Ovarian CancerDiagnosis

Surgery

First-line Chemotherapy

Consolidation

Platinum-sensitive RecurrenceSurgery

Chemotherapy

Platinum-resistant Recurrence

Ovarian Cancer

Diagnosis

Surgery

EORTC 55971CHORUS

Closed Trials Open Trials

Upfront Surgery vs Neoadjuvant Chemotherapy

Patients closed / 550

Leading EORTC

Participating NCIC CTG

Presentation planned at IGCS 2008

EORTC 55971/CHORUS

Ovarian Cancer

First-lineChemotherapy

Consolidation

AGO-OVAR-9CT ± GEM

EORTC 55041Tarceva

Closed Trials Open Trials

SCOTROC-4

GOG-218

ICON-7

Carbo Paclitaxel +/- Gemcitabine

Patients closed 1742

Leading AGO-OVAR

Participating GINECO, NSGO,

AGO-OVAR-9

Carbo Flat Dosing vs Intrapatient Dose Escalation

Patients closed 932Leading SGCTG

Participating ANZGOG

SCOTROC 4

Tarceva consolidation 2 yearsPrimary Chemotherapy

Control

Patients closed / 835

Leading EORTC

Participating AGO-AUSTRIA, ANZGOG, GINECO, MRC/NCIC, MANGO

Tarceva Trial EORTC 55041

TC ± BEVACIZUMAB

Patients closed / 1520

Leading MRC/NCRI

Participating NCIC CTG, AGO OVAR, GINECO, GEICO EORTC, ANZGOG, NSGO

ICON-7

CT vs CT + Bevacizumab Placebo vs CT + Bevacizumab concurrent and extended

Patients closed / 1800

Leading GOG

Participating ECOG, NCCTG, NSABP, SWOG

GOG 218

Ovarian Cancer

Platinum-sensitive Recurrence

SurgeryChemotherapy

Platinum-resistantRecurrence

Closed Trials Open Trials

AGO-OVAR OP-2Desktop II

CALYPSO

Evaluation of predictive factors for complete resection in platinum-sensitive recurrent ovarian cancer

Patients closed/412

Leading AGO-OVAR

Participating AGO-AUSTRIA, MITO,selected Canadian+Australian centers

Report IGCS 2008

AGO-OVAR-OP.2 DESKTOP II

© P. Harter 2008

08/06 – 03/08: Screening of 516 pts with platinum-sensitive relapse in 46 centres

Score positive261 pts (51%)

Score negative255 pts (49%)

Surgery148 pts (57%)

No surgery113 pts (43%)

Surgery80 pts (31%)

No surgery175 pts (69%)

1st relapse64 pts(80%)

2nd relapse19 pts(13%)

2nd relapse16 pts(20%)

Selection process:

228 pts (44.2%) had cytoreductive surgery for recurrent OC

-> Primary study collective (AGO score +, 1st relapse) : 129 pts (25%)

AGO DESKTOP OVAR II – FLOW CHART

Study collective:AGO score +1st relapse

129 pts (87%)

© P. Harter 2008

Frequency of complete resection by applying the AGO Score

AGO DESKTOP OVAR II – SURGICAL RESULTS

complete resection in 76% of the study collective =

AGO score could predict complete resection in at least 2 out of 3 patients

75 7668

0

10

20

30

40

50

60

70

80

90

100

Score positive Score positive Score positive

all patients 1st relapse 2nd relapse

DESKTOPHypothesis

© P. Harter 2008

AGO DESKTOP OVAR II: CONCLUSIONS

A surgical multicentre study within the GCIG is feasible and could answer complex questions in an appropriate interval

The AGO-Score is a useful and reliable tool to predict complete resection in at least 2 out of 3 patients

First score succesfully validated in surgery for ovarian cancer

The comorbidity is comparable to surgery in primary ovarian cancer

Outcome in the score negative subgroup will be further analysed

TC vs C + CaelyxPatients closed / 976

Leading GINECO

Participating AGO-AUSTRIA, AGO-OVAR, ANZGOG, EORTC, MANGO, MITO, NCIC/CTG, NSGO

Presentation ASCO 2009

CALYPSO

Ovarian Cancer

Diagnosis

Surgery

EORTC 55971CHORUS

AGO-OVAR OP-3LION

Closed Trials Open Trials

R

System. Lymphadenectomy

pelvic

para-aortic

no Lymphadenectomy

epithelial invasive ovarian cancer

FIGO IIB - IV

ECOG 0/1 and no CI against LNE

no visible extra- and intra-abdominal

tumor residuals

no bulky lymph nodes

Endpoints: OS, PFS, QoL Strata: centre, PS ,age

Lymphadenectomy In Ovarian Neoplasms

AGO – OVAR OP.3 (LION)

n = 640

Supported by Deutsche Forschungsgemeinschaft

Participating groups/sites:

AGO Study Group (24 centres initiated)

MITO (11 centres planned – ethical approval 06/09)

KGOG

AGO Austria

Single sites: Leuven

Recruitment: 26 / 640 pts

Ovarian Cancer

First-lineChemotherapy

Consolidation

JGOG-3017Clear cell carcinoma

mEOC

MITO-7

AGO-OVAR-12

AGO-OVAR-16VEG 110655

Closed Trials Open Trials

AGO-OVAR-9CT ± GEM

EORTC 55041Tarceva

SCOTROC-4

GOG-218

ICON-7

JGOG IP Trial

Weekly CT vs 3-weekly CT (QoL)

Patients 25 / 500

Leading MITO

Participating MaNGO, AGO-OVAR

MITO-7

Aim of the trial is to compare the two schedules in terms of quality of life Risk of progression at 18 months as primary end-point

RANDOM

Carboplatin AUC 2Paclitaxel 60 mg/mq

day 1,8 15 - every 21days

Carboplatin AUC 6Paclitaxel 175 mg/mq

day 1 - every 21days

First line weekly carboplatin and paclitaxel vs every 3 weeks carboplatin/paclitaxel in

patients with ovarian cancer:

the MITO – 7 trial

IP vs IV carboplatin + weekly Paclitaxel

Patients

Leading JGOG

Participating

JGOG IP Trial

PLANNED JAPANESE IP TRIAL

Epithelial Ovarian CancerStages II-IV

Excluding Clear Cell Carcinoma

Paclitaxel 80 mg/m2 IV WeeklyCarboplatin AUC 6 IV

Q21, 6-8 Cycles

Paclitaxel 80 mg/m2 IV WeeklyCarboplatin AUC 6 IP

Q21, 6-8 Cycles

Randomization

Primary Endpoint: PFSSecondary Endpoint: OS, Toxicity, QOL, Cost

IP/IV Platinum/T vs IV CT optimally debulked following NACT

Patients 0 / 780

Leading NCIC CTG

Participating GEICO, NCRI, SWOG

NCIC CTG OV.21

Basic Design

Patients with EOC

3-4 cycles neoadjuvant chemo

Initial surgery: < 1 cm residual

3 cycles IV Carbo/Taxol

3 cycles IP/IV platinum and taxol

Endpoints: PFS and OS

IV CarboIV Taxol

IP Carbo (Taxol)IV Taxol

IP Cisplatin (Taxol)IV TaxolPhase II

R

Then…..

IV CarboIV Taxol

IP Carbo (Taxol)IV Taxol

IP Cisplatin (Taxol)IV TaxolPhase II

IV CarboIV Taxol

IP Carbo (Taxol)IV Taxol

R

Phase III

This or…..

IV CarboIV Taxol

IP Carbo (Taxol)IV Taxol

IP Cisplatin (Taxol)IV TaxolPhase II

IV CarboIV Taxol

R

Phase III

IP Cisplatin (Taxol)IV Taxol

This…..

Study Arms: Phase II

Arm 1

Day 1:Paclitaxel 135 mg/m2 IV day 1 plus carboplatin AUC 5 (measured)/ AUC 6 (calculated) IV

Day 8:Paclitaxel 60 mg/m2 IV day 8

Q 21 days x 3 cycles

Study Arms: Phase II

Arm 2

Day 1: Paclitaxel 135 mg/m2 IV plus Cisplatin 75 mg/m2 IP

Day 8: Paclitaxel 60 mg/m2 IP

Q 21 days x 3 cycles

Study Arms: Phase II

Arm 3

Day 1: Paclitaxel 135 mg/m2 IV plus carboplatin AUC 5 (measured)/ AUC 6 (calculated) IV IP

Day 8: Paclitaxel 60 mg/m2 IP

Q 21 days x 3 cycles

Statistics Phase III Portion• Progression free survival:

– Seek improvement of IP over control with hazard ratio of 0.8 (Median increase PFS 4.3 mo, 17 21.3 mo)

– 80% power, 2-sided alpha 0.05

– Need 631 progression events

– To detect need additional 630 patients randomized after phase II completed

– Overall Survival: Same numbers will detect hazard ratio of 0.80 once 631 deaths seen (10 month increase in median survival)

– Total no of patients =780

Carbo Paclitaxel +/- BIBF 1120 (Vargatef)

Patients 0 / 1300 (2:1 random)

Leading AGO-OVAR

Participating AGO Austria, BGOG, GINECO,

MANGO, MITO, NSGO, US Oncology

AGO-OVAR-12

Multicenter, randomised, double-blind, Phase III trial to investigate the efficacy and safety of Vargatef (BIBF 1120) in combination with standard

treatment of carboplatin and paclitaxel compared to placebo plus carboplatin and paclitaxelin patients with advanced ovarian cancer

AGO-OVAR12

R

C

T

C

T

C

T

C

T

C

T

C

T

C

T

C

T

C

T

C

T

C

T

C

T

= Vargatef 2 x 200 mg po qd

= Placebo

120 weeks

C = Carboplatin AUC 5-6 d1

T = Paclitaxel 175 mg/m2 (3h) d1

q21d / 6 courses

Vargatef / Placebo :- no intake on days of chemotherapy

- dose: 200 mg po bid (combi + mono)- dose adaptation in case of undue toxicity

- max. duration of 120 weeks in non-progressing pts

2

1

SURGERY

n=1300

Pazopanib consolidation 1 yrFirst Line Chemotherapy

Control

Patients 0 / 900

Leading AGO-OVAR

Participating AGO Austria, ANZGOG, BGOG, GEICO, GINECO, ICORG, JGOG, KGOG, MANGO, MITO, NSGO, US-Sites: California Consortium, NY GOG, SWOG

AGO-OVAR 16

AGO-OVAR16A Phase III Study to Evaluate the Efficacy and Safety of Pazopanib Monotherapy Versus Placebo in Women Who Have not Progressed after First Line Chemotherapy for Epithelial Ovarian, Fallopian Tube,

or Primary Peritoneal Cancer

Survival Follow-up(post-PD)

First-line Chemotherapy

(allow ip, neoadj) Placebo

(12 months)

Pazopanib (12 months)

If not PD

Treatment PeriodR

ANDOMIZE

Observation (to PD)

ScreeningBaseline

Post-Treatment Period

Follow-up Period

Primary surgery Randomised after

surgeryNAC

Randomised before neoadjuvant chemo to 3 cycles chemo,

surgery, then 3 cycles chemo)

ARM1: C q 3/52 P q 3/52

ARM2: C q 3/52 P q 3/52

Bevacizumab q 3/52

ARM3: C q 3/52 P q 1/52

ARM4: C q 3/52 P q 1/52

Bevacizumab q 3/52

ARM5: C q 1/52 P q 1/52

ARM6: C q 1/52 P q 1/52

Bevacizumab q 3/52

Standard

~GOG218 & ICON7

Proposed MITO

Novel

JGOG study

NOVEL

Aim of stage 1 is to establish which arms should be taken into stage 2

based. Primary outcome measures:

ToxicityFeasibility

GOG218 15m bevacizumab 15mg/kg (concurrent and extended) or

bevacizuamb 15mg/kg 6 cycles (concurrent only)

ICON7 12 months treatment with bevacizumab 7.5mg/kg

ICON8: bevacizumab 7.5mg/kg for 6 cycles (concurrent only)

ICON8 Stage 1 trial designRandomisation weighted in favour of research

arms 1:2:2:2:2:2 Number of patients requires further discussion on

what is needed to demonstrate feasibility

Primary surgery Randomised after

surgeryNAC

Randomised before chemo to 3 cycles

chemo, surgery, then 3 cycles chemo)

ARM2: C q 3/52 P q 3/52

Bevacizumab q 3/52

ARM3: C q 3/52 P q 1/52

ARM4: C q 3/52 P q 1/52

Bevacizumab q 3/52

ARM5: C q 1/52 P q 1/52

ARM6: C q 1/52 P q 1/52

Bevacizumab q 3/52

~GOG218 & ICON7

Proposed MITO

NOVEL

JGOG study

NOVEL

ICON8 Stage 2 trial design if ICON7 and GOG 218 are positive are ‘positive’ for PFS

Option 1 2:1 randomisation*Total 2000 patients

GOG218 concurrent arm not worse than control will provide support for 6

cycles of bevacizumab

Subgroup analyses to explore effect of effect of treatments in subgroups defined by primary surgery or NAC

PRIMARY OUTCOME MEASURE:OS

SECONDARY OUTCOME MEASURES:PFS

TOXICITYHE

QOLTR2:1 randomisation in favour of standard arm ( 800 patients) and 400 in

each research arm gives 1,200 patients in each pairwise comparison loses a little power but will save patients (total 2000)

Primary surgery Randomised after

surgeryNeoadjuvant

chemotherapy randomised before chemo to 3 cycles

chemo, surgery, then 3 cycles chemo)

ARM1: C q 3/52 P q 3/52

ARM3: C q 3/52 P q 1/52

ARM5: C q 1/52 P q 1/52

3 weeks out of 4

Standard

Proposed MITO

JGOG study

ICON 8 If bevacizumab trials ‘negative’ for PFS3 arm 1:1: 1 randomisation

600 patients per arm, Total 1800- 3yrs recruitment 2 years follow up

Aim of trial is to compare efficacy of dose dense chemotherapy against standard 3 weekly regimens

(Arm 1 vs Arm 2 and Arm 1 vs Arm 3

If dose dense regimens both better than standard, compare dose dense paclitaxel with dose dense

carboplatin and paclitaxel (Arm 2 vs Arm 3)

Subgroup analyses to explore effect of effect of treatments in subgroups defined by primary surgery

or NAC

Primary outcome measure:OS

Secondary outcome measures:PFS

ToxicityHEQoLTR

Ovarian Cancer

Platinum-sensitive Recurrence

SurgeryChemotherapy

Platinum-resistantRecurrence

Closed Trials Open Trials

AGO-OVAR OP-2Desktop II

AGO-OVAR OP-7Desktop III

CALYPSO

SGCTG / NCRI

HECTORC-Topo vs CT or CG

ICON-6

MITO-8

Cytoreductive surgery vs NO surgery in platinum-sensitive recurrent EOC

Patients 0 / 385

Leading AGO-OVAR

Participating ?

AGO-OVAR-OP.4 DESKTOP III

AGO-OVAR DESKTOP III (Protocol AGO - OVAR OP.4)

A randomized trial evaluating cytoreductive surgery in patients with platinum-sensitive recurrent ovarian cancer

Complete resection

seems feasible and a

positive AGO-score

Strata:

Platinum-free-interval

6-12 vs > 12 months

- 1st line platinum

based chx: yes vs no

RANDOM

Cytoreductivesurgery

platinum-basedchemotherapy*recommended

* Recommended platinum-based chemotherapy regimens: - carboplatin/paclitaxel

- carboplatin/gemcitabine- carboplatin/pegliposomal doxorubicin

(if calypso-trial shows equivalence to carboplatin-paclitaxel)-or other platinum combinations in prospective trials

no surgery

Carbo Topo vs Chemo (CT or CG) in recurrent Platinum-sensitive ovarian cancer

Patients 452 / 550

Leading NOGGO/AGO-OVAR

Participating AGO-AUSTRIA, GEICO

HECTOR

PLD vs CT cross-overin 6-12 m platinum-free interval

Patients 25 / 253

Leading MITO

Participating MaNGO, AGO-OVAR

MITO-8

RANDOM

LIPOSOMALDOXORUBICIN

40 mg/mqday1 every 28 days

CARBOPLATIN AUC 5 +PACLITAXEL 175 mg/mq

day1 every 21 days

Cross-over atProgression

CARBOPLATIN AUC 5 +PACLITAXEL 175 mg/mq

day1 every21gg

LIPOSOMALDOXORUBICIN 40 mg/mq

day1 every 28 days

Trial design

The objective of this trial is the efficacy determined through analysis of overall survival (OS) of the different sequence (CP→PLD vs PLD→CP) in recurrent ovarian cancer patients with platinum-free interval 6-12 months

Ovarian Cancer

Diagnosis

Surgery

First-line Chemotherapy

Consolidation

Platinum-sensitive RecurrenceSurgery Chemotherapy

Platinum-resistant Recurrence

Closed Trials Open Trials

JGOG-3017Clear cell carcinoma

mEOC

MITO-7

AGO-OVAR-12

AGO-OVAR-16VEG 110655

JGOG IP Trial

AGO-OVAR-9CT ± GEM

EORTC 55041Tarceva

SCOTROC-4

GOG-218

ICON-7

AGO-OVAR OP-7Desktop III

SGCTG / NCRI

HECTORC-Topo vs CT or CG

ICON-6

MITO-8

AGO-OVAR OP-2Desktop II

CALYPSO

GCIG has demonstrated to perform very efficient important clinical trials which have changed the standard of care in the treatment of ovarian cancerMain focus has been first-line chemotherapySurgical questions have been raised recentlyTreatment options in platinum-resistant recurrent disease should be further develloped

Thank you for attention