A randomized, placebo-controlled phase III trial of masitinib plus gemcitabine in the treatment of advanced pancreatic cancer

Ann Oncol. 2015 Jun;26(6):1194-1200. doi: 10.1093/annonc/mdv133. Epub 2015 Apr 9.


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.

Keywords: ACOX1; PDAC; genetic biomarker; pain; pancreatic cancer; tyrosine–kinase inhibitor.

Publication types

  • Clinical Trial, Phase III
  • Comparative Study
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antimetabolites, Antineoplastic / adverse effects
  • Antimetabolites, Antineoplastic / therapeutic use*
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Benzamides
  • Biomarkers, Tumor / genetics
  • Carcinoma, Pancreatic Ductal / drug therapy*
  • Carcinoma, Pancreatic Ductal / enzymology
  • Carcinoma, Pancreatic Ductal / genetics
  • Carcinoma, Pancreatic Ductal / mortality
  • Carcinoma, Pancreatic Ductal / pathology
  • Deoxycytidine / adverse effects
  • Deoxycytidine / analogs & derivatives*
  • Deoxycytidine / therapeutic use
  • Europe
  • Female
  • Gemcitabine
  • Humans
  • Intention to Treat Analysis
  • Male
  • Middle Aged
  • Oxidoreductases / genetics
  • Pancreatic Neoplasms / drug therapy*
  • Pancreatic Neoplasms / enzymology
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / mortality
  • Pancreatic Neoplasms / pathology
  • Pharmacogenetics
  • Piperidines
  • Precision Medicine
  • Predictive Value of Tests
  • Proportional Hazards Models
  • Prospective Studies
  • Protein Kinase Inhibitors / adverse effects
  • Protein Kinase Inhibitors / therapeutic use*
  • Pyridines
  • Risk Factors
  • Thiazoles / adverse effects
  • Thiazoles / therapeutic use*
  • Time Factors
  • Treatment Outcome
  • United States


  • Antimetabolites, Antineoplastic
  • Benzamides
  • Biomarkers, Tumor
  • Piperidines
  • Protein Kinase Inhibitors
  • Pyridines
  • Thiazoles
  • Deoxycytidine
  • Oxidoreductases
  • masitinib
  • Gemcitabine

Associated data

  • ClinicalTrials.gov/NCT00789633