Transcript GOG0182ICON5

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
Proc ASCO 25: Abstract 5002
GOG0182-ICON5: Steering Committee
David S Alberts MD (US-SWOG)*
Peter Harper MD (UK-MRC)*
Michael A Bookman MD (US-GOG)*
William Hoskins MD (US-GOG)
Mark F. Brady PhD (US-GOG)*
Maurie Markman MD (US-GOG)
A Hilary Calvert, MD (UK)
William P McGuire III MD (US-GOG)*
Nicoletta Colombo MD (M Negri, Italy)*
Robert F Ozols MD PhD (US-GOG)
Angela Cooper MD (UK)
Mahesh Parmar PhD (UK-MRC)
Larry J Copeland MD (US-GOG)
Christopher J Poole MD (UK)
Andreas du Bois MD PhD (AGO)
Ann Marie Swart (UK-MRC)*
Michael Friedlander MD PhD (ANZGOG)*
James Tate Thigpen MD (US-GOG)
Martin Gore, FRCP PhD (UK)
Valter Torri MD (M Negri, Italy)
Steen W Hansen MD (Denmark)
Edward Trimble MD (US-CTSU, NCI)*
* Member of Writing Committee
Proc ASCO 25: Abstract 5002
GOG0182-ICON5: Study Chairs, GOG
Chair:
Michael A Bookman, MD
Statistician:
Mark F. Brady, PhD
Co-Chairs:
Pathology:
William P McGuire, III, MD
Stephen D Williams, MD
Thomas Herzog, MD
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
Carboplatin
Paclitaxel
Topotecan
Gemcitabine
PEG-Lipo
Doxorubicin
DNA
b-tubulin
Topo-I
RN-reductase,
Nucleotide pool
Topo-II
DNA adduct
Formation
Tubulin
Aggregation
Stabilize
DNA-Topo
Complex
DNA synth
DNA synth
Schedule: Independent
Dependent
(toxicity)
Dependent
(efficacy)
Dependent
Phosporylation
Prolonged
clearance
Resistance:
GSH,
tolerance,
retention
MDR-MRP,
tubulin
mutations
Topo-I,
BCRP
RN-reductase
MDR-MRP
Topo-II
Platinum
Interaction:
N/A
Platelet
Sparing
Target:
Mechanism:
---- Enhanced Toxicity ---Proc ASCO 25: Abstract 5002
Developmental Therapy and Context
Incorporation of Paclitaxel
(GOG111, OV10)
Feasibility of Gemcitabine
Triplet (GOG9801, Hansen)
Feasibility of PEG-LipoDox
Triplet (GOG9703)
Sequence of Topotecan
Doublet (GOG9906)
Sequence of Gemcitabine
Doublet (Iaffaioli)
Non-Feasibility of Etoposide
Triplet (GOG9603)
Substitution of Carboplatin for
Cisplatin (GOG158, AGO)
GOG0182-ICON5
GOG, MRC, ANZGOG
SWOG, M Negri, CTSU
Phase III Trial
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
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
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
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
Proc ASCO 25: Abstract 5002
RANDOMIZE
GOG0182-ICON5: Schema
I
Carboplatin AUC 6 (d1)
Paclitaxel 175 mg/m2 (d1)
x8
II
Carboplatin AUC 5 (d1)
Paclitaxel 175 mg/m2 (d1)
Gemcitabine 800 mg/m2 (d1,8)
x8
III
Carboplatin AUC 5 (d1)
Paclitaxel 175 mg/m2 (d1)
Doxil 30 mg/m2 (d1, every other cycle)
x8
IV
Carboplatin AUC 5 (d3)
x4
Topotecan 1.25 mg/m2 (d1-3)
V
Carboplatin AUC 6 (d8)
Gemcitabine 1 g/m2 (d1,8)
Carboplatin AUC 6 (d1)
x4
Paclitaxel 175 mg/m2 (d1)
x4
Proc ASCO 25: Abstract 5002
GOG0182-ICON5 Accrual
Final (Total) 4312
4000
Accrual
3000
Actual
2000
Projected 1000 / yr
1000
0
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
Proc ASCO 25: Abstract 5002
GOG0182-ICON5 Accrual
Open:
29-JAN-2001
ANZGOG
22-Jun-02
n=184
(4%)
CTSU
24-Jun-02
n=65 (2%)
M Negri
30-Oct-03
n=67
(2%)
MRC-UK
22-Jul-02
n=363
(8%)
Closed: 01-SEP-2004
Accrual: 4312 patients
GOG
07-Feb-01
n=3435
(79%)
SWOG
23-Oct-01
n=198
(5%)
Proc ASCO 25: Abstract 5002
GOG0182-ICON5: Characteristics
C+P
C+P+G
C+P+D
CTCP CGCP
(n = 864) (n = 864) (n = 862) (n = 861) (n = 861)
ARM:
Age (Median)
57.7 y
59.1 y
59.5 y
58.5 y
59.3 y
FIGO Stg IV
1º Peritoneal
16.2%
13.3%
13.3%
13.0%
13.8%
14.5%
13.7%
12.7%
16.3%
12.8%
100%
Other / Pending 75%
Mucinous
Clear Cell
50%
Endometrioid
Papillary Serous 25%
0%
Proc ASCO 25: Abstract 5002
GOG0182-ICON5: Stratification
C+P
C+P+G
C+P+D
CTCP CGCP
(n = 864) (n = 864) (n = 862) (n = 861) (n = 861)
ARM:
100%
Microscopic
75%
<=1 cm Optimal 50%
> 1 cm Subopt
25%
0%
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
Proc ASCO 25: Abstract 5002
GOG0182-ICON5: Rx Completion
100%
75%
Other / Pending
Death
50%
Toxicity / Refusal
Progressed
Completed
25%
0%
C+P
C+P+G
C+P+D
CT-CP
CG-CP
(n = 693)
(n = 660)
(n = 658)
(n = 716)
(n = 688)
Proc ASCO 25: Abstract 5002
GOG0182-ICON5: Carboplatin Delivery
Proc ASCO 25: Abstract 5002
GOG0182-ICON5: Heme Toxicity
80%
Control
Gem Triplet
PLD Triplet
Topo Doublet
Gem Doublet
70%
60%
50%
40%
30%
20%
10%
0%
ANC*
(Grade:4+)
Plts*
(Grade:3+)
Hgb*
(Grade:3+)
Fever/Inf*
(Grade:3+)
* p < 0.001 global test of null hypothesis
Proc ASCO 25: Abstract 5002
GOG0182-ICON5: Non-Heme Toxicity
30%
Control
Gem Triplet
PLD Triplet
Topo Doublet
Gem Doublet
25%
20%
15%
10%
5%
0%
Neuropathy*
(Grade:2+)
Pulmonary
(Grade:2+)
Hepatic*
(Grade:2+)
* p < 0.001 global test of null hypothesis
Proc ASCO 25: Abstract 5002
GOG0182-ICON5: Progression-Free Survival
Median PFS and HR (95% CI)
16.1
16.4
16.4
15.3
15.4
1.000
0.990
0.998
1.094
1.052
(0.884-1.107)
(0.891-1.117)
(0.979-1.224)
(0.940-1.176)
Proc ASCO 25: Abstract 5002
GOG0182-ICON5: Overall Survival
Median OS and HR (95% CI)
40.0
40.4
42.8
39.1
40.2
1.000
0.978
0.972
1.068
1.035
(0.838-1.141)
(0.832-1.136)
(0.918-1.244)
(0.888-1.206)
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
25,580
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.
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 advancedstage 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