title: Gemcitabine and capecitabine with or without telomerase peptide vaccine GV1001 in patients with locally advanced or metastatic pancreatic cancer (TeloVac): an open-label, randomised, phase 3 trial.
abstract: BACKGROUND
  We aimed to assess the efficacy and safety of sequential or simultaneous telomerase vaccination (GV1001) in combination with chemotherapy in patients with locally advanced or metastatic pancreatic cancer.
  
  
  METHODS
  TeloVac was a three-group, open-label, randomised phase 3 trial. We recruited patients from 51 UK hospitals. Eligible patients were treatment naive, aged older than 18 years, with locally advanced or metastatic pancreatic ductal adenocarcinoma, and Eastern Cooperative Oncology Group performance status of 0-2. Patients were randomly assigned (1:1:1) to receive either chemotherapy alone, chemotherapy with sequential GV1001 (sequential chemoimmunotherapy), or chemotherapy with concurrent GV1001 (concurrent chemoimmunotherapy). Treatments were allocated with equal probability by means of computer-generated random permuted blocks of sizes 3 and 6 in equal proportion. Chemotherapy included six cycles of gemcitabine (1000 mg/m(2), 30 min intravenous infusion, at days 1, 8, and 15) and capecitabine (830 mg/m(2) orally twice daily for 21 days, repeated every 28 days). Sequential chemoimmunotherapy included two cycles of combination chemotherapy, then an intradermal lower abdominal injection of granulocyte-macrophage colony-stimulating factor (GM-CSF; 75 μg) and GV1001 (0·56 mg; days 1, 3, and 5, once on weeks 2-4, and six monthly thereafter). Concurrent chemoimmunotherapy included giving GV1001 from the start of chemotherapy with GM-CSF as an adjuvant. The primary endpoint was overall survival; analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN4382138.
  
  
  RESULTS
  The first patient was randomly assigned to treatment on March 29, 2007, and the trial was terminated on March 27, 2011. Of 1572 patients screened, 1062 were randomly assigned to treatment (358 patients were allocated to the chemotherapy group, 350 to the sequential chemoimmunotherapy group, and 354 to the concurrent chemoimmunotherapy group). We recorded 772 deaths; the 290 patients still alive were followed up for a median of 6·0 months (IQR 2·4-12·2). Median overall survival was not significantly different in the chemotherapy group than in the sequential chemoimmunotherapy group (7·9 months [95% CI 7·1-8·8] vs 6·9 months [6·4-7·6]; hazard ratio [HR] 1·19, 98·25% CI 0·97-1·48, p=0·05), or in the concurrent chemoimmunotherapy group (8·4 months [95% CI 7·3-9·7], HR 1·05, 98·25% CI 0·85-1·29, p=0·64; overall log-rank of χ(2)2df=4·3; p=0·11). The commonest grade 3-4 toxic effects were neutropenia (68 [19%] patients in the chemotherapy group, 58 [17%] patients in the sequential chemoimmunotherapy group, and 79 [22%] patients in the concurrent chemoimmunotherapy group; fatigue (27 [8%] in the chemotherapy group, 35 [10%] in the sequential chemoimmunotherapy group, and 44 [12%] in the concurrent chemoimmunotherapy group); and pain (34 [9%] patients in the chemotherapy group, 39 [11%] in the sequential chemoimmunotherapy group, and 41 [12%] in the concurrent chemoimmunotherapy group).
  
  
  CONCLUSIONS
  Adding GV1001 vaccination to chemotherapy did not improve overall survival. New strategies to enhance the immune response effect of telomerase vaccination during chemotherapy are required for clinical efficacy.
  
  
  BACKGROUND
  Cancer Research UK and KAEL-GemVax.
authors: University of Birmingham, Edgbaston, Birmingham, UK.
authors: Gary
authors: G
authors: Middleton
authors: Liverpool Cancer Research UK Cancer Trials Unit and GCLP Facility, University of Liverpool, Liverpool, UK.
authors: Paul
authors: P
authors: Silcocks
authors: Liverpool Cancer Research UK Cancer Trials Unit and GCLP Facility, University of Liverpool, Liverpool, UK.
authors: Trevor
authors: T
authors: Cox
authors: Manchester Academic Health Sciences Centre, Christie Hospital NHS Foundation Trust and University of Manchester, Manchester UK.
authors: Juan
authors: J
authors: Valle
authors: Weston Park Hospital, Sheffield Teaching Hospital NHS Foundation Trust, Sheffield, UK.
authors: Jonathan
authors: J
authors: Wadsley
authors: St Bartholomew's Hospital, Barts Health NHS Trust, West Smithfield, London, UK.
authors: David
authors: D
authors: Propper
authors: Northern Centre for Cancer Care, The Newcastle upon Tyne Hospitals NHS Foundation Trust, Freeman Hospital, Newcastle upon Tyne, UK.
authors: Fareeda
authors: F
authors: Coxon
authors: Guy's Hospital, Guy's and St Thomas' NHS Foundation Trust, London, UK.
authors: Paul
authors: P
authors: Ross
authors: Nottingham City Hospital, Nottingham University Hospitals NHS Trust, Nottingham, UK.
authors: Srinivasan
authors: S
authors: Madhusudan
authors: Norfolk and Norwich University Hospital, Norfolk and Norwich University Hospital NHS Foundation Trust, Norwich, UK.
authors: Tom
authors: T
authors: Roques
authors: The Royal Marsden, The Royal Marsden NHS Foundation Trust, London, UK.
authors: David
authors: D
authors: Cunningham
authors: Bristol Haematology And Oncology Centre, University Hospital Bristol NHS Foundation Trust, Bristol, UK.
authors: Stephen
authors: S
authors: Falk
authors: The James Cook University Hospital, South Tees Hospitals NHS Foundation Trust, Middleborough, UK.
authors: Nick
authors: N
authors: Wadd
authors: Mount Vernon Hospital, The Hillingdon Hospitals NHS Foundation Trust, Northwood, UK.
authors: Mark
authors: M
authors: Harrison
authors: Addenbrookes Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
authors: Pippa
authors: P
authors: Corrie
authors: Southampton General Hospital, University Hospital Southampton NHS Foundation Trust, Southampton, Hampshire, UK.
authors: Tim
authors: T
authors: Iveson
authors: Conquest Hospital, East Sussex Healthcare NHS Trust, The Ridge, St Leonards-on-Sea, East Sussex, UK.
authors: Angus
authors: A
authors: Robinson
authors: Peterborough City Hospital, Peterborough and Stamford Hospitals NHS Foundation Trust, Edith, Cavell Campus, Peterborough, UK.
authors: Karen
authors: K
authors: McAdam
authors: Belfast City Hospital, Belfast Health and Social Care Trust, Belfast, UK.
authors: Martin
authors: M
authors: Eatock
authors: University of Glasgow, Beatson West of Scotland Cancer Centre, Glasgow, UK.
authors: Jeff
authors: J
authors: Evans
authors: Queen Alexandra Hospital, Portsmouth Hospitals NHS Trust, Cosham, Portsmouth, UK.
authors: Caroline
authors: C
authors: Archer
authors: Royal Bournemouth Hospital, The Royal Bournemouth and Christchurch Hospitals NHS Foundation Trust, Bournemouth, UK.
authors: Tamas
authors: T
authors: Hickish
authors: Glan Clwyd Hospital, University Health Board, Rhyl, Denbighshire, UK.
authors: Angel
authors: A
authors: Garcia-Alonso
authors: Abderdeen Royal Infirmary, NHS Grampian, Aberdeen, UK.
authors: Marianne
authors: M
authors: Nicolson
authors: Leicester Royal Infirmary, University Hospitals of Leicester NHS Trust, Leicester, UK.
authors: William
authors: W
authors: Steward
authors: St James University Hospital, The Leeds Teaching Hospital Trust, Beckett Street, Leeds, UK.
authors: Alan
authors: A
authors: Anthoney
authors: Liverpool Cancer Research UK Cancer Trials Unit and GCLP Facility, University of Liverpool, Liverpool, UK.
authors: William
authors: W
authors: Greenhalf
authors: Liverpool Cancer Research UK Cancer Trials Unit and GCLP Facility, University of Liverpool, Liverpool, UK.
authors: Victoria
authors: V
authors: Shaw
authors: Liverpool Cancer Research UK Cancer Trials Unit and GCLP Facility, University of Liverpool, Liverpool, UK.
authors: Eithne
authors: E
authors: Costello
authors: Liverpool Cancer Research UK Cancer Trials Unit and GCLP Facility, University of Liverpool, Liverpool, UK.
authors: Dean
authors: D
authors: Naisbitt
authors: Liverpool Cancer Research UK Cancer Trials Unit and GCLP Facility, University of Liverpool, Liverpool, UK.
authors: Charlotte
authors: C
authors: Rawcliffe
authors: Liverpool Cancer Research UK Cancer Trials Unit and GCLP Facility, University of Liverpool, Liverpool, UK.
authors: Gemma
authors: G
authors: Nanson
authors: Liverpool Cancer Research UK Cancer Trials Unit and GCLP Facility, University of Liverpool, Liverpool, UK. Electronic address: j.p.neoptolemos@liverpool.ac.uk.
authors: John
authors: J
authors: Neoptolemos
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000556:secondary; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D019496:Cancer Vaccines / Q000008:administration & dosage* / Q000009:adverse effects; D000069287:Capecitabine; D049109:Cell Proliferation; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D018572:Disease-Free Survival; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000031:analogs & derivatives; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage; D006801:Humans; D007155:Immunologic Factors / Q000008:administration & dosage; D057194:Intention to Treat Analysis; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009503:Neutropenia / Q000139:chemically induced; D010146:Pain / Q000139:chemically induced; D010183:Pancreatic Ducts; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010446:Peptide Fragments / Q000008:administration & dosage* / Q000009:adverse effects; D013601:T-Lymphocytes / Q000276:immunology; D019098:Telomerase / Q000008:administration & dosage* / Q000009:adverse effects; D000093542:Gemcitabine
chemical_list: D019496:Cancer Vaccines; D007155:Immunologic Factors; D010446:Peptide Fragments; D003841:Deoxycytidine; D000069287:Capecitabine; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; C514987:GV1001 peptide; D019098:Telomerase; D005472:Fluorouracil; D000093542:Gemcitabine