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ICON8 Evaluating Weekly Chemotherapy Scheduling in the First–line Management of Ovarian Cancer

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. Background. Current standard-of-care 3-weekly carboplatin-paclitaxel

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ICON8 Evaluating Weekly Chemotherapy Scheduling in the First–line Management of Ovarian Cancer

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  1. ICON8Evaluating 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

  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/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

  5. JGOG3016: Updated PFS Katsumata et al ASCO 2012 dd-TC c-TC median follow-up period: 6.4 years

  6. OS: by residual disease Katsumata et al ASCO 2012 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 Patients surviving (%) 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

  7. Cox model for OS

  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 No cycles received Katsumata et al; Lancet 2009

  9. 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 Pharmacogenomics 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) Delayed Primary Surgery (planned) Randomise1:1:1 Randomise1:1:1 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 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

  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 months Median = 10.0 months

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

  16. ICON 7 RANDOMISE Carboplatin AUC 6 • Front-line: epithelial OV, PP or FT cancer • stage I or IIa (grade 3 or clear cell) • stage IIb–IV • N=1,528 Paclitaxel 175mg/m2 Carboplatin AUC 6 Paclitaxel 175mg/m2 Bevacizumab7.5mg/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. 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 Bevacizumab

  18. Phase III endpoints

  19. 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? Proposed modification

  20. Diagnosis of Stage IC-IV EOC/PPC/FTC Randomise1:1:1 Arm 1 6 cycles Arm 2 6 cycles Arm 3 6 cycles ICON 8A 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

  21. Diagnosis of Stage III-IV EOC/PPC/FTC with >1cm residual disease or planned for neoadjuvant therapy Randomise1:1:1 Arm 1 6 cycles Arm 2 6 cycles Arm 3 6 cycles 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 Paclitaxel 80mg/m2 q1w Bevacizumab 7.5mg/kg q3w ICON 8B • 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 5 q3w ddTC Paclitaxel 80mg/m2 q1w Arm 3 Carboplatin AUC 5 q3w Hybrid Paclitaxel 80mg/m2 q1w Bevacizumab 7.5mg/kg q3w

  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(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

  24. 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 Summary

  25. Feedback welcome Chief Investigators 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

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