1. Senior Lecturer in Medical Oncology
ICON8 Evaluating Weekly Chemotherapy Scheduling in the First–line Management of Ovarian Cancer
Awarded central funding by CRUK. As academic trial with no pharmaceutical industry involvement there is no per patient fees.
Build on results of JGOG3016
Extrapolation to European popn/ patients undergoing DPS
Andrew Clamp
Senior Lecturer in Medical Oncology
The Christie
BGCS-NCRI Meeting
Westminster
5th July 2012 1 1

2. Background Current standard-of-care 3-weekly carboplatin-paclitaxel
No improvement with additional cytotoxics/ maintenance therapy
Increasing role of neoadjuvant chemotherapy with delayed primary surgery
McGuire et al NEJM 1996; Piccart et al JNCI 2000; Ozols et al JCO 2003
Vergote et al NEJM 2010

3. Weekly Paclitaxel Dose density Dose intensity
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
Dose density- given dose administered over a shorter time interval
Dose intensity- greater total dose of drug
Norton-Simon hypothesis- chemotherapy results in rate of regression in tumour volume proportional to rate of growth for an unperturbed tumour of that size
Dose-dense manner- ensures more constant exposure of tumour cells to phase of growth when most cells in mitosis.
Duration of exposure to PTX above a threshold concentration key for cytotoxic effects rather than peak concentration.

4. Stage II-IV EOC/FTC/PPC n=637
JGOG 3016
Stage II-IV EOC/FTC/PPC n=637
1:1 randomisation
Carboplatin AUC6 q3w
Paclitaxel 180mg/m2 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
18% stage II, 15% stage IV- allowed histologically or cytologically confirmed cancer
Age >20, PS 0-3, adequate organ function.
Stratified on basis of residual disease, FIGO stage, histological type (clear cell or mucinous vs other)
Katsumata et al; Lancet 2009/ ASCO 2012

5. JGOG3016: Updated PFS median follow-up period: 6.4 years dd-TC c-TC
Katsumata et al ASCO 2012
dd-TC
c-TC
median follow-up period: 6.4 years
Treatment n
Event, n (%)
Median PFS
P value HR
95%CI
dd-TC
312
197 (63)
28.2 mos.
0.0037
0.76
c-TC
319
229 (72)
17.5 mos. 5

6. OS: by residual disease
Median OS- all comers
ddTC- 312 pts 139 deaths (45%), median OS –NR 5yr OS- 58.7%
cTC- 319 pts 168 deaths (53%), media nOS-62.2mo 5yr OS- 51.1%
HR 0.79 p=0.039
Katsumata et al ASCO 2012
Median OS
< 1cm, dd-TC (n=144) not reached
< 1cm, c-TC (n=145) not reached
Patients surviving (%)
HR 0.76 ( ), P = 0.234
Median OS
> 1cm, dd-TC (n=174) 51.2 mos.
> 1cm, c-TC (n=168) 33.5 mos.
HR 0.75 ( ), P =
Interaction: P = 0.925 6

7. Cox model for OS Variable Univariate Multivariate HR 95% CI P 0.79
Treatment, c-TC v dd-TC
0.79
0.039
0.68
0.0015
Disease, ovary v fallopian tube
0.41
0.0142
0.570
0.1218
ovary v peritoneal
2.17
<.0001
1.627
0.0024
Stage, II v III
4.91
3.058
II v IV
9.22
4.146
Histology, serous v clear/mucinous
0.83
0.22
Residual disease, <1cm v >1 cm
3.70
2.338
Age, < 60 v > 60
1.61
PS, 0-1 v 2-3
2.65
1.572
0.0068
RBC transfusion, no v yes
0.001
Relative dose intensity (Carboplatin) >80% v <80%
1.62
Relative dose intensity
(Paclitaxel) >80% v <80%
1.77
<.001
1.424
0.004 7

8. JGOG treatment delivery and toxicity
Discontinuation due to toxicity 36% vs 22%
Haematological 60% vs 43%
Gd 3-4 Anaemia 69% vs 44%
Dose intensity
Carboplatin (AUC/wk 1.54 vs 1.71)
Paclitaxel (mg/m2/wk 63 vs 52)
% patients
Figures for dose-dense arms first.
Main reason for discontinuation –haem parameters 60% vs 43% of those discontinuing therapy
Neuro 3% vs 7%
Allergy 4% vs 10% ie. Higher in conventional arm!
Dose reductions occurred in higher propn on dose dense arm 48% vs 35%
No cycles received
Katsumata et al; Lancet 2009

9. 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
Carboplatin AUC6/ PTX 225mg/m2
Similar disease profiles
PFS- 6 vs 4mo
OS 14 vs 9mo
Febrile neut- 12% vs 2%
Paclitaxel primarily eliminated through multiple hydroxylation reactions via cytochrome pathways (including CYP3A4) *1B assoc with increased activity.
Du Bois study (2003)- dose reductions 11% and delays 30% vs 35% and 67% in JGOG
No data on pharmacogenomics and weekly paclitaxel.
Gandara et al J Clin Oncol 2009

10. Weekly carboplatin- paclitaxel
reduce myelosuppression
improve tolerability
allow delivery of increased dose intensity
incorporate dose-dense platinum
Little preclinical supporting evidence
Cmax probably more important for platinum than paclitaxel
Used in several UK centres for patients of poor PS.

11. 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 2
6 cycles
Arm 3
6 cycles
Arm 1
3 cycles
Arm 2
3 cycles
Arm 3
3 cycles
Cycle 3 d15 omitted
Arm 1 Carboplatin AUC q3w
(control) Paclitaxel 175mg/m q3w
Delayed Primary Surgery (DPS)
Arm 2 Carboplatin AUC q3w
Paclitaxel 80mg/m q1w
Three-arm study
Pre-specified stratification for immediate or delayed primary surgery.
30-40% UK patients with IIIc/IV undergo DPS.
6 possible treatment pathways.
Arm 1
3 cycles
Arm 2
3 cycles
Arm 3
3 cycles
Arm 3 Carboplatin AUC q1w
Paclitaxel 80mg/m q1w
Single trial with a pre-specified stratification for IPS vs. DPS 11 11

12. 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
Stage 1- at least 37 of 50 pts in exptal arms complete protocol therapy- excludes a completion rate of <60%. Would anticipate completion rates of >80% in control arm form ICON3/5 and EORTC Also assessment of dose intensity.
Toxicity- total gd3/4 toxicity in exptal arms exceeds control arms by 15% need to reassess.
Stage 2- futility analysis- based on 9mo PFS after 62pts per arm completed 9mo therapy 44 alive without PD. Give 80% power to detect 9-mo PFS of <60%. Based on expected of 75%.
Stage 3- final jointly powered for PFS and OS. 12 12

13. ICON8 recruitment 38 Open sites 149 patients recruited
38 sites currently open. Number in set-up
Ahead of recruitment target currently- 149 in (end June), 131 expected.
47 sites in set-up.
5 International groups committed to participate- Korea/Mexico/Ireland close to opening. Mayo clinic/ANZGOG further behind.
149 patients recruited
47 additional sites in set-up
5 International groups collaborating

14. ICON8-time to R&D approval
Median =6.1 months
Median = 10.0 months

15. Is ICON8 still valid in the era of bevacizumab?

16. ICON 7 Best overall response 48% CT vs 67% Bev-CT 1:1
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
Paclitaxel 175mg/m2
Carboplatin AUC 6
Bevacizumab 7.5mg/kg
Best overall response
48% CT vs 67% Bev-CT
1:1
High risk – FIGO IV or III with >1cm residual disease
HR-0.87
HR-0.64
PFS- ITT population
OS- ‘high risk’
Perren et al NEJM 2011

17. 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 IIIB-IV 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
JGOG update to be presented by Prof Katsumata on Saturday
Median PFS 28.1 mo vs 17.5 mo p=0.0037
5yr OS 58.6% vs 51.0% p=0.045

18. Increase median PFS (mo) Increase median OS (mo)
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
1528
0.87
2.4
0.85 (NS)
High risk
465
0.73
5.5
0.64
7.8
GOG218
1248
0.77
3.8
0.88 (NS)
496

19. 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?

20. Diagnosis of Stage IC-IV EOC/PPC/FTC
ICON 8A
Arm 2
6 cycles
Arm 3
Arm 1
Randomise 1:1:1
Diagnosis of Stage IC-IV EOC/PPC/FTC
Arm 1 Carboplatin AUC q3w
(control) Paclitaxel 175mg/m q3w
Arm 2 Carboplatin AUC q3w
Paclitaxel 80mg/m q1w
Arm 3 Carboplatin AUC q1w
Paclitaxel 80mg/m 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
Targetting HR0.75 with 3yr recruitment and 2yr FU
for 90% power pts
80% power allows reduction in sample size to 1050

21. 16 cycles maintenance Bevacizumab
ICON 8B
Diagnosis of Stage III-IV EOC/PPC/FTC with >1cm residual disease or planned for neoadjuvant therapy
Arm 2
6 cycles
Arm 3
Arm 1
Randomise 1:1:1
16 cycles maintenance Bevacizumab
Arm 1 Carboplatin AUC q3w
Paclitaxel 175mg/m q3w
Bevacizumab 7.5mg/kg q3w
Arm 2 Carboplatin AUC q3w
Paclitaxel 80mg/m q1w
Arm 3 Carboplatin AUC q3w
Bevacizumab 7.5mg/kg q3w
Non-inferiority comparison not feasible- requires c.2500 pts and 2100 progression events targeting a HR of 0.87
Targetting HR0.75 2α=0.025 with 80% power requires 300 pts per arm
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

22. ICON 8B Arm 1 Carboplatin AUC 5 q3w ICON7 Paclitaxel 175mg/m2 q3w
Bevacizumab 7.5mg/kg q3w
Arm 2 Carboplatin AUC q3w
ddTC Paclitaxel 80mg/m q1w
Arm 3 Carboplatin AUC q3w
Hybrid Paclitaxel 80mg/m q1w
Bevacizumab 7.5mg/kg q3w 22 22 22

23. Carboplatin-Paclitaxel q3w + Bevacizumab
GOG218: Stge III sub-opt debulked & Stge IV post surgery
ICON7: Stge IC-IV; high-risk sub-group Stge III sub-opt debulked & Stge IV
GOG262: Stge III sub-opt debulked & Stge IV post surgery
ICON8B: Stge III sub-opt debulked/primary chemo & Stge IV
GOG218 HR 0.717( )
ICON8B, GOG262
ICON7 HR 0.81 ( )
Carboplatin-Paclitaxel q3w
Carboplatin-Paclitaxel q1w
+ Bevacizumab
(ICON8B)
ICON8B
JGOG 3016 HR 0.71 ( )
ICON8A
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

24. 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

25. Feedback welcome Chief Investigators Trials Unit ICON8@ctu.mrc.ac.uk
Andrew Clamp
Jonathan Ledermann
Trials Unit
Jane Hook Trial Physician/CTU Project Lead
Laura Farrelly Project Manager
Monique Tomiczek Trial Manager
Cheryl Courtney Senior Data Manager
Tim Brush Data Manager
Suzanne Freeman Statistician