[PPT] - Contributions of EORTC trials to Contributions of EORTC trials to PowerPoint Presentation

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EORTC STBSG EORTC STBSG

8th PMH Conference: New developments in cancer management

Contributions of EORTC trials to Contributions of EORTC trials to the management of sarcoma the management of sarcoma the management of sarcoma the management of sarcoma

Ole Steen Nielsen Ole Steen Nielsen Ole Steen Nielsen Ole Steen Nielsen

n behalf of the EORTC STBSG
n behalf of the EORTC STBSG

STBSG PMH/OSN

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EORTC STBSG EORTC STBSG

Not 50 years but 20 years Not 50 years but 20 years since I was at PHM!

STBSG PMH/OSN

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EORTC STBSG EORTC STBSG

Molecular biological knowledge Molecular biological knowledge in sarcomas increases

Genetic involvement
Genetic involvement.
Many genes are affected:

p53 Rb ras myc MDM2 CDK4 GLI etc – p53, Rb, ras, myc, MDM2, CDK4, GLI etc.

Genetic changes (cytogenetic aberrationer):

– t(X;18) (p11;q11) - SSX1&2 SYT: Synovial sarcomas t(X;18) (p11;q11) - SSX1&2, SYT: Synovial sarcomas – t(12;22) (q13;q12) - ATF1, EWS: Clear Cell sarcomas – t(12;16) (q13;p11) - CHOP, TLS: Myxoid liposarcomas (2 13)( 37 14) PAX3 FKHR Rh bd – t(2;13)(q37;q14) - PAX3, FKHR: Rhabdomyosarcomas – t(11;22) (q24;q12) - FLI-1, EWS: Ewing family (EFT) – Others (lipomas, fibrosis, schwannomas, chondros. etc.)

STBSG PMH/OSN

f

Etc ……..

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EORTC STBSG EORTC STBSG

SARCOMAS SARCOMAS Treatment and research problems

A rare disease

p

Too few patients locally!
Many subtypes!
Many subtypes!
Molecular biological knowledge!
Nationally: Centralisation!
Internationally: Collaboration!

STBSG PMH/OSN

Internationally: Collaboration!

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EORTC STBSG EORTC STBSG

European Organization for Research and Treatment of Cancer

A l f I t ti l An example of International Cooperation: EORTC STBSG

To develop stimulate and coordinate

Cooperation: EORTC STBSG

To develop, stimulate and coordinate

studies on all aspects of sarcomas within the framework of the EORTC framework of the EORTC.

To organize congresses, conferences and

s mposia to promote these st dies

STBSG PMH/OSN

symposia to promote these studies.

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EORTC STBSG EORTC STBSG

EORTC Soft Tissue and Bone EORTC Soft Tissue and Bone Sarcoma Group

52 member institutions from 13 countries
> 500 patients / year in clinical trials
> 3000 patients in the central database

p

58 clinical trials conducted so far
Strict quality control programs
Strict quality control programs

– Strict membership policy (site visits, recruitment, data quality) Strict membership policy (site visits, recruitment, data quality) – Review of pathology and response Review of pathology and response On site visits

STBSG PMH/OSN

– On site visits

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EORTC STBSG EORTC STBSG

Patient recruitment

1200 1000 1200 Phase I Phase II 600 800 Phase III - Advanc.dis. Phase III - Adjuvant 400 600 200

STBSG PMH/OSN <86 86 87 88 89 90 91 92 93 94 95 96 97 98 99 1 2 3 4 5 6 7

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EORTC STBSG EORTC STBSG

(Neo)-adjuvant phase III trials in STS

The STBSG has conducted the largest adjuvant trials:

( ) j p

– CYVADIC vs observation after surgery +/- radiotherapy (77-88: 468 pts) Advantage of CYVADIC only in delaying local recurrences for pts with localizations other than limbs

No proof of effect!

– Neo-adjuvant DOXO-IFOS vs immediate surgery (88-95: 150 pts) No advantage in survival

No proof of effect!

– DOXO-IFOS-GCSF vs observation after surgery (95-03: 351 pts) No advantage in survival Neo adjuvant VP16 IFOS DOXO±hyperthermia (97 06: 341 / 340 pts) – Neo-adjuvant VP16-IFOS-DOXO±hyperthermia (97-06: 341 / 340 pts) Advantage in disease free survival for the hyperthermia arm – Imatinib vs observation after surgery in GIST (05-ongoing: 879 / 900 pts)

STBSG PMH/OSN

with ISG, FSG, GEIS, AGITG

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EORTC STBSG EORTC STBSG

Projects based on the STBSG j database of adjuvant studies

Data originating from centers with a large recruitment

(> 5 pts in a study) is of better quality

Validation of the Trojani grading system
Development of a prognostic index based on mitotic count,

necrosis and tumor size necrosis and tumor size

Inclusion of the results of the CYVADIC study in the

Sarcoma Meta-Analysis Collaborative group project P ti t ith i l ti l d ti t ld

Patients with marginal resection, males, and patients older

than 40 years benefit more from chemotherapy than

thers; tumor size and histological grade have no

di ti l

STBSG PMH/OSN

predictive value.

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EORTC STBSG EORTC STBSG

EORTC STBSG STUDY STRATEGY EORTC STBSG STUDY STRATEGY ADVANCED/METASTATIC STS

Standard is doxorubicin
Only multicenter studies.
Study strategy:

Study strategy:

– Phase 1: Selected centres – Phase 2: 2nd line chemotherapy – Phase 2: 2nd line chemotherapy – Phase 2: 1st line chemotherapy Phase 3: New drug vs standard

STBSG PMH/OSN

– Phase 3: New drug vs standard

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EORTC STBSG EORTC STBSG

Phase I-II trials in STS (1977-2008) Phase I II trials in STS (1977 2008)

Examples 1st and 2nd line chemotherapy

Cisplatin

ACNU
Cisplatin
Chlorozotocin
Methotrexate
PALA
ACNU
Fotemustine
Miltefosine
Docetaxel

PALA

Ellipticinium
Mitomycin
Etoposide (iv/oral)
Lipo. doxorubicin
Temozolomide
Raltitrexed
Gemcitabine

p ( )

DTIC (high dose)
TGU
MDS
Gemcitabine
Ecteinascidin-743
Brostallicin
Exatecan

fi i ib

MT-PPE
Mitozolomide
MZPES
Gefitinib
Razopanib
Eribulin mesylate
And more …

STBSG PMH/OSN

And more … NEW DRUGS STILL NEEDED!

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EORTC STBSG EORTC STBSG

Phase III trials in advanced STS Phase III trials in advanced STS

E l 1 l h h E l 1 l h h Examples 1st line chemotherapy Examples 1st line chemotherapy

CYVADIC

CYVADIC (comparison of 2 schedules) (comparison of 2 schedules)

Oct 76 Oct 76 - Mar 80 (312 pts) Mar 80 (312 pts) Oct 76 Oct 76 Mar 80 (312 pts) Mar 80 (312 pts)

DOXORUBICIN

DOXORUBICIN (75 mg/m (75 mg/m2) ) vs vs EPIRUBICIN EPIRUBICIN (75 mg/m (75 mg/m2)

Dec 80 Dec 80 -

Jun 83 (210 pts)

Jun 83 (210 pts)

CYVADIC

CYVADIC vs vs DOX DOX-

IFOS

IFOS vs vs DOX DOX

NO SUPERIORITY IN SURVIVAL

Oct 85 Oct 85 -

Jun 90 (729 pts)

Jun 90 (729 pts)

DOX

DOX (75) (75) vs vs EPI EPI (150) (150) vs vs EPI EPI (3 x 50) (3 x 50)

Nov 90 Nov 90 -

Nov 94 (334 pts)

Nov 94 (334 pts)

DOX DOX (50) (50) IFOS IFOS (5) (5) DOX DOX (75) (75) IFOS IFOS (5) (5) G CSF CSF

COMPARED TO SINGLE AGENT DOXORUBICIN

DOX

DOX (50) (50) - IFOS IFOS (5) (5) vs vs DOX DOX (75) (75) -

IFOS

IFOS (5) (5) -

Gm

Gm-

CSF

CSF

Mar 92 Mar 92 -

Jan 95 (296 pts)

Jan 95 (296 pts)

IFOS (5 g/m2/24 h) vs IFOS (3 x 3 g/m2/4h

Mar 92 Mar 92 Jul 96 (182 pts) Jul 96 (182 pts) Mar 92 Mar 92 - Jul 96 (182 pts) Jul 96 (182 pts)

DOX (75)

DOX (75) vs vs DOX (75) DOX (75) -

IFOS (9 g/m

IFOS (9 g/m2/72h) /72h)

Feb 98 Feb 98 – – Oct 01 (326 pts) Oct 01 (326 pts)

DOX (75)

DOX (75) vs vs IFOS (3 x 3 g/m IFOS (3 x 3 g/m2

2/4h)

/4h) vs vs IFOS (9 g/m IFOS (9 g/m2/72h) /72h)

STBSG PMH/OSN

DOX (75)

DOX (75) vs vs IFOS (3 x 3 g/m IFOS (3 x 3 g/m /4h) /4h) vs vs IFOS (9 g/m IFOS (9 g/m /72h) /72h)

Mar 03 Mar 03 – – ongoing

ngoing

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EORTC STBSG EORTC STBSG

Summary Ad d STS 1 li h Advanced STS - 1st line therapy

Systematic evaluation in phase II and phase III trials of :

y p p

– CYVADIC (Doxo, CPH, DTIC) – Doxorubicin, 75 mg/m2 Epirubicin 75 mg/m2 and 150 mg/m2 – Epirubicin, 75 mg/m2 and 150 mg/m2 – Ifosfamide, 5 g/m2, 9 g/m2, 12 g/m2 – Doxorubicin – Ifosfamide combinations – Docetaxel – Liposomal doxorubicin

Doxorubicin, 75 mg/m2, q 3 weeks remains the “golden

Doxorubicin, 75 mg/m2, q 3 weeks remains the golden standard”

On-going phase III trial

STBSG PMH/OSN

– Doxo 75 mg/m2 vs Doxo 75 mg/m2 + Ifos 9 g/m2 + GCSF

Accumulation of a database of > 3000 cases

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EORTC STBSG EORTC STBSG

Projects based on the STBSG database of 1st line studies

A potentially curable disease…

( EJC 39, 2003, p.64 )

OS

( , , p )

80 90 100

5 years survival: 8% OS

50 60 70 80

y

Long terms survivors observed

in all prognostic groups

20 30 40 (years) 2 4 6 8 10 12 10

STBSG PMH/OSN

O N Number of patients at risk : All DB patients 1832 2187 406 112 44 11 2 All

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EORTC STBSG EORTC STBSG

Summary Summary Advanced STS 2nd and 3rd line therapy

28 phase II trials on various drugs

A l ti f d t b f 380 ti t

Accumulation of a database of 380 patients

treated with active and inactive drugs R f l f h II t i l i

Reference values for phase II trials using

PFR as the primary end-point (i.e. for cytostatic drugs or targeted therapies) cytostatic drugs or targeted therapies)

STBSG PMH/OSN

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EORTC STBSG EORTC STBSG

100

Progression free rate observed in STBSG

80 90 100

2nd/3rd line phase II studies in STS

50 60 70

Agents 3 mon. 6 mon.

Estim. s.e Estim.

s.e.

Active (4 trials) 39 %

4 %

14 %

3 %

30 40 50

Active (4 trials) 39 %

4 %

14 %

3 %

Inactive (9 trials) 21 %

3 %

8 %

2 %

(months) 10 20 (months) 3 6 9 12 15 O N Number of patients at risk : 221234 47 16 5 1 I ti t

STBSG PMH/OSN

221234 47 16 5 1 136146 55 18 14 11 Inactive agents Active agents

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EORTC STBSG EORTC STBSG

i ib d G S ! Imatinib and GIST! The Garden of Delights The Garden of Delights

Hieronymus Bosch (1450 1516) STBSG PMH/OSN Hieronymus Bosch (1450-1516)

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EORTC STBSG EORTC STBSG

Dose response?

I i ib 400 800 Imatinib 400 mg vs 800 mg

N diff

Theoretical Study Accrual of study 62005 900 800

No response difference
Longer PFS after 800 mg

800 700 600 500

700

3 groups

g g

No survival difference

T i it 800 > 400

400 300 200

400 500 600

13 countries 56 institutions 946 patients

Toxicity 800 > 400 mg

05/12/2002 05/06/2002 05/12/2001 05/06/2001 100

13 2 02 - 8 2 02

100 200 300

946 patients

STBSG PMH/OSN

13.2.02 - 8.2.02

Verweij et al , Lancet 2004 EORTC AGITC ISG

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EORTC STBSG EORTC STBSG

Discontinuation of Imatinib Increases Risk of GIST Progression

%

100 80 Continuous therapy (n = 23)

atients, %

60 40 P = 0.0001

Pa

20 Stop therapy (n = 25) Median PFS: 6 months

Months After Randomization

16 14 12 10 8 6 4 2

STBSG PMH/OSN

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EORTC STBSG EORTC STBSG

R i GIST di Response rate in GIST according to mutational status for c-KIT mutational status for c KIT

80% 50% 60% 70% 30% 40% 50% Exon 11 Exon 9 WT 10% 20% 30% 0% Response Rate

STBSG PMH/OSN

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EORTC STBSG EORTC STBSG

PFS (%)

90 100

Progression Progression-

free survival advantage for 800 mg

free survival advantage for 800 mg dose in GISTs with dose in GISTs with KIT KIT exon 9 mutations exon 9 mutations

PFS (%)

60 70 80

P = 0.0013

30 40 50 400 mg 800 mg 10 20 30 Years 1 2 3 4

Debiec-Rychter et al Eur J Cancer 2007

STBSG PMH/OSN

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EORTC STBSG EORTC STBSG

Adjuvant Imatinib?

Phase III EORTC Trial Study Design

No treatment Follow for 5 years Complete resection of Follow for 5 years Glivec (400 mg/d resection of GIST (400 mg/d for 2 years) Discontinued treatment*

STBSG PMH/OSN

2005 - ongoing: 879/900 pts with ISG, FSG, GEIS, AGITG

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EORTC STBSG EORTC STBSG

Interactive risk calculator for predicting p g imatinib toxicities in GIST patients

Interactive risk calculator for predicting toxicities in GIST patients treated with imatinib mesylate Patient's characteristics Probability of ▼ Imatinib dose (/day) 400 Edema (g2+) 18 % Age (years) 60 Lethargy (g2+) 24 % Patient s characteristics Probability of g

(y )

gy (g

)

Sex (1=M, 2=F) 1 Rash (g2+) 9 % PS (WHO) 1 Nausea (g2+) 9 % Pr.chem. (0=N, 1=Y) Diarrhea (g2+) 14 % Largest diam.(mm) 80 Anemia (g3+) 6 % GI origin (0=N, 1=Y) 1 Neutrop.(g3+) 2 % HGB (mmol/l) 8 ANC (10**9/l) 9 ANC (10**9/l) 9

STBSG PMH/OSN

Van Glabbeke et al

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EORTC STBSG EORTC STBSG

Phase III trials in other tumor types Phase III trials in other tumor types

EOI osteosarcoma phase III trial

p

Aug 93 – Sep 02 In cooperation with MRC, UKCCSG, CSG, SIOP

Euro-EWING phase III trial

Jun 01 – on-going In cooperation with GPOH, UKCCSG, SFOP, SIAK

Phase II trial of moderate dose radiotherap for
Phase II trial of moderate dose radiotherapy for

inoperable aggressive fibromatosis

Nov 01 – Mar 08 In cooperation with the EORTC Radiotherapy group

STBSG PMH/OSN

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EORTC STBSG EORTC STBSG

New concept in Soft Tissue Sarcomas New concept in Soft Tissue Sarcomas EORTC STBSG EORTC STBSG

Selected drugs for selected sarcomas Selected drugs for selected sarcomas and/or and/or and/or and/or specific agent for specific tumour targets specific agent for specific tumour targets

STBSG PMH/OSN

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EORTC STBSG EORTC STBSG

Disease specific studies Disease specific studies Disease specific studies Disease specific studies

Before: Before: Ewing/PNET, osteosarcomas Ewing/PNET, osteosarcomas Now: Agressive fibromatosis, GIST, Synovial sarcomas Agressive fibromatosis, GIST, Synovial sarcomas A i DFSP A i DFSP Angiosarcomas, DFSP Angiosarcomas, DFSP and in the near future and in the near future... Chondrosarcomas, uterine sarcomas and … Chondrosarcomas, uterine sarcomas and …

STBSG PMH/OSN

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EORTC STBSG EORTC STBSG

Conclusions

In soft tissue sarcoma, relevant clinical trials can
nly be conducted by cooperative groups
Studies conducted in specific histological subtypes

may require the collaboration of several groups ay equ e t e co abo at o o seve a g oups

The complexity of the disease requires strict quality

control procedures that should preferably be control procedures, that should preferably be centrally managed C li i f h d b d d di i f

Centralization of the database and standardization of

the collected data set enable to conduct retrospective research projects leading to a better understanding of

STBSG PMH/OSN

research projects leading to a better understanding of this (these) disease(s)

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EORTC STBSG EORTC STBSG

From EORTC STBSG (and me)

STBSG PMH/OSN Stbsg SSG/osn STBSG PMH/OSN