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.

CE-207/23/07

Agenda

I. SPARC overview

II. Response to FDA Briefing Document

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

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

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

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

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.

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

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.

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

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

CE-12

SPARC

Efficacy

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%

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

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

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

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)

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.

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.

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

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

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)

CE-23

SPARC

Safety

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

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

CE-26

SPARC

Summary and Discussion

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

CE-2807/23/07

Summary—Satraplatin Positive Outcomes

Delay in pain progression

Pain response

PSA response

Objective tumor response

SourceCE-67

CE-2907/23/07

Summary—Satraplatin Safety

Safety well established

Myelosuppression and GI manifestations most frequent adverse events

Adverse events mostly mild to moderate

CE-3007/23/07

Agenda

I. SPARC overview

II. Response to FDA Briefing Document

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

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

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)

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

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.

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.”

CE-3707/23/07

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

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.

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

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

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.

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

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

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

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

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

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