BACKGROUND: Masitinib is a selective oral tyrosine-kinase inhibitor. The efficacy and safety of masitinib combined with gemcitabine was compared against single-agent gemcitabine in patients with advanced pancreatic ductal adenocarcinoma (PDAC). PATIENTS AND METHODS: Patients with inoperable, chemotherapy-naïve, PDAC were randomized (1 : 1) to receive gemcitabine (1000 mg/m(2)) in combination with either masitinib (9 mg/kg/day) or a placebo. The primary endpoint was overall survival (OS) in the modified intent-to-treat population. Secondary OS analyses aimed to characterize subgroups with poor survival while receiving single-agent gemcitabine with subsequent evaluation of masitinib therapeutic benefit. These prospectively declared subgroups were based on pharmacogenomic data or a baseline characteristic. RESULTS: Three hundred and fifty-three patients were randomly assigned to receive either masitinib plus gemcitabine (N = 175) or placebo plus gemcitabine (N = 178). Median OS was similar between treatment-arms for the overall population, at respectively, 7.7 and 7.1 months, with a hazard ratio (HR) of 0.89 (95% CI [0.70; 1.13]. Secondary analyses identified two subgroups having a significantly poor survival rate when receiving single-agent gemcitabine; one defined by an overexpression of acyl-CoA oxidase-1 (ACOX1) in blood, and another via a baseline pain intensity threshold (VAS > 20 mm). These subgroups represent a critical unmet medical need as evidenced from median OS of 5.5 months in patients receiving single-agent gemcitabine, and comprise an estimated 63% of patients. A significant treatment effect was observed in these subgroups for masitinib with median OS of 11.7 months in the 'ACOX1' subgroup [HR = 0.23 (0.10; 0.51), P = 0.001], and 8.0 months in the 'pain' subgroup [HR = 0.62 (0.43; 0.89), P = 0.012]. Despite an increased toxicity of the combination as compared with single-agent gemcitabine, side-effects remained manageable. CONCLUSIONS: The present data warrant initiation of a confirmatory study that may support the use of masitinib plus gemcitabine for treatment of PDAC patients with overexpression of ACOX1 or baseline pain (VAS > 20mm). Masitinib's effect in these subgroups is also supported by biological plausibility and evidence of internal clinical validation. TRIAL REGISTRATION: ClinicalTrials.gov:NCT00789633.

Clinical Development AB Science Paris

Clinical Development AB Science Paris; Department of Clinical Hematology Necker Hospital Paris; INSERM UMR 1163 Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutic Implications Paris; Paris Descartes Sorbonne Paris Cité University Imagine Institute Paris; CNRS ERL 8254 Paris; Laboratory of Excellence GR Ex Paris; National Reference Center on Mastocytosis Paris

Clinical Development Acobiom Montpellier

Department of Biostatistics University of Texas School of Public Health Houston USA

Department of Clinical and Experimental Oncology Maria Skłodowska Curie Memorial Cancer Center and Institute of Oncology Gliwice Poland

Department of Gastroenterology Hôpital Beaujon Clichy France

Department of Medical Oncology Saint Joseph Hospital Paris

Department of Medical Oncology University Hospital Lille France

Department of Medical Oncology University Hospital of Besançon Besançon

Department of Oncology Palacký University Medical School and Teaching Hospital Olomouc Czech Republic

Metro Minnesota Community Clinical Oncology Program Park Nicollet Institute Minneapolis USA

Signaling Hematopoiesis and Mechanism of Oncogenesis Inserm U1068 CRCM Marseille; Institut Paoli Calmettes Marseille; Aix Marseille University UM 105 Marseille; CNRS UMR7258 CRCM Marseille; Clinical Development AB Science Paris

Southeastern Medical Oncology Center Goldsboro USA

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Different clinical presentations of metachronous pulmonary metastases after resection of pancreatic ductal adenocarcinoma: Retrospective study and review of the literature

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ClinicalTrials.gov
NCT00789633