I

S

G

taliantalian

SSarcomaarcoma

GG

ActivatedJune 1997ActivatedJune 1997

FormalizedOctober 2002Formalized

October 2002

www.italiansarcomagroup.orgwww.italiansarcomagroup.org

rouproup

II

53 Centers

• 10 I.R.C.C.S.

• 12 Universities

• 25 Public Hospitals

• 6 Private Hospitals

53 Centers

• 10 I.R.C.C.S.

• 12 Universities

• 25 Public Hospitals

• 6 Private Hospitals

Italian Sarcoma GroupItalian Sarcoma Group

172 Members172 Members

11

1 21

11

198 2

1

1 111

1 3

1

1

1 at 24 March 2004at 24 March 2004

11

21 1

1

2

3

1

1BELGIO

Osteosarcoma ISG/SSG I - Localized diseaseOsteosarcoma ISG/SSG I - Localized disease

MTX: Methotrexate 12 g/m2 as 4 hours i.v. infusion, increase by 2 g/m2 if 4 hours serum MTX in previous course was < 1000 µmol/l

CDP1: Cisplatin 60 mg/m2/24 hour as 48 hours continuous i.v. infusion CDP2: Cisplatin 75 mg/m2/24 hour as 48 hours continuous i.v. infusion ADM1: Adriamycin (Doxorubicin) 75 mg/m2 as 24 hours continuous i.v. InfusionADM2: Adriamycin (Doxorubicin) 90 mg/m2 as 24 hours continuous i.v. infusionIfo: Ifosfamide 3 g/m2/24 hour as 120 hours (5 day) continuous i.v. infusion

MTX: Methotrexate 12 g/m2 as 4 hours i.v. infusion, increase by 2 g/m2 if 4 hours serum MTX in previous course was < 1000 µmol/l

CDP1: Cisplatin 60 mg/m2/24 hour as 48 hours continuous i.v. infusion CDP2: Cisplatin 75 mg/m2/24 hour as 48 hours continuous i.v. infusion ADM1: Adriamycin (Doxorubicin) 75 mg/m2 as 24 hours continuous i.v. InfusionADM2: Adriamycin (Doxorubicin) 90 mg/m2 as 24 hours continuous i.v. infusionIfo: Ifosfamide 3 g/m2/24 hour as 120 hours (5 day) continuous i.v. infusion

PRE-OP PRE-OP MTXMTX--CDP1CDP1//ADM1ADM1--IFOIFO X 2 X 2

POST-OP POST-OP ADM2ADM2--IFOIFO--MTXMTX--CDP2 CDP2 X 3 (4 IN POOR)X 3 (4 IN POOR)

ISG/SSG I (localized osteosarcoma)ISG/SSG I (localized osteosarcoma)

March 1997 – May 2000March 1997 – May 2000Total cases: 182Total cases: 182

Manuscript ready for submissionManuscript ready for submission

0

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0 12 24 36 48 60 72 84months

OS

EFS

Osteosarcoma ISG/SSG II - Metastases at diagnosis

Postoperative treatmentOsteosarcoma ISG/SSG II - Metastases at diagnosis

Postoperative treatment

ADM2ADM2 ADM2ADM2

HDEC+PBSC rescueHDEC+PBSC rescue

E1E1E1E1E1E1

CyCy

PBSC if necessary

PBSC if necessary

ADM2ADM2 ADM2ADM2

HDEC+PBSC rescueHDEC+PBSC rescue

E1E1E1E1E1E1

CyCy

PBSC if necessary

PBSC if necessary

15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 week

15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 week

ADM2: Adriamycin (Doxorubicin) 90 mg/m2 as 24 hours continuous i.v. infusionCy: Cyclofosfamide 4000 mg/m2 as 3 hour continuous i.v. infusion

E1: Etoposide 200 mg/m2/day as 72 hour (3 day ) continuous i.v. infusion

HDEC+PBSC rescue:Etoposide 450 mg/m2/day as 4 day continuous i.v. infusion Carboplatin 375 mg/m2/day for 4 days (2 hour infusion)Peripheral blood stem cell (PBSC) rescue at 72 hours after and of chemotherapy

ADM2: Adriamycin (Doxorubicin) 90 mg/m2 as 24 hours continuous i.v. infusionCy: Cyclofosfamide 4000 mg/m2 as 3 hour continuous i.v. infusion

E1: Etoposide 200 mg/m2/day as 72 hour (3 day ) continuous i.v. infusion

HDEC+PBSC rescue:Etoposide 450 mg/m2/day as 4 day continuous i.v. infusion Carboplatin 375 mg/m2/day for 4 days (2 hour infusion)Peripheral blood stem cell (PBSC) rescue at 72 hours after and of chemotherapy

Abstract to be presented ASCO 2005Abstract to be presented ASCO 2005

ISG/SSG II

(metastatic osteosarcoma)

ISG/SSG II

(metastatic osteosarcoma)

March 1998 – December 2003March 1998 – December 2003

Total cases: 47Total cases: 47

RANDOMRANDOMRANDOMRANDOM

Arm AArm A(M-P/A) x 2(M-P/A) x 2

Arm AArm A(M-P/A) x 2(M-P/A) x 2

Arm BArm BM-P/A- M-I/P- M-P/A- M-I/P-

M-I/AM-I/A

Arm BArm BM-P/A- M-I/P- M-P/A- M-I/P-

M-I/AM-I/A

Necrosis ≥ 90% A-M-PNecrosis ≥ 90% A-M-P

Necrosis < 90% A-I-M-PNecrosis < 90% A-I-M-P

Necrosis ≥ 90% A-M-PNecrosis ≥ 90% A-M-P

Necrosis < 90% A-I-M-PNecrosis < 90% A-I-M-P

P/A-M-M-I/P-I/AP/A-M-M-I/P-I/AP/A-M-M-I/P-I/AP/A-M-M-I/P-I/A

LOCALIZED OSTEOSARCOMALOCALIZED OSTEOSARCOMA

ISG/OS-1ISG/OS-1April 2001 – OngoingApril 2001 – Ongoing

At october 2004: 166 pts.At october 2004: 166 pts.

LOCALIZED OSTEOSARCOMALOCALIZED OSTEOSARCOMA

ISG/OS-1ISG/OS-1April 2001 – OngoingApril 2001 – Ongoing

At october 2004: 166 pts.At october 2004: 166 pts.

Pts. expected: 264 in 5 yrsPts. expected: 264 in 5 yrs..Pts. expected: 264 in 5 yrsPts. expected: 264 in 5 yrs..

EURO-B.O.S.S.EUROpean Bone Over 40 Sarcoma Study

EURO-B.O.S.S.EUROpean Bone Over 40 Sarcoma Study

IItalian talian SSarcoma arcoma GGrouproup CCooperative ooperative OSOSteosarcoma teosarcoma SStudytudy SScandinavian candinavian SSarcoma arcoma GGrouproup

IItalian talian SSarcoma arcoma GGrouproup CCooperative ooperative OSOSteosarcoma teosarcoma SStudytudy SScandinavian candinavian SSarcoma arcoma GGrouproup

CDP-ADM-IFO as adjuvant or neoadjuvant CDP-ADM-IFO as adjuvant or neoadjuvant treatment (MTX only in selected patients)treatment (MTX only in selected patients)

December 2002-ongoingDecember 2002-ongoing

At october 2004: 30 patients ISGAt october 2004: 30 patients ISG

CDP-ADM-IFO as adjuvant or neoadjuvant CDP-ADM-IFO as adjuvant or neoadjuvant treatment (MTX only in selected patients)treatment (MTX only in selected patients)

December 2002-ongoingDecember 2002-ongoing

At october 2004: 30 patients ISGAt october 2004: 30 patients ISG

R 1R 1 VACA-IEVACA-IE

R 2R 2

R 3R 3

HiperVAI+CEHiperVAI+CE

NecrosisNecrosis

LLOOCCAALL

TTHHEERRAAPPYY

LLOOCCAALL

TTHHEERRAAPPYY

ISG/SSG III and IV (Ewing family tumors)ISG/SSG III and IV (Ewing family tumors)

VAC+IEVAC+IE

VAC+IEVAC+IE

StandardStandard

HDTHDT

HDTHDT

HiperCEHiperCE VAC+IEVAC+IEMini-alloMini-allo

HDTHDT

ISG/SSG III (Standard risk)ISG/SSG III (Standard risk)

June 1999 – ongoingJune 1999 – ongoing

At October 2004: 223 patientsAt October 2004: 223 patients

June 1999 – ongoingJune 1999 – ongoing

At October 2004: 223 patientsAt October 2004: 223 patients

GOOD RESPONDERS 53%

RESPONSE 183 pts.

POOR RESPONDERS 47%

GOOD RESPONDERS 53%

RESPONSE 183 pts.

POOR RESPONDERS 47%

70 pts. completed HD treatment70 pts. completed HD treatment- No major organ toxicity

- No toxic death

- No major organ toxicity

- No toxic death

ISG/SSG IV (High risk)ISG/SSG IV (High risk)

41 PTS completed HD treatment41 PTS completed HD treatment

- 10 progression disease

- 1 toxic death

- 10 progression disease

- 1 toxic death

Abstract to be presented at ASCO 2005Abstract to be presented at ASCO 2005

June 1999 – ongoingJune 1999 – ongoing

At October 2004: 72 patientsAt October 2004: 72 patients

June 1999 – ongoingJune 1999 – ongoing

At October 2004: 72 patientsAt October 2004: 72 patients

0

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0 10 20 30 40 50 60 70Time

Kaplan-Meier Cum. Survival Plot for OS T Censor Variable: CENS OS

3 year OS 54% (38-69)Median FU 19 months (1-62)

• IFO 9 g/m2 in 3 days• EPI 120 mg/m2 2 days• MESNA 3000 mg/m2 3 days• G-CSF 300 mcg days + 5 +15

• IFO 9 g/m2 in 3 days• EPI 120 mg/m2 2 days• MESNA 3000 mg/m2 3 days• G-CSF 300 mcg days + 5 +15

Localized High Risk STS Protocol (ISG/STS1)Localized High Risk STS Protocol (ISG/STS1)

IFO + EPI x 3 IFO + EPI x 3

RANDOM

RANDOM

IFO + EPI x 2IFO + EPI x 2

CONTROLCONTROL

Italian Sarcoma GroupItalian Sarcoma Group

Milano INT 38Bologna IOR 36Milano ICH 11Torino Gradenigo 9Aviano/Gorizia 8Brescia 6Milano IEO 2Napoli INT 2Torino IRCC 2Ravenna 1

------115

Milano INT 38Bologna IOR 36Milano ICH 11Torino Gradenigo 9Aviano/Gorizia 8Brescia 6Milano IEO 2Napoli INT 2Torino IRCC 2Ravenna 1

------115

ISG 115

GEIS Jan 2004 22

ISG 115

GEIS Jan 2004 22

Jan 2002Jan 2002

137137

ISG/STS1 (neoadjuvant EpiDOX+IFX, in localized high-risk disease)

HD-IFX cont inf (2nd-4th line)

Gemcytabine in leiomyosarcoma (2nd-3rd line)

Paclitaxel in angiosarcoma (2nd line)

Miniallogenic transplant (advanced disease, responsive patients)

ISG/STS1 (neoadjuvant EpiDOX+IFX, in localized high-risk disease)

HD-IFX cont inf (2nd-4th line)

Gemcytabine in leiomyosarcoma (2nd-3rd line)

Paclitaxel in angiosarcoma (2nd line)

Miniallogenic transplant (advanced disease, responsive patients)

Adult soft tissue sarcoma…Adult soft tissue sarcoma…

GIOTTO (observational study, 2004, in collaboration with Novartis)

REGISTER (pathology retrospective study)

62024 (adjuvant Imatinib), intergroup EORTC-led trial

SU11248 (company’s sponsored international study)

PTK787 (international study)

GIOTTO (observational study, 2004, in collaboration with Novartis)

REGISTER (pathology retrospective study)

62024 (adjuvant Imatinib), intergroup EORTC-led trial

SU11248 (company’s sponsored international study)

PTK787 (international study)

GIST…GIST…

ITALIAN SARCOMA GROUPPOTENTIAL OF ACCRUAL

ITALIAN SARCOMA GROUPPOTENTIAL OF ACCRUAL

Italian Population: 57 MillionItalian Population: 57 Million

OSTEOSARCOMA: 90/120 = 75%

EWING’S FAMILY: 50/60 > 80%

SOFT TISSUE SARCOMAS: 700/1400 = 50%

OSTEOSARCOMA: 90/120 = 75%

EWING’S FAMILY: 50/60 > 80%

SOFT TISSUE SARCOMAS: 700/1400 = 50%

A European Project within the VI framework

Dr. Piero Picci (Co-ordinator)

*Partner 1 Istituti Ortopedici Rizzoli (IOR, Italy)

Dr.ssa Katia Scotlandi

*Partner 2 Institut National de la Santé et de la Recherche Médicale (INSERM, France)

Pr. Alain Bernard

*Partner 3 Laboratory for Experimental Orthopaedic Research (UKM, Germany)

Dr. Frans van Valen

*Partner 4 University of Helsinki (UH.DMG, Finland)

Prof. Sakari Knuutila

*Partner 5 Department of Pathology, University of Valencia (UVEG, Spain)Prof. Antonio Lombart-Bosch

*Partner 6 Children´s Cancer Research Institute (CCRI, Austria)

Assoc. Prof. Dr. Heinrich Kovar

*Partner 7 Université Paris 7 Denis-Diderot (UP7 DD, France)

Dr. Bernard Perbal

*Partner 8 Centre National de la Recherche Scientifique (CNRS, France)

Dr. Claude Malvy

*Partner 9 Belozersky Inst. of Physico-Chemical Biology of the Moscow State Univ. (BI.MSU)

Dr.ssa Marina Gottikh

*Partner 10 GenX Laboratories srl (GENX, Italy)

Dr. Alessandro Borsatti

*Partner 11 MABGENE S.A. (MABG, France)Agnès Leconte

Dr. Piero Picci (Co-ordinator)

*Partner 1 Istituti Ortopedici Rizzoli (IOR, Italy)

Dr.ssa Katia Scotlandi

*Partner 2 Institut National de la Santé et de la Recherche Médicale (INSERM, France)

Pr. Alain Bernard

*Partner 3 Laboratory for Experimental Orthopaedic Research (UKM, Germany)

Dr. Frans van Valen

*Partner 4 University of Helsinki (UH.DMG, Finland)

Prof. Sakari Knuutila

*Partner 5 Department of Pathology, University of Valencia (UVEG, Spain)Prof. Antonio Lombart-Bosch

*Partner 6 Children´s Cancer Research Institute (CCRI, Austria)

Assoc. Prof. Dr. Heinrich Kovar

*Partner 7 Université Paris 7 Denis-Diderot (UP7 DD, France)

Dr. Bernard Perbal

*Partner 8 Centre National de la Recherche Scientifique (CNRS, France)

Dr. Claude Malvy

*Partner 9 Belozersky Inst. of Physico-Chemical Biology of the Moscow State Univ. (BI.MSU)

Dr.ssa Marina Gottikh

*Partner 10 GenX Laboratories srl (GENX, Italy)

Dr. Alessandro Borsatti

*Partner 11 MABGENE S.A. (MABG, France)Agnès Leconte

PROTHETS - OBJECTIVESPROTHETS - OBJECTIVES

1. Prognostic factors: fusion transcripts, secondary cytogenetic and molecular alterations, CD99, IGF-IR, NOVH, erbB-2, TTF1

2. Targeted therapeutic approaches: EWS/FLI1, CD99, erbB-2, IGF-IR, (TRAIL)

3. Genomic profiles for evaluation of tumor progression and response to chemotherapy

1. Prognostic factors: fusion transcripts, secondary cytogenetic and molecular alterations, CD99, IGF-IR, NOVH, erbB-2, TTF1

2. Targeted therapeutic approaches: EWS/FLI1, CD99, erbB-2, IGF-IR, (TRAIL)

3. Genomic profiles for evaluation of tumor progression and response to chemotherapy

Graphical presentationof work packages Graphical presentationof work packages

WP12 Validation of ESFT arrarays and definition of new therapeutic strategies (1-2-3-4-5-6-7-8-9-10-11)*

WP13 Dissemination (1-2-3-4-5-6-7-8-9-10-11)*

WP11 Preparation and Preclinical

assessment of chimeric CD99 Mab (11-2-1)*

WP10 Construction of ESFT-specific

microarrays (10-1-2-3-4-5-6-7-8)*

WP4 Identification of genetic

markers and array construction (1-2-3-4-5-6-7-8)*

WP12 Validation of ESFT arrarays and definition of new therapeutic strategies (1-2-3-4-5-6-7-8-9-10-11)*

WP13 Dissemination (1-2-3-4-5-6-7-8-9-10-11)*

WP11 Preparation and Preclinical

assessment of chimeric CD99 Mab (11-2-1)*

WP10 Construction of ESFT-specific

microarrays (10-1-2-3-4-5-6-7-8)*

WP4 Identification of genetic

markers and array construction (1-2-3-4-5-6-7-8)*

WP1 Project Management (1)*

WP1 Project Management (1)*

WP2 Preparatory activities and prospective data collection (1-2-3-4-5-6-7-8-9)*

WP2 Preparatory activities and prospective data collection (1-2-3-4-5-6-7-8-9)*

WP5 Definition of

the therapeutic value of EWS/

FLI1 and creation of therapeutic

tools for clinical application (4-6-8-9)*

WP6 Therapeutic value of tar-

geted therapies against erbB-2

and IGF-IR (1-3-4-5-9)*

WP7 Development

of new therapeutic strategies

targeting CD99 molecule (1-2-4)*

WP8 Anti-Ewing tu-mour activity of

TNF-related apoptosis-

inducing ligand (TRAIL)

(1-2-3-4-5)*

WP9 Role of NOVH

in the progression

of ESFT (1-4-7)*

WP3 Prognostic

relevance of selected prom-ising markers

in classical Ewing’s sar-coma versus

peripheral neu-roectodermal

tumours (1-3-4-5-8)*

WP5 Definition of

the therapeutic value of EWS/

FLI1 and creation of therapeutic

tools for clinical application (4-6-8-9)*

WP6 Therapeutic value of tar-

geted therapies against erbB-2

and IGF-IR (1-3-4-5-9)*

WP7 Development

of new therapeutic strategies

targeting CD99 molecule (1-2-4)*

WP8 Anti-Ewing tu-mour activity of

TNF-related apoptosis-

inducing ligand (TRAIL)

(1-2-3-4-5)*

WP9 Role of NOVH

in the progression

of ESFT (1-4-7)*

WP3 Prognostic

relevance of selected prom-ising markers

in classical Ewing’s sar-coma versus

peripheral neu-roectodermal

tumours (1-3-4-5-8)*

WP2 Preparatory activities and prospective data collection (1-2-3-4-5-6-7-8-9)*

WP3 Prognostic

relevance of selected prom-ising markers

in classical Ewing’s sar-coma versus

peripheral neu-roectodermal

tumours (1-3-4-5-8)*

WP4 Identification of genetic

markers and array construction (1-2-3-4-5-6-7-8)*

WP12 Validation of ESFT arrarays and definition of new therapeutic strategies (1-2-3-4-5-6-7-8-9-10-11)*

WP9 Role of NOVH in the progres-sion of ESFT

(1-4-7)*

WP4 Identification of genetic

markers and array construction (1-2-3-4-5-6-7-8)*

WP10 Construction of ESFT-specific

microarrays (10-1-2-3-4-5-6-7-8)*

WP5 Definition of

the therapeutic value of EWS/FLI1 and crea-tion of thera-

peutic tools for clinical applica-

tion (4-6-8-9)*

WP6 Therapeutic value of tar-

geted therapies against erbB-2

and IGF-IR (1-3-4-5-9)*

WP7 Development

of new therapeutic strategies

targeting CD99 molecule (1-2-4)*

WP8 Anti-Ewing tu-mour activity of

TNF-related apoptosis-

inducing ligand (TRAIL)

(1-2-3-4-5)*

WP11 Preparation and Preclinical

assessment of chimeric CD99 Mab (11-2-1)*

WP12 Validation of ESFT arrarays and definition of new therapeutic strategies (1-2-3-4-5-6-7-8-9-10-11)*

WP10 Construction of ESFT-specific

microarrays (10-1-2-3-4-5-6-7-8)*

WP11 Preparation and Preclinical

assessment of chimeric CD99 Mab (11-2-1)*

Starting January 1st, 2005 - 3 year projectStarting January 1st, 2005 - 3 year project

Total grant: 2.530.500,00 EuroTotal grant: 2.530.500,00 Euro

Website: WWW.PROTHETS.ORG

May 24-25ISGAnnualMeeting

May 24-25ISGAnnualMeeting

May 27Meeting ofEuropeanSarcomaGroups- ISG- SSG- GEIS- EORTC- France- Poland- Germany- etc.

May 27Meeting ofEuropeanSarcomaGroups- ISG- SSG- GEIS- EORTC- France- Poland- Germany- etc.