6. GOG 111 andOV 10(Intergroup)
McGuireetal, N Eng J Med, 1996;
n=386,suboptimalcytoreduction III/IV
SLPSG
PT 18m 38m
PC 13m 24m
Piccartetal, J Nat CancerInst, 2000;
n=668, debulkingsurgery, II-IV
SLPSG
PT 17m 35m
PC 12m 25m
7. GOG 172
Standard arm IV
D1 Paclitaxel IV 135mg/m2/24hs
D1 D2
D2 CisplatinIV 75mg/m2
IV IV
Experimental arm IV/IP D1 Paclitaxel EV 135mg/m2/24hs
D2 CisplatinIP100mg/m2
D1 D2 D8
D8 PaclitaxelIP60mg/m2
IVIP IP
Armostrong e al, NEJM, 2006;
N=429, optimaldebulkingsurgery, stage III
SLPSG
PT IV 19m 50m
PT IV/IP 24m 65m
Only 42% ofptscompletedtreat. IV/IP arm
8. GOG randomized studies: IV vs IP
PFS (m) %Advantage OS (m) %Advantage
IV IP IV IP
Alberts -- -- 41 49
Markman 22 28 27 52 63
Armstrong 19 24 20 50 65 25
* Statisticallysignificant : p < 0.05
9. CarboplatinAUC 6 + Paclitaxel
R 180mg/m2
A
N
D
q 21 days x 6 cycles
AdvancedOvaria
O
nCancer M
I CarboplatinAUC 6 + Paclitaxel
(n = 637) Z
A 80mg/m2 d1,8,15
T
I q 21 days x 6 cycles
O
N
Katsumata N, Lancet: 374, 2009
11. PrimaryCitoreduc Platinun-CT
R
A tion x 6 cycles
N
D
AdvancedOv O
arianCancer M
I
(III/IV) Z
A
(n = 718) T
I Platinun-CT Platinun-CT
IntervalCytored
O
N x 3 cycles uction x 3 cycles
Vergote I, NEJM: 363 2010
14. Citoreduction CT
CT Citoreductio
n
Pos-op Death 2.5% 0.7%
Hemorraghe G III/IV
Infection 7.1%
8.1% 4.1%
1.7%
DVT/PE 2.5% 0%
Vergote I, NEJM: 363 2010
15. GOG-0218: Scheme Arm
Carboplatin(C) AUC 6
Paclitaxel (P) 175 mg/m2
I
R
First-line : Epithelial A Placebo
OV, PP or F N
D 1:1:1 Carboplatin(C) AUC 6
• Stage III optimal
• Stage III suboptimal
O
M Paclitaxel (P) 175 mg/m2
II
• Stage IV
I
n=1800 (planned) Z
BEV 15 mg/kg Placebo
E
Carboplatin(C) AUC 6
Stratification III
• PS Paclitaxel (P) 175 mg/m2
• Stage/Citoreduction BEV 15 mg/kg
15 months
16. GOG-218: Progression-Free Survival
Arm I Arm II Arm III
1.0 CP CP + BEV CP + BEV BEV
(n=625) (n=625) (n=623)
Proportion surviving progression free
0.9 423 418 360
Patients with event, n (%)
(67.7) (66.9) (57.8)
0.8 Median PFS, months 10.3 11.2 14.1
0.7 Stratified analysis HR 0.908 0.717
(95% CI) (0.759–1.040) (0.625–0.824)
0.6 One-sided p-value (log rank) 0.080a <0.0001a
0.5
0.4
0.3
0.2
CP (Arm I)
0.1 + BEV (Arm II)
+ BEV → BEV maintenance (Arm III)
0
0 12 24 36
Months since randomization
17. GOG-218: Select Adverse Events
Onset between cycle 2 and 30 days after date of last treatment
Arm I Arm II Arm III
CP CP + BEV CP + BEV BEV
Adverse event (grade when limited), n (%)
(n=601) (n=607) (n=608)
GI eventsa (grade ≥2) 7 (1.2) 17 (2.8) 16 (2.6)
Hypertension (grade ≥2) 43 (7.2)b 100 (16.5)b 139 (22.9)b
Proteinuria (grade ≥3) 4 (0.7) 4 (0.7) 10 (1.6)
Pain (grade ≥2) 250 (41.7) 252 (41.5) 286 (47.1)
Neutropenia (grade ≥4) 347 (57.7) 384 (63.3) 385 (63.3)
Febrile neutropenia 21 (3.5) 30 (4.9) 26 (4.3)
Venous thromboembolic event 35 (5.8) 32 (5.3) 41 (6.7)
Arterial thromboembolic event 5 (0.8) 4 (0.7) 4 (0.7)
CNS bleeding 0 0 2 (0.3)
Non-CNS bleeding (grade ≥3) 5 (0.8) 8 (1.3) 13 (2.1)
RPLS 0 1 (0.2) 1 (0.2)
RPLS = reversible posterior leukoencephalopathy syndrome
aPerforation/fistula/necrosis/leak
bp<0.05
18. ICON 7: Scheme
CarboplatinAUC6* q3w
Stage I or IIa (grade Paclitaxel 175mg/m2 q3w
3 or clear cell) or
stage IIb–IV EOC,
PP, FTC CarboplatinAUC6* q3w
(n=1,520) Paclitaxel 175mg/m2 q3w
Bevacizumab 7.5mg/kg q3w
• Open-label study 18 cycles
• Endpoints
– primary: PFS
– secondary: RR, OS, safety, QoL, cost effectiveness, translational
• Stratification
– FIGO stage/surgery; time since surgery; GCIG group
21. GOG 218 and ICON 7: Comparison of Trials
Trial GOG-0218 ICON7
Number of patients 1,800 1,520
Setting/design •Double-blinded, placebo-controlled • Open-label
•First-line setting •First-line setting
•3-arm study: • 2-arm study:
Arm I: CT + placebo Arm A: carboplatin/paclitaxel (CT)
Arm II: CT + Bevacizumab (5 cycles) Arm B: CT + Bevacizumab
Arm III: CT + Bevacizumab (extended) •Bevacizumab continued for 12 months
•Bevacizumab continued for 16 months •Bevacizumab dose: 2.5mg/kg/week
•Bevacizumab dose: 5mg/kg/week •Flexibility in AUC for carboplatin
•Rigid AUC for carboplatin
Patient population Post-cytoreductive surgery Post-cytoreductive surgery
Sub-optimally debulked stage III/IV I or IIa (grade 3 or clear-cell histology)
Macroscopic optimally debulked stage III IIb–IV (all grades and histological types)
Target disease Epithelial ovarian, fallopian tube or primary Epithelial ovarian, fallopian tube or primary
peritoneal cancer peritoneal cancer
Stratification • PS (0–1 vs 2) • FIGO stage
• Stage (III vs IV) • ≤ vs>4 weeks after surgery
• GCIG group
Primary endpoint • Investigator-assessed PFS data • Investigator-assessed PFS data
• Exploratory: IRC-assessed PFS data
22. P
R
I 0 3 6 12 18 24
M
A Refractory Months
R
Y
T
Resistent
R
E
Sensitive
A
T
M
E Highlysensitive
N
T
25. ICON-4/AGO-OVAR-2.2 Trial
CarboplatinAUC 5 a 6 EV
R OR
A
N Cisplatin75mg/m2 EV
D q 21 days
Platinum- O
sensitiveovariancancer M
ΔT >6 m I CarboplatinAUC 5 EV
Z OR
A Cisplatin50mg/m2 EV
T +
I Paclitaxel 175mg/m2 EV
O Q 21 days
N
Parmar MK, Lancet: 361, 2003
27. CALYPSO: Scheme
R
A
Inclusion Criteria: N CarboplatinAUC 5 EV + Paclitaxel 175
D mg/m2 IV 3
• Platinum-sensitive (> 6 O
m) M q21dx6 cycles
• 1 or 2 prior platinum- I
based CT Z
• Measurable disease A
(image or CA125) T CarboplatinAUC 5 EV + DoxoLipossomal
I 30 mg/m2 IV 1 h
O
N q 28 days x6 cycles*
*or until PD in patients with stable disease or response
Pujades E etal, J ClinOncol, 2010