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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:

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



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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



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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


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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


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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


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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


Gog0182 icon5 schema l.jpg

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


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GOG0182-ICON5 Accrual

Final (Total) 4312

Actual

Projected 1000 / yr


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GOG0182-ICON5 Accrual

Open: 29-JAN-2001

Closed: 01-SEP-2004

Accrual: 4312 patients




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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




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GOG0182-ICON5: Heme Toxicity

* p < 0.001 global test of null hypothesis


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GOG0182-ICON5: Non-Heme Toxicity

* p < 0.001 global test of null hypothesis


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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)


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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)



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GOG0182-ICON5: Treatment HR by Residual


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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.


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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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