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

Phase III: ICON7 Carboplatin: AUC6; Paclitaxel 175mg/m 2 Cycles: 21 days High risk early stage/Advanced stage Ovarian, primary peritoneal, or fallopian tube cancer Carboplatin/Paclitaxel x 6 cycles Observation Bevacizumab 7.5 mg/kg x 5-6 cycles Bevacizumab 7.5 mg/kg x 12 cycles Target Accrual: 1520 Primary endpoint: PFS

IP Therapy: Randomized Trials IV ARMIP ARMP value GOG 104 IV cyclophosphamide + IV or IP CDDP OS41 mos49 mos0.02 GOG 114 IV Pac + IV CDDP or IV carbo then IV Pac + IP CDDP PFS22 mos28 mos0.01 OS52 mos63 mos0.05 GOG 172 IV Pac + IV CDDP or IV/IP Pac + IP CDDP PFS18.3 mos23.8 mos0.05 OS49.7 mos65.6 mos0.03 Alberts et al. NEJM 1996, Markman et al. JCO 2001, Armstrong et al. NEJM 2006

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

IP Chemotherapy: Modification GOG 172 Modified D1: IV Paclitaxel (135 mg/m 2 /24h) D2: IP Cisplatin (100 mg/m 2 ) D8: IP Paclitaxel (60 mg/m 2 ) D1: IV Paclitaxel (135 mg/m 2 /3h) D2: IP Cisplatin (75 mg/m 2 ) D8: IP Paclitaxel (60 mg/m 2 ) D1 IV D2 IP D1 IV D2 IP D8 IP D8 IP

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

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

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

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/m 2 ) weekly Primary endpoint PFS –0.8 power to detect 5 month difference TreatmentNMedian PFS P valueHR95% CI TC mos TC-T- T mos year OS TC % TC-T-T % Isonishi et al. J Clin Oncol 26: 2008, abs 5506

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

Relapse Therapy: Past Primary treatment RELAPSE < 6 months> 6 months Platinum ResistantPlatinum Sensitive

Bevacizumab in Recurrent Ovarian Cancer StudyNTreatmentRR (%) PF 6 mo (%) Prior RxGIP GOG 170-D 1 62BV 15 mg/kg IV q 3 wk % platinum resistant, 1-2 priors 0 NCI BV 10 mg/kg IV q 2 wk + CTX 50 mg daily % platinum resistant, 1-3 priors 4 (5.7%) AVF BV 15 mg/kg IV q 3 wk Platinum resistant, 1-3 priors 5 (11%) 1 Burger et al. JCO 2007, 2 Garcia et al. JCO 2008, 3 Cannistra et al. JCO 2007

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

Single Agent Activity of Bevacizumab Tumor TypeDoseORR (PR+CR) Ovarian Cancer15mg/kg q3wk16-21% Renal Cell10mg/kg q2wk10% Met Breast Cancer 3-20mg/kg q2wk7% NHL10mg/kg q2wk5% CRC10mg/kg q2wk3% HRPC10mg/kg q2wk0%

Ovarian Cancer: Biologics STUDYAGENTNRR (%)PFS at 6 months (%) 170-CGefitinib DBevacizumab EImatinib FSorafenib GLapatinib HVorinostat ITemsirolimusBoth stages of accrual completed 170-JEnzastaurin KMifepristoneClosed after first stage 170-MDasatinibFirst stage accrual completed

ASCO 2008 Agent/ Abstract No. NRR (%)PFSPrior RX Sorafenib (5537) (2/59)23.7% PF at 6 mo 1-2 priors Cediranib (5501) (6/32)-1-3 priors Cediranib (5521) (2/26) – Pl-S 0 – Pl-R -1-2 priors Sunitinib (5522) (2/17)-1-2 priors

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

Recurrent Disease: Platinum Sensitive ICON4 1 AGO 2 1 ICON4 Lancet 2003 and 2 Pfisterer et al JCO 2006

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

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

PaclitaxelCarboplatinBevacizumabPaclitaxelCarboplatin GOG 213 –PHASE III MaintenanceBevacizumab Surgical Candidate? Randomize No Yes Randomize Surgery No Surgery Primary endpoint: OS Target accrual: 660

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

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

Selected Combinations in Trials TargetsClinical trialsTumor types VEGF + VEGFR BV + SorafenibRCC, Ovarian, Melanoma BV + CederanibPhase I BV + SunitinibRCC VEGF + mTORBV + CCI-779*RCC, Ovary, Endometrial, HCC, NEC Sorafenib + CCI-779RCC, Melanoma, GBM VEGF + PDGFBV + Imatinib*Melanoma, GIST, RCC VEGFR + IntegrinBV + Medi-552RCC BV + CilengitideGBM Angio + Tumor targetsVEGF Ab or TKIs + EGFR, HER2, HDAC inhibitors, Immunotherapy, etc

Combination of anti-angiogenesis agents – preliminary toxicity data (Phase I experience) MTDToxicities CCI SunitinibNot tolerable (15 mg + 25 mg) DLT: Mucocutaneous (no further development) CCI SorafenibDose reduction (for one agent) DLT: Mucocutaneous, Plts  BV + SorafenibDose reduction (both agents: 50%  ) DLT: HUS, HTN, proteinuria SAEs: GI perf, fistula, bleeding BV + SunitinibNot Tolerability at full doses in RCC SAEs: HUS/TTP-like syndrome HTN BV + CCI-779Full doseNonspecific Exposures in more pts and for longer duration may reveal additional serious toxicities that are relatively low-frequency

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