title: Phase 2 placebo-controlled, double-blind trial of dasatinib added to gemcitabine for patients with locally-advanced pancreatic cancer.
abstract: Pancreatic ductal adenocarcinoma (PDAC) has a high mortality rate with limited treatment options. Gemcitabine provides a marginal survival benefit for patients with advanced PDAC. Dasatinib is a competitive inhibitor of Src kinase, which is overexpressed in PDAC tumors. Dasatinib and gemcitabine were combined in a phase 1 clinical trial where stable disease was achieved in two of eight patients with gemcitabine-refractory PDAC.
  
  
  
  This placebo-controlled, randomized, double-blind, phase II study compared the combination of gemcitabine plus dasatinib to gemcitabine plus placebo in patients with locally advanced, non-metastatic PDAC. Patients received gemcitabine 1000 mg/m2 (30-min IV infusion) on days 1, 8, 15 of a 28-day cycle combined with either 100 mg oral dasatinib or placebo tablets daily. The primary objective was overall survival (OS), with safety and progression-free survival (PFS) as secondary objectives. Exploratory endpoints included overall response rate, freedom from distant metastasis, pain and fatigue progression and response rate, and CA19-9 response rate.
  
  
  
  There was no statistically significant difference in OS between the two treatment groups (HR = 1.16; 95% confidence interval [CI]: 0.81-1.65; P = 0.5656). Secondary and exploratory endpoint analyses also showed no statistically significant differences. The burden of toxicity was higher in the dasatinib arm.
  
  
  
  Dasatinib failed to show increased OS or PFS in patients with locally advanced PDAC. Alternative combinations or trial designs may show a role for src inhibition in PDAC treatment.
authors.affiliation: Beatson West of Scotland Cancer Centre, University of Glasgow, Glasgow, UK.
authors.forename: T R J
authors.initials: TRJ
authors.lastname: Evans
authors.affiliation: Department of Oncology, University Hospitals Leuven and KU Leuven, Leuven, Belgium.
authors.forename: E
authors.initials: E
authors.lastname: Van Cutsem
authors.affiliation: Princess Margaret Cancer, Toronto, Canada.
authors.forename: M J
authors.initials: MJ
authors.lastname: Moore
authors.affiliation: Federal State Budgetary Institution, Dubna, Russia.
authors.forename: I S
authors.initials: IS
authors.lastname: Bazin
authors.affiliation: Surgery, Florida Hospital, Tampa, Tampa, USA.
authors.forename: A
authors.initials: A
authors.lastname: Rosemurgy
authors.affiliation: Oncology, St.László Teaching Hospital, Budapest, Hungary.
authors.forename: G
authors.initials: G
authors.lastname: Bodoky
authors.affiliation: Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
authors.forename: G
authors.initials: G
authors.lastname: Deplanque
authors.affiliation: East and North Hertfordshire NHS Trust, Northwood, Middlesex, UK.
authors.forename: M
authors.initials: M
authors.lastname: Harrison
authors.affiliation: Department of Oncology, Lekarska Fakulta Univerzity Palackeho a Fakultni Nemocnice, Olomouc, Czech Republic.
authors.forename: B
authors.initials: B
authors.lastname: Melichar
authors.affiliation: CHU Estaing, Clermont-Ferrand, France.
authors.forename: D
authors.initials: D
authors.lastname: Pezet
authors.affiliation: Otsuka Pharmaceutical Development and Commercialization, Princeton.
authors.forename: A
authors.initials: A
authors.lastname: Elekes
authors.affiliation: Otsuka Pharmaceutical Development and Commercialization, Princeton.
authors.forename: E
authors.initials: E
authors.lastname: Rock
authors.affiliation: Otsuka Pharmaceutical Development and Commercialization, Princeton.
authors.forename: C
authors.initials: C
authors.lastname: Lin
authors.affiliation: Bristol-Myers Squibb Company, Princeton.
authors.forename: L
authors.initials: L
authors.lastname: Strauss
authors.affiliation: Abramson Cancer Center, University of Pennsylvania, Philadelphia, USA.
authors.forename: P J
authors.initials: PJ
authors.lastname: O'Dwyer
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D000069439:Dasatinib / Q000008:administration & dosage; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D016016:Proportional Hazards Models; D016896:Treatment Outcome; D000093542:Gemcitabine
chemical_list: D003841:Deoxycytidine; D000069439:Dasatinib; D000093542:Gemcitabine
keywords: anticancer therapy; dasatinib; gemcitabine; pancreatic cancer