Download - SCH 717454 in Subjects with Relapsed Osteosarcoma or Ewing’s Sarcoma Protocol P04720 CTOS Nov 2008
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SCH 717454 in Subjects with Relapsed
Osteosarcoma or Ewing’s Sarcoma
Protocol P04720
CTOS Nov 2008
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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
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Days (post dosing)
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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
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Baseline 2 wks after Single Dose (Trough Level)
SubsequentDoses (at Trough)
IGF
-1 b
loo
d le
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g/m
l)
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IGF-1R Occupancy On Peripheral Blood Mononuclear Cells
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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?