title: A randomized, placebo-controlled phase III trial of masitinib plus gemcitabine in the treatment of advanced pancreatic cancer.
abstract: 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).
  
  
  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.
  
  
  BACKGROUND
  ClinicalTrials.gov:NCT00789633.
authors: Department of Medical Oncology, Saint Joseph Hospital, Paris. Electronic address: gdeplanque@hpsj.fr.
authors: G
authors: G
authors: Deplanque
authors: Department of Medical Oncology, University Hospital of Besançon, Besançon.
authors: M
authors: M
authors: Demarchi
authors: Department of Medical Oncology, University Hospital, Lille, France.
authors: M
authors: M
authors: Hebbar
authors: Metro-Minnesota Community Clinical Oncology Program, Park Nicollet Institute, Minneapolis, USA.
authors: P
authors: P
authors: Flynn
authors: Department of Oncology, Palacký University Medical School & Teaching Hospital, Olomouc, Czech Republic.
authors: B
authors: B
authors: Melichar
authors: Southeastern Medical Oncology Center, Goldsboro, USA.
authors: J
authors: J
authors: Atkins
authors: Department of Clinical and Experimental Oncology, Maria Skłodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice, Poland.
authors: E
authors: E
authors: Nowara
authors: Department of Biostatistics, University of Texas School of Public Health, Houston, USA.
authors: L
authors: L
authors: Moyé
authors: Clinical Development, Acobiom, Montpellier.
authors: D
authors: D
authors: Piquemal
authors: Clinical Development, Acobiom, Montpellier.
authors: D
authors: D
authors: Ritter
authors: 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.
authors: P
authors: P
authors: Dubreuil
authors: Clinical Development, AB Science, Paris.
authors: C D
authors: CD
authors: Mansfield
authors: Clinical Development, AB Science, Paris.
authors: Y
authors: Y
authors: Acin
authors: Clinical Development, AB Science, Paris.
authors: A
authors: A
authors: Moussy
authors: 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 (CEREMAST), Paris.
authors: O
authors: O
authors: Hermine
authors: Department of Gastroenterology, Hôpital Beaujon, Clichy, France.
authors: P
authors: P
authors: Hammel
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001549:Benzamides; D014408:Biomarkers, Tumor / Q000235:genetics; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000401:mortality / Q000473:pathology; D003841:Deoxycytidine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D005060:Europe; D005260:Female; D006801:Humans; D057194:Intention to Treat Analysis; D008297:Male; D008875:Middle Aged; D010088:Oxidoreductases / Q000235:genetics; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000401:mortality / Q000473:pathology; D010597:Pharmacogenetics; D010880:Piperidines; D057285:Precision Medicine; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D011446:Prospective Studies; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D011725:Pyridines; D012307:Risk Factors; D013844:Thiazoles / Q000009:adverse effects / Q000627:therapeutic use*; D013997:Time Factors; D016896:Treatment Outcome; D014481:United States; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D001549:Benzamides; D014408:Biomarkers, Tumor; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D013844:Thiazoles; D003841:Deoxycytidine; D010088:Oxidoreductases; C526575:masitinib; D000093542:Gemcitabine
keywords: ACOX1; PDAC; genetic biomarker; pain; pancreatic cancer; tyrosine–kinase inhibitor