Proc ASCO 25: Abstract 5002 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 on behalf of GCIG, including GOG, MRC, SWOG, ANZGOG, GOG, MRC, SWOG, ANZGOG, M Negri, and NCI-CTSU M Negri, and NCI-CTSU Fox Chase Cancer Center Fox Chase Cancer Center Philadelphia, PA Philadelphia, PA

Proc ASCO 25: Abstract 5002 GOG0182-ICON5: Steering Committee David S Alberts MD (US-SWOG)* Michael A Bookman MD (US-GOG)* Mark F. Brady PhD (US-GOG)* A Hilary Calvert, MD (UK) Nicoletta Colombo MD (M Negri, Italy)* Angela Cooper MD (UK) Larry J Copeland MD (US-GOG) Andreas du Bois MD PhD (AGO) Michael Friedlander MD PhD (ANZGOG)* Martin Gore, FRCP PhD (UK) Steen W Hansen MD (Denmark) * Member of Writing Committee Peter Harper MD (UK-MRC)* William Hoskins MD (US-GOG) Maurie Markman MD (US-GOG) William P McGuire III MD (US-GOG)* Robert F Ozols MD PhD (US-GOG) Mahesh Parmar PhD (UK-MRC) Christopher J Poole MD (UK) Ann Marie Swart (UK-MRC)* James Tate Thigpen MD (US-GOG) Valter Torri MD (M Negri, Italy) Edward Trimble MD (US-CTSU, NCI)*

Proc ASCO 25: Abstract 5002 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 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

Proc ASCO 25: Abstract 5002 Developmental Therapy CarboplatinPaclitaxelTopotecanGemcitabine PEG-Lipo Doxorubicin Target:DNA  -tubulin Topo-IRN-reductase, Nucleotide pool Topo-II Mechanism: DNA adduct FormationTubulinAggregationStabilizeDNA-TopoComplex  DNA synth Schedule:IndependentDependent(toxicity)Dependent(efficacy)DependentPhosporylationProlongedclearance Resistance:  GSH,  tolerance,  retention  MDR-MRP, tubulinmutations  Topo-I,  BCRP  RN-reductase  MDR-MRP  Topo-II PlatinumInteraction:N/APlateletSparing ---- Enhanced Toxicity ----

Proc ASCO 25: Abstract 5002 Developmental Therapy and Context Substitution of Carboplatin for Cisplatin (GOG158, AGO) Incorporation of Paclitaxel (GOG111, OV10) Feasibility of Gemcitabine Triplet (GOG9801, Hansen) Feasibility of PEG-LipoDox Triplet (GOG9703) Sequence of Topotecan Doublet (GOG9906) Non-Feasibility of Etoposide Triplet (GOG9603) Sequence of Gemcitabine Doublet (Iaffaioli) Epirubicin Triplet NCIC, EORTC, NSGO and AGO-OVAR, GINECO Gemcitabine Triplet AGO-OVAR, GINECO, NSGO Topotecan Doublet NCIC, EORTC, NSGO Extended Topotecan AGO-OVAR, GINECO GOG0182-ICON5 GOG, MRC, ANZGOG SWOG, M Negri, CTSU Phase III Trial GOG0182-ICON5 GOG, MRC, ANZGOG SWOG, M Negri, CTSU Phase III Trial

Proc ASCO 25: Abstract 5002 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 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

Proc ASCO 25: Abstract 5002 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 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

Proc ASCO 25: Abstract 5002 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 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

Proc ASCO 25: Abstract 5002 GOG0182-ICON5: Schema R A N D O M I Z E x8 Carboplatin AUC 5 (d1) Paclitaxel 175 mg/m 2 (d1) Doxil 30 mg/m 2 (d1, every other cycle) III x8 Carboplatin AUC 6 (d1) Paclitaxel 175 mg/m 2 (d1) I Carboplatin AUC 6 (d1) Paclitaxel 175 mg/m 2 (d1) x4 x4 Carboplatin AUC 6 (d8) Gemcitabine 1 g/m 2 (d1,8) V x4 Carboplatin AUC 5 (d3) Topotecan 1.25 mg/m 2 (d1-3) IV x8 Carboplatin AUC 5 (d1) Paclitaxel 175 mg/m 2 (d1) Gemcitabine 800 mg/m 2 (d1,8) II

Proc ASCO 25: Abstract 5002 GOG0182-ICON5 Accrual Projected 1000 / yr Final (Total) 4312 Actual

Proc ASCO 25: Abstract 5002 GOG0182-ICON5 Accrual Open: 29-JAN-2001 Closed: 01-SEP-2004 Accrual: 4312 patients Open: 29-JAN-2001 Closed: 01-SEP-2004 Accrual: 4312 patients

Proc ASCO 25: Abstract 5002 GOG0182-ICON5: Characteristics ARM: C+P (n = 864) C+P+G (n = 864) C+P+D (n = 862) CT  CP (n = 861) CG  CP (n = 861) Age (Median)57.7 y59.1 y59.5 y58.5 y59.3 y FIGO Stg IV 1º Peritoneal 16.2% 13.3% 13.0% 13.8% 14.5% 13.7% 12.7% 16.3% 12.8%

Proc ASCO 25: Abstract 5002 GOG0182-ICON5: Stratification ARM: C+P (n = 864) C+P+G (n = 864) C+P+D (n = 862) CT  CP (n = 861) CG  CP (n = 861) Measurable Interval Surgery 21.6% 7.7% 22.6% 8.2% 22.7% 7.7% 23.3% 7.1% 24.2% 7.8%

Proc ASCO 25: Abstract 5002 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 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

Proc ASCO 25: Abstract 5002 GOG0182-ICON5: Rx Completion

Proc ASCO 25: Abstract 5002 GOG0182-ICON5: Carboplatin Delivery

Proc ASCO 25: Abstract 5002 GOG0182-ICON5: Heme Toxicity * p < global test of null hypothesis

Proc ASCO 25: Abstract 5002 GOG0182-ICON5: Non-Heme Toxicity * p < global test of null hypothesis

Proc ASCO 25: Abstract 5002 GOG0182-ICON5: Progression-Free Survival Median PFS and HR (95% CI) ( ) ( ) ( ) ( )

Proc ASCO 25: Abstract 5002 GOG0182-ICON5: Overall Survival Median OS and HR (95% CI) ( ) ( ) ( ) ( )

Proc ASCO 25: Abstract 5002 GOG0182-ICON5: Overall Survival

Proc ASCO 25: Abstract 5002 GOG0182-ICON5: Treatment HR by Residual

Proc ASCO 25: Abstract 5002 GOG0182-ICON5: Annual Accrual (US) Annual 25,580New cases of ovarian cancer diagnosed in 2004 (ACS estimate) 19,185New cases of advanced-stage disease (75%) 1,200Patients enrolled through GOG, SWOG, CTSU Annual 25,580New cases of ovarian cancer diagnosed in 2004 (ACS estimate) 19,185New cases of advanced-stage disease (75%) 1,200Patients 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.

Proc ASCO 25: Abstract 5002 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 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