ce-1 the sparc trial: satraplatin in patients with androgen independent prostate cancer that has...
TRANSCRIPT
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CE-1
The SPARC Trial:Satraplatin in Patients With Androgen Independent Prostate Cancer That Has Failed First-Line Chemotherapy
Marcel Rozencweig, MD
Chief Medical OfficerGPC Biotech, Inc.
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CE-207/23/07
Agenda
I. SPARC overview
II. Response to FDA Briefing Document
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CE-307/23/07
Trial Design—Double-blind, Placebo-controlled Study
2:1
RANDOMIZE
Metastatic HRPC after 1 prior
chemotherapy
ECOG PS 0 - 1 vs 2
PPI 0 - 1 vs 2 - 5
PSA vs tumor progression
Stratify
Placebo 80 mg/mPlacebo 80 mg/m22 d1-5 q 35d d1-5 q 35dPlacebo 1 mg BID d1-5 q 35d Placebo 1 mg BID d1-5 q 35d
Prednisone 5 mg BIDPrednisone 5 mg BID
Satraplatin 80 mg/mSatraplatin 80 mg/m22 d1-5 q 35d d1-5 q 35dGranisetron 1 mg BID d1-5 q 35dGranisetron 1 mg BID d1-5 q 35d
Prednisone 5 mg BIDPrednisone 5 mg BID
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CE-407/23/07
Endpoints
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)
SourceCE-40
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CE-507/23/07
Statistical Considerations
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
p 19 CE - DVCE-41
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CE-607/23/07
Composite PFS Endpoint(Excluded PSA)
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
pp 16-17 COCE-43
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CE-707/23/07
Disease-Related Pain Assessments
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
p 17 CO – DV 5/8CE-45
a Tannock. J Clin Oncol. 1996;14:1756; b Melzack. Pain. 1975;1:277.
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CE-807/23/07
Pain Progression Assessment
SPARC NDA 19-297/S-014PPI assessment
Continuous One day q3wks
Confirmed Δ 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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CE-907/23/07
Central Adjudication of Progression Events Independent Review Committee (IRC)
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
p 17 CO- DV 5/8CE-47
a Except for the first 53 patients.
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CE-1007/23/07
Enrollment by Country (N = 950)
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
SourceCE-51
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CE-1107/23/07
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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CE-12
SPARC
Efficacy
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CE-1307/23/07
0
10
20
30
40
50
60
70
80
90
100
0 10 20 30 40 50 60 70 80 90
Time, weeks
% P
ati
en
ts
Satraplatin + prednisone
Placebo + prednisone
Primary Endpoint—Progression-Free Survival (IRC Adjudicated)
HR = 0.6795% CI: 0.57, 0.77
Stratified log-rank p < 0.0001
Satraplatin 635 363 229 143 90 63 43 24 18 12
Placebo 315 140 63 37 24 11 5 5 1 0
Number at risk
Page 53 of CE - DVCE-11
30%
17%
16%7%
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CE-1407/23/07
Distribution of IRC-Defined PFS Events
Satraplatin +prednisone
n = 528(%)
Placebo + prednisone
n = 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
SourceCE-66
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CE-1507/23/07
Progression-Free Survival—Prior Docetaxel (IRC)
0
10
20
30
40
50
60
70
80
90
100
0 10 20 30 40 50 60 70 80 90
Time, weeks
% P
ati
en
ts
Satraplatin + prednisone Placebo + prednisone
HR = 0.6795% CI: 0.54, 0.83
Stratified log-rank p = 0.0006
Satraplatin 327 167 107 69 39 28 19 13 9 5
Placebo 160 61 28 16 8 4 1 1 0 0
Number at risk
efficacy odac.ppt s 12; Page 74 of SCE EF-49
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CE-1607/23/07
PFS Hazard Ratios by Patient SubsetsHR (95% CI), log scale
0.2 1.0 2.00.5Favors satraplatin Favors placebo
Subgroup N HRITT 950 0.67ECOG = 0 - 1 848 0.66ECOG = 2 102 0.72PPI = 0 327 0.70PPI ≥ 1 584 0.67Tumor progression 522 0.62PSA progression only 426 0.74Age < 65 273 0.74Age ≥ 65 677 0.63LDH < 2 × ULN 776 0.66LDH ≥ 2 × ULN 89 0.50Hemoglobin < 11 g/dL 204 0.54Hemoglobin ≥ 11 g/dL 744 0.69Alkaline phosphatase < 1.5 × ULN 562 0.68Alkaline phosphatase ≥ 1.5 × ULN 374 0.60Prior docetaxel 487 0.67No prior docetaxel 463 0.67No bisphosphonate 669 0.62Bisphosphonate 281 0.74Caucasians 841 0.68Non-Caucasians 109 0.60North America 261 0.67Outside North America 689 0.65
SCE Fig 2 p 57 - DVCE-17
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CE-1707/23/07Page 60 of CE - DV
HR (95% CI), log scale
0.2 1.0 2.00.5Favors satraplatin Favors placebo
Subgroup N HRITT 950 0.64ECOG = 0 - 1 848 0.63ECOG = 2 102 0.69PPI = 0 327 0.69PPI ≥ 1 584 0.63Tumor progression 529 0.51PSA progression only 420 0.86Age < 65 273 0.69Age ≥ 65 677 0.61LDH < 2 × ULN 776 0.59LDH ≥ 2 × ULN 89 0.59Hemoglobin < 11 g/dL 204 0.52Hemoglobin ≥ 11 g/dL 744 0.64Alkaline phosphatase < 1.5 × ULN 562 0.71Alkaline phosphatase ≥ 1.5 × ULN 374 0.55Prior docetaxel 487 0.66No prior docetaxel 463 0.60No bisphosphonate 600 0.59Bisphosphonate 350 0.71Caucasians 841 0.64Non-Caucasians 109 0.67North America 261 0.62Outside North America 689 0.62
CE-25Time to Pain Progression—Prespecified Secondary Endpoint (IRC)
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CE-1807/23/07
Pain Responsea (Pre-specified Analysis)
13.8%
24.2%
0
5
10
15
20
25
30
Satraplatin + prednisone Placebo + prednisone
% p
atie
nts
wit
h p
ain
res
po
nse
p < 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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CE-1907/23/07
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 > 8 (p = 0.005)
a 40 mg morphine po = 8.
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CE-2007/23/07
Exploratory Analysis—Weekly Percentage of Patients With ≥ 50% PPI Decrease
Satraplatin Placebo
0 10 20 30 40 50 60
0
Time, wk
10
20
30
40
Cu
mu
lati
ve %
of
pat
ien
ts
Odds ratioa = 1.98 95% CI: 1.81, 2.16
p < 0.0001
a OR derived from a Repeated Measures Logistic Regression model with baseline PPI as covariate.
Satraplatin n = 432 287 161 90 55 37 21
Placebo n = 222 132 46 27 12 7 4
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CE-2107/23/07
Pre-specified PSA and Tumor Response Rates
12.4%
25.4%
0
5
10
15
20
25
30
Satraplatin +prednisone
Placebo +prednisone
% p
ati
en
ts w
ith
≥ 5
0%
de
cre
as
e i
n P
SA
p < 0.0001
n = 476 n = 225
8.0%
0.7%
0
1
2
3
4
5
6
7
8
Satraplatin +prednisone
Placebo +prednisone
% p
ati
en
ts
p = 0.002
n = 274 n = 134
Bubley criteria RECIST criteria
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CE-2207/23/07
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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CE-23
SPARC
Safety
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CE-2407/23/07
Grade 3 - 4 Myelosuppression
Grade 3 - 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
p 21 SCS, Table 7 - DVCE-61
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CE-2507/23/07
Nonhematologic Adverse Events With Higher Incidence in Satraplatin Arm
All grades 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
Clin overview Tables 18, 19, 20 SA-3
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CE-26
SPARC
Summary and Discussion
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CE-2707/23/07
Summary—Satraplatin Efficacy
Primary endpoint (PFS) achieved with very robust results– 33% risk reduction of disease progression
or death– p < 0.0001
Clinical relevance– Primarily driven by a delay in tumor progression
and pain progressionConsistency across sensitivity and
subset analyses– Prior or no prior docetaxel
SourceCE-63
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CE-2807/23/07
Summary—Satraplatin Positive Outcomes
Delay in pain progression
Pain response
PSA response
Objective tumor response
SourceCE-67
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CE-2907/23/07
Summary—Satraplatin Safety
Safety well established
Myelosuppression and GI manifestations most frequent adverse events
Adverse events mostly mild to moderate
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CE-3007/23/07
Agenda
I. SPARC overview
II. Response to FDA Briefing Document
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CE-3107/23/07
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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CE-3207/23/07
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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CE-3307/23/07
Topic #2 38.6% Adjudication by Third Reader
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
< 7 days disagreement 19
Total adjudications 367 (38.6)
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CE-3407/23/07
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
0.5 1.0 2.0
Favors Satraplatin Placebo
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CE-3507/23/07
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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CE-3607/23/07
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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CE-3707/23/07
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CE-3807/23/07
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 < 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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CE-3907/23/07
Topic #3: No Substantive Effect of Culture, Language, or Region on PPI
Linear mixed effects model of within patient variationa
– Region effect < 1%
– Country effect = 1.2%
– Site effect < 5%
a Accounting for baseline PS, baseline analgesics, treatment effect, and between-patient effects.
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CE-4007/23/07
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 10 20 30 40 50 60 70 80 90
Time, wk
Pro
po
rtio
n e
ve
nt
fre
e
PPI 0PPI 1PPI 2PPI 3PPI 4
Stratified log-rank p < 0.0001
404 394 361 297 231 184 138 82 46 22220 219 193 153 108 72 52 36 26 14153 146 125 89 56 35 20 13 6 160 55 42 26 15 9 6 1 0 012 9 5 2 2 2 2 0 0 0
At riskPPI 0PPI 1PPI 2PPI 3PPI 4
F_4.2.12.xls; F_4.2.12_KM_OS_RespNoResp.doc
Topic #3: Landmark Analysis at Week 5 ― Overall Survival by PPI Score
F_4.2L_KM_OS_ByPPI_at5wk.xls; F_4.2L_KM_OS_ByPPI_at5.doc
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CE-4107/23/07
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 10 20 30 40 50 60 70 80 90
Time, wk
Su
rviv
al
pro
ba
bil
ity
Pain non-responders
Pain responders
p < 0.0001
F_4.2.12.xls; F_4.2.12_KM_OS_RespNoResp.doc
Topic #3: Landmark Analysis at 3 Months― Overall Survival in Pain Responders vs Non-responders
Treatment Total Dead Alive Median
Pain non-responders 485 285 200 34.9
Pain responders 99 32 67 71.0
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CE-4207/23/07
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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CE-4307/23/07
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
0.02 0.1 1.0 2.0
Favors Satraplatin Placebo
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CE-4407/23/07
Topic #3: PPI Decrease ≥ 50% by Week in Patients With No NSAIDs On Study
0
10
20
30
40
0 10 20 30 40 50 60
Time, weeks
% P
atie
nts
Satraplatin (n = 346)
Placebo (n = 168)
Odds ratio = 1.7395% CI: 1.57, 1.91
Stratified log-rank p < 0.0001
Num
ber
of
pat
ien
ts w
ith p
ain
da
ta
an
d %
of
patie
nts
with
PP
I de
cre
ase
by
50%
by
We
ek f
or
No
NS
AID
s.xl
s%
of
Pa
in R
esp
on
de
rs o
ver
time
in N
o N
SA
ID p
op
ula
tion
.gif
NE
ED
SO
UR
CE
FO
R P
AT
IEN
T N
UM
BE
RS
346 223 124 67 42 31 17
168 98 37 22 10 5 2
Patients
Satraplatin
Placebo
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CE-4507/23/07
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
Favors satraplatin Favors placebo0.5 1.0 2.0
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CE-4607/23/07
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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CE-4707/23/07
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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CE-4807/23/07
Proposed Indication
Orplatna® (satraplatin capsules) is indicated for the treatment of patients with androgen independent (hormone refractory) prostate cancer that has failed prior chemotherapy.
CC-4 Source