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ICON8 Evaluating Weekly Chemotherapy Scheduling in the First–line Management of Ovarian Cancer Andrew Clamp Senior Lecturer in Medical Oncology The Christie.

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Presentation on theme: "ICON8 Evaluating Weekly Chemotherapy Scheduling in the First–line Management of Ovarian Cancer Andrew Clamp Senior Lecturer in Medical Oncology The Christie."— Presentation transcript:

1 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 5 th July 2012

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 –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

4 JGOG 3016 Stage II-IV EOC/FTC/PPC n=637 1:1 randomisation Carboplatin AUC6 q3w Paclitaxel 180mg/m 2 q3w Carboplatin AUC6 q3w Paclitaxel 80mg/m 2 q1w 66% stage III 98% ECOG PS % 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

5 JGOG3016: Updated PFS TreatmentnEvent, n (%)Median PFSP valueHR95%CI dd-TC (63)28.2 mos c-TC (72)17.5 mos. dd-TC c-TC median follow-up period: 6.4 years Katsumata et al ASCO 2012

6 OS: by residual disease Patients surviving (%) Interaction: P = HR 0.75 ( ), P = Median OS > 1cm, dd-TC (n=174)51.2 mos. > 1cm, c-TC (n=168)33.5 mos. HR 0.76 ( ), P = < 1cm, dd-TC (n=144)not reached < 1cm, c-TC (n=145)not reached Median OS Katsumata et al ASCO 2012

7 Cox model for OS Variable UnivariateMultivariate HR95% CIPHR95% CIP Treatment, c-TC v dd-TC Disease,ovary v fallopian tube ovary v peritoneal < Stage,II v III < <.0001 II v IV < <.0001 Histology,serous v clear/mucinous Residual disease, 1 cm < <.0001 Age, <.0001 PS, 0-1 v < RBC transfusion,no v yes Relative dose intensity (Carboplatin) >80% v <80% <.0001 Relative dose intensity (Paclitaxel) >80% v <80% <

8 JGOG treatment delivery and toxicity No cycles received % patients 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/m 2 /wk 63 vs 52) 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 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

11 Diagnosis of Stage IC-IV EOC/PPC/FTC Immediate Primary Surgery (IPS) Arm 1 6 cycles Arm 2 6 cycles Arm 3 6 cycles Arm 1 3 cycles Arm 2 3 cycles Arm 3 3 cycles Arm 1 3 cycles Arm 2 3 cycles Arm 3 3 cycles Delayed Primary Surgery (DPS) Arm 1 Carboplatin AUC 5 q3w (control) Paclitaxel 175mg/m 2 q3w Arm 2 Carboplatin AUC 5 q3w Paclitaxel 80mg/m 2 q1w Arm 3 Carboplatin AUC 2 q1w Paclitaxel 80mg/m 2 q1w Single trial with a pre-specified stratification for IPS vs. DPS Cycle 3 d15 omitted Randomise 1:1:1 Delayed Primary Surgery (planned)

12 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 Three-Stage Trial Design

13 ICON8 recruitment 38 Open sites 149 patients recruited 47 additional sites in set-up 5 International groups collaborating

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

15 Is ICON8 still valid in the era of bevacizumab?

16 ICON 7 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 RANDOMISERANDOMISE Paclitaxel 175mg/m 2 Carboplatin AUC 6 Paclitaxel 175mg/m 2 Bevacizumab 7.5mg/kg PFS- ITT population OS- ‘high risk’ Perren et al NEJM 2011 HR-0.87HR-0.64 Best overall response 48% CT vs 67% Bev-CT High risk – FIGO IV or III with >1cm residual disease

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

18 Phase III endpoints Surgical status No ptsPFS (HR)Increase median PFS (mo) OS (HR)Increase median OS (mo) 3-weekly C +ddT vs. 3-weekly CT JGOG 3016 All NA >1cm residual NR Bevacizumab+3-weekly CT vs. 3-weekly CT ICON7All (NS)NA High risk GOG218All (NS)NA >1cm residual NR

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 Arm 2 6 cycles Arm 3 6 cycles Arm 1 6 cycles Randomise 1:1:1 Diagnosis of Stage IC-IV EOC/PPC/FTC 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 8A Arm 3 Carboplatin AUC 2 q1w Paclitaxel 80mg/m 2 q1w Arm 2 Carboplatin AUC 5 q3w Paclitaxel 80mg/m 2 q1w Arm 1 Carboplatin AUC 5 q3w (control) Paclitaxel 175mg/m 2 q3w

21 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 6 cycles Arm 1 6 cycles Randomise 1:1:1 16 cycles maintenance Bevacizumab Arm 1 Carboplatin AUC 5 q3w Paclitaxel 175mg/m 2 q3w Bevacizumab 7.5mg/kg q3w Arm 2 Carboplatin AUC 5 q3w Paclitaxel 80mg/m 2 q1w Arm 3 Carboplatin AUC 5 q3w Paclitaxel 80mg/m 2 q1w Bevacizumab 7.5mg/kg q3w 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 Arm 1 Carboplatin AUC 5 q3w ICON7 Paclitaxel 175mg/m 2 q3w Bevacizumab 7.5mg/kg q3w Arm 2 Carboplatin AUC 5 q3w ddTC Paclitaxel 80mg/m 2 q1w Arm 3 Carboplatin AUC 5 q3w Hybrid Paclitaxel 80mg/m 2 q1w Bevacizumab 7.5mg/kg q3w ICON 8B

23 Carboplatin-Paclitaxel q3w Carboplatin-Paclitaxel q3w + Bevacizumab Carboplatin-Paclitaxel q1w + 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 JGOG3016: Stge II-IV ICON8A: Stge IC-IV GOG262: Stge III sub-opt debulked & Stge IV post surgery ICON8B: Stge III sub-opt debulked/primary chemo & Stge IV ICON8B: Stge III sub-opt debulked, primary chemo & Stge IV 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 –Andrew –Jonathan Trials Unit –Jane Hook Trial Physician/CTU Project Lead –Laura FarrellyProject Manager –Monique TomiczekTrial Manager –Cheryl CourtneySenior Data Manager –Tim BrushData Manager –Suzanne FreemanStatistician


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