ovarian cancer diagnosis surgery first-line chemotherapy consolidation platinum-sensitive recurrence...
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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