T R J Evans1, E Van Cutsem2, M J Moore3, I S Bazin4, A Rosemurgy5, G Bodoky6, G Deplanque7, M Harrison8, B Melichar9, D Pezet10, A Elekes11, E Rock11, C Lin11, L Strauss12, P J O'Dwyer13. 1. Beatson West of Scotland Cancer Centre, University of Glasgow, Glasgow, UK. 2. Department of Oncology, University Hospitals Leuven and KU Leuven, Leuven, Belgium. 3. Princess Margaret Cancer, Toronto, Canada. 4. Federal State Budgetary Institution, Dubna, Russia. 5. Surgery, Florida Hospital, Tampa, Tampa, USA. 6. Oncology, St.László Teaching Hospital, Budapest, Hungary. 7. Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland. 8. East and North Hertfordshire NHS Trust, Northwood, Middlesex, UK. 9. Department of Oncology, Lekarska Fakulta Univerzity Palackeho a Fakultni Nemocnice, Olomouc, Czech Republic. 10. CHU Estaing, Clermont-Ferrand, France. 11. Otsuka Pharmaceutical Development and Commercialization, Princeton. 12. Bristol-Myers Squibb Company, Princeton. 13. Abramson Cancer Center, University of Pennsylvania, Philadelphia, USA.
Abstract
Background: 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. Patients and methods: 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. Results: 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. Conclusions: 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.
RCT Entities:
Background: 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 PDACtumors. 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. Patients and methods: 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. Results: 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. Conclusions: 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.
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