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

Biliary tract cancers: epidemiology

• Rare tumours CholangiocarcinomaGallbladder 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

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

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

Background: ABC-01 - schema

Eligible patients (n=86)

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)

Randomized 1:1

(stratified by centre, primary site, PS, prior therapy and locally advanced vs. metastatic)

Upon disease progression, management will be on clinician’s discretion (mostly best supportive care)

D1,8 q 21d

ASCO GI 2006 abstr #98

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

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

ABC-02 - Study schemaEligible patients (n=400*)

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)

Randomized 1:1

(stratified by centre, primary site, PS, prior therapy and locally advanced vs. metastatic)

Upon disease progression, management will be on clinician’s discretion (mostly best supportive care)

D1,8 q 21d

* Including 86 patients in ABC-01

+ QoL

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

ABC-02 statistical methodsPrimary endpoint:

OVERALL SURVIVAL: ITT analysis

(pre-planned ABC-01 and ABC-02)

Secondary endpoints:

Progression-free survival Toxicity Quality of life (EORTC QLQ C-30)

Sample size:

Powered to detect increase in median survival from 8 to 11 months n=354 patients (315 OS events), n=400 to allow for drop-out Log-rank test with 80% power and two-sided 5% level

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

Summary of study conduct (ii):

410 patients randomised

Gem (n=206)3 did not receive treatment

Cis / Gem (n=204)5 did not receive treatment

206 patients included in survival analysis ITT165 patients included in toxicity assessments132 patients assessable for response

204 patients included in survival analysis ITT159 patients included in toxicity assessments148 patients assessable for response

Baseline characteristics of patients

 Gem

(n=206)Cis/Gem(n=204)

Age (yr, median) 63 64

Male/female (%) 48 / 52 47 / 53

Extent of diseaseLocally advanced / metastatic (%) 23 / 77 27 / 73

Primary siteGallbladder / bile duct / ampulla (%) 37 / 58 / 5 36 / 60 / 4

ECOG Performance score 0 / 1 / 2 (%) 31 / 57 / 12 32 / 54 / 13

Prior therapyNone (%) 24 25

Biliary stenting (%) 44 46

Surgery (curative / palliative, %) 24 / 20 18 / 19

Radiotherapy (%) 2 1

Adverse events: Grade 3-4

 Toxicity by patient Gem Cis/Gem

  n % n %

White blood cells 18 11.0% 24 15.1%

Platelets 13 8.0% 13 8.2%

Haemoglobin 6 3.7% 10 6.3%

Neutrophils 29 17.9% 36 22.6%

Infection + neutropaenia 12 7.5% 16 10.2%

Infection - neutropaenia 14 8.6% 10 6.4%

Bilirubin 21 13.1% 17 10.7%

ALT 28 18.1% 15 9.6%

AST 17 11.4% 12 8.2%

Adverse events: Grade 3-4

Toxicity by patient Gem (n, %) Cis/Gem (n, %)

Anorexia 4 2.5% 3 1.9%

Lethargy 27 16.6% 29 18.6%

Nausea 5 3.1% 5 3.2%

Renal function 2 1.2% 3 1.9%

Vomiting 8 3.0% 8 5.1%

Constipation 3 1.8% 2 1.3%

Diarrhoea 4 2.5% 7 4.5%

Dyspnoea 2 1.2% 5 3.2%

Pedal oedema 5 3.1% 4 2.6%

Pain 12 7.5% 14 9.0%

Any grade ≥3 events 108 65.5% 102 64.2%

Radiological response (investigator-assessed)

ResultGemn (%)

Gem + Cisn (%)

Not assessed * 74 (36%) 56 (27%)

Assessed * 132 (64%) 148 (73%)

Complete Response 1 (0.8%) 1 (0.7%)

Partial Response 20 (15.2%) 37 (25.0%)

Stable Disease 73 (55.3%) 79 (53.4%)

Progressive Disease 33 (25.0%) 28 (18.9%)

CR + PR + SD 94 (71.2%) 117 (79.1%)

p-value 0.256

* Patients not required to have measurable disease at study entry, some patients still in follow-up

Duration of treatment

Reason for discontinuation: Gem (n) Cis / Gem (n)

Completed 53 77

Disease progression 49 26

Death 26 17

Co-morbidity 14 6

Toxicity 11 8

Withdrew consent 8 8

SAE 2 8

Clinician’s decision 3 2

Adverse events 1 1

Unknown 4 7

• Median duration of treatment:Gemcitabine 13.0 weeksCisplatin / gemcitabine 19.7 weeks p= 0.007

ABC-02 Results: Progression-free survival

(ITT)

Treatment arm Gem Gem + Cis

Number of patients n=206 n=204

PFS events n(%) 155 (75.2) 135 (66.2)

Median PFS (mo) 6.5 8.4

Log rank p value 0.003

Hazard ratio (95% CI) 0.72 (0.57, 0.90)

ABC-02 - Results: Overall Survival (ITT)

Treatment arm Gem Gem + Cis

Number of patients n=206 n=204

Deaths n(%)141

(68.5) 122 (59.8)

Median survival (mo) 8.3 11.7

Log rank p value 0.002

Hazard ratio (95% CI) 0.70 (0.54, 0.89)

ABC-02 - Overall Survival Exploratory sub-group

analysis

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

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)