Patient
Reported Outcome Measures, 2006.
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Topic 3 Draft FDA Guidance on Patient Reported
Outcome Measures, 2006

• If documentation exists that a single item is a
  reliable and valid measure of the concept of
  interest (eg, pain severity), a one-item PRO
  instrument may be a reasonable measure to support
  a claim concerning that concept.

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(No Transcript)
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Topic 3Psychometric Properties

• Single-item numeric pain measure
• Internal consistency and inter-rater reliability
  not applicable to PPI
• Test-retest (baseline - week 1) r 0.8, p lt
  0.001
• Standard deviation of PPI in SPARC at baseline
  (1.09) suggests 0.5 reduction/ increase on this
  scale is a moderate effect (clinically
  significant)
• Pre-specified 1-unit increase in PPI reflects
  clinically significant pain progression

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Topic 3 No Substantive Effect of Culture,
Language, or Region on PPI

• Linear mixed effects model of within patient
  variationa
• Region effect lt 1
• Country effect 1.2
• Site effect lt 5

a Accounting for baseline PS, baseline
analgesics, treatment effect, and between-patient
effects.
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Topic 3 Landmark Analysis at Week 5 ? Overall
Survival by PPI Score
F_4.2.12.xls F_4.2.12_KM_OS_RespNoResp.doc
F_4.2L_KM_OS_ByPPI_at5wk.xls F_4.2L_KM_OS_ByPPI_a
t5.doc
Stratified log-rank p lt 0.0001
At risk
PPI 0
PPI 1
PPI 2
PPI 3
PPI 4
404 394 361 297 231 184 138 82 46 22
220 219 193 153 108 72 52 36 26 14
153 146 125 89 56 35 20 13 6 1
60 55 42 26 15 9 6 1 0 0
12 9 5 2 2 2 2 0 0 0
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Topic 3 Landmark Analysis at 3 Months? Overall
Survival in Pain Responders vs Non-responders
F_4.2.12.xls F_4.2.12_KM_OS_RespNoResp.doc
p lt 0.0001
Treatment Total Dead Alive Median
Pain non-responders 485 285 200 34.9
Pain responders 99 32 67 71.0
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Topic 3 Association of Pain Progression and
Bone Progression
Total number of pain progressions 199a
Pain progression with no documented bone progression 27.6
Pain and bone progression 72.4
a Minimum follow-up of 35 days after pain or bone
scan progression.
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Topic 3 PFS Favors Satraplatin Regardless of
Presence or Absence of Adverse Events
Grade Events, n HR HR (95 CI), log scale
Neutropenia 0 - 2 807 0.72
3 - 4 135 0.16
Thrombocytopenia 0 - 2 805 0.70
3 - 4 137 0.23
Gastrointestinal 0 - 2 902 0.68
3 - 4 40 0.46
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Topic 3 PPI Decrease 50 by Week in Patients
With No NSAIDs On Study
Odds ratio 1.7395 CI 1.57, 1.91 Stratified
log-rank p lt 0.0001
Number of patients with pain data and of
patients with PPI decrease by 50 by Week for No
NSAIDs.xls of Pain Responders over time in No
NSAID population.gif NEED SOURCE FOR PATIENT
NUMBERS
Patients
Satraplatin
Placebo
346 223 124 67 42 31 17
168 98 37 22 10 5 2
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Topic 3 PFS Analysis Excluding Pain Progression
Favors Satraplatin
Events, n HR HR (95 CI), log scale
All PFS events (ITT analysis) 802 0.67
All PFS events excluding pain progression 504 0.71
0.5
1.0
2.0
Favors satraplatin
Favors placebo
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Topic 4Only 51 of Patients Had Prior Docetaxel

• Docetaxel approved for HRPC 9 months after
  initiation of SPARC
• In SPARC, superiority of satraplatin arm over
  control arm not affected by prior docetaxel
• In the US, 90 of patients with HRPC currently
  receive first-line chemotherapy with docetaxel
• Claim for second-line chemotherapy
• Treatment following failure of the current
  standard of care

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Topic 5 Should FDA Wait for the Final Survival
Analysis Before Taking Action?

• Subpart H
• Created to make drugs available on the basis of
  preliminary evidence
• HRPC that has failed prior chemotherapy
• Unmet need
• Painful and debilitating disease
• Satraplatin
• Evidence of disease control
• Evidence of symptom control
• Well-established safety

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Proposed Indication
CC-4
Source

• Orplatna (satraplatin capsules) is indicated for
  the treatment of patients with androgen
  independent (hormone refractory) prostate cancer
  that has failed prior chemotherapy.