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ESGO Patient Seminar
Current options and the ongoing future of clinical trials
Jalid SehouliDirector of Dpt. of GynecologyDirector of Dpt. of Gynecology
European Comptence Center for Ovarian Cancer (EKZE)Charité/ Campus Virchow-Klinikum
University of Berlin
German Ovarian Cancer Foundation
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Advantages of studies
• Optimizing therapies are only possible via clinical
trials (increasing knowledge helps every patient!)
• High transparency of therapy
(detailed analyzes of effects and side effects)
• Additional alternative of modern and innovative • Additional alternative of modern and innovative treatment of agents which are generally not current available (one more imprortant option!)
• Study participation is a marker for quality!
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Standard therapy in FIGO I-IIA: Study- vs Non-Study clinic
Study clinic (n= 56 pts)
German Quality program QIII 2001AGO OVAR
25%
Non-study clinic (n= 68)
Ovarian Cancer
Standard
Inferior therapy
52% 48%75%
3 times higher 3 times higher chance to chance to
receive a better receive a better therapy!therapy!
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M. Gnant, ASCO 2000
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0,75
1
Survival in FIGO IIBSurvival in FIGO IIB--IVIV
0
0,25
0,5
0 6 12 18 24 30 36
Study clinics
Non-study clinics
LogrankLogrank testtest:: pp == 00..006006
HRHR == 11..5050 [[9595%%--KIKI:: 11..1212––22..0101]]
[months]
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The end of conventional chemotherapy trials?
GOG0182-ICON5: Overall Survival1.0
0.8
0.6
Pro
port
ion S
urv
ivin
g
Bookman J Clin Oncol 2010
0.4
0.2
0
0 12 24 36 48
Pro
port
ion S
urv
ivin
g
Months from Randomization
Treatment Alive Dead Total
C+P 538 326 864
C+P+G 546 318 864
C+P+D 555 307 862
C+T->C+P 521 340 861
C+G->C+P 529 332 861
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What happen in the tumor cell?
Hanahan & Weinberg, 2000
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Tumor networks: Different levels of –omics for predictive tumor biology
Griffin, Nature Reviews 2004
What is the
best biomarker?
What is the best
approach?
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� New drugs: Epothilone, Pemetrexed, Trabectedin TLK 286, Paclitaxel poliglumex, Trabectidin
� Modulators of resistance: Bortezomib, Zosuquidar, ASAP, MERM LY2933111, Phenoxidol
Many agents on the horizon
MERM LY2933111, Phenoxidol
• ngiogenesis inhibitors: Gefitinib (EGF-RTKI), Erlotinib (EGF-RTKI), ZD 6474 (EGF-/VEGF-RTKI), Sorafenib (VEGF-R-/Ras-Inhibition, Enzastaurin (PTK/ZK), DXMAA, VEGF trap, PlGFab, Cetuximab (anti-EGF-Rezeptor-AK), -Bevacizumab (anti-VEGF-AK), AZD 2171
• Others: FTI (Lonafarnib, SCH6636, R115777, BMS214662), Anti-Epcam, 17 AAG, ACA125, VEGF, EGF-R, c-erb-family (Trastuzumab, TAK-165, CP724,714, 2C4, IMC-225, EMD72000), Lapatinib (GW572016), FTI (Lonafarnib, SCH6636, R115777, BMS214662), Raf-1 (Bay 43-90006), MEK (CI-1040), Erbitux,), M-tor inhibitors, LHRH-Doxorubicin
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Durchblutung
Tumor growth and metastasis based on NEOANGIOGENESIS
Metastase
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Tumor cell
VEGF Angiogenesis
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Aszites – Abdomen full of tears
ascitesWritten by a patient 30.05.2007
„My eys were not able to follow my crying-follow my crying-
therefore my abdomen is full of tears!
Persephone aka Tharanis
©Sehouli 2011
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Biomarker Candidates
Tumor Cell
ADCCPhagocytosis
Apoptosis
LysisApoptosis
T-Cell
ActivationIL-1, IL-2
IL-12, IL-6
TNF-α, IFN-γ
DC-CK1CD40 / B7.1-2 / LFA-3
CD40L / CD28 / CD2
Signal1 2
CD3
2
2
EpCAM
EpCAM: Epithelial Cell Adhesion MoleculeSource: Ruf & Lindhofer, Blood 98, 2526-34, 2001
Apoptosis
Fcγγγγ-RI, Rlla or RIII+ Accessory Cellsmacrophages, dendritic cells, natural killer cells
DC-CK1
GM-CSF
CD40 / B7.1-2 / LFA-3
Immunization3
1
Fcγγγγ RI/IIa/III
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How to improve the outcome?...or how to place the new promising agents?
Nu
mb
er
of
tum
or
ce
lls
108
107
106
105
SurgeryImmuno- or chemotherapy
Chemotherapy
Nu
mb
er
of
tum
or
ce
lls
105
104
103
102
10
1
0time
Chemotherapy
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Phases of drug developement: drug identfication unti drug aproval
study outlinechem.synthesisor isolation screening preclinic
clinicalstudiesI - III
aproval
10.000Basic science
• periode (years)
• 1 - 2
costs (Mio €)
10.000
20
10
2
2
Markterfolg 1 von 4
preclinic
clinic
aproval
• 3 - 4
• 5 - 6
• 1 - 2
10 - 14
110
84
350
17
567
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Traditional Therapy:All pts receive the same therapy
Therapy A
R = Responder
R R
Study designs
Classical therapies vs individualized therapies
Predictive therapy R = Responder
Subgroup A Subgroup B
Individualized therapy:Different patients receive
different therapies
Better results
Tx. A Tx B
R R R R
Predictive therapy based on individual genetic pattern
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Collection of tumor specimens
Transfer of Preoperative
Collection
Surgery
Transfer of
tumor specimensPreoperative
informed consent
Documentation of clinical and surgical data Online-
Documentation
Storage
Labelling
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What are the objectives of clinical trials?
•Increasing the cure rate
•Increasing overall survival rate
•Increasing progression free survival
•Improving the symptom free interval
•Improving quality of life
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Primary1. I am hoping for a complete healing without any further
complications 45%2. I am hoping for no recurrence of tumour related symptoms 33%3. I am hoping to live longer than I otherwise would 18%4. I am hoping for just a less painful course of sickness 2%5. Others 2%
„What are your hopes from the therapy? “
Recurrent1. I am hoping for no recurrence of tumour related symptoms 35%2. I am hoping for a complete healing without any further
complications 28%3. I am hoping to live longer than I otherwise would 24%4. I am hoping for just a less painful course of sickness 6%5. Others 6%
multiple answers possible
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Primary1. Doctors should have more time for explanations 19%2. The therapy should not go on until hair loss 16% 3. There must be more done to counter exhaustion 14%4. If the therapy is successful, it should be made known to me 11%5. The teamwork between the doctors should be improved 10%6. The treatment should be shorter in its duration 7%7. The therapy should be made to be more effective 6%
„Which would be the most important things to improve in the treatment of ovarian cancer?“
7. The therapy should be made to be more effective 6%
Recurrent1. The therapy should be made to be more effective 18%2. The therapy should not go on until hair loss 17%3. Doctors should have more time for explanations 16%4. The teamwork between the doctors should be improved 10%5. If the therapy is successful, it should be made known to me 9%6. There must be more done to counter exhaustion 8%7. The treatment should be shorter in its duration 7%8. The nurses should strive to be more caring 4%
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www.Expression3.de Current State
counted patients per country (state: 06.09.2011)
Patients all countries: 1276
nu
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256
168
335
190
online
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9
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20
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Germ
any
Belgium
Bulgaria
Poland
Italy
Austria
United
Kingdom
France
Romania
Spain
nu
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3119 2 72 8
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Future aspects of clinical trials
in gynecological oncology
• More individualized therapies based on profiles in tumor biopsies
• High need of early predictive marker• High need of early predictive marker
• High need of therapies for subgroups in rare tumors (eg. specific histology)
• High need of studies designed for elderly patients
• High need to focus on patient´s quality of life and preferences