Asparagine Synthetase Expression and Phase I Study With L-Asparaginase Encapsulated in Red Blood Cells in Patients With Pancreatic Adenocarcinoma.
OBJECTIVE
Asparaginase encapsulated in erythrocytes (ERY-ASP) is a potentially effective drug in patients with pancreatic adenocarcinoma (PAC) with null/low asparagine synthetase (ASNS) expression. Our aims were to assess ASNS expression in PAC from a large cohort and its prognostic and/or predictive value and to conduct a phase I trial with ERY-ASP in patients with metastatic PAC.


METHODS
Asparagine synthetase expression was evaluated using immunohistochemistry in resected PAC (471 patients) and in pairs of primary tumor and metastases (55 patients). Twelve patients were included in the phase I trial and received a single administration of ERY-ASP (25-150 IU/kg).


RESULTS
Null/low ASNS expression was found in 79.4% of the resected PAC with a high concordance between primary tumor and metastases. Asparagine synthetase expression was significantly correlated with sex and CXCR4 expression. In the phase I trial, ERY-ASP was well tolerated by patients with metastatic PAC. No patient had DLTs, and 6 patients had at least 1 ERY-ASP causally related adverse event out of the 12 adverse events reported.


CONCLUSIONS
Given the high rate of PAC with null/low ASNS expression and the good tolerability profile of ERY-ASP, ERY-ASP should be evaluated in further clinical studies in metastatic PAC.
From the *Department of Hepato-Gastroenterology, Pitié Salpêtrière Hospital, Paris; and †Erytech Pharma, Lyon, France; ‡Department of Gastroenterology, Erasme University Hospital, Brussels, Belgium; §Department of Oncology, Centre François Baclesse, Caen; ∥Department of Oncology, Centre Oscar Lambret, Lille; and ¶Pathology Department, Beaujon Hospital, Paris, France; #Department of Pathology, Erasme Hospital, Brussels, Belgium; **Department of Pathology, Saint Antoine Hospital; and ††Department of Pathology, Pitié Salpêtrière Hospital, Paris; ‡‡Department of Pathology, Ambroise Paré Hospital, Boulogne-Billancourt; and §§Department of Gastroenterology, Beaujon Hospital; and Departments of ∥∥Medical Oncology and ¶¶Oncology, Saint-Antoine Hospital, Paris, France.
Jean-Baptiste
JB
Bachet
Fabien
F
Gay
Raphaël
R
Maréchal
Marie-Pierre
MP
Galais
Antoine
A
Adenis
David Salako
DS
MsC
Jerome
J
Cros
Pieter
P
Demetter
Magali
M
Svrcek
Armelle
A
Bardier-Dupas
Jean-François
JF
Emile
Pascal
P
Hammel
Christelle
C
Ebenezer
Willy
W
Berlier
Yann
Y
Godfrin
Thierry
T
André
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000201:enzymology; D061605:Administration, Intravenous; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D001215:Asparaginase / Q000009:adverse effects / Q000096:biosynthesis / Q000627:therapeutic use*; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology; D015331:Cohort Studies; D004342:Drug Hypersensitivity / Q000209:etiology; D017707:Erythrocyte Transfusion / Q000009:adverse effects / Q000379:methods; D004912:Erythrocytes / Q000201:enzymology*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D017063:Outcome Assessment, Health Care / Q000379:methods / Q000706:statistics & numerical data; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D011379:Prognosis; D016016:Proportional Hazards Models
D000970:Antineoplastic Agents; D001215:Asparaginase