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GOG0182-ICON5:

GOG0182-ICON5: Phase III Randomized Trial of Paclitaxel and Carboplatin vs Combinations with Gemcitabine, PEG-Lipososomal Doxorubicin, or Topotecan in Patients with Advanced-Stage Epithelial Ovarian or Primary Peritoneal Carcinoma. Michael A Bookman, MD on behalf of GCIG, including

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GOG0182-ICON5:

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  1. GOG0182-ICON5: Phase III Randomized Trial of Paclitaxel and Carboplatin vs Combinations with Gemcitabine, PEG-Lipososomal Doxorubicin, or Topotecan in Patients with Advanced-Stage Epithelial Ovarian or Primary Peritoneal Carcinoma Michael A Bookman, MD on behalf of GCIG, including GOG, MRC, SWOG, ANZGOG, M Negri, and NCI-CTSU Fox Chase Cancer Center Philadelphia, PA

  2. GOG0182-ICON5: Steering Committee

  3. GOG0182-ICON5: Study Chairs, GOG Chair: Michael A Bookman, MD Statistician: Mark F. Brady, PhD Co-Chairs: William P McGuire, III, MD Stephen D Williams, MD Thomas Herzog, MD Pathology: Lawrence M Roth, MD Lab Science: Holly H Gallion, MD Nurse Contacts: Judy Parham, RN Chrisann Accario-Winslow, RN, MSN Data Coord: Suzanne Baskerville, CCRA SWOG Coord: David S Alberts, MD

  4. Developmental Therapy

  5. Substitution of Carboplatin for Cisplatin (GOG158, AGO) Incorporation of Paclitaxel (GOG111, OV10) GOG0182-ICON5 GOG, MRC, ANZGOG SWOG, M Negri, CTSU Phase III Trial Feasibility of Gemcitabine Triplet (GOG9801, Hansen) Feasibility of PEG-LipoDox Triplet (GOG9703) Epirubicin Triplet NCIC, EORTC, NSGO and AGO-OVAR, GINECO Sequence of Topotecan Doublet (GOG9906) Gemcitabine Triplet AGO-OVAR, GINECO, NSGO Sequence of Gemcitabine Doublet (Iaffaioli) Topotecan Doublet NCIC, EORTC, NSGO Extended Topotecan AGO-OVAR, GINECO Non-Feasibility of Etoposide Triplet (GOG9603) Developmental Therapy and Context

  6. GOG0182-ICON5: Primary Objective • To compare efficacy of each experimental arm with the control arm… • Efficacy determined through analysis of overall survival (OS) and progression-free survival (PFS) • A single interim analysis based on PFS will be performed to select promising arms for full accrual • Survival analysis determined by an event-triggered pair-wise comparison to the standard regimen (intent-to-treat) • 90% chance of detecting a true hazard ratio (HR) of 1.33 • Type I error limited to 1.25% (two-tailed) for each comparison • Final sample size adjusted based on accrual rate and planned interim analysis

  7. GOG0182-ICON5: Design • Eligibility • Adequate initial surgery to establish diagnosis • Epithelial ovarian or primary peritoneal carcinoma • FIGO Stage III or IV • GOG PS 0, 1, or 2 • Stratification • Microscopic, optimal (≤ 1 cm), or suboptimal (> 1 cm) residual • Measurable or non-measurable disease • Intent to perform interval cytoreductive surgery

  8. GOG0182-ICON5: Design • Treatment • Carboplatin-Paclitaxel reference arm (x8 cycles) • Four experimental arms, equitoxic dosing (x8 cycles) • Minimum of 4 cycles with experimental regimens • Management • No initial use of hematopoietic growth factors • Dose modifications based on nadir and delayed recovery • Second-look surgery not permitted • Maintenance or consolidation not permitted • Allowance for CA125-based progression

  9. Carboplatin AUC 6 (d1) Paclitaxel 175 mg/m2 (d1) I x8 R A N D O M I Z E Carboplatin AUC 5 (d1) Paclitaxel 175 mg/m2 (d1) Doxil 30 mg/m2 (d1, every other cycle) III x8 Carboplatin AUC 5 (d3) Topotecan 1.25 mg/m2 (d1-3) IV x4 Carboplatin AUC 6 (d1) Paclitaxel 175 mg/m2 (d1) x4 Carboplatin AUC 5 (d1) Paclitaxel 175 mg/m2 (d1) Gemcitabine 800 mg/m2 (d1,8) Carboplatin AUC 6 (d8) Gemcitabine 1 g/m2 (d1,8) V x4 II x8 GOG0182-ICON5: Schema

  10. GOG0182-ICON5 Accrual Final (Total) 4312 Actual Projected 1000 / yr

  11. GOG0182-ICON5 Accrual Open: 29-JAN-2001 Closed: 01-SEP-2004 Accrual: 4312 patients

  12. GOG0182-ICON5: Characteristics

  13. GOG0182-ICON5: Stratification

  14. GOG0182-ICON5: Interim Analysis • Planned Interim Analysis of PFS • Triggered by 240 events in reference arm • Designed to optimize accrual in arms with promising hazard ratios < 0.87 • If too few events, suspend accrual at 4000 • Outcomes of Interim Analysis • Data locked May-2004; 3836 patients (61 not eligible) • 272 events on reference arm, 1345 events overall • < 1% of deaths potentially treatment-related without clustering on any arm • No justification for additional accrual, recommended for international closure effective 01-SEP-2004

  15. GOG0182-ICON5: Rx Completion

  16. GOG0182-ICON5: Carboplatin Delivery

  17. GOG0182-ICON5: Heme Toxicity * p < 0.001 global test of null hypothesis

  18. GOG0182-ICON5: Non-Heme Toxicity * p < 0.001 global test of null hypothesis

  19. GOG0182-ICON5: Progression-Free Survival Median PFS and HR (95% CI) 16.1 1.000 16.4 0.990 (0.884-1.107) 16.4 0.998 (0.891-1.117) 15.3 1.094 (0.979-1.224) 15.4 1.052 (0.940-1.176)

  20. GOG0182-ICON5: Overall Survival Median OS and HR (95% CI) 40.0 1.000 40.4 0.978 (0.838-1.141) 42.8 0.972 (0.832-1.136) 39.1 1.068 (0.918-1.244) 40.2 1.035 (0.888-1.206)

  21. GOG0182-ICON5: Overall Survival

  22. GOG0182-ICON5: Treatment HR by Residual

  23. GOG0182-ICON5: Annual Accrual (US) Annual 25,580 New cases of ovarian cancer diagnosed in 2004 (ACS estimate) 19,185 New cases of advanced-stage disease (75%) 1,200 Patients enrolled through GOG, SWOG, CTSU Overall, during 2003 and 2004, approximately 6.25% of all new advanced-stage ovarian cancer patients were enrolled on GOG0182-ICON5 through GOG, CTSU, and SWOG member institutions, reflecting strong participation among Gynecologic Oncologists throughout the US.

  24. GOG0182-ICON5: Conclusions • Phase III trials with international collaboration are feasible, with attention to regional regulatory issues, drug availability, funding, and data management • Enrollment was facilitated by including all categories of advanced-stage disease, and the trial provides a valuable prospective database to support exploratory analyses • The addition of a third cytotoxic agent was associated with increased, but manageable, hematologic toxicity • Among the regimens evaluated, the addition of a third cytotoxic agent was not associated with improved clinical outcomes, including progression-free and overall survival • After more than 25 years, carboplatin remains the dominant agent for treatment of advanced ovarian cancer, with an impact on evaluation of new agents and potential non-platinum alternatives

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