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Investigating the Role of Anti-Angiogenic Agents in Ovarian Cancer

Investigating the Role of Anti-Angiogenic Agents in Ovarian Cancer. Carol Aghajanian, M.D. Chief, Gynecologic Medical Oncology Memorial Sloan-Kettering Cancer Center. Phase III: GOG 218. Carboplatin/Paclitaxel - cycles 1-6 Concurrent Placebo - cycles 2-6 Placebo - cycles 7-22.

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Investigating the Role of Anti-Angiogenic Agents in Ovarian Cancer

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  1. Investigating the Role of Anti-Angiogenic Agents in Ovarian Cancer Carol Aghajanian, M.D. Chief, Gynecologic Medical Oncology Memorial Sloan-Kettering Cancer Center

  2. Phase III: GOG 218 Carboplatin/Paclitaxel - cycles 1-6 Concurrent Placebo - cycles 2-6 Placebo - cycles 7-22 Stage III* or IV, Ovarian, primary peritoneal, or fallopian tube cancer Carboplatin/Paclitaxel – cycles 1-6 Concurrent Bevacizumab – cycles 2-6 Placebo – cycles 7-22 Carboplatin/Paclitaxel – cycles 1-6 Concurrent Bevacizumab – cycles 2-6Bevacizumab – cycles 7-22 • Activated: 9/26/05 • Accrual goal: 1800 pts • Primary end point: PFS *optimal (gross residual) or suboptimal

  3. Phase III: ICON7 Carboplatin/Paclitaxel x 6 cycles Observation High risk early stage/Advanced stage Ovarian, primary peritoneal, or fallopian tube cancer Carboplatin/Paclitaxel x 6 cycles Bevacizumab 7.5 mg/kg x 5-6 cycles Bevacizumab 7.5 mg/kg x 12 cycles Target Accrual: 1520 Primary endpoint: PFS Carboplatin: AUC6; Paclitaxel 175mg/m2 Cycles: 21 days

  4. IP Therapy: Randomized Trials Alberts et al. NEJM 1996, Markman et al. JCO 2001, Armstrong et al. NEJM 2006

  5. Modulating Toxicity of IP Therapy • New approaches to improve toxicity profile while maintaining efficacy • Dose/schedule modifications • Docetaxel instead of paclitaxel • IP Carboplatin instead of IP cisplatin • The role of bevacizumab

  6. IP Chemotherapy: Modification GOG 172 D1: IV Paclitaxel (135 mg/m2/24h) D2: IP Cisplatin (100 mg/m2) D8: IP Paclitaxel (60 mg/m2) D8 IP D1 IV D2 IP Modified D1: IV Paclitaxel (135 mg/m2/3h) D2: IP Cisplatin (75 mg/m2) D8: IP Paclitaxel (60 mg/m2) D2 IP D1 IV D8 IP

  7. Phase I - GOG 9916 D1: IV Paclitaxel (175 mg/m2/3h) D1: IP Carboplatin (AUC 6) D8: IP Paclitaxel (60 mg/m2) 9916 Part A D1 IV D1 IP D8 IP 9916 Part B D1: IV Docetaxel (75 mg/m2/1h) D1: IP Carboplatin (AUC 6) D8: IP Paclitaxel (60 mg/m2) D1 IV D1 IP D8 IP 9916 Part C D1: IV Paclitaxel (175 mg/m2/3h) D1: IP Carboplatin (AUC 6) D1: IV Bevacizumab (15 mg/kg)* D8: IP Paclitaxel (60 mg/m2) D1 IV D1 IP D8 IP *beginning cycle 2, day 1 and continuing for 17 total cycles

  8. Phase I - GOG 9917 D1: IV Paclitaxel (175 mg/m2/3h) D1: IP Carboplatin (AUC 6) 9917 Part A D1 IV D1 IP D8 IP 9917 Part B D1: IV Paclitaxel (175 mg/m2/3h) D1: IP Carboplatin (AUC 6) D1: IV Bevacizumab 15 mg/kg* D1 IV D1 IP D8 IP *beginning cycle 2, day 1 and continuing for 17 total cycles

  9. MSKCC 06-064 Modified GOG-0172 D1: IV Paclitaxel (135 mg/m2/3h) D2: IP Cisplatin (75 mg/m2) D8: IP Paclitaxel (60 mg/m2) D8 IP D1 IV D2 IP 06-064 D1: IV Paclitaxel (135 mg/m2/3h) D1: IV Bevacizumab (15 mg/kg)* D2: IP Cisplatin (75 mg/m2) D8: IP Paclitaxel (60 mg/m2) D2 IP D1 IV D8 IP PI: Dr. Jason Konner *beginning cycle 2, day 1 and continuing through cycle 22

  10. ASCO 2008: Phase III IV paclitaxel and carboplatin vs. dose dense (TC-T-T) • JGOG: 637 patients randomized, Stage III diagnosis • TC vs TC-T-T (80 mg/m2) weekly • Primary endpoint PFS • 0.8 power to detect 5 month difference Isonishi et al. J Clin Oncol 26: 2008, abs 5506

  11. Phase III: GOG 0252 Paclitaxel 80 mg/m2/1h IV, Days 1, 8, 15, Cycles 1-6 Carboplatin AUC 6 IV, Day 1, Cycles 1-6 Bevacizumab 15 mg/kg IV, Cycles 2-22 RANDOMIZE Stage II or III (<1cm residual), Ovarian, primary peritoneal, or fallopian tube cancer Paclitaxel 80 mg/m2/1h IV, Days 1, 8, 15, Cycles 1-6 Carboplatin AUC 6 IP, Day 1, Cycles 1-6 Bevacizumab 15 mg/kg IV, Cycles 2-22 Paclitaxel 135 mg/m2/3h IV, Day 1, Cycles 1-6 Cisplatin 75 mg/m2IP, Day 2, Cycles 1-6 Paclitaxel 60 mg/m2 IP, Day 8, Cycles 1-6 Bevacizumab 15 mg/kg IV, Cycles 2-22 • Accrual goal: 1100 pts • Primary end point: PFS

  12. Relapse Therapy: Past Primary treatment RELAPSE < 6 months > 6 months Platinum Resistant Platinum Sensitive

  13. Bevacizumab in Recurrent Ovarian Cancer 1Burger et al. JCO 2007, 2Garcia et al. JCO 2008, 3Cannistra et al. JCO 2007

  14. AVF2949g: Risk Factors for GI Perforation Radiographic Prior Treatment P < 0.05 P <0.1 Cannistra, et al JCO 2007

  15. Single Agent Activity of Bevacizumab

  16. Ovarian Cancer: Biologics

  17. ASCO 2008

  18. VEGF-TRAP VEGF Trap 2 mg/kg IV q 2 weeks Recurrent ovarian cancer 3 - 4 lines treatment Platinum-resistant Resistant: Topotecan and/or Liposomal Doxorubicin Randomized (1:1) Double-Blinded N = 200 VEGF Trap 4 mg/kg IV q 2 weeks Primary endpoint: RR Preliminary results: 8% (blinded pooled summary of first 162 patients) 50% of patients with 4 prior chemotherapy regimens Tew et al. ASCO 2007

  19. Recurrent Disease: Platinum Sensitive ICON41 AGO2 1ICON4 Lancet 2003 and 2Pfisterer et al JCO 2006

  20. OCEANS STUDY –PHASE III Gemcitabine 1000 mg/m² days 1 and 8 Carboplatin AUC 4 day 1 Bevacizumab 15 mg/kg day 1 q 21 days x 6 RANDOMIZATION Bevacizumab until PD Gemcitabine 1000 mg/m² days 1 and 8 Carboplatin AUC 4 day 1 Placebo IV day 1 q 21 days x 6 Placebo until PD *Up to 10 cycles of gemcitabine/carboplatin allowed

  21. OCEANS STUDY • Recurrent Ovarian Cancer • > 6 months off platinum • Measurable disease • Strata: • Platinum-free interval (>6-12, > 12 months) • Cytoreductive surgery for recurrent ovarian cancer (yes/no) • Primary Objective • PFS (Investigator determined) – HR 0.73 • Sample size • 450 pts

  22. GOG 213 –PHASE III Surgical Candidate? Yes Randomize No Surgery No Surgery Randomize Paclitaxel Carboplatin Paclitaxel Carboplatin Bevacizumab Primary endpoint: OS Target accrual: 660 Maintenance Bevacizumab

  23. ICON6 Carboplatin/Paclitaxel* x 6 cycles Concurrent Placebo Maintenance Placebo First platinum-sensitive recurrence Ovarian, primary peritoneal, or fallopian tube cancer Carboplatin/Paclitaxel* x 6 cycles Concurrent Cediranib Maintenance Placebo Carboplatin/Paclitaxel* x 6 cycles Concurrent Cediranib Maintenance Cediranib *Carboplatin alone is allowed

  24. Future Directions • Combinations • GOG 186G: Randomized Phase II study of bevacizumab/everolimus vs. bevacizumab/placebo • Novel Agents

  25. Selected Combinations in Trials

  26. Combination of anti-angiogenesis agents – preliminary toxicity data (Phase I experience) Exposures in more pts and for longer duration may reveal additional serious toxicities that are relatively low-frequency

  27. Conclusions • Angiogenesis is an important target in Ovarian Cancer • Initial treatment • GOG 218 • ICON7 • IP Therapy • First Platinum-Sensitive Recurrence • Oceans • GOG 213 • ICON6 • Recurrent Disease • Multiple single agent phase II trials • Platinum resistant disease • Chemotherapy combinations • “First” platinum resistant recurrence • Combinations • Toxicity will limit the number of agents that can be given simultaneously • When dose reduction is required, optimal dose ratio unknown for optimal therapeutic index

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