GOG0172: The DingsThe recommended regimen is not feasibleSubstitution of carboplatin for cisplatinReduce cisplatin from 100 mg/m2 to 75 mg/m2Change paclitaxel infusion and/or scheduleNeed for 6 cycles not establishedRole of intraperitoneal delivery not establishedTrial design flawed (too many variables)Dose-intensity hypothesis not validatedPotential role of biology, angiogenesis, microenvironmentThis should not be our research priority

GOG157: Ovarian (adjuvant) Epithelial Ovarian Cancer Stage IC/II any grade Stage IA/B high grade No prior therapyOpen:20-Mar-95Closed:25-May-98Accrual:457 ptsx 3x 6Paclitaxel 175 mg/m2 (3 h)Carboplatin AUC=7.5IIIPaclitaxel 175 mg/m2 (3 h)Carboplatin AUC=7.5 Only 70% met eligibility criteria (133 excluded) 107/457 (23%) were incompletely staged Hematologic toxicity and neuropathy increased with 6 cyclesBell JG, et al. Gynecol Oncol 102:432-9, 2006

GOG157: Ovarian (adjuvant)Carbo-Paclitaxel (x6)(n = 214) 83% @ 5 yCarbo-Paclitaxel (x3)(n = 213) 81% @ 5 yHazard Ratio = 1.0295% CI = 0.662 1.57, p=0.94(includes 107 surgical exclusions)Bell JG, et al. Gynecol Oncol 102:432-9, 2006

GOG111: Ovarian (suboptimal III/IV)Cisplatin 75 mg/m2Cyclophosphamide 650 mg/m2Cisplatin 75 mg/m2Paclitaxel 135 mg/m2 (24 h) Epithelial Ovarian Cancer Suboptimal Stage III/IV No prior therapyOpen:13-Apr-90Closed:02-Mar-92Accrual:410 ptsIIIMcGuire, et al. N Engl J Med 334:1-6, 1996

GOG132: Ovarian (suboptimal III/IV)Cisplatin 100 mg/m2Cisplatin 75 mg/m2Paclitaxel 135 mg/m2 (24 h) Epithelial Ovarian Cancer Suboptimal Stage III/IV No prior therapy Crossover allowedOpen:20-Mar-92Closed:09-May-94Accrual:648 ptsIIIIIIPaclitaxel 200 mg/m2 (24 h)Muggia, et al. J Clin Oncol 18:106, 2000

GOG111 & 132: Ovarian (subopt III/IV)GOG-111 (n = 184)CDDP 75 and Paclitaxel 135Median = 37 mGOG-132 (n = 201)CDDP 75 and Paclitaxel 135Median = 27 mMuggia, et al. J Clin Oncol 18:106, 2000McGuire, et al. N Engl J Med 334:1-6, 1996

GOG158: Ovarian (optimal III)Cisplatin 75 mg/m2Paclitaxel 135 mg/m2 (24 h)Carboplatin AUC 7.5Paclitaxel 175 mg/m2 (3 h) Epithelial Ovarian Cancer Optimal Stage III No prior therapy Elective Second-Look Non-Inferiority DesignOpen:03-Apr-95Closed:26-Jan-98Accrual:792 pts (evaluable)IIIOzols, et al. Proc J Clin Oncol 21:3194, 2003

GOG172: Ovarian (optimal III)Cisplatin 75 mg/m2Paclitaxel 135 mg/m2 (24 h)Cisplatin 100 mg/m2 IP d1Paclitaxel 135 mg/m2 (24 h) IV d1Paclitaxel 60 mg/m2 IP d8 Epithelial Ovarian Cancer Optimal Stage III No prior therapy Elective Second-LookOpen:23-Mar-98Closed:29-Jan-01Accrual:416 pts (evaluable)IIIArmstrong, et al. NEJM 354:34-43, 2006

GOG172 & 158: Exploratory AnalysisArmstrong, et al. NEJM 354:34-43, 2006CDDP (IV) Paclitaxel (IV)(n = 210)CDDP (IP) Paclitaxel (IP+IV)(n = 206)

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

Ovarian Cancer: Biologic OpportunitiesUnique Biology of the Mllerian Epithelium and Peritoneal CavitySpecialized relationship; spread via implantationFrequent production of ascites, associated with VEGFNegative immunoregulation (VEGF, IL-10, IL-6, IL-12, APC)Growth Factor ReceptorsEGF-R frequently expressed, mutations uncommon, frequency of overexpression variableHER2/neu frequently expressed, high-level overexpression

GOG-DTC: Ovary, Biologic Studies

GOG0170D: Bevacizumab Phase IIBevacizumab 15 mg/kg q3wkEpithelial Ovarian Cancer 2 Prior TherapiesRECIST MeasurablePS 0,1Two-stage accrual designPrimary endpoint PFS @6 m

Open:Apr-02Closed:Aug-04Accrual:62 ptsIBurger et al., Proc Ann Meet ASCO 24:A5009Overall response rate 12/62 (19.4%), including 3 CR42% of pts alive and free of progression at 6 mMedian number of cycles = 7, range = 1 to 29

GOG0170D: Bevacizumab Phase IIBurger et al., Proc Ann Meet ASCO 24:A5009

GOG218: Ovarian (stage III-IV) Epithelial Ovarian or Primary Peritoneal Cancer Suboptimal Cytoreduction Collaborative design (GOG, NCI, Genentech)x 6Paclitaxel 175 mg/m2 (3 h)Carboplatin AUC=6.0Bevacizumab 15 mg/kg q21d*IIx 6IPaclitaxel 175 mg/m2 (3 h)Carboplatin AUC=6.0Placebo q21d*Placebo(14 m total)Placebo(14 m total)Bevacizumab(14 m total)x 6Paclitaxel 175 mg/m2 (3 h)Carboplatin AUC=6.0Bevacizumab 15 mg/kg q21d*IIIOpen:26-Sep-05Closed:---Target Accrual:2000 pts (3 Y)Burger, et al.*starting with C2

If IP Therapy is Really So ImportantWhy 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,

^two cycles of

^some

^