Transcript ICON8 British Gynaecological Cancer Society annual meeting slides

ICON8
Evaluating Weekly Chemotherapy
Scheduling in the First–line Management
of Ovarian Cancer
Andrew Clamp
Senior Lecturer in Medical Oncology
The Christie
BGCS-NCRI Meeting
Westminster
5th July 2012
Background
• Current standard-of-care 3-weekly carboplatinpaclitaxel
McGuire et al NEJM 1996; Piccart et al JNCI 2000;
Ozols et al JCO 2003
• No improvement with additional cytotoxics/
maintenance therapy
• Increasing role of neoadjuvant chemotherapy
with delayed primary surgery
Vergote et al NEJM 2010
Weekly Paclitaxel
• Dose density
– Acceleration of schedule to maximise exposure of
tumour cells to PTX in accelerated growth phase
• Dose intensity
– Achieve higher total dose
• Reduced toxicity (myelosuppression)
• Anti-angiogenic activity
JGOG 3016
Stage II-IV EOC/FTC/PPC n=637
1:1 randomisation
Carboplatin AUC6 q3w
Paclitaxel 180mg/m2 q3w
Carboplatin AUC6 q3w
Paclitaxel 80mg/m2 q1w
• 66% stage III
• 98% ECOG PS 0-2
• 89% primary debulking, 10% delayed debulking
• 55% residual disease >1cm
• 56% serous, 12% endometrioid, 11% clear cell, 5% mucinous
Katsumata et al; Lancet 2009/ ASCO 2012
JGOG3016: Updated PFS
dd-TC
c-TC
Katsumata et al ASCO 2012
median follow-up period: 6.4 years
Treatment
n
dd-TC
c-TC
312
319
Event, n (%) Median PFS
197 (63)
229 (72)
28.2 mos.
17.5 mos.
P value
HR
95%CI
0.0037
0.76
0.62-0.91
OS: by residual disease
Katsumata et al ASCO 2012
Patients surviving (%)
Median OS
< 1cm, dd-TC (n=144) not reached
< 1cm, c-TC (n=145) not reached
HR 0.76 (0.49-1.19), P = 0.234
Median OS
> 1cm, dd-TC (n=174)
> 1cm, c-TC (n=168)
51.2 mos.
33.5 mos.
HR 0.75 (0.57-0.97), P = 0.0267
Interaction: P = 0.925
Cox model for OS
Variable
Univariate
Multivariate
HR
95% CI
P
HR
95% CI
P
Treatment, c-TC v dd-TC
0.79
0.63-0.99
0.039
0.68
0.54-0.86
0.0015
Disease,
ovary v fallopian tube
0.41
0.21-0.84
0.0142
0.570 0.28-1.16
0.1218
ovary v peritoneal
2.17
1.59-2.95
<.0001
1.627 1.19-2.23
0.0024
II v III
4.91
2.95-8.16
<.0001
3.058 1.81-5.17
<.0001
II v IV
9.22
5.36-15.8
<.0001
4.146 2.33-7.38
<.0001
Histology, serous v clear/mucinous
0.83
0.61-1.12
0.22
Residual disease,
3.70
2.85-4.78
<.0001
2.338 1.77-3.09
<.0001
1.572 1.13-2.18
0.0068
1.424 1.12-1.81
0.004
Stage,
<1cm v >1 cm
Age,
< 60 v > 60
1.61
1.29-2.01
<.0001
PS,
0-1 v 2-3
2.65
1.94-3.62
<.0001
1.61
1.21-2.13
0.001
Relative dose intensity (Carboplatin)
>80% v <80%
1.62
1.27-2.06
<.0001
Relative dose intensity
(Paclitaxel)
>80% v <80%
1.77
1.40-2.24
<.001
RBC transfusion,
no v yes
JGOG treatment delivery
and toxicity
standard
•Discontinuation due to toxicity
36% vs 22%
dose-dense
80
•Haematological 60% vs 43%
70
•Gd 3-4 Anaemia 69% vs 44%
% patients
60
50
•Dose intensity
40
Carboplatin
(AUC/wk 1.54 vs 1.71)
30
20
Paclitaxel
(mg/m2/wk 63 vs 52)
10
0
≤1
2
3
4
No cycles received
5
≥6
Katsumata et al; Lancet 2009
Pharmacogenomics
• Delivery of carboplatin- paclitaxel associated
with more toxicity in Japanese population
– Completion rate 6 cycles >85% in European trials
• Lung cancer data
–
–
–
–
–
Parallel NSCLC phase III trials US/Japan
Common CT control arm
Improved survival outcomes in Japan
Greater haematological toxicity
Association of ethnically- distributed PG SNPs
(CYP3A4*1B/ ERCC2K751Q) with survival and
toxicity
Gandara et al J Clin Oncol 2009
Weekly carboplatin- paclitaxel
• reduce myelosuppression
• improve tolerability
• allow delivery of increased dose intensity
• incorporate dose-dense platinum
Diagnosis of Stage IC-IV EOC/PPC/FTC
Immediate Primary Surgery (IPS)
Delayed Primary Surgery (planned)
Randomise 1:1:1
Randomise 1:1:1
Arm 1
6 cycles
Arm 1
(control)
Arm 2
6 cycles
Arm 3
6 cycles
Carboplatin AUC 5
Paclitaxel 175mg/m2
Arm 1
3 cycles
Arm 2
3 cycles
Arm 3
3 cycles
Cycle 3 d15 omitted
q3w
q3w
Delayed Primary Surgery (DPS)
Arm 2
Carboplatin AUC 5
Paclitaxel 80mg/m2
q3w
q1w
Arm 3
Carboplatin AUC 2
Paclitaxel 80mg/m2
q1w
q1w
Arm 1
3 cycles
Arm 2
3 cycles
Single trial with a pre-specified stratification for IPS vs. DPS
Arm 3
3 cycles
Three-Stage Trial Design
• Stage 1 - Feasibility and Toxicity
– Feasibility = ability to deliver 6 cycles of chemotherapy (at least 2
out of 3 planned weekly doses) for each arm
– Toxicity with special reference to neuropathy and febrile
neutropenia
– Stage 1A – First 50 patients randomised per arm
– Stage 1B – First 50 patients undergoing DPS randomised per arm
• Stage 2 – Activity (9-month PFS rate)
– First 62 patients randomised per arm
• Stage 3 – Efficacy
– Primary outcome measures: PFS and OS
– Secondary: Toxicity, quality of life and health economics
– Sample size required = 1485 women
ICON8 recruitment
ICON8 Expected vs Actual Cumulative Accrual
38
Open sites
140
120
100
80
60
40
20
Jun-12
May-12
Apr-12
Mar-12
Feb-12
Jan-12
Dec-11
Nov-11
Oct-11
Sep-11
Aug-11
Jul-11
0
Jun-11
No. patients recruited / No. of
activated sites
160
Month
Monthly Accrual
Target Accrual
No. of activated sites
•149 patients recruited
• 47 additional sites in set-up
• 5 International groups collaborating
ICON8-time to R&D
approval
Median =6.1 months
Median = 10.0 months
Is ICON8 still valid in the era
of bevacizumab?
ICON 7
Front-line:
epithelial OV, PP
or FT cancer
● stage I or IIa
(grade 3 or clear
cell)
● stage IIb–IV
N=1,528
R
A
N
D
O
M
I
S
E
Carboplatin AUC 6
Paclitaxel 175mg/m2
•Best overall response
•48% CT vs 67% Bev-CT
Carboplatin AUC 6
1:1
Paclitaxel 175mg/m2
Bevacizumab 7.5mg/kg
High risk – FIGO IV or
III with >1cm residual
disease
HR-0.87
PFS- ITT population
HR-0.64
OS- ‘high risk’
Perren et al NEJM 2011
Bevacizumab
• Carboplatin-paclitaxel + bevacizumab is becoming a
standard of care for “high-risk” ovarian cancer following
publication of GOG218/ICON7 PFS and interim results
– ICON7 final OS analysis expected 2013
• Bevacizumab is now licensed for the treatment of Stage IIIBIV ovarian cancer in combination with carboplatin/paclitaxel
in Europe and is available in England via CDF for “high-risk”
disease
– Not available for collaborating groups or in Scotland/
Wales
Phase III endpoints
Surgical
status
No pts
PFS (HR)
Increase
median
PFS (mo)
OS (HR)
Increase
median
OS (mo)
3-weekly C +ddT vs. 3-weekly CT
JGOG
3016
All
631
0.76
10.7
0.79
NA
>1cm
residual
342
0.67
NR
0.75
17.7
Bevacizumab+3-weekly CT vs. 3-weekly CT
ICON7
GOG218
All
1528
0.87
2.4
0.85 (NS)
NA
High risk
465
0.73
5.5
0.64
7.8
All
1248
0.77
3.8
0.88 (NS)
NA
>1cm
residual
496
0.76
NR
NR
NR
Proposed modification
• Two parallel randomisations
– ICON8A - dose fractionation
• still important in patients with optimally debulked disease
– ICON8B- dose fractionation and bevacizumab
• Two new ‘standards of care’ in high risk disease
• Compare ICON7 bevacizumab regimen with JGOG dose-dense paclitaxel
• Combination BEV and dose-dense paclitaxel
• To address additional questions of interest post-GOG218/ICON7
– Can we achieve the same improvement in PFS by dose-fractionation
rather than using BEV?
– Can we further improve outcomes by combining dose-fractionation and
BEV- Is there an interaction?
– Is BEV safe and effective in patients undergoing delayed primary
surgery?
ICON 8A
Diagnosis of Stage IC-IV EOC/PPC/FTC
Randomise 1:1:1
Arm 1
6 cycles
Arm 2
6 cycles
Arm 3
6 cycles
Arm 1
(control)
Carboplatin AUC 5
Paclitaxel 175mg/m2
q3w
q3w
Arm 2
Carboplatin AUC 5
Paclitaxel 80mg/m2
q3w
q1w
Arm 3
Carboplatin AUC 2
Paclitaxel 80mg/m2
q1w
q1w
Eligibility criteria
• Stage IC-II or III with <1cm residual after immediate primary surgery
• III with >1cm residual disease after primary surgery, IV, or primary
chemotherapy with delayed primary surgery if;
• contraindications to bevacizumab
• patient declines bevacizumab
• or if not able to participate in ICON8B
ICON 8B
Diagnosis of Stage III-IV EOC/PPC/FTC with >1cm
residual disease or planned for neoadjuvant therapy
Arm 1
Carboplatin AUC 5
q3w
2
Paclitaxel 175mg/m
q3w
Bevacizumab 7.5mg/kg q3w
Arm 2
Carboplatin AUC 5
Paclitaxel 80mg/m2
Arm 3
Carboplatin AUC 5
q3w
2
Paclitaxel 80mg/m
q1w
Bevacizumab 7.5mg/kg q3w
Randomise 1:1:1
Arm 1
6 cycles
Arm 2
6 cycles
Arm 3
6 cycles
16 cycles maintenance Bevacizumab
• In neoadjuvant setting, surgery between C3 and C4 omit BEV C3 and
C4. At least 6 weeks between BEV and surgery
•To detect HR-0.75 in 2 superiority comparisons between Arm 3 and Arms
1 and 2 requires c.300 pts per arm
q3w
q1w
ICON 8B
Arm 1 Carboplatin AUC 5
q3w
ICON7 Paclitaxel 175mg/m2
q3w
Bevacizumab 7.5mg/kg q3w
Arm 2 Carboplatin AUC 5
ddTC Paclitaxel 80mg/m2
q3w
q1w
Arm 3 Carboplatin AUC 5
q3w
Hybrid Paclitaxel 80mg/m2
q1w
Bevacizumab 7.5mg/kg q3w
Carboplatin-Paclitaxel q3w
+ Bevacizumab
GOG218: Stge III
sub-opt debulked &
Stge IV post surgery
GOG262: Stge III
sub-opt debulked &
Stge IV post
surgery
ICON7: Stge IC-IV;
high-risk sub-group
Stge III sub-opt
debulked & Stge IV
ICON8B: Stge III
sub-opt
debulked/primary
chemo & Stge IV
Carboplatin-Paclitaxel q3w
Carboplatin-Paclitaxel q1w
+ Bevacizumab
ICON8B: Stge III
sub-opt debulked,
primary chemo &
Stge IV
JGOG3016: Stge II-IV
ICON8A: Stge IC-IV
Carboplatin-Paclitaxel q1w
Other trials: MITO-7, Stge IC-IV, C-Pq3w vs wCwP 60mg/m2
Summary
• ICON8 remains open to recruitment and
currently meeting target
• Bevacizumab will be incorporated if secure
funding available
• TRICON8 sample collection (Brenton) awaiting
outcome of CTAAC review
Feedback welcome
• Chief Investigators
– Andrew Clamp
– Jonathan Ledermann
• Trials Unit
–
–
–
–
–
–
Jane Hook
Laura Farrelly
Monique Tomiczek
Cheryl Courtney
Tim Brush
Suzanne Freeman
[email protected]
[email protected]
[email protected]
Trial Physician/CTU Project Lead
Project Manager
Trial Manager
Senior Data Manager
Data Manager
Statistician