SCH 717454 in Subjects with Relapsed

Osteosarcoma or Ewing’s Sarcoma

Protocol P04720

CTOS Nov 2008

2

Disclosure

• Neither I , nor my colleagues have any stock nor have we been paid consultants of Schering-Plough

• Investigators have received research funds for this study (P04720).

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Insulin Growth Factor Pathway

IGF-II/IGF-I

IGF-1R

PP

PERK1/2

AKT

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SCH 717454: A Potent & Specific anti-IGF-1R Monoclonal Antibody

High Affinity Fully Human IgG1 clone 19D12

Does Not Recognize Insulin Receptor

Properties and Activities That May Contribute To Antitumor Effects:

• Inhibits IGF ligand binding and IGF-1R signaling

• Downregulation of IGF-1R protein level

• Antibody-dependent cellular cytotoxicity

• Enhances other agents in pre-clinical studies

IGF-1R IGF-1R/IR

dimer

InsulinReceptor

(IR)

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SCH717454 & Osteosarcoma Xenografts

• Inhibits osteosarcoma, Ewing’s sarcoma & neuroblastoma xenografts

• Pediatric preclinical testing program: complete responses in 2 out of 6 osteosarcoma (OS1, OS9) & 1 Ewing’s sarcoma cell line (EW5). Improved Event Free survival in 4/6 osteosarcoma and 2/5 Ewing’s models.

•Kolb, Gorlick et al. 2008

SCH 717454 Inhibits SJSA-1 Growth in vivo

Staged model, 2 x weekly

SCH 717454 Causes Regression of OS-1 in vivo (PPTP / NCI)

1 2 3 4 5 60

4.0

3.0

2.0

1.0

0.0

Treatment

Control

Rel

ativ

e T

um

or

Vo

lum

e

Time (weeks)

0

250

500

750

1000

1250

1500

1750

2000

0 2 4 6 8 10 12 14 16 18 20 22 24

Days (post dosing)

Tu

mo

r S

ize

(m

m3 )

Vehicle Control 0.02 mg SCH 7174540.1 mg SCH 7174540.5 mg SCH 717454

Staged model, starting tumor volume: 250 mm3, 0.5 mg SCH 717454, 2 x weekly

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Endpoints Primary: Response Secondary: TTP, Safety, PK, PD

Recurrent/refractoryOsteosarcoma or Ewing’s Sarcoma(N25-50 each)

Recurrent/refractoryOsteosarcoma or Ewing’s Sarcoma(N25-50 each)

SCH 717454 10 mg/kg

Q 2 weeks

SCH 717454 10 mg/kg

Q 2 weeks

Refractory Osteosarcoma or Ewing’s Sarcoma Cohorts

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Key Inclusion/Exclusion Criteria

• Key Inclusions– ≥11 years of age – Osteosarcoma or Ewing’s sarcoma

• Key Exclusions

– Diabetics: hemoglobin A1C >7.5% – Heart disease, hepatitis or active infection– Prior anti-IGF-1R drug

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Serum IGF-1 Concentrations During Treatment

0

100

200

300

400

500

600

700

Baseline 2 wks after Single Dose (Trough Level)

SubsequentDoses (at Trough)

IGF

-1 b

loo

d le

ve

l (n

g/m

l)

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IGF-1R Occupancy On Peripheral Blood Mononuclear Cells

0

10

20

30

40

50

60

Baseline Two Weeks Post-Dose (Obtained at Trough)

% o

f IG

F-1

R u

n-o

ccu

pie

d Flow cytometry assay measuring the percent of cells that bind labeled SCH

717454at baseline (blue)

versus2 weeks post single dose of

SCH 717454 (purple)

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Preliminary Response Data

• Osteosarcoma: stable disease in >5* (1 stable to >6 months; another ongoing response with both lung and bone metastases)

• Ewings: 3 PRs; some of subjects with mixed responses

*Initial data on subject at 8 weeks on study

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Preliminary Ewing’s Response

Before After Single Dose

11 year old female with recurrent/refractory Ewing’s Sarcoma s/p 3 prior therapies

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Responding Ewing’s Sarcoma

Before After (8 weeks)

29 year old male with recurrent/refractory Ewing’s Sarcoma s/p 3 prior therapies

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Near Complete Response in Ewing’s

Before at 8 week assessment

28 year old male with recurrent/refractory Ewing’s Sarcoma s/p 2 prior therapies

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Most Common Adverse Events

Adverse EventIncidence

Grade 1 Grade 2 Grade 3 Grade 4

Headache 5 (8%) 1 (2%) 0 0

Fatigue 1 (2%) 3 (5%) 0 0

Hyperglycemia 3 (5%) 0 1 (2%) 0

Pruritus 3 (5%) 1 (2%) 0 0

Nausea 3 (5%) 1 (2%) 0 0

Back Pain 0 0 3 (5%) 0

Constipation 1 (2%) 1 (2%) 1 (2%) 0

Dyspnoea 1 (2%) 1 (2%) 1 (2%) 0

Pneumothorax 2 (3%) 0 1 (2%) 0

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Safety/Tolerability Summary

• Well tolerated

– Most AEs mild or moderate

• Hyperglycemia

– Generally mild if present

– Only 1 moderate/severe event in an adult diabetic

– No severe or life-threatening drug-related AEs

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P04720: Group 1

Recurrence

TTP

ResectableDisease

ResectableDisease

SCH 717454 Dose Level

1

SCH 717454 Dose Level

1

Prior Surgery

Prior Surgery

Recurrence

Surgery

SCH 717454 Dose Level 2SCH 717454 Dose Level 2

Tumor Proliferation

Tumor Proliferation

TTP

SCH 717454 Dose Level

1

SCH 717454 Dose Level

1

SCH 717454 Dose Level

2

SCH 717454 Dose Level

2

Primary Endpoint: tumor proliferation Secondary Endpoint: TTP/Time to relapse

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Summary

• Potent in preclinical models

• Clinically well-tolerated

– Hyperglycemia uncommon, mostly mild

• Clinically active in Ewing’s sarcoma

• Stable disease in Osteosarcoma

• Enrollment continuing- North America, Europe, and South America

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Acknowledgements

• Contributing Investigators

– Drs. Anderson, Skubitz, Miller, Meyer, Arico, Mita, Chawla, Katzenstein, O’Day, Desai, Villarroel, Lopez, Van de Graaf, Mas, Sandoval, Marec-Berard, Jean-Gentet, Bielack, and Klingelbiel

• Schering Plough Personnel– Drs. Lu, and Wang; Ms. Whitman

• All the patients and their families

• ? Questions?