S. Pignata 1 , G. Scambia 2 , A. Savarese 3 , R. Sorio 4 , E. Breda 5 ,

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.

2. 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.

3. 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

4. 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

5. 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

6. Study design Control arm Random CarboplatinAUC 5, day 1 Paclitaxel175 mg/m2, day 1 Treatment repeatedevery 21 days, for 6 cycles 1:1 Experimental arm CarboplatinAUC 5, day 1 PLD 30 mg/m2, day 1 Treatment repeatedevery 21 days, for 6 cycles • Strata: • Center • PS (0-1, 2) • Stage (IC, II, III, IV) • Residual disease after surgery • (absent, 1 cm, 1 cm, no surgery)

7. 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

8. 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)

9. 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

10. 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

11. Baseline characteristics

12. Treatment compliance *p=0.39

13. Treatment compliance: delays Carboplatin + Paclitaxel Carboplatin + PLD Number of patients Cycle 2 Cycle 3 Cycle 4 Cycle 5 Cycle 6 Delays due to non hematologic toxicity Delays due to hematologic toxicity

14. Toxicity (1) C+P: carboplatin + paclitaxel, 399 patients; C+PLD: carboplatin + PLD, 386 patients *Chi square or Fisher exact test as appropriate

15. Toxicity (2) C+P: carboplatin + paclitaxel, 399 patients; C+PLD: carboplatin + PLD, 386 patients *Chi square or Fisher exact test as appropriate

16. Activity analysis: flow of patients Carbo + PLD (n=410) Carbo + Paclitaxel (n=410) 18 pts Pending information 10 pts Eligible for RECIST 156 (38%) 134 (33%) Analysis performed according to “intention to treat” principle

17. Objective response – RECISTWomen with target lesions *Objective response vs no response

18. Activity Women not eligible for RECIST * Complete response vs not ** Ca125 normalized vs not

19. 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

20. Progression-free survival* Months *May 2009

21. Overall survival* Months *May 2009

22. 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

23. 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

24. All the patients and their families The Investigators and the staff at each participating center: Acknowledgements