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J. W. Valle , H. S. Wasan, D. D. Palmer,

Gemcitabine with or without cisplatin in patients with advanced or metastatic biliary tract cancer (ABC): results of a multicentre, randomized phase III trial (the UK ABC-02 trial). J. W. Valle , H. S. Wasan, D. D. Palmer,

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J. W. Valle , H. S. Wasan, D. D. Palmer,

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  1. Gemcitabine with or without cisplatin in patients with advanced or metastatic biliary tract cancer (ABC): results of a multicentre, randomized phase III trial (the UK ABC-02 trial) J. W. Valle, H. S. Wasan, D. D. Palmer, D. Cunningham, D. A. Anthoney, A. Maraveyas, S. K. Hughes, M. Roughton, J. A. Bridgewater on behalf of NCRI Upper GI Clinical Studies Group

  2. Biliary tract cancers: epidemiology • Rare tumours Cholangiocarcinoma Gallbladder cancer Ampullary cancer • Cholangiocarcinoma accounts for 3% of all GI cancers globally 1 • Second commonest primary hepatic tumour but more lethal than HCC 2 • Incidence of IH-CCA is rising (USA, Japan, UK, Australia) 3 • Incidence: 1200 / year (Eng & Wales) 4 • Surgery is only chance of cure – but most cases are inoperable • 5YS (all patients) 5-10% 1 Vauthey Sem Liver Dis 1994; 2 Taylor-Robinson Gut 2001; 3 Khan J Hepatol 2002; 4 Cancer Research Campaign Cancerstats: Mortality UK 1999

  3. Advanced biliary tract cancers: no standard of care • Disease-related factors • Uncommon malignancies • Unwell, elderly population, infection/obstruction • Histological / cytological confirmation difficult • Lack of evidence • Disease often not measurable (unreliable response assessment) • Few underpowered phase III chemotherapy studies • Primarily small phase II studies, mostly 5-FU or gemcitabine-based • Mixed populations of HPB malignancy • Lack of multi-centre collaboration

  4. Background: ABC-01 study • Randomised phase II study • First-line, patients with advanced BTC • Primary endpoint: PFS • Accrual dates: Feb 2002 – May 2004 n=86 patients • Rationale: • Gemcitabine has documented activity • Cisplatin: pre-clinical / clinical synergies with gemcitabine ASCO GI 2006 abstr #98

  5. Background: ABC-01 - schema Eligible patients (n=86) Randomized 1:1 (stratified by centre, primary site, PS, prior therapy and locally advanced vs. metastatic) Arm A Gem 1000 mg/m2 D1,8,15 q 28d 24 weeks (6 cycles) Arm B Cisplatin 25 mg/m2 + Gem 1000 mg/m2 24 weeks (8 cycles) D1,8 q 21d Upon disease progression, management will be on clinician’s discretion (mostly best supportive care) ASCO GI 2006 abstr #98

  6. Background:ABC-01 results • Both regimens demonstrated some activity • Activity of Cis-Gem combination appeared superior • Improved 6-mo PFS (57.1 vs. 47.7%) • Improved median TTP (8.0 vs. 4.0 months) • Improved RR (24 vs. 15%) • Improved tumour control rate (76 vs. 58%) ASCO GI 2006 abstr #98

  7. Background:ABC-01 results • Both regimens demonstrated some activity • Activity of Cis-Gem combination appeared superior • Improved 6-mo PFS (57.1 vs. 47.7%) • Improved median TTP (8.0 vs. 4.0 months) • Improved RR (24 vs. 15%) • Improved tumour control rate (76 vs. 58%) • However: • Does this translate into a survival benefit? • Increased toxicity (lethargy) • What is the effect on QoL? • What is correlation with CA 19-9? ASCO GI 2006 abstr #98

  8. ABC-02 - Study schema Eligible patients (n=400*) + QoL Randomized 1:1 (stratified by centre, primary site, PS, prior therapy and locally advanced vs. metastatic) Arm A Gem 1000 mg/m2 D1,8,15 q 28d 24 weeks (6 cycles) Arm B Cisplatin 25 mg/m2 + Gem 1000 mg/m2 24 weeks (8 cycles) D1,8 q 21d Upon disease progression, management will be on clinician’s discretion (mostly best supportive care) * Including 86 patients in ABC-01

  9. ABC-02: study design • Prospective, national, multicentre, phase III study • Main inclusion criteria: • Histologically / cytologically verified disease • Adequate biliary drainage, no uncontrolled infection • ECOG PS 0-2 • LFTs: bilirubin  1.5 x ULN, ALT/ AST/ alk phos  3 x ULN ( 5 if liver metastases) • No prior systemic treatment* • Consenting informed-patients * Allowed: palliative surgery, relapse following curative surgery, PDT, radiotherapy with documented progression

  10. ABC-02 statistical methods

  11. Summary of study conduct (i): Approvals: • Approved by Ethics Committee • MHRA registration: CTA 21266/0005/001 • EUDRACT registration: 2004-004882-14 • ISRCTN82956140 • Adopted by National Cancer Research Institute • Sponsored by University College, London • Coordinated by CR-UK & UCL Cancer Trials Centre, London Recruitment dates • ABC-01: Feb 2002 – May 2004 (n=86) • ABC-02: May 2005 – Sep 2008 (n=324) • Interim analysis: 02 Dec 2008 • Events: 263 deaths (83% of sample size) • DMC recommendation: findings unlikely to change with additional patients

  12. Summary of study conduct (ii):

  13. Baseline characteristics of patients

  14. Adverse events: Grade 3-4

  15. Adverse events: Grade 3-4

  16. Radiological response (investigator-assessed) * Patients not required to have measurable disease at study entry, some patients still in follow-up

  17. Duration of treatment • Median duration of treatment: • Gemcitabine 13.0 weeks • Cisplatin / gemcitabine 19.7 weeks p= 0.007

  18. ABC-02 Results: Progression-free survival (ITT)

  19. ABC-02 - Results: Overall Survival (ITT)

  20. ABC-02 - Overall Survival Exploratory sub-group analysis

  21. ABC-02 conclusions • Combination chemotherapy with cisplatin and gemcitabine • Significantly improves overall survival: Increased median survival (11.7 vs. 8.3 months) Reduced risk of death by 30% (hazard ratio 0.70, p=0.002) • Significantly improves progression-free survival: reduces risk of disease progression by 28% (HR 0.72, p=0.003) • First demonstration of survival benefit in advanced BTC • Benefit gained with no clinically significant added toxicity • Large, collaborative, randomised studies in patients with BTC are feasible • CisGem is recommended as a worldwide standard of care and the backbone for further studies

  22. Acknowledgments • Participating patients and families • National Cancer Research Institute • Cancer Research UK (C1813/A4853) • UCL (sponsor) and UCL CTU (coordination) • Lilly Oncology (unrestricted educational grant) • Co-investigators & their research staff at the following hospitals: Aberdeen Royal Infirmary (Dr Marianne Nicholson), Addenbrooke’s (Dr Pippa Corrie), Belfast City (Dr Martin Eatock), Bristol Royal Infirmary (Dr Stephen Falk), Cheltenham General (Dr Sean Elyan), Christie (Dr Juan Valle), Clatterbridge (Dr Sun Myint), Cookridge (Dr Allan Anthony), Cumberland Infirmary (Dr Jonathan Nicoll), Derbyshire Royal Infirmary (Dr Rajendra Kulkarni), Glan Clwyd (Dr Angel Garcia Alonso), Hammersmith (Dr Harpreet Wasan), Maidstone (Dr Justin Waters), Mount Vernon (Dr Mark Harrison), Ninewells Hospital (Dr Douglas Adamson), North Hampshire (Dr Charlotte Rees), Nottingham City (Dr Sarah Ayres), Peterborough (Dr Karen McAdam), Princess Royal (Dr Anthony Maraveyas), Queen Elizabeth Birmingham (Dr Daniel Palmer), Royal Bournemouth (Dr Tamas Hickish), Royal Free (Dr Tim Meyer), Royal Marsden (Dr David Cunningham), Royal Surrey County (Dr Gary Middleton), Saint Bartholomews (Dr Sarah Slater), Saint Mary's Portsmouth (Dr Caroline Archer), Southampton General, Salisbury (Dr Timothy Iveson), University College London, Princess Alexandra, North Middlesex (Dr John Bridgewater), Velindre Cancer Centre (Dr Somnath Mukherjee), Weston Park (Dr Jonathan Wadsley), Wrexham Maelor (Dr Simon Gollins)

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