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Cediranib or placebo in combination with cisplatin and gemcitabine chemotherapy for patients with advanced biliary tract cancer (ABC-03): a randomised phase 2 trial

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posted on 20.01.2017, 16:08 by J. W. Valle, H. Wasan, A. Lopes, A. C. Backen, D. H. Palmer, K. Morris, M. Duggan, D. Cunningham, D. A. Anthoney, P. Corrie, S. Madhusudan, A. Maraveyas, P. J. Ross, J. S. Waters, Will P. Steward, C. Rees, S. Beare, C. Dive, J. A. Bridgewater
Background Cisplatin and gemcitabine is the standard first-line chemotherapy regimen for patients with advanced biliary tract cancer; expression of VEGF and its receptors is associated with adverse outcomes. We aimed to assess the effect of the addition of cediranib (an oral inhibitor of VEGF receptor 1, 2, and 3) to cisplatin and gemcitabine on progression-free survival. Methods In this multicentre, placebo-controlled, randomised phase 2 study, we recruited patients aged 18 years or older with histologically confirmed or cytologically confirmed advanced biliary tract cancer from hepatobiliary oncology referral centres in the UK. Patients were eligible if they had an ECOG performance status of 0–1 and an estimated life expectancy of longer than 3 months. Patients were given first-line cisplatin and gemcitabine chemotherapy (25 mg/m2 cisplatin and 1000 mg/m2 gemcitabine [on days 1 and 8 every 21 days, for up to eight cycles]) with either 20 mg oral cediranib or placebo once a day until disease progression. We randomly assigned patients (1:1) with a minimisation algorithm, incorporating the stratification factors: extent of disease, primary disease site, previous treatment, ECOG performance status, and centre. The primary endpoint was progression-free survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00939848, and was closed on Sept 30, 2014; results of the final analysis for the primary endpoint are presented. Findings Between April 5, 2011, and Sept 28, 2012, we enrolled 124 patients (62 in each group). With a median follow-up of 12·2 months (IQR 7·3–18·5), median progression-free survival was 8·0 months (95% CI 6·5–9·3) in the cediranib group and 7·4 months (5·7–8·5) in the placebo group (HR 0·93, 80% CI 0·74–1·19, 95% CI 0·65–1·35; p=0·72). Patients who received cediranib had more grade 3–4 toxic effects than did patients who received placebo: hypertension (23 [37%] vs 13 [21%]; p=0·05), diarrhoea (eight [13%] vs two [3%]; p=0·05); platelet count decreased (ten [16%] vs four [6%]; p=0·09), white blood cell decreased (15 [24%] vs seven [11%]; p=0·06) and fatigue (16 [24%] vs seven [11%]; p=0·04). Interpretation Cediranib did not improve the progression-free survival of patients with advanced biliary tract cancer in combination with cisplatin and gemcitabine, which remains the standard of care. Although patients in the cediranib group had more adverse events, we recorded no unexpected toxic effects. The role of VEGF inhibition in addition to chemotherapy for patients with advanced biliary tract cancer remains investigational. Funding Cancer Research UK and AstraZeneca Pharmaceuticals.

Funding

This study was funded by Cancer Research UK (grants CRUK/09/029, C2930/A11428, and C480/A15578) and AstraZeneca Pharmaceuticals. Funding from Cancer Research UK and AstraZeneca supported the central coordination of the trial and off set research costs at study sites. AstraZeneca provided cediranib and matching placebo free of charge. AstraZeneca also covered the cost of the interactive web-based response system and of packaging and distribution of cediranib and placebo. The CRUK Manchester Experimental Medicines Centre and the CRUK Manchester Cancer Research Centre provided support for the biomarker analyses and quality assurance of the biomarker data. We thank all patients participating in ABC-03 and their families. We acknowledge the support the Cancer Research UK Manchester Institute (Clinical and Experimental Pharmacology laboratory) where the circulating biomarkers were studied. DC is supported by the NIHR Royal Marsden/Institute of Cancer Research Biomedical Research Centre. JAB is supported by the UCLH/UCL Biomedical Research Centre. We also acknowledge the support of the AMMF cholangiocarcinoma charity and support and insights from the International Biliary Tract Cancer Collaboration. Open Access funded by Cancer Research UK

History

Citation

Lancet Oncology 2015; 16: 967–78

Author affiliation

/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/School of Medicine/Department of Cancer Studies and Molecular Medicine

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VoR (Version of Record)

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Lancet Oncology 2015; 16: 967–78

Publisher

Elsevier

issn

1470-2045

eissn

1474-5488

Available date

20/01/2017

Publisher version

http://www.sciencedirect.com/science/article/pii/S1470204515001394

Language

en

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