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INTERGROUP COALITION AGAINST SARCOMAS (ICAS)
• SCIENTIFIC STEERING COMMITTEE: EC Borden, G Demetri, M von Mehren, K Albritton, P Pisters
• BIOSTATISTICS: C Rankin, J Crowley• OPERATIONS: G Goetz (SWOG)
A COMMITTEE FOCUSED ON INTERGROUP A COMMITTEE FOCUSED ON INTERGROUP
DEVELOPMENT OF NEW SARCOMA THERAPEUTICSDEVELOPMENT OF NEW SARCOMA THERAPEUTICS
CALGB ECOG NCIC SWOG CALGB ECOG NCIC SWOG
Collaborations with COG and ACOSOGCommunication with SARC and RTOG
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2001-20062001-2006INTERGROUP COALITION AGAINST SARCOMASINTERGROUP COALITION AGAINST SARCOMAS
Goals and Hypotheses • Sharpen definition of histologic subtypes to improve
therapeutic outcomes and prognosis– Hypothesis: Molecular pathology will better define subtypes and thus improve
clinical management and outcomes
• Emphasize targeted therapeutics– Hypothesis: Signal transduction modulators will be effective and histology
specific
• Facilitate intergroup collaborations– Hypothesis: Increased intergroup collaboration will stimulate sarcoma research
State of Science Clin Cancer Research 2003
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ICAS STUDIESICAS STUDIES
Metastatic Disease: CompletedMetastatic Disease: Completed ICAS # Sarcoma Target Inhibitor Prior Rx
S0033 GIST KIT imatinib Y
S0218 Mesothelioma EGF-R erlotinib N
S0330 MPNST EGF-R erlotinib N
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OVERALL SURVIVAL GIST ON OVERALL SURVIVAL GIST ON IMATINIB (ICAS S0033)IMATINIB (ICAS S0033)
0%0%
20%20%
40%40%
60%60%
80%80%
100%100%
00 22 44 66Years after RegistrationYears after Registration
400 mg/day400 mg/day800 800 mg/daymg/day
NN345345345345
DeathsDeaths168168 174174
MEDIAN (m)MEDIAN (m)55555151 CR=4%
PR=48%
2y=74%2y(historical)=26%
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S0502: SCHEMA
Imatinib mesylate 400 mg/d po continuously
Bevacizumab 15 mg/kg iv q3 weeks
Imatinib mesylate 400 mg/d po continuously
Incurable GIST
RANDOMIZE
Stratify PS 0-1 vs. 2-3
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S0502: ObjectivesS0502: Objectives• Primary: PFS of imatinib + bevacizumab vs
imatinib alone
• Secondary:– Compare response between arms– Compare frequency and severity of toxicities– Assess survival differences– Correlative
• Mutations VEGF and Receptors
• PET PK
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Study Coordinators
• OVERALL CHAIR: Charles Blanke SWOG
• Translational Medicine: Michael Heinrich SWOG
• Pathology: Christopher Corless SWOG
• ECOG: Meg von Mehren
• CALGB: George Demetri
• NCIC: Vivien Bramwell
• Imaging: Janet Eary
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ICAS STUDIESICAS STUDIESMetastatic Disease: ActiveMetastatic Disease: Active
ICAS # Sarcoma Target Inhibitor Prior Rx Accrual
S0345 DFSP PDGF-R imatinib Y 7
S0346 Synovial HER2* trastuzumab Y 0
S0505 STS VEGF sorafenib Y 22
S0423 Chondro MTAP pemetrexed Y 11
S0344 Chondro ---- Surgery N 16
CTSU!!!!CTSU!!!!!!!!
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ICAS STUDIESICAS STUDIESMetastatic Disease: PlannedMetastatic Disease: Planned
ICAS # Sarcoma Target Inhibitor Prior Rx PI
0405 synovial (neoaj) bcl-2 antisense+AI N Albritton
0502 GIST c-kit VEGF Imatbbevamab N Blanke
0612 GIST KIT GW786034 Y Budd
0418 GIST <30y KIT imatinib N Pappo
0631 MFH/Osteo SRC dasatinib Y Chu
CTSU!!!!CTSU!!!!!!
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ICAS STUDIESICAS STUDIESMetastatic Disease: Proposals for Executive CommitteeMetastatic Disease: Proposals for Executive Committee
Sarcoma Target Inhibitor Prior Rx PI
Desmoid PDGF-R sunitinib Y Ryan
STS VEGF bevacizumab N* Verschraegen
* Phase III: AI
MFH m-TOR temsirolimus Y TBD
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CHALLENGES SARCOMAS: 2006CHALLENGES SARCOMAS: 2006
• CLINICAL BIOLOGY AND OUTCOMES
• CURRENT MANAGEMENT AND STANDARDS OF CARE
• EMPHASIZE CLINICAL PROGRESS
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CHALLENGES SARCOMAS: 2006CHALLENGES SARCOMAS: 2006
• CLINICAL BIOLOGY AND OUTCOMES– What do we know?
• CURRENT MANAGEMENT AND STANDARDS OF CARE– How are we doing?
• FUTURE RESEARCH CHALLENGES – Where should we be going?
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CHALLENGES SARCOMAS: CHALLENGES SARCOMAS: 20062006
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Euramos 1 Phase 3 TrialEuropean and American Osteosarcoma Study Group
• Collaborators: COG German Austrian Swiss (COSS) European (EOI) Scandinavian (SSG) Trial Mgmt Group Chair M Bernstein Montreal COG
• Objectives: Improve EFS – Will IE when added to MAP for poor histological responders?– Will PEG-IFN when added to MAP for good histological responders?
• Eligibility– Resectable axial or extremity osteosarcoma– <40
• Registration2 cycles MAPsurgery path reveiw Random MAPx2 MAPx2 MPx2PEG-IFNx2y or IEx3– n=1400– 10% improvement in EFS
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INTERGROUP COALITION AGAINST SARCOMAS (ICAS)Ernest C. Borden Chair•
• Catherine Rankin Biostatistics SWOG• John Crowley Biostatistics SWOG• Gretchen Goetz Operations SWOG
– SWOG ECOG CALGB NCIC – collaboration with COG ACOSOG
• M von Mehren G Demetri B Redman V Bramwell • K Albritton P Pisters
– Communication with SARC
A COMMITTEE FOCUSED ON INTERGROUP A COMMITTEE FOCUSED ON INTERGROUP
DEVELOPMENT OF NEW SARCOMA THERAPEUTICSDEVELOPMENT OF NEW SARCOMA THERAPEUTICS
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SARCOMAS SARCOMAS NEW ERA 2000NEW ERA 2000
• MOLECULAR REDEFINITION
• IMPROVE PRIMARY TREATMENT
• TARGETED THERAPIES
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IMPROVING GIST PATIENT OUTCOMESIMPROVING GIST PATIENT OUTCOMES• Eliminating GIST stem cell
– Few residual clones: ACOSOG #Z9001 – Imatinib with other KIT/PDGF-R tyrosine kinase inhibitors
• S0612
• Targeting of specific mutations– S0033 – S0033 and EORTC combined analysis– new inhibitors: S0612
• Inhibition of alternate pathways– Angiogenesis: Bevacizumab S0502
• Improved resonse assessement – S0502
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ICASICAS
HER2 Expression in Synovial SarcomasHER2 Expression in Synovial Sarcomas
Her2/neuHer2/neu
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S0346 Trastuzumab for Synovial Sarcomas
• Eligibility– Metastatic Synovial Sarcomas – Central confirmation of her2 expression 2+ 1 prior treatment
• Dose/Schedule– IV weekly 4 mg/kg loading, then 2 mg/kg
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SARCOMAS SARCOMAS NEW ERA 2000NEW ERA 2000
•MOLECULAR REDEFINITIONMOLECULAR REDEFINITION
•IMPROVED PRIMARY IMPROVED PRIMARY OUTCOMES OUTCOMES
•TARGETED THERAPIESTARGETED THERAPIESCase Comprehensive Cancer Center CCF Taussig Cancer Center
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IMPACT OF DOSE OF IMATINIB IMPACT OF DOSE OF IMATINIB ON TOXICITY: ICAS S0033ON TOXICITY: ICAS S0033
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EGF-R EXPRESSION AND INHIBITION IN MPNST
Intense membrane Intense membrane stainingstaining
EGF-R inhibitors EGF-R inhibitors DeClue et al JCI DeClue et al JCI
20002000