Proc ASCO 25: Abstract 5002 GOG0182-ICON5: Phase III Randomized Trial of Paclitaxel and Carboplatin...

Proc ASCOProc ASCO 25: Abstract 5002 25: Abstract 5002

GOG0182-ICON5:GOG0182-ICON5:

Phase III Randomized Trial of Paclitaxel and Phase III Randomized Trial of Paclitaxel and Carboplatin Carboplatin vsvs Combinations with Gemcitabine, Combinations with Gemcitabine, PEG-Lipososomal Doxorubicin, or Topotecan in PEG-Lipososomal Doxorubicin, or Topotecan in Patients with Advanced-Stage Epithelial Ovarian Patients with Advanced-Stage Epithelial Ovarian

or Primary Peritoneal Carcinomaor Primary Peritoneal Carcinoma

Michael A Bookman, MDMichael A Bookman, MD on behalf of on behalf of GCIG, includingGCIG, including GOG, MRC, SWOG, ANZGOG,GOG, MRC, SWOG, ANZGOG, M Negri, and NCI-CTSUM Negri, and NCI-CTSU

Fox Chase Cancer CenterFox Chase Cancer Center Philadelphia, PAPhiladelphia, PA


GOG0182-ICON5: Steering CommitteeGOG0182-ICON5: Steering Committee

David S Alberts MDDavid S Alberts MD (US-SWOG)* (US-SWOG)*

Michael A Bookman MDMichael A Bookman MD (US-GOG)* (US-GOG)*

Mark F. Brady PhDMark F. Brady PhD (US-GOG)* (US-GOG)*

A Hilary Calvert, MD (UK)A Hilary Calvert, MD (UK)

Nicoletta Colombo MDNicoletta Colombo MD (M Negri, Italy)* (M Negri, Italy)*

Angela Cooper MD (UK)Angela Cooper MD (UK)

Larry J Copeland MD (US-GOG)Larry J Copeland MD (US-GOG)

Andreas du Bois MD PhD (AGO)Andreas du Bois MD PhD (AGO)

Michael Friedlander MD PhDMichael Friedlander MD PhD (ANZGOG)* (ANZGOG)*

Martin Gore, FRCP PhD (UK)Martin Gore, FRCP PhD (UK)

Steen W Hansen MD (Denmark)Steen W Hansen MD (Denmark)

* * Member of Writing CommitteeMember of Writing Committee

Peter Harper MDPeter Harper MD (UK-MRC)* (UK-MRC)*

William Hoskins MD (US-GOG)William Hoskins MD (US-GOG)

Maurie Markman MD (US-GOG)Maurie Markman MD (US-GOG)

William P McGuire III MDWilliam P McGuire III MD (US-GOG)* (US-GOG)*

Robert F Ozols MD PhD (US-GOG)Robert F Ozols MD PhD (US-GOG)

Mahesh Parmar PhD (UK-MRC)Mahesh Parmar PhD (UK-MRC)

Christopher J Poole MD (UK)Christopher J Poole MD (UK)

Ann Marie SwartAnn Marie Swart (UK-MRC)* (UK-MRC)*

James Tate Thigpen MD (US-GOG)James Tate Thigpen MD (US-GOG)

Valter Torri MD (M Negri, Italy)Valter Torri MD (M Negri, Italy)

Edward Trimble MDEdward Trimble MD (US-CTSU, NCI)* (US-CTSU, NCI)*


GOG0182-ICON5: Study Chairs, GOGGOG0182-ICON5: Study Chairs, GOG

Chair: Michael A Bookman, MD

Statistician: Mark F. Brady, PhD

Co-Chairs: William P McGuire, III, MDStephen D Williams, MDThomas Herzog, MD

Pathology: Lawrence M Roth, MD

Lab Science: Holly H Gallion, MD

Nurse Contacts: Judy Parham, RNChrisann 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, MDStephen D Williams, MDThomas Herzog, MD

Pathology: Lawrence M Roth, MD

Lab Science: Holly H Gallion, MD

Nurse Contacts: Judy Parham, RNChrisann Accario-Winslow, RN, MSN

Data Coord: Suzanne Baskerville, CCRA

SWOG Coord: David S Alberts, MD


Developmental TherapyDevelopmental Therapy

CarboplatinCarboplatin PaclitaxelPaclitaxel TopotecanTopotecan GemcitabineGemcitabine PEG-Lipo PEG-Lipo DoxorubicinDoxorubicin

Target:Target: DNADNA -tubulin-tubulin Topo-ITopo-I RN-reductase,RN-reductase,Nucleotide poolNucleotide pool Topo-IITopo-II

Mechanism:Mechanism: DNA adductDNA adductFormationFormation

TubulinTubulinAggregationAggregation

StabilizeStabilizeDNA-TopoDNA-TopoComplexComplex

DNA synthDNA synth DNA synthDNA synth

Schedule:Schedule: IndependentIndependent DependentDependent(toxicity)(toxicity)

DependentDependent(efficacy)(efficacy)

DependentDependentPhosporylationPhosporylation

ProlongedProlongedclearanceclearance

Resistance:Resistance:GSH, GSH,

tolerance, tolerance, retentionretention

MDR-MRP,MDR-MRP,tubulintubulin

mutationsmutations

Topo-I,Topo-I,BCRPBCRP RN-reductaseRN-reductase MDR-MRPMDR-MRP

Topo-IITopo-II

PlatinumPlatinumInteraction:Interaction: N/AN/A PlateletPlatelet

SparingSparing ---- Enhanced Toxicity -------- Enhanced Toxicity ----


Developmental Therapy and ContextDevelopmental Therapy and Context

Substitution of Carboplatin for Cisplatin (GOG158, AGO)

Incorporation of Paclitaxel (GOG111, OV10)

Feasibility of GemcitabineTriplet (GOG9801, Hansen)

Feasibility of PEG-LipoDoxTriplet (GOG9703)

Sequence of TopotecanDoublet (GOG9906)

Non-Feasibility of EtoposideTriplet (GOG9603)

Sequence of GemcitabineDoublet (Iaffaioli)

Epirubicin TripletEpirubicin TripletNCIC, EORTC, NSGONCIC, EORTC, NSGO

and AGO-OVAR, GINECOand AGO-OVAR, GINECO

Gemcitabine TripletGemcitabine TripletAGO-OVAR, GINECO, NSGOAGO-OVAR, GINECO, NSGO

Topotecan DoubletTopotecan DoubletNCIC, EORTC, NSGONCIC, EORTC, NSGO

Extended TopotecanExtended TopotecanAGO-OVAR, GINECOAGO-OVAR, GINECO

GOG0182-ICON5GOG0182-ICON5GOG, MRC, ANZGOGGOG, MRC, ANZGOGSWOG, M Negri, CTSUSWOG, M Negri, CTSU

Phase III TrialPhase III Trial

GOG0182-ICON5GOG0182-ICON5GOG, MRC, ANZGOGGOG, MRC, ANZGOGSWOG, M Negri, CTSUSWOG, M Negri, CTSU

Phase III TrialPhase III Trial


GOG0182-ICON5: Primary ObjectiveGOG0182-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


GOG0182-ICON5: DesignGOG0182-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


GOG0182-ICON5: DesignGOG0182-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


GOG0182-ICON5: SchemaGOG0182-ICON5: SchemaR

A N

D O

M I

Z E

R A

N D

O M

I Z

E

x8x8Carboplatin AUC 5 (d1)Carboplatin AUC 5 (d1)Paclitaxel 175 mg/mPaclitaxel 175 mg/m22 (d1) (d1)Doxil 30 mg/mDoxil 30 mg/m2 2 (d1, every other cycle)(d1, every other cycle)

IIIIII

x8x8Carboplatin AUC 6 (d1)Carboplatin AUC 6 (d1)Paclitaxel 175 mg/mPaclitaxel 175 mg/m22 (d1) (d1)

II

Carboplatin AUC 6 (d1)Carboplatin AUC 6 (d1)Paclitaxel 175 mg/mPaclitaxel 175 mg/m22 (d1) (d1)

x4x4

x4x4Carboplatin AUC 6 (d8)Carboplatin AUC 6 (d8)Gemcitabine 1 g/mGemcitabine 1 g/m2 2 (d1,8)(d1,8)

VV

x4x4Carboplatin AUC 5 (d3)Carboplatin AUC 5 (d3)Topotecan 1.25 mg/mTopotecan 1.25 mg/m2 2 (d1-3)(d1-3)

IVIV

x8x8

Carboplatin AUC 5 (d1)Carboplatin AUC 5 (d1)Paclitaxel 175 mg/mPaclitaxel 175 mg/m22 (d1) (d1)Gemcitabine 800 mg/mGemcitabine 800 mg/m2 2 (d1,8)(d1,8)

IIII


0

1000

2000

3000

4000

29-Jan-01 31-Jul-01 30-Jan-02 01-Aug-02 31-Jan-03 02-Aug-03 01-Feb-04 02-Aug-04

Date

Acc

rual

0

1000

2000

3000

4000

29-Jan-01 31-Jul-01 30-Jan-02 01-Aug-02 31-Jan-03 02-Aug-03 01-Feb-04 02-Aug-04

Date

Acc

rual

GOG0182-ICON5 AccrualGOG0182-ICON5 Accrual

Projected 1000 / yrProjected 1000 / yr

Final (Total) 4312

Actual


GOG0182-ICON5 AccrualGOG0182-ICON5 Accrual

Open:Open: 29-JAN- 29-JAN-20012001

Closed:Closed: 01-SEP- 01-SEP-20042004

Accrual: 4312 patientsAccrual: 4312 patients

Open:Open: 29-JAN- 29-JAN-20012001

Closed:Closed: 01-SEP- 01-SEP-20042004

Accrual: 4312 patientsAccrual: 4312 patients

GOG07-Feb-01

n=3435 (79%)

SWOG23-Oct-01

n=198(5%)

MRC-UK22-Jul-02

n=363(8%)

ANZGOG 22-Jun-02

n=184 (4%)

M Negri30-Oct-03

n=67(2%)

CTSU24-Jun-02 n=65 (2%)


GOG0182-ICON5: CharacteristicsGOG0182-ICON5: Characteristics

ARM:C+P

(n = 864)C+P+G

(n = 864)C+P+D

(n = 862)CTCP

(n = 861)CGCP

(n = 861)

Age (Median) 57.7 y 59.1 y 59.5 y 58.5 y 59.3 y

FIGO Stg IV1º Peritoneal

16.2%13.3%

13.3%13.0%

13.8%14.5%

13.7%12.7%

16.3%12.8%

0%

25%

50%

75%

100%

Other / PendingMucinous Clear Cell Endometrioid Papillary Serous


GOG0182-ICON5: StratificationGOG0182-ICON5: Stratification

ARM:C+P

(n = 864)C+P+G

(n = 864)C+P+D

(n = 862)CTCP

(n = 861)CGCP

(n = 861)

MeasurableInterval Surgery

21.6% 7.7%

22.6% 8.2%

22.7% 7.7%

23.3% 7.1%

24.2% 7.8%

0%

25%

50%

75%

100%

Microscopic

<=1 cm Optimal

> 1 cm Subopt


GOG0182-ICON5: Interim AnalysisGOG0182-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


GOG0182-ICON5: Rx CompletionGOG0182-ICON5: Rx Completion

0%

25%

50%

75%

100%

C+P C+P+G C+P+D CT-CP CG-CP

(n = 693) (n = 660) (n = 658) (n = 716) (n = 688)

Other / Pending

Death

Toxicity / Refusal

Progressed

Completed


GOG0182-ICON5: Carboplatin DeliveryGOG0182-ICON5: Carboplatin Delivery


GOG0182-ICON5: Heme ToxicityGOG0182-ICON5: Heme Toxicity

0%

10%

20%

30%

40%

50%

60%

70%

80%

ANC*(Grade:4+)

Plts*(Grade:3+)

Hgb*(Grade:3+)

Fever/Inf*(Grade:3+)

ControlGem TripletPLD TripletTopo DoubletGem Doublet

* * pp < 0.001 global test of null hypothesis < 0.001 global test of null hypothesis


GOG0182-ICON5: Non-Heme ToxicityGOG0182-ICON5: Non-Heme Toxicity

0%

5%

10%

15%

20%

25%

30%

Neuropathy*(Grade:2+)

Pulmonary(Grade:2+)

Hepatic*(Grade:2+)

ControlGem TripletPLD TripletTopo DoubletGem Doublet

* * pp < 0.001 global test of null hypothesis < 0.001 global test of null hypothesis


GOG0182-ICON5: Progression-Free SurvivalGOG0182-ICON5: Progression-Free Survival

Median PFS and HR (95% CI)Median PFS and HR (95% CI)

16.1 1.00016.1 1.00016.4 0.990 (0.884-1.107)16.4 0.990 (0.884-1.107)16.4 0.998 (0.891-1.117)16.4 0.998 (0.891-1.117)15.3 1.094 (0.979-1.224)15.3 1.094 (0.979-1.224)15.4 1.052 (0.940-1.176)15.4 1.052 (0.940-1.176)


GOG0182-ICON5: Overall SurvivalGOG0182-ICON5: Overall Survival

Median OS and HR (95% CI)Median OS and HR (95% CI)

40.0 1.00040.0 1.00040.4 0.978 (0.838-1.141)40.4 0.978 (0.838-1.141)42.8 0.972 (0.832-1.136)42.8 0.972 (0.832-1.136)39.1 1.068 (0.918-1.244)39.1 1.068 (0.918-1.244)40.2 1.035 (0.888-1.206)40.2 1.035 (0.888-1.206)


GOG0182-ICON5: Overall SurvivalGOG0182-ICON5: Overall Survival


GOG0182-ICON5: Treatment HR by ResidualGOG0182-ICON5: Treatment HR by Residual


GOG0182-ICON5: Annual Accrual (US)GOG0182-ICON5: Annual Accrual (US)

Annual

25,580 New cases of ovarian cancer diagnosed in2004 (ACS estimate)

19,185 New cases of advanced-stage disease (75%)

1,200 Patients enrolled through GOG, SWOG, CTSU

Annual

25,580 New cases of ovarian cancer diagnosed in2004 (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.


GOG0182-ICON5: ConclusionsGOG0182-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

Proc ASCO 25: Abstract 5002 GOG0182-ICON5: Phase III Randomized Trial of Paclitaxel and Carboplatin...

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