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Ann Oncol. 2015 Jun;26(6):1194-200. doi: 10.1093/annonc/mdv133. Epub 2015 Apr 9.

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

Author information

1
Department of Medical Oncology, Saint Joseph Hospital, Paris gdeplanque@hpsj.fr.
2
Department of Medical Oncology, University Hospital of Besançon, Besançon.
3
Department of Medical Oncology, University Hospital, Lille, France.
4
Metro-Minnesota Community Clinical Oncology Program, Park Nicollet Institute, Minneapolis, USA.
5
Department of Oncology, Palacký University Medical School & Teaching Hospital, Olomouc, Czech Republic.
6
Southeastern Medical Oncology Center, Goldsboro, USA.
7
Department of Clinical and Experimental Oncology, Maria Skłodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice, Poland.
8
Department of Biostatistics, University of Texas School of Public Health, Houston, USA.
9
Clinical Development, Acobiom, Montpellier.
10
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.
11
Clinical Development, AB Science, Paris.
12
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.
13
Department of Gastroenterology, Hôpital Beaujon, Clichy, France.

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).

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

PMID:
25858497
PMCID:
PMC4516046
DOI:
10.1093/annonc/mdv133
[Indexed for MEDLINE]
Free PMC Article

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