1. UNANSWERED QUESTIONS IN UPFRONT THERAPY CHEMOTHERAPY ISSUES: WEEKLY DOSING Andrés Poveda, MD Fundación Instituto Valenciano de Oncología apoveda@fivo.org On behalf of GEICO and GCIG Ovarian Cancer Clinical Trials Planning Meeting Friday, May 29, 2009

2. 3rd International Ovarian Cancer Consensus Conference

3. 4-A4:Which regimen / kind of regimens can be regarded as standard comparator for future first-line trials? Within a given trial the chemotherapy regimen should be standardized and consistent with respect to drugs, dose, and schedule. The recommended standard comparator for trials on medical treatment in advanced ovarian cancer (FIGO IIB-IV) is carboplatin-paclitaxel The recommended regimen is carboplatin with a dose of AUC 5 - 7.5 and paclitaxel 175 mg/m²/ 3h given every three weeks for 6 courses The recommended standard in early stage ovarian cancer (FIGO I-IIA) patients in whom adjuvant chemotherapy is indicated should contain at least carboplatin AUC 5 -7.5 Level of Acceptance: 13 / 13

4. UNANSWERED QUESTIONS IN UPFRONT THERAPY WEEKLY DOSING RATIONALE Antiangiogenic property of Paclitaxel independent of its anti-proliferative action Lau DH et al. Proc ASCO 17:4141, 1998 Antiangiogenic scheduling chemotherapy improves efficacy against experimental drug-resistant cancer Browder T, Cancer Res; 2000 Norton-Simon hypothesis: a more frequent drug administration would be a more effective way of avoiding the regrowth of cell populations resistant to the agents used (Gomperzian model of tumor growth). Proven activity in other tumours (Breast Cancer,..) Better tolerance schedule

5. Mechanisms of Paclitaxel-induced cell death are concentration dependent Paclitaxel-mediated cell death may result from two different mechanisms: –At low Paclitaxel concentrations (<9 nM), cell death may occur after an aberrant mitosis by Raf-1 independent pathway –At higher Paclitaxel concentrations (>9 nM) cell death may be the result of a terminal mitotic arrest occurring by a Raf-1 dependent pathway Torres R and Horwitz B: Cancer Res 1998, 58:3620

6. Potential Advantages of Weekly Paclitaxel  Greater dose intensity greater inhibition of mitotic cellular activity  Higher frequency of administration Higher cellular exposure in M phase Higher inhibition of mitotic cellular activity  Cause of cellular death mediated by other mechanisms (apoptosis)  Inhibition of neovascularization  Better pharmacodynamic profile

8. 0 2 4 6 8 10 12 14 IIIIIIIVV ANC (  1000/µL) Level Fennelly et al. JCO 15: 187-92; 1997 WEEKLY PACLITAXEL: NO INCREASE IN MYELOSUPPRESSION WITH DOSE ESCALATION

9. UNANSWERED QUESTIONS IN UPFRONT THERAPY WEEKLY DOSING PHASE II STUDIES paclitaxel in platinum-resistant ovarian cancer Schedule (mg/m2)PPNRRPFSOS 1)60-80 weekly100%3253%6.110.4 2)80 weekly100%4821%3.6- 3)80 weekly x 3/ 4~10%1428% 4)80 weekly100%5325%24 w58 w 5)80 weekly x 6/ 896%2850%6*8* 6)80-100 weekly (1)45%2770%4.8**13.5** 7)80 weekly68%5756%513.7 1) Canada Le. Gyn Oncol 2005: 2) GOG Markman. Gyn Oncol 2006; 3) Japan Kita Gyn Oncol 2004; 4) Markman at Cleveland. Markman. JCO 2002; 5) Roswell Park. Ghamande. Int J Gynecol Cancer 2003; * in responders; 6) Royal Mardsden Lynch. Gyn Oncol 2008 ** including the platinum sensitive patients (1) retrospective; 7) Norwegian Kaern Eur J Gynecol Oncol 2002

10. UNANSWERED QUESTIONS IN UPFRONT THERAPY WEEKLY DOSING PHASE II STUDIES paclitaxel in combination in platinum-resistant ovarian cancer TDose/m2/wk C AUC Author NRR % DFS months OS months T90 C AUC4 d1,8,q 21 Cadron Gynecol Oncol 2007 8386.758 T80 C AUC2 d1,8,15, q 28 Havrilesky, Gynecol Oncol 2003 837.53.211.4 T90 C AUC4 d1,8,15, q 28 Van der Burg, Int J Gynecol Cancer, 2005 23611115 T80 C AUC3 d1,8,15 q28 Roxburgh P ESMO 08 A # 668 5450-634.7-7.57.5-9 T70 C AUC 3 d1,8,15, q28 Sharma R Br J Cancer 2009 20 60 7,9 13,3

11. UNANSWERED QUESTIONS IN UPFRONT THERAPY WEEKLY DOSING RANDOMIZED PHASE II STUDIES 3weekly vs weekly paclitaxel in ovarian cancer AuthorNScenarioT Doses/m2Conclusion Wu, 200129Front-lineT175 C AUC6 T60 C AUC 2 Equal RR Less toxicity Rosenberg, 02208Second-lineT 200 T 67 Equal RR,TTP, OS Less toxicity Shen, 05 CGOG 125Front-lineTC Twkly C Equal RR,TTP, OS Less toxicity

12. UNANSWERED QUESTIONS IN UPFRONT THERAPY WEEKLY DOSING PHASE II STUDIES paclitaxel in combination in front-line ovarian cancer AuthorNScenarioT Doses/m2Conclusion Pignata, 2008 (MITO5) 26Front-line elderlyT60 C AUC2 d1,8,15 q28 RR: 38,5% mPFS: 13,6m mOS: 32 m Sehouli, 2008 (NOGGO) 129Front-line IIb-IV radical resected T100 C AUC2 d1,8, q21 RR: 74% mPFS: 21m mOS: 43m Safra, 2009 (Tel Aviv) 64Front-line Ic-IVT 80 C AUC2 d1,8,15 q28 RR: 92,1% mPFS:25,5m mOS: 52m

13. AGO Ovarian Cancer Study Group (AGO- OVAR) What else?

14. UNANSWERED QUESTIONS IN UPFRONT THERAPY WEEKLY DOSING Randomized PHASE III TC vs DDT+C in first-line AOC patients : a JGOG Study Isohishi S et al. ASCO 2008,Abstract-5506

15. UNANSWERED QUESTIONS IN UPFRONT THERAPY WEEKLY DOSING Randomized PHASE III TC vs DDT+C in first-line AOC patients : a JGOG Study Endpoint: PFS n: 637 pts PFS (median follow up 29 m): –17,1m vs 27,9m (p:0.0014) log-rank test OS (at 2 years): –77,7% vs 83,6% (p:0.05) RR: similar Toxicity: Anemia G3-4 in weekly arm more freq Isohishi S et al. ASCO 2008,Abstract-5506 (Oral)

16. TreatmentnEventMedian PFSP valueHR95%CI c-TC31920017.2 mos. dd-TC31216028.0 mos.0.00150.7140.581-0.879 Isohishi et al, ASCO 2008 (abstract #5506, oral) JGOG: Conventional TC vs Dose-Dense TC in ADOVCA Progression-free survival

17. UNANSWERED QUESTIONS IN UPFRONT THERAPY WEEKLY DOSING ONGOING STUDIES in front-line ovarian cancer GroupStudy Design Tmg/m2 nPrimary Objetive Secondary Objetives Status Intergroup MO22225 (OCTAVIA) GEICO, GINECO, NSGO, MITO Phase II T80 d1,8,15 q21 + C AUC 6 q21 + Beva 7.5q21 180PFSORR RR Duration OS Safety Open in June 09 MITO-7 Particip: MANGO Phase III R C AUC6+ T175 vs T60 d1,8,15, q21 C AUC 2 q 21 500QoLORR PFS, OS Safety Open

18. UNANSWERED QUESTIONS IN UPFRONT THERAPY Weekly Dosing Conclusion Results of trials with impact in FRONT-LINE: –TC remains standard since 2003 and after many trials including more than 6000 patients!!! CP vs TC: GOG-111, OV10 Carbo T vs Cis T: GOG, AGO, SWOG –Weekly T + C (JGOG) : improved PFS (phase III) –Ongoing: Triplet: TC + Avastin: –ICON-7: (recently closed) –GOG-218 –GOG-213

19. UNANSWERED QUESTIONS IN UPFRONT THERAPY Weekly Dosing Open Questions Which is the optimal weekly dose? Which drugs should be administered in a weekly schedule –Only Taxane? –Taxane + carboplatin? How to incorporate weekly dose to –i.p strategy? –biologic agents combination? How to determine the appropriate duration of weekly dose therapy?