View
215
Download
1
Category
Preview:
Citation preview
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
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!
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!
M. Gnant, ASCO 2000
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]
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
What happen in the tumor cell?
Hanahan & Weinberg, 2000
Tumor networks: Different levels of –omics for predictive tumor biology
Griffin, Nature Reviews 2004
What is the
best biomarker?
What is the best
approach?
� 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
Durchblutung
Tumor growth and metastasis based on NEOANGIOGENESIS
Metastase
Tumor cell
VEGF Angiogenesis
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
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
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
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
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
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
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
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
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%
www.Expression3.de Current State
counted patients per country (state: 06.09.2011)
Patients all countries: 1276
nu
mb
er
of
pa
tie
nts
137
256
168
335
190
online
10
2
0
3
0
4
0
5
0
6
0
7
0
8
0
9
0
1
00
20
0
30
0
Germ
any
Belgium
Bulgaria
Poland
Italy
Austria
United
Kingdom
France
Romania
Spain
nu
mb
er
of
pa
tie
nts
3119 2 72 8
50
3 0
32
0 0310
2
0
3
0
4
0
5
0
6
0
7
0
8
0
9
0
1
00
20
0
30
0
33
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
Tumor Zentrum Berlin e.V.
www.tzb.de tumorzentrum@tzb.deˆaxäxÜ áàÉÑ tá~|Çz Öâxáà|ÉÇáÂ
Recommended