title: Vandetanib plus gemcitabine versus placebo plus gemcitabine in locally advanced or metastatic pancreatic carcinoma (ViP): a prospective, randomised, double-blind, multicentre phase 2 trial.
abstract: Erlotinib is an EGFR tyrosine kinase inhibitor that has shown a significant but only marginally improved median overall survival when combined with gemcitabine in patients with locally advanced and metastatic pancreatic cancer. Vandetanib is a novel tyrosine kinase inhibitor of VEGFR2, RET, and EGFR, all of which are in involved in the pathogenesis of pancreatic cancer. We investigated the clinical efficacy of vandetanib when used in combination with gemcitabine in patients with advanced pancreatic cancer.
  
  
  
  The Vandetanib in Pancreatic Cancer (ViP) trial was a phase 2 double-blind, multicentre, randomised placebo-controlled trial in previously untreated adult patients (aged ≥18 years) diagnosed with locally advanced or metastatic carcinoma of the pancreas confirmed by cytology or histology. Patients had to have an Eastern Cooperative Oncology Group (ECOG) score of 0-2 and a documented life expectancy of at least 3 months. Patients were randomly assigned 1:1 to receive vandetanib plus gemcitabine (vandetanib group) or placebo plus gemcitabine (placebo group) according to pre-generated sequences produced on the principle of randomly permuted blocks with variable block sizes of two and four. Patients were stratified at randomisation by disease stage and ECOG performance status. All patients received gemcitabine 1000 mg/m2as a 30-min intravenous infusion, weekly, for 7 weeks followed by a 1-week break, followed by a cycle of 3 weeks of treatment with a 1-week break, until disease progression, and either oral vandetanib 300 mg per day once daily or matching placebo. Patients and investigators were masked to treatment assignment. The primary outcome measure was overall survival (defined as the difference in time between randomisation and death from any cause or the censor date) in the intention-to-treat population. This trial has been completed and the final results are reported. The study is registered at EudraCT, number 2007-004299-38, and ISRCTN, number ISRCTN96397434.
  
  
  
  Patients were screened and enrolled between Oct 24, 2011, and Oct 7, 2013. Of 381 patients screened, 142 eligible patients were randomly assigned to treatment (72 to the vandetanib group and 70 to the placebo group). At database lock on July 15, 2015, at a median follow-up of 24·9 months (IQR 24·3 to not attainable), 131 patients had died: 70 (97%) of 72 in the vandetanib group and 61 (87%) of 70 in the placebo group. The median overall survival was 8·83 months (95% CI 7·11-11·58) in the vandetanib group and 8·95 months (6·55-11·74) in the placebo group (hazard ratio 1·21, 80·8% CI 0·95-1·53; log rank χ21df1·1, p=0·303). The most common grade 3-4 adverse events were neutropenia (35 [49%] of 72 patients in the vandetanib group vs 22 [31%] of 70 in the placebo group), thrombocytopenia (20 [28%] vs 16 [23%]), hypertension (nine [13%] vs 11 [16%]), leucopenia (12 [17%] vs 13 [19%]), and fatigue (17 [24%] vs 15 [21%]). No treatment-related deaths occurred during the study.
  
  
  
  The addition of vandetanib to gemcitabine monotherapy did not improve overall survival in advanced pancreatic cancer. Tyrosine kinase inhibitors might still have potential in the treatment of pancreatic cancer but further development requires the identification of biomarkers to specifically identify responsive cancer subtypes.
  
  
  
  Cancer Research UK and AstraZeneca.
authors.affiliation: University of Birmingham, Edgbaston, Birmingham, UK.
authors.forename: Gary
authors.initials: G
authors.lastname: Middleton
authors.affiliation: Liverpool Cancer Research UK Cancer Trials Unit and LCTU-GCPLabs, University of Liverpool, Liverpool, UK; Clatterbridge Cancer Centre NHS Foundation Trust, Wirral, UK.
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Palmer
authors.affiliation: Liverpool Cancer Research UK Cancer Trials Unit and LCTU-GCPLabs, University of Liverpool, Liverpool, UK.
authors.forename: William
authors.initials: W
authors.lastname: Greenhalf
authors.affiliation: Liverpool Cancer Research UK Cancer Trials Unit and LCTU-GCPLabs, University of Liverpool, Liverpool, UK.
authors.forename: Paula
authors.initials: P
authors.lastname: Ghaneh
authors.affiliation: Liverpool Cancer Research UK Cancer Trials Unit and LCTU-GCPLabs, University of Liverpool, Liverpool, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Jackson
authors.affiliation: Liverpool Cancer Research UK Cancer Trials Unit and LCTU-GCPLabs, University of Liverpool, Liverpool, UK.
authors.forename: Trevor
authors.initials: T
authors.lastname: Cox
authors.affiliation: Liverpool Cancer Research UK Cancer Trials Unit and LCTU-GCPLabs, University of Liverpool, Liverpool, UK.
authors.forename: Anthony
authors.initials: A
authors.lastname: Evans
authors.affiliation: Liverpool Cancer Research UK Cancer Trials Unit and LCTU-GCPLabs, University of Liverpool, Liverpool, UK.
authors.forename: Victoria E
authors.initials: VE
authors.lastname: Shaw
authors.affiliation: Weston Park Hospital, Sheffield Teaching Hospital NHS Foundation Trust, Sheffield, UK.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Wadsley
authors.affiliation: Division of Molecular and Clinical Cancer Sciences, University of Manchester, Manchester, UK; Christie NHS Foundation Trust, Manchester, UK.
authors.forename: Juan W
authors.initials: JW
authors.lastname: Valle
authors.affiliation: Centre for Cancer and Inflammation, Barts Cancer Institute, London, UK.
authors.forename: David
authors.initials: D
authors.lastname: Propper
authors.affiliation: Hammersmith Hospital, London, UK.
authors.forename: Harpreet
authors.initials: H
authors.lastname: Wasan
authors.affiliation: Bristol Haematology and Oncology Centre, University Hospital Bristol NHS Foundation Trust, Bristol, UK.
authors.forename: Stephen
authors.initials: S
authors.lastname: Falk
authors.affiliation: Royal Marsden, Royal Marsden NHS Foundation Trust, London, UK.
authors.forename: David
authors.initials: D
authors.lastname: Cunningham
authors.affiliation: Northern Centre for Cancer Care, Newcastle upon Tyne Hospitals NHS Foundation Trust, Freeman Hospital, Newcastle upon Tyne, UK.
authors.forename: Fareeda
authors.initials: F
authors.lastname: Coxon
authors.affiliation: Guy's Hospital, Guy's and St Thomas' NHS Foundation Trust, London, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Ross
authors.affiliation: Nottingham City Hospital, Nottingham University Hospitals NHS Trust, Nottingham, UK.
authors.forename: Srinivasan
authors.initials: S
authors.lastname: Madhusudan
authors.affiliation: James Cook University Hospital, South Tees Hospitals NHS Foundation Trust, Middlesborough, UK.
authors.forename: Nick
authors.initials: N
authors.lastname: Wadd
authors.affiliation: Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
authors.forename: Pippa
authors.initials: P
authors.lastname: Corrie
authors.affiliation: Poole Hospital NHS Foundation Trust, Bournemouth University, Poole, UK.
authors.forename: Tamas
authors.initials: T
authors.lastname: Hickish
authors.affiliation: Liverpool Cancer Research UK Cancer Trials Unit and LCTU-GCPLabs, University of Liverpool, Liverpool, UK.
authors.forename: Eithne
authors.initials: E
authors.lastname: Costello
authors.affiliation: Liverpool Cancer Research UK Cancer Trials Unit and LCTU-GCPLabs, University of Liverpool, Liverpool, UK.
authors.forename: Fiona
authors.initials: F
authors.lastname: Campbell
authors.affiliation: Liverpool Cancer Research UK Cancer Trials Unit and LCTU-GCPLabs, University of Liverpool, Liverpool, UK.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Rawcliffe
authors.affiliation: Liverpool Cancer Research UK Cancer Trials Unit and LCTU-GCPLabs, University of Liverpool, Liverpool, UK. Electronic address: j.p.neoptolemos@liverpool.ac.uk.
authors.forename: John P
authors.initials: JP
authors.lastname: Neoptolemos
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000556:secondary; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004311:Double-Blind Method; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010880:Piperidines / Q000008:administration & dosage; D011379:Prognosis; D011799:Quinazolines / Q000008:administration & dosage; D015996:Survival Rate; D000093542:Gemcitabine
chemical_list: D010880:Piperidines; D011799:Quinazolines; D003841:Deoxycytidine; C452423:vandetanib; D000093542:Gemcitabine