Transcript Marth - the Gynecologic Cancer InterGroup

Ovarian Cancer
Diagnosis
Surgery
First-line Chemotherapy
Consolidation
Platinum-sensitive Recurrence
Surgery
Chemotherapy
Platinum-resistant Recurrence
Ovarian Cancer
Open Trials
Closed Trials
Diagnosis
EORTC 55971
CHORUS
Surgery
EORTC 55971/CHORUS
Upfront Surgery
vs
Neoadjuvant Chemotherapy
Patients
closed / 550
Leading
EORTC
Participating
NCIC CTG
Presentation planned at IGCS 2008
Ovarian Cancer
Open Trials
Closed Trials
AGO-OVAR-9
CT ± GEM
First-line
Chemotherapy
SCOTROC-4
ICON-7
GOG-218
EORTC 55041
Tarceva
Consolidation
AGO-OVAR-9
Carbo Paclitaxel +/- Gemcitabine
Patients
closed 1742
Leading
AGO-OVAR
Participating
GINECO, NSGO,
SCOTROC 4
Carbo Flat Dosing vs Intrapatient Dose Escalation
Patients
Leading
closed 932
SGCTG
Participating
ANZGOG
Tarceva Trial EORTC 55041
Tarceva consolidation 2 years
Primary Chemotherapy
Control
Patients
closed / 835
Leading
EORTC
Participating
AGO-AUSTRIA, ANZGOG, GINECO,
MRC/NCIC, MANGO
ICON-7
TC
±
BEVACIZUMAB
Patients
closed / 1520
Leading
MRC/NCRI
Participating
NCIC CTG, AGO OVAR, GINECO, GEICO
EORTC, ANZGOG, NSGO
GOG 218
CT vs CT + Bevacizumab
Placebo vs
CT + Bevacizumab concurrent and extended
Patients
closed / 1800
Leading
GOG
Participating
ECOG, NCCTG, NSABP, SWOG
Ovarian Cancer
Closed Trials
AGO-OVAR OP-2
Desktop II
Open Trials
Platinum-sensitive
Recurrence
Surgery
Chemotherapy
CALYPSO
Platinum-resistant
Recurrence
AGO-OVAR-OP.2 DESKTOP II
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 DESKTOP OVAR II – FLOW CHART
08/06 – 03/08: Screening of 516 pts with platinum-sensitive relapse in 46 centres
Score positive
261 pts (51%)
Surgery
148 pts
(57%)
Study collective:
AGO score +
1st relapse
129 pts (87%)
No surgery
113 pts
(43%)
2nd relapse
19 pts
(13%)
Score negative
255 pts (49%)
Surgery
80 pts
(31%)
1st relapse
64 pts
(80%)
No surgery
175 pts
(69%)
2nd relapse
16 pts
(20%)
Selection process:
228 pts (44.2%) had cytoreductive surgery for recurrent OC
-> Primary study collective (AGO score +, 1st relapse) : 129 pts (25%)
© P. Harter 2008
AGO DESKTOP OVAR II – SURGICAL RESULTS
Frequency of complete resection by applying the AGO Score
100
90
80
70
DESKTOP
Hypothesis
60
50
40
75
76
Score positive
Score positive
Score positive
all patients
1st relapse
2nd relapse
30
68
20
10
0
complete resection in 76% of the study collective =
AGO score could predict complete resection in at least 2 out of 3 patients
© 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
© P. Harter 2008
CALYPSO
TC
vs
C + Caelyx
Patients
closed / 976
Leading
GINECO
Participating
AGO-AUSTRIA, AGO-OVAR,
ANZGOG, EORTC, MANGO,
MITO, NCIC/CTG, NSGO
Presentation ASCO 2009
Ovarian Cancer
Open Trials
Closed Trials
Diagnosis
EORTC 55971
CHORUS
Surgery
AGO-OVAR OP-3
LION
AGO – OVAR OP.3 (LION)
Lymphadenectomy In Ovarian Neoplasms
epithelial invasive
ovarian cancer
System. Lymphadenectomy
 pelvic
FIGO IIB - IV
 para-aortic
ECOG 0/1 and
no CI against LNE
R
no visible extraand intra-abdominal
tumor residuals
n = 640
no Lymphadenectomy
no bulky lymph nodes
Endpoints: OS, PFS, QoL
Strata: centre, PS ,age
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
Open Trials
Closed Trials
AGO-OVAR-9
CT ± GEM
First-line
Chemotherapy
JGOG-3017
Clear cell carcinoma
mEOC
SCOTROC-4
MITO-7
ICON-7
JGOG IP Trial
GOG-218
EORTC 55041
Tarceva
AGO-OVAR-12
Consolidation
AGO-OVAR-16
VEG 110655
MITO-7
Weekly CT vs 3-weekly CT (QoL)
Patients
25 / 500
Leading
MITO
Participating
MaNGO, AGO-OVAR
First line weekly carboplatin and paclitaxel vs
every 3 weeks carboplatin/paclitaxel in
patients with ovarian cancer:
the MITO – 7 trial
 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
Carboplatin AUC 6
Paclitaxel 175 mg/mq
RANDOM
day 1 - every 21days
Carboplatin AUC 2
Paclitaxel 60 mg/mq
day 1,8 15 - every 21days
JGOG IP Trial
IP vs IV carboplatin + weekly Paclitaxel
Patients
Leading
Participating
JGOG
PLANNED JAPANESE IP TRIAL
Epithelial Ovarian Cancer
Stages II-IV
Excluding Clear Cell Carcinoma
Randomization
Paclitaxel 80 mg/m2 IV Weekly
Carboplatin AUC 6 IV
Q21, 6-8 Cycles
Paclitaxel 80 mg/m2 IV Weekly
Carboplatin AUC 6 IP
Q21, 6-8 Cycles
Primary Endpoint: PFS
Secondary Endpoint: OS, Toxicity, QOL, Cost
NCIC CTG OV.21
IP/IV Platinum/T vs IV CT
optimally debulked following NACT
Patients
0 / 780
Leading
NCIC CTG
Participating
GEICO, NCRI, SWOG
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
R
Phase II
IV Carbo
IV Taxol
IP Carbo (Taxol)
IV Taxol
Then…..
IP Cisplatin (Taxol)
IV Taxol
This or…..
Phase II
R
IV Carbo
IV Taxol
IP Carbo (Taxol)
IV Taxol
IV Carbo
IV Taxol
IP Carbo (Taxol)
IV Taxol
Phase III
IP Cisplatin (Taxol)
IV Taxol
This…..
Phase II
IV Carbo
IV Taxol
R
IP Carbo (Taxol)
IV Taxol
IP Cisplatin (Taxol)
IV Taxol
Phase III
IV Carbo
IV Taxol
IP Cisplatin (Taxol)
IV Taxol
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
AGO-OVAR-12
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-OVAR12
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
S
U
R
G
E
R
Y
C
C
C
C
C
C
T
T
T
T
T
T
= Vargatef 2 x 200 mg po qd
2
R
C
= Carboplatin AUC 5-6
d1
T
= Paclitaxel 175 mg/m2 (3h)
d1
q21d / 6 courses
1
n=1300
C
C
C
C
C
C
T
T
T
T
T
T
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
= Placebo
 120 weeks
AGO-OVAR 16
Pazopanib consolidation 1 yr
First 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-OVAR16
A 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
Screening
Baseline
First-line
Chemotherapy
(allow ip, neoadj)
If not PD
R
A
N
D
O
M
I
Z
E
Treatment
Period
Pazopanib
(12 months)
Placebo
(12 months)
Post-Treatment
Period
Follow-up
Period
Observation
(to PD)
Survival
Follow-up
(post-PD)
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 Stage 1 trial design
Randomisation 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
Standard
ARM1: C q 3/52
P q 3/52
ICON8: bevacizumab 7.5mg/kg for 6
cycles (concurrent only)
~GOG218 & ICON7
Primary surgery
Randomised after
surgery
NAC
Randomised before
neoadjuvant chemo
to 3 cycles chemo,
surgery, then 3 cycles
chemo)
ARM2: C q 3/52
P q 3/52
Bevacizumab q 3/52
JGOG study
ARM3: C q 3/52
P q 1/52
Novel
ARM4: C q 3/52
P q 1/52
Bevacizumab q 3/52
Proposed MITO
ARM5: C q 1/52
P q 1/52
NOVEL
ARM6: C q 1/52
P q 1/52
Bevacizumab q 3/52
Aim of stage 1 is to establish which
arms should be taken into stage 2
based.
Primary outcome measures:
Toxicity
Feasibility
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 & ICON7 GOG218 concurrent arm not worse
than control will provide support for
ARM2: C q 3/52
P q 3/52
6 cycles of bevacizumab
Bevacizumab q 3/52
JGOG study
ARM3: C q 3/52
P q 1/52
Primary surgery
Randomised after
surgery
NAC
Randomised before
chemo to 3 cycles
chemo, surgery, then 3
cycles chemo)
Subgroup analyses to explore effect
of effect of treatments in subgroups
defined by primary surgery or NAC
NOVEL
ARM4: C q 3/52
P q 1/52
Bevacizumab q 3/52
Proposed MITO
ARM5: C q 1/52
P q 1/52
NOVEL
ARM6: C q 1/52
P q 1/52
Bevacizumab q 3/52
2:1 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 OUTCOME MEASURE:
OS
SECONDARY OUTCOME MEASURES:
PFS
TOXICITY
HE
QOL
TR
ICON 8 If bevacizumab trials ‘negative’ for PFS
3 arm 1:1: 1 randomisation
600 patients per arm, Total 1800- 3yrs recruitment 2 years follow up
Standard
ARM1: C q 3/52
P q 3/52
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
Primary surgery
Randomised after
surgery
Neoadjuvant
chemotherapy
randomised before
chemo to 3 cycles
chemo, surgery, then
3 cycles chemo)
JGOG study
ARM3: C q 3/52
P q 1/52
Proposed MITO
ARM5: C q 1/52
P q 1/52
3 weeks out of 4
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
Toxicity
HE
QoL
TR
Ovarian Cancer
Open Trials
Closed Trials
AGO-OVAR OP-2
Desktop II
Platinum-sensitive
Recurrence
Surgery
Chemotherapy
CALYPSO
AGO-OVAR OP-7
Desktop III
HECTOR
C-Topo vs CT or CG
ICON-6
MITO-8
Platinum-resistant
Recurrence
SGCTG / NCRI
AGO-OVAR-OP.4 DESKTOP III
Cytoreductive surgery vs NO surgery
in platinum-sensitive recurrent EOC
Patients
0 / 385
Leading
AGO-OVAR
Participating
?
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
R
A
N
D
O
M
Cytoreductive
surgery
no surgery
platinum-based
chemotherapy*
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
HECTOR
Carbo Topo vs Chemo (CT or CG) in recurrent
Platinum-sensitive ovarian cancer
Patients
452 / 550
Leading
NOGGO/AGO-OVAR
Participating
AGO-AUSTRIA, GEICO
MITO-8
PLD vs CT cross-over
in 6-12 m platinum-free interval
Patients
25 / 253
Leading
MITO
Participating
MaNGO, AGO-OVAR
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
RANDOM
LIPOSOMAL
DOXORUBICIN 40 mg/mq
CARBOPLATIN AUC 5 +
PACLITAXEL 175 mg/mq
day1 every 28 days
day1 every21gg
Cross-over at
Progression
LIPOSOMAL
DOXORUBICIN
40 mg/mq
day1 every 28 days
CARBOPLATIN AUC 5 +
PACLITAXEL 175 mg/mq
day1 every 21 days
Ovarian Cancer
Closed Trials
AGO-OVAR-9
CT ± GEM
Diagnosis
JGOG-3017
Clear cell carcinoma
Surgery
mEOC
SCOTROC-4
ICON-7
Open Trials
First-line Chemotherapy
MITO-7
JGOG IP Trial
GOG-218
Consolidation
AGO-OVAR-12
AGO-OVAR-16
VEG 110655
EORTC 55041
Tarceva
AGO-OVAR OP-7
Desktop III
AGO-OVAR OP-2
Desktop II
CALYPSO
Platinum-sensitive Recurrence
Surgery Chemotherapy
HECTOR
C-Topo vs CT or CG
ICON-6
MITO-8
Platinum-resistant Recurrence
SGCTG / NCRI
GCIG has demonstrated to perform very
efficient important clinical trials which have
changed the standard of care in the
treatment of ovarian cancer
Main focus has been first-line chemotherapy
Surgical questions have been raised
recently
Treatment options in platinum-resistant
recurrent disease should be further
develloped
Thank you for attention