Transcript Slide 1

Carboplatin plus Paclitaxel versus
Carboplatin plus Stealth Liposomal Doxorubicin
in patients with advanced ovarian cancer:
activity and safety results of the
MITO-2 randomized multicenter trial
S. Pignata1, G. Scambia2, A. Savarese3, R. Sorio4, E. Breda5,
G. Ferrandina2, V. Gebbia6, P. Musso7, C. Gallo8, F. Perrone9
1Istituto
Nazionale Tumori, Napoli; 2Università Cattolica del Sacro Cuore, Roma; 3Istituto Regina Elena, Roma;
4CRO, Aviano; 5Ospedale Fatebenefratelli, Isola Tiberina, Roma;
6Casa di Cura La Maddalena, Università di Palermo; 7Ospedale Oncologico M.Ascoli A.R.N.A.S., Palermo;
8Seconda Università di Napoli; 9Istituto Nazionale Tumori di Napoli,Italy.
ASCO conflict of interest statement
• MITO-2 is an independent, academic study.
• Sponsor of the study is NCI Naples, that is responsible for
trial design, study coordination, data analysis and has the
property of the database.
• The study was partially supported by funds from ScheringPlough.
• Schering-Plough Italy supplied pegylated liposomal
doxorubicin (PLD).
Sandro Pignata received honoraria from Schering-Plough.
Introduction (1)
• Carboplatin plus paclitaxel is standard first-line
chemotherapy for patients with advanced ovarian
cancer 1-3
• Single-agent pegylated liposomal doxorubicin
(PLD) is a standard option for platinum resistant
relapsed ovarian cancer 4
1Ozols
RF et al, J Clin Oncol 2003, 21: 3194-3200
2Neijt JP et al , J Clin Oncol 2000, 18: 3084-3092
3du Bois A et al , J Natl Cancer Inst 2003, 95:1320-1330
4Gordon AN et al, J Clin Oncol 2001, 19: 3312-3322
Introduction (2)
• Combination of carboplatin and PLD is highly
active as second-line chemotherapy in patients
with advanced ovarian cancer in late relapse 1-2
1Ferrero
JM et al, Proc Am Soc Clin Oncol 2002
2Ferrero
JM et al, Ann Oncol 2007, 18: 263-268
Study objective
MITO-2 is a randomized phase III study
testing whether carboplatin plus PLD is more
effective than carboplatin plus paclitaxel as
first-line treatment of patients with advanced
ovarian cancer
Study design
R
a
n
d
o
m
Control arm
Carboplatin AUC 5, day 1
Paclitaxel 175 mg/m2, day 1
1:1
Treatment repeated every 21 days, for 6 cycles
Experimental arm
Carboplatin AUC 5, day 1
PLD 30 mg/m2, day 1
Strata:
•Center
•PS (0-1, 2)
Treatment
•Stage (IC, II, III, IV)
•Residual disease after surgery
(absent, 1 cm, 1 cm, no surgery)
repeated every 21 days, for 6 cycles
Study population
Inclusion criteria
•
•
•
•
•
Cyto/histological diagnosis of ovarian cancer
FIGO Stage IC – II – III – IV
Age  75
ECOG Performance Status 0-2
No previous chemotherapy
Main exclusion criteria
• ANC  2000/L, platelets  100000/L
• Creatinine  1.25 x UNL, SGOT and SGPT  1.25 x UNL
• Life expectancy of less than 3 months
Study endpoints
Primary endpoint
• Progression-free survival (PFS)
Secondary endpoints
• Overall survival (OS)
• Objective response rate (RECIST)
• Toxicity (NCI – CTC v2.0)
• Quality of Life (EORTC QLQ C30)
Sample size
• 2-tailed : 0.05
• Power: 80%
• Hazard Ratio: 0.80
• Median PFS in control arm: 18 months
• Median PFS in experimental arm: 22.5 months
 632 events (progressions) needed
 820 patients planned
Study conduction
• First patient enrolled: January 17, 2003
• Last patient enrolled: November 9, 2007
• 42 active Institutions
• 820 randomized pts
(41 Italy, 1 Portugal)
(809 Italy, 11 Portugal)
• Preplanned early safety analysis:
– first 50 pts receiving carboplatin + PLD 1
• Preplanned interim activity analysis:
– first 50 pts eligible for RECIST assigned to carboplatin + PLD 2
1Pignata
S, BMC Cancer 2006; 6: 202
2Pignata S, Oncology 2009; 76: 49-54
Baseline characteristics
Carbo + Paclitaxel
(n = 410)
Age median (range)
57 (21-77)
ECOG Performance Status
0-1
398 (97%)
2
12 (3%)
FIGO Stage
IC
38 (9%)
II
40 (10%)
III
243 (59%)
IV
89 (22%)
Residual disease after surgery
Absent
152 (37%)
 1 cm
68 (17%)
 1 cm
117 (28%)
No surgery
73 (18%)
Carbo + PLD
(n=410)
57 (25-77)
397 (97%)
13 (3%)
38
37
247
88
(9%)
(9%)
(60%)
(22%)
150
69
114
67
(37%)
(19%)
(28%)
(16%)
Treatment compliance
Carbo + Paclitaxel
Carbo + PLD
(n = 410)
(n=410)
Pending information
29 (7%)
27 (7%)
Did not start treatment
4 (1%)
6 (1%)
1
10 (3%)
11 (3%)
2
13 (3%)
19 (5%)
3
8 (2%)
13 (4%)
4
6 (2%)
11 (3%)
5
10 (3%)
14 (4%)
6
330 (88%)
309 (82%)
Number of cycles received*
*p=0.39
Treatment compliance: delays
350
Carboplatin + Paclitaxel
Carboplatin + PLD
300
Number 250
of
200
patients
150
100
50
0
Cycle 2
2 CP
Cycle 3
Cycle 4
Cycle 5
Cycle 6
3 4 CP x
5 6 CP x
Delays due to non hematologic
CLD
CLD toxicity
Delays due to hematologic toxicity
Toxicity (1)
Any grade
C+P
C+PLD
Severe (G3)
p*
Toxic deaths
Anemia
59%
68%
0.007
RBC transfusions
Neutropenia
73%
80%
0.04
Febrile neutropenia
Thrombocytopenia
19%
48%
0.001
Platelet transfusions
Bleeding
0.3%
1%
0.37
C+P
C+PLD
p*
0.8%
0.5%
1
4%
10%
0.001
2%
6%
0.002
49%
43%
0.09
2%
1%
0.21
2%
16%
0.001
0.3%
2%
0.06
-
1%
0.24
C+P: carboplatin + paclitaxel, 399 patients; C+PLD: carboplatin + PLD, 386 patients
*Chi square or Fisher exact test as appropriate
Toxicity (2)
Any grade
Allergy
Heart
Fatigue
Constipation
Nausea
Vomiting
Diarrhoea
Hair loss
Skin toxicity
Stomatitis
Neurotoxicity
C+P
6%
2%
44%
32%
47%
29%
13%
63%
6%
9%
47%
C+PLD
5%
4%
43%
32%
51%
30%
6%
14%
20%
20%
15%
Severe (G3)
p*
0.60
0.26
0.86
0.99
0.21
0.83
0.001
0.001
0.001
0.001
0.001
C+P
2%
0.3%
3%
1%
2%
2%
1%
C+PLD
2%
2%
3%
1%
2%
3%
-
p*
0.86
0.06
0.94
0.73
0.95
0.42
0.25
0.3%
3%
2%
0.5%
0.2%
0.01
0.62
0.004
C+P: carboplatin + paclitaxel, 399 patients; C+PLD: carboplatin + PLD, 386 patients
*Chi square or Fisher exact test as appropriate
Activity analysis: flow of patients
Carbo + PLD
(n=410)
Carbo + Paclitaxel
(n=410)
10 pts
Pending information
18 pts
Not eligible for RECIST
83 pts
Non-target lesions only
99 pts
88 pts
Elevated CA-125 only
80 pts
73 pts
156 (38%)
No lesions, normal CA-125 79 pts
Eligible for RECIST
134 (33%)
Analysis performed according to “intention to treat” principle
Objective response – RECIST
Women with target lesions
Carbo
+ Paclitaxel
(n=156)
Carbo
+ PLD
(n=134)
p (2)*
92 (59%)
76 (57%)
0.70
Complete response
24 (15%)
22 (16%)
Partial response
68 (44%)
54 (40%)
64 (41%)
58 (43%)
45 (29%)
41 (31%)
Progressive disease
9 (6%)
7 (5%)
Not evaluated
10 (6%)
10 (7%)
Objective response
No response
Stable disease
*Objective response vs no response
Activity
Women not eligible for RECIST
Carbo
+ Paclitaxel
Carbo
+ PLD
p (2)
Complete response (CR)
27 / 83 (33%)
29 / 99 (29%)
0.64*
No CR / No PD
46 / 83 (55%)
48 / 99 (48%)
2 / 83 (2%)
4 / 99 (4%)
8 / 83 (10%)
18 / 99 (18%)
73 / 88 (83%)
69 / 80 (86%)
Non-target lesions only
Progressive disease
Not evaluated
Elevated Ca125 only
Ca125 normalized
*
**
Complete response vs not
Ca125 normalized vs not
0.56**
Primary endpoint
• Number of events required for final
analysis (632) has not been reached yet
• As of May 4, 2009, with a median follow-up
of 35 months, 531 progressions have been
recorded
• Only overall curves are shown
0.8
Events
820
531
1-yr
PFS
2-yr
PFS
17.7
(95%CI
16.3-19.9)
65.0%
41.9%
48
60
72
69
21
-
0.2
0.4
0.6
Patients
Median PFS
(months)
0.0
Probability of progression-free survival
1.0
Progression-free survival*
Patients at risk
0
12
24
36
Months
820
531
258
134
*May 2009
Patients
Events
820
269
1-yr
OS
2-yr
OS
56.3
(95%CI
48.3-n.a.)
88.8%
73.8%
0.4
0.6
Median OS
(months)
0.0
0.2
Overall survival
0.8
1.0
Overall survival*
Patients at risk
0
12
24
820
712
413
36
48
60
72
228
90
38
-
Months
Months
*May 2009
Preliminary conclusions (1)
• Toxicity profile of carboplatin plus PLD as first-line
treatment of advanced ovarian cancer is markedly
different from carboplatin plus paclitaxel
• Carboplatin plus PLD is associated with:
– Higher incidence of anemia and
thrombocytopenia (rarely requiring transfusions)
– Higher incidence of stomatitis and cutaneous
toxicity (that are rarely severe)
– Lower incidence of hair loss and neurotoxicity
Preliminary conclusions (2)
• There was no statistically significant difference in
response rate between carboplatin plus PLD and
carboplatin plus paclitaxel
• Final analysis for the primary endpoint (PFS) will
be performed as soon as the required number of
events will be reached
Acknowledgements
All the patients and their families
The Investigators and the staff at each participating center:
S.Pignata, S. Greggi, C.Pisano – Napoli
G.Scambia, D.Lorusso – Roma
F.Cognetti, A.Savarese – Roma
A.Veronesi, R.Sorio – Aviano
V.Zagonel, E.Breda – Roma
G.Ferrandina – Campobasso
V. Gebbia, R.Agueli – Palermo
C.Malzoni, A.Vernaglia – Avellino
L.Frigerio, L.Carlini – Bergamo
M.Nardi, P.Del Medico – Reggio C.
P.Musso – Palermo
A.Febbraro, MC Merola – Benevento
P.Scollo, G.Scibilia – Cannizzaro
E.Galligioni, V.Murgia – Trento
A.Gambi, S.Tamberi – Faenza
A.Brandes, S.Rimondini – Bologna
A.Ravaioli, E.Pasquini – Rimini
N.Gebbia, MR.Valerio – Palermo
E.Aitini, G.Cavazzini – Mantova
D.Natale, C.Chiapperino – Penne
F.Artioli, L.Scaltriti – Carpi
V. Lorusso, A. Latorre – Bari / Lecce
AM.D’Arco, A. Fabbrocini – Nocera Inf
C.Gridelli, F.DelGaizo – Avellino
B.Massidda, V.Pusceddu – Cagliari
S. De Placido, R. Lauria – Napoli
G.Lelli, M.Marzola - Ferrara
V.Fosser, R.De Vivo – Vicenza
S.Tumolo, M.Boccalon - Pordenone
G.Giardina, S.Danese – Torino
G.Colucci, E.Naglieri – Bari
D. Amadori, N. Riva – Forlì
A. De Matteis, E.Rossi – Napoli
G.Lucarelli, G.Nettis – Acquaviva d.F.
T.Gamucci,M.Giampaolo - Frosinone
S.Palazzo,R.Biamonte – Cosenza
V.Montesarchio – Napoli
A.Cardone, G.Balbi – Napoli
G.Fasola, C.Sacco – Udine
ML.Geminiani, V.Arigliano – Budrio
O.Campos, I.Henriques – Coimbra, Portugal
Coordinating center:
F.Perrone, M.Di Maio, A.Morabito, E.De Maio, J.Bryce, G.Canzanella – Napoli
Statistician center:
C.Gallo, G. Signoriello, P.Chiodini, N.Lama - Napoli