european and american osteosarcoma study … · recent multiinstitutional osteosarcoma studies....

AOST 0331

EUROPEAN AND AMERICAN OSTEOSARCOMA STUDY (EURAMOS1)

Need for international

collaboration in rare diseases

Supported by the European Science Foundation (ESF) under the EUROCORESProgram European Clinical Trials (ECT), through contract No. ERASCT-2003-980409 of the European Commission, DG Research, FP6

Stefan BielackCooperative Osteosarcoma Study Group

Klinikum Stuttgart - OlgahospitalPediatrics 5 (Oncology, Hematology, Immunology)

Stuttgart, [email protected]

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What is aWhat is arare rare

disease?disease?

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Rare Disease Act of 2002 (HR 4013)affects < 200,000 persons in the US (< .07% of US population)

European Commission on Public Health"life-threatening or chronically debilitating diseases which are

of such low prevalence that special combined efforts are needed to address them.”

low prevalence: < 5 / 10,000 in the community(< .05% of the overall population)

Rare Disease DefinitionRare Disease Definition

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Cancer in children & adolecents < 20 years of age

12,400 affected / year

Malignancies of the bone• average annual incidence rate 8.7 per million• about 6% of childhood cancer

=> 400 osteosarcoma+ 200 Ewing’s sarcoma.

rare disease: < 200,000 persons in the US

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Osteosarcomaage (years) incidence/10,000/year

5-9 .024 10-14 .06815-19 .084

rare disease: < 5 / 10,000

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Trial participation• young patients• high grade central OS• no primary mets• extremity primaries

Osteosarcoma

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• POG/CCG-INT0133 662 4.0 years 166/year Meyers, J Clin Oncol 2005&8

• EOI-80931 497 9.3 years 53/year Lewis, J Natl Cancer Inst 2007

• COSS-96 442 5.5 years 80/year Kempf-Bielack, SIOP 2008

• SFOP-94 234 7.0 years 33/year Le Deley, Eur J Cancer 2007

• SSG/ISG-I 181 3.5 years 52/year Ferrari, J Clin Oncol 2005

study n recruitment Reference

Recent Recent MultiinstitutionalMultiinstitutional Osteosarcoma StudiesOsteosarcoma Studies

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Do we need Do we need international international

collaboration ?collaboration ?

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61 100

0

10

20

30

40

50

60

70

80

90

100

present new miracle drug

Osteosarcoma Osteosarcoma 5 year survival5 year survival

Perfect FuturePerfect Future

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• Similar Regimens(AP) - MAP- (MAPI)

• Similar Results

• Progress Slow

• Similar Regimens(AP) - MAP- (MAPI)

• Similar Results

• Progress Slow

OsteosarcomaOsteosarcoma

RealityReality

37

58 59 61

0

10

20

30

40

50

60

70

1978-1982 1983-1987 1988-1992 1993-1997

Osteosarcoma: 5-year survival rates

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Salvage of poor Salvage of poor responders ?responders ?

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Osteosarcoma: Response & Survival

good (n=734)

73.4% (SE 2%)

47.2% (SE 3%)

poor (n=586)

p<.0001COSS:Bielacket al 2002

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3 a EFS: good ≈≈≈≈ 75%

poor ≈≈≈≈ 50%

Salvage-Question Statistics


Osteosarcoma Osteosarcoma

EURAMOSEURAMOS

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3 a EFS: good ≈≈≈≈ 75%

poor ≈≈≈≈ 50%

Significance 5%Power 80%50% ⇒⇒⇒⇒ 60%




EURAMOSEURAMOS

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3 a EFS: good ≈≈≈≈ 75%

poor ≈≈≈≈ 50%

Significance 5%Power 80%50% ⇒⇒⇒⇒ 60%

needed: ± 700 poor responders⇒ ±±±± 1400 patients




EURAMOSEURAMOS

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• COG 166/year 8.4 years

group recruitment study duration

MultiinstitutionalMultiinstitutional Osteosarcoma Groups Osteosarcoma Groups

& Salvage Question& Salvage Question

POG/CCG-INT0133Meyers et al, J Clin Oncol 2005&8

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• COSS 80/year 17.5 years




COSS-96Kempf-Bielack et al, SIOP 2008

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• EOI 53/year 26.4 years




EOI-80931Lewis, J Natl Cancer Inst 2007

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• SSG/ISG 52/year 26.9 years




SSG/ISG-IFerrari et al, J Clin Oncol 2005

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• SSG/ISG 52/year 26.9 years

• SFOP 33/year 42.4 years




SFOP-94Le Deley et al, Eur J Cancer 2007

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How can we How can we increase increase

recruitment ?recruitment ?

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• include adults too (challenging)

• include high grade surface OS (few)

• include resectable axial primaries(few)

• include resectable primary mets(10-15%)

Osteosarcoma: Increased recruitment

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recruitment max. + 20%

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• include adults too (challenging)

• include high grade surface OS (few)

• include resectable axial primaries(few)

• include resectable primary mets (10-15%)

Osteosarcoma: Increased recruitment

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Salvage question:

International, intergroupcollaboration necessary

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Intergroup collaborationIntergroup collaboration

CaveatsCaveats

• intergroup compromizes necessary

• additional infrastructure requirements

• more committees & agencies to please

• “worst” national regulation may apply for all

• no uniform funding

• less glory / investigator

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Intergroup collaborationIntergroup collaboration

ProPro’’ss• increased recruitment

=> quicker answers=> potential to address more questions

• synergy

- multiple areas of expertise- rapid knowledge exchange

• stronger “lobbying” power

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Pan-European/American Cooperation

EURAMOS / AOST 0331PanPan--European/American CooperationEuropean/American Cooperation

EURAMOS / AOST 0331EURAMOS / AOST 0331SSG

COG

EOI

COSS

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EURAMOSEURAMOS--1 / AOST 03311 / AOST 0331

aims

• investigation of

salvage therapy for poor responders(+/- HD-IFOS/ETO)

• investigation of

maintenance therapy for good responders(+/- pegylated interferon)

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EURAMOS / AOST 0331 population (million)

583 million=

8.7% of world population

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USA

osteosarcoma incidenceca. 2-3 / mio/ year

ca. 50% eligible (approx. 730 /year)

EURAMOS-countries: max. recruitment / year

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EU-Clinical Trials Directive EC 2001/20

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Documentation to be held by investigator/ institution for clinical trials• Investigators brochure (+ updates) or SmPC• Protocol and amendments (signed)• Information sheet and consent form (+ updates)• Financial aspects• Insurance statements• Signed agreements between parties• EC opinion and composition• MRHA authorisation• Investigators CVs• Medical and laboratory tests, including normal ranges• Medicine labels• Instructions for medicine use• Shipping records• Certificates of analysis• Decoding procedures• Master randomisation list• Monitoring reports (pre-trial, initiation, close-out etc)• List of persons responsibilities delegated to (+ updates)• CRFs and corrections• SAE notifications from investigators and to EC and MRHA• EC/MRHA annual reports and final reports• Subject screening log• Subject identification code list• Subject enrolment log• IMP accountability at site• Record of retained tissues• Documentation of IMP destruction• Completed subject identification code list• Audit certificate• Clinical study report

Detailed guidance for the principles of GCP in the conduct in the EU of clinical trialson medicinal products for human use. ENTR/6416/01, July 2002

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EURAMOS Recruitment as of August 31, 2008EURAMOSEURAMOS Recruitment as of August 31, 2008

Thanks to EURAMOS-CDC, MRC London

1115 patientsfrom 281 institutions

in 15 countries

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EURAMOS Recruitment as of August 31, 2008EURAMOSEURAMOS Recruitment as of August 31, 2008

Courtesy of EURAMOS-CDC,

MRC London

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centers patients p/c

133 493 3.765 239 3.726 148 5.7

4 49 12.314 46 3.3

7 27 3.86 22 3.7

centers patients p/c

3 22 7.37 22 3.12 11 5.51 10 10.06 12 2.03 8 2.73 5 1.71 1 1.0

EURAMOSCountry-Specific Recruitment as of August 31, 2008

EURAMOSEURAMOSCountry-Specific Recruitment as of August 31, 2008

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0% 25% 50% 75% 100%

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EURAMOS-countries: Osteosarcomasnumber recruited vs. max. number possible (3.5 years)

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EURAMOSEURAMOS--1 / AOST 03311 / AOST 0331

• recruitment- surprisingly good- largest osteosarcoma study of all times in <3 years

• randomization- rate not quite as high as expected- room for improvement (???)

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Support of Participating CentersSupport of Participating Centers

• Monitoring

• Training

• Lobbying

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• Stuttgart, December 2005

• Oslo, October 2006

• London, January 2008

• Oslo, 2009

Training Courses

Supported by the

European Science Foundation (ESF)under the

EUROCORES Program European Clinical Trials (ECT), through contract No. ERASCT-2003-980409 of the European Commission, DG Research, FP6

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European Commission – EMEA Conference on the Operation of the Clinical Trials Directive (Directive

2001/20/EC) and Perspectives for the Future

3. October 2007, EMEA, London

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