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

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

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.

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

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 0.62-0.91 c-TC 319 229 (72) 17.5 mos. 5

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 (0.49-1.19), P = 0.234 Median OS > 1cm, dd-TC (n=174) 51.2 mos. > 1cm, c-TC (n=168) 33.5 mos. HR 0.75 (0.57-0.97), P = 0.0267 Interaction: P = 0.925 6

Cox model for OS Variable Univariate Multivariate HR 95% CI P 0.79 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 Stage, II v III 4.91 2.95-8.16 3.058 1.81-5.17 II v IV 9.22 5.36-15.8 4.146 2.33-7.38 Histology, serous v clear/mucinous 0.83 0.61-1.12 0.22 Residual disease, <1cm v >1 cm 3.70 2.85-4.78 2.338 1.77-3.09 Age, < 60 v > 60 1.61 1.29-2.01 PS, 0-1 v 2-3 2.65 1.94-3.62 1.572 1.13-2.18 0.0068 RBC transfusion, no v yes 1.21-2.13 0.001 Relative dose intensity (Carboplatin) >80% v <80% 1.62 1.27-2.06 Relative dose intensity (Paclitaxel) >80% v <80% 1.77 1.40-2.24 <.001 1.424 1.12-1.81 0.004 7

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

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

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.

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 5 q3w (control) Paclitaxel 175mg/m2 q3w Delayed Primary Surgery (DPS) Arm 2 Carboplatin AUC 5 q3w Paclitaxel 80mg/m2 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 2 q1w Paclitaxel 80mg/m2 q1w Single trial with a pre-specified stratification for IPS vs. DPS 11 11

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 55791. 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

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

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 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

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

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

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?

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 5 q3w (control) Paclitaxel 175mg/m2 q3w Arm 2 Carboplatin AUC 5 q3w Paclitaxel 80mg/m2 q1w Arm 3 Carboplatin AUC 2 q1w Paclitaxel 80mg/m2 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- 1485 pts 80% power allows reduction in sample size to 1050

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 5 q3w Paclitaxel 175mg/m2 q3w Bevacizumab 7.5mg/kg q3w Arm 2 Carboplatin AUC 5 q3w Paclitaxel 80mg/m2 q1w Arm 3 Carboplatin AUC 5 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

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

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(0.625-0.824) ICON8B, GOG262 ICON7 HR 0.81 (0.70-0.94) Carboplatin-Paclitaxel q3w Carboplatin-Paclitaxel q1w + Bevacizumab (ICON8B) ICON8B JGOG 3016 HR 0.71 (0.58-0.88) 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

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 Trials Unit ICON8@ctu.mrc.ac.uk Andrew Clamp andrew.clamp@christie.nhs.uk Jonathan Ledermann j.ledermann@ctc.ucl.ac.uk Trials Unit ICON8@ctu.mrc.ac.uk 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