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

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137

256

168

335

190

print

online

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1

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20

0

30

0

Germ

any

Belgium

Bulgaria

Poland

Italy

Austria

United

Kingdom

France

Romania

Spain

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3119 2 72 8

50

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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

Tumor Zentrum Berlin e.V.

www.tzb.de tumorzentrum@tzb.deˆaxäxÜ áàÉÑ tá~|Çz Öâxáà|ÉÇáÂ