intergroup coalition against sarcomas (icas) scientific steering committee: ec borden, g demetri, m...

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

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

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

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%

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

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

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

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!!!!!!!!

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!!!!!!

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

CHALLENGES SARCOMAS: 2006CHALLENGES SARCOMAS: 2006

• CLINICAL BIOLOGY AND OUTCOMES

• CURRENT MANAGEMENT AND STANDARDS OF CARE

• EMPHASIZE CLINICAL PROGRESS

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?

CHALLENGES SARCOMAS: CHALLENGES SARCOMAS: 20062006

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

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

SARCOMAS SARCOMAS NEW ERA 2000NEW ERA 2000

• MOLECULAR REDEFINITION

• IMPROVE PRIMARY TREATMENT

• TARGETED THERAPIES

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

ICASICAS

HER2 Expression in Synovial SarcomasHER2 Expression in Synovial Sarcomas

Her2/neuHer2/neu

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

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

IMPACT OF DOSE OF IMATINIB IMPACT OF DOSE OF IMATINIB ON TOXICITY: ICAS S0033ON TOXICITY: ICAS S0033

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