GOG0172: The Dings The recommended regimen is not feasible –Substitution of carboplatin for cisplatin –Reduce cisplatin from 100 mg/m 2 to 75 mg/m 2 –Change paclitaxel infusion and/or schedule –Need for 6 cycles not established Role of intraperitoneal delivery not established –Trial design flawed (too many variables) –Dose-intensity hypothesis not validated –Potential role of biology, angiogenesis, microenvironment This should not be our research priority The recommended regimen is not feasible –Substitution of carboplatin for cisplatin –Reduce cisplatin from 100 mg/m 2 to 75 mg/m 2 –Change paclitaxel infusion and/or schedule –Need for 6 cycles not established Role of intraperitoneal delivery not established –Trial design flawed (too many variables) –Dose-intensity hypothesis not validated –Potential role of biology, angiogenesis, microenvironment This should not be our research priority

Epithelial Ovarian Cancer Epithelial Ovarian Cancer Stage IC/II any grade Stage IC/II any grade Stage IA/B high grade Stage IA/B high grade No prior therapy No prior therapy Open:20-Mar-95 Closed:25-May-98 Accrual:457 pts x 3 x 6 Paclitaxel 175 mg/m 2 (3 h) Carboplatin AUC=7.5 II I GOG157: Ovarian (adjuvant) Paclitaxel 175 mg/m 2 (3 h) Carboplatin AUC=7.5 Only 70% met eligibility criteria (133 excluded) Only 70% met eligibility criteria (133 excluded) 107/457 (23%) were incompletely staged 107/457 (23%) were incompletely staged Hematologic toxicity and neuropathy increased with 6 cycles Hematologic toxicity and neuropathy increased with 6 cycles Bell JG, et al. Gynecol Oncol 102:432-9, 2006

GOG157: Ovarian (adjuvant) Carbo-Paclitaxel (x6) (n = 214) 5 y Carbo-Paclitaxel (x3) (n = 213) 5 y Hazard Ratio = % CI = – 1.57, p=0.94 (includes 107 surgical exclusions) Bell JG, et al. Gynecol Oncol 102:432-9, 2006

Cisplatin 75 mg/m 2 Cyclophosphamide 650 mg/m 2 Cisplatin 75 mg/m 2 Paclitaxel 135 mg/m 2 (24 h) Epithelial Ovarian Cancer Epithelial Ovarian Cancer Suboptimal Stage III/IV Suboptimal Stage III/IV No prior therapy No prior therapy Open:13-Apr-90 Closed:02-Mar-92 Accrual:410 pts I II McGuire, et al. N Engl J Med 334:1-6, 1996 GOG111: Ovarian (suboptimal III/IV)

Cisplatin 100 mg/m 2 Cisplatin 75 mg/m 2 Paclitaxel 135 mg/m 2 (24 h) Epithelial Ovarian Cancer Epithelial Ovarian Cancer Suboptimal Stage III/IV Suboptimal Stage III/IV No prior therapy No prior therapy Crossover allowed Crossover allowed Open:20-Mar-92 Closed:09-May-94 Accrual:648 pts I III II Paclitaxel 200 mg/m 2 (24 h) Muggia, et al. J Clin Oncol 18:106, 2000 GOG132: Ovarian (suboptimal III/IV)

GOG111 & 132: Ovarian (subopt III/IV) GOG-111 (n = 184) CDDP 75 and Paclitaxel 135 Median = 37 m GOG-132 (n = 201) CDDP 75 and Paclitaxel 135 Median = 27 m Muggia, et al. J Clin Oncol 18:106, 2000 McGuire, et al. N Engl J Med 334:1-6, m

GOG158: Ovarian (optimal III) Cisplatin 75 mg/m 2 Paclitaxel 135 mg/m 2 (24 h) Carboplatin AUC 7.5 Paclitaxel 175 mg/m 2 (3 h) Epithelial Ovarian Cancer Epithelial Ovarian Cancer Optimal Stage III Optimal Stage III No prior therapy No prior therapy Elective Second-Look Elective Second-Look Non-Inferiority Design Non-Inferiority Design Open:03-Apr-95 Closed:26-Jan-98 Accrual:792 pts (evaluable) I II Ozols, et al. Proc J Clin Oncol 21:3194, 2003

GOG172: Ovarian (optimal III) Cisplatin 75 mg/m 2 Paclitaxel 135 mg/m 2 (24 h) Cisplatin 100 mg/m 2 IP d1 Paclitaxel 135 mg/m 2 (24 h) IV d1 Paclitaxel 60 mg/m 2 IP d8 Epithelial Ovarian Cancer Epithelial Ovarian Cancer Optimal Stage III Optimal Stage III No prior therapy No prior therapy Elective Second-Look Elective Second-Look Open:23-Mar-98 Closed:29-Jan-01 Accrual:416 pts (evaluable) I II Armstrong, et al. NEJM 354:34-43, 2006

CDDP (IV) Paclitaxel (IV) (n = 400) Ozols, et al. J Clin Oncol 21:3194, 2003 GOG172 & 158: Exploratory Analysis Armstrong, et al. NEJM 354:34-43, 2006 CDDP (IV) Paclitaxel (IV) (n = 210) CDDP (IP) Paclitaxel (IP+IV) (n = 206)

GOG: Combined Exploratory Analysis Ozols, et al. Gynecol Oncol 103:1-6, 2006 GOG172 to GOG158: HR = 0.81 (95% CI 0.59 – 1.11)

Ovarian Cancer: Biologic Opportunities Unique Biology of the Müllerian Epithelium and Peritoneal Cavity –Specialized relationship; spread via implantation –Frequent production of ascites, associated with  VEGF –Negative immunoregulation (  VEGF,  IL-10,  IL-6,  IL-12,  APC) Growth Factor Receptors –EGF-R frequently expressed, mutations uncommon, frequency of overexpression variable –HER2/neu frequently expressed, high-level overexpression <15%, gene amplification uncommon –ER/PR/AR frequently expressed, variable functionality –Other receptors less well characterized Growth Factor Production –Frequent high-level expression of VEGF –Increased expression of IL10, IL6, TNF, TGFα Unique Biology of the Müllerian Epithelium and Peritoneal Cavity –Specialized relationship; spread via implantation –Frequent production of ascites, associated with  VEGF –Negative immunoregulation (  VEGF,  IL-10,  IL-6,  IL-12,  APC) Growth Factor Receptors –EGF-R frequently expressed, mutations uncommon, frequency of overexpression variable –HER2/neu frequently expressed, high-level overexpression <15%, gene amplification uncommon –ER/PR/AR frequently expressed, variable functionality –Other receptors less well characterized Growth Factor Production –Frequent high-level expression of VEGF –Increased expression of IL10, IL6, TNF, TGFα

GOG-DTC: Ovary, Biologic Studies StudyClosedReagentsChairResponse & Comments 160Jan-00TrastuzumabBookman 3/41 (7.3%)Inactive 170-BMar-99 IL-12 (IV) Hurteau 1/26 (3.8%)Inactive 170-CJun-02GefitinibSchilder 1/27 (3.7%)TK-mut 170-DAug-04BevacizumabBurger 12/62 (19.4%), 10+ m PFS 170-EAug-04ImatinibSchilder Under Analysis (Stg 2) 170-FOngoingBAY Matei Accrual in Process (Stg 2) 170-GMay-06LapatinibGarcia Under Analysis (Stg 1) 170-HApr-06SAHAModesitt 170-JPendingTemserolimusBehbakht Under Development 170-IPendingEnzastaurinUsha

GOG0170D: Bevacizumab Phase II Bevacizumab 15 mg/kg q3wk Epithelial Ovarian CancerEpithelial Ovarian Cancer ≤ 2 Prior Therapies≤ 2 Prior Therapies RECIST MeasurableRECIST Measurable PS 0,1PS 0,1 Two-stage accrual designTwo-stage accrual design Primary endpoint mPrimary endpoint m Open:Apr-02 Closed:Aug-04 Accrual:62 pts I Burger et al., Proc Ann Meet ASCO 24:A5009 Overall response rate 12/62 (19.4%), including 3 CROverall response rate 12/62 (19.4%), including 3 CR 42% of pts alive and free of progression at 6 m42% of pts alive and free of progression at 6 m Median number of cycles = 7, range = 1 to 29Median number of cycles = 7, range = 1 to 29

GOG0170D: Bevacizumab Phase II Burger et al., Proc Ann Meet ASCO 24:A5009 GOG0126 Series (n = 220) Platinum-Resistant Disease 6 m = 0.16 (  SE 0.025) GOG0170-D (n = 62) 6 m = 0.42

Epithelial Ovarian or Primary Peritoneal Cancer Epithelial Ovarian or Primary Peritoneal Cancer Suboptimal Cytoreduction Suboptimal Cytoreduction Collaborative design (GOG, NCI, Genentech) Collaborative design (GOG, NCI, Genentech) GOG218: Ovarian (stage III-IV) x 6 Paclitaxel 175 mg/m 2 (3 h) Carboplatin AUC=6.0 Bevacizumab 15 mg/kg q21d* II x 6 I Paclitaxel 175 mg/m 2 (3 h) Carboplatin AUC=6.0 Placebo q21d* Placebo (14 m total) Placebo (14 m total) Bevacizumab (14 m total) x 6 Paclitaxel 175 mg/m 2 (3 h) Carboplatin AUC=6.0 Bevacizumab 15 mg/kg q21d* III Open:26-Sep-05 Closed:--- Target Accrual:2000 pts (3 Y) Burger, et al. *starting with C2

If IP Therapy is Really So Important… Why has it been more than 2 years without an active GOG phase III trial for women with ovarian cancer and optimal cytoreductive surgery? Where is the funding to support scientific investigation of IP therapy using generic off-patent medications (cisplatin and paclitaxel)? Should our patients commit to increased toxicity and 2-3 days in the hospital with each cycle of “recommended” therapy? Are we prepared to evaluate all new agents “IP” and “IV”? Should IP therapy have a higher priority than evaluation of targeted agents, immunomodulation, and tumor molecular profiling? Why has it been more than 2 years without an active GOG phase III trial for women with ovarian cancer and optimal cytoreductive surgery? Where is the funding to support scientific investigation of IP therapy using generic off-patent medications (cisplatin and paclitaxel)? Should our patients commit to increased toxicity and 2-3 days in the hospital with each cycle of “recommended” therapy? Are we prepared to evaluate all new agents “IP” and “IV”? Should IP therapy have a higher priority than evaluation of targeted agents, immunomodulation, and tumor molecular profiling?

NCI Clinical Announcement (05-JAN-2006) and potential risks ^ compared to standard IV chemotherapy ^ route ^ such as GOG0218 and ICON7, ^ Revised 14-Oct-2006 two cycles of ^ some ^