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
andrew.clamp@christie.nhs.uk
j.ledermann@ctc.ucl.ac.uk
ICON8@ctu.mrc.ac.uk
Trial Physician/CTU Project Lead
Project Manager
Trial Manager
Senior Data Manager
Data Manager
Statistician