s. pignata 1 , g. scambia 2 , a. savarese 3 , r. sorio 4 , e. breda 5 ,

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 Schering-Plough.

• 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, 95:1320-13304Gordon 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

Random

Strata:•Center•PS (0-1, 2)•Stage (IC, II, III, IV)•Residual disease after surgery(absent, 1 cm, 1 cm, no surgery)

Control armCarboplatin AUC 5, day 1 Paclitaxel 175 mg/m2, day 1

Treatment repeated every 21 days, for 6 cycles

Experimental arm

1:1

Study design

Carboplatin AUC 5, day 1 PLD 30 mg/m2, day 1

Treatment repeated every 21 days, for 6 cycles

Study populationInclusion 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 (41 Italy, 1 Portugal)• 820 randomized pts (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 characteristicsCarbo + Paclitaxel Carbo + PLD

(n = 410) (n=410)Age median (range)

57 (21-77) 57 (25-77)

ECOG Performance Status 0-1 398 (97%) 397 (97%) 2 12 (3%) 13 (3%)FIGO Stage IC 38 (9%) 38 (9%) II 40 (10%) 37 (9%) III 243 (59%) 247 (60%) IV 89 (22%) 88 (22%)Residual disease after surgery Absent 152 (37%) 150 (37%) 1 cm 68 (17%) 69 (19%) 1 cm 117 (28%) 114 (28%) No surgery 73 (18%) 67 (16%)

Treatment complianceCarbo +

PaclitaxelCarbo + PLD

(n = 410) (n=410)

Pending information 29 (7%) 27 (7%)

Did not start treatment 4 (1%) 6 (1%)

Number of cycles received*

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%)*p=0.39

Treatment compliance: delays

Cycle 2 Cycle 3 Cycle 4 Cycle 5 Cycle 6

Delays due to hematologic toxicityDelays due to non hematologic toxicity

Carboplatin + Paclitaxel

Carboplatin + PLD

Number of

patients

Toxicity (1)Any grade Severe (G3)

C+P C+PLD p* C+P C+PLD p*

Toxic deaths 0.8% 0.5% 1

Anemia 59% 68% 0.007 4% 10% 0.001

RBC transfusions 2% 6% 0.002

Neutropenia 73% 80% 0.04 49% 43% 0.09

Febrile neutropenia 2% 1% 0.21

Thrombocytopenia 19% 48% 0.001

2% 16% 0.001

Platelet transfusions 0.3% 2% 0.06

Bleeding 0.3% 1% 0.37 - 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 Severe (G3)

C+P C+PLD p* C+P C+PLD p*

Allergy 6% 5% 0.60 2% 2% 0.86

Heart 2% 4% 0.26 0.3% 2% 0.06Fatigue 44% 43% 0.86 3% 3% 0.94Constipation 32% 32% 0.99 1% 1% 0.73

Nausea 47% 51% 0.21 2% 2% 0.95Vomiting 29% 30% 0.83 2% 3% 0.42Diarrhoea 13% 6% 0.001 1% - 0.25Hair loss 63% 14% 0.001Skin toxicity 6% 20% 0.001 - 2% 0.01Stomatitis 9% 20% 0.001 0.3% 0.5% 0.62Neurotoxicity 47% 15% 0.001 3% 0.2% 0.004

*Chi square or Fisher exact test as appropriate

C+P: carboplatin + paclitaxel, 399 patients; C+PLD: carboplatin + PLD, 386 patients

Activity analysis: flow of patients

Analysis performed according to “intention to treat” principle

Pending information

Eligible for RECIST

Not eligible for RECIST

Non-target lesions only

Elevated CA-125 only

No lesions, normal CA-125

Carbo + Paclitaxel(n=410)

10 pts

83 pts

88 pts

73 pts

156 (38%)

18 pts

99 pts

80 pts

79 pts 134 (33%)

Carbo + PLD(n=410)

Objective response – RECISTWomen with target lesions

Carbo+ Paclitaxel

(n=156)

Carbo+ PLD

(n=134)p (2)*

Objective response 92 (59%) 76 (57%) 0.70

Complete response 24 (15%) 22 (16%)

Partial response 68 (44%) 54 (40%)

No response 64 (41%) 58 (43%)

Stable disease 45 (29%) 41 (31%)

Progressive disease 9 (6%) 7 (5%)

Not evaluated 10 (6%) 10 (7%)

*Objective response vs no response

Activity Women not eligible for RECIST

Carbo + Paclitaxel

Carbo+ PLD p (2)

Non-target lesions onlyComplete response (CR) 27 / 83 (33%) 29 / 99 (29%) 0.64*

No CR / No PD 46 / 83 (55%) 48 / 99 (48%)

Progressive disease 2 / 83 (2%) 4 / 99 (4%)

Not evaluated 8 / 83 (10%) 18 / 99 (18%)

Elevated Ca125 onlyCa125 normalized 73 / 88 (83%) 69 / 80 (86%) 0.56**

* Complete response vs not** Ca125 normalized vs not

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 12 24 36 48 60 72

0.0

0.2

0.4

0.6

0.8

1.0

Pro

babili

ty o

f pro

gre

ssio

n-f

ree s

urv

ival

Patients Events

Median PFS

(months)

1-yr

PFS

2-yr

PFS

820 531 17.7

(95%CI

16.3-19.9)

65.0% 41.9%

Patients at risk 820 531 258 134 69 21 -

Progression-free survival*

Months

*May 2009

Patients Events

Median OS

(months)

1-yr

OS

2-yr

OS

820 269 56.3

(95%CI

48.3-n.a.)

88.8% 73.8%

Patients at risk 820 712 413 228 90 38 -

Overall survival*

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

All the patients and their familiesThe 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

Acknowledgements