L-asparaginase loaded red blood cells (RBC) in pancreatic cancer: A phase I clinical study.

Abstract

e14650 Background: L-asparaginase (L-asp) efficacy is based on sensitivity of tumoral cells to asparagine deprivation due to a lack of asparagine synthethase (ASNS). However its use is hampered by significant toxicities of which allergic reaction, coagulation disorders and pancreatic impairment take a prominent place. Deficiency in ASNS and therefore potential sensitivity to L-asp treatment has been reported in multiple tumor cell lines including pancreatic cancer, however tentative to use L-asp in solid tumor, and especially in pancreatic cancer is reported in the literature but all attempts so far have failed due to toxicity. Recently, a new formulation of L-asp loaded inside RBC (GRASPA) has shown a very promising safety profile in leukemic patients. Methods: GRASPANC is the first phase I clinical study with GRASPA in patients with pancreatic carcinoma. Primary objective was to find the Dose Limiting Toxicity (DLT) of this cell-based formulation in this setting. Secondary objectives were to assess overall safety profile and activity (defined as serum asparagine depletion) of GRASPA. Patients with non resectable, relapsed pancreatic cancer were included by cohort of 3 and treated with one injection of increasing dose (25, 50, 100 or 150 IU/kg) of GRASPA. An independent Safety Monitoring Board assessed toxicities at the end of follow-up of each cohort to decide for next dose. Results: Twelve patients were included between Dec 2009 and Feb 2011 by 3 centres in France. Mean age was 60.4 years (min: 42.6; max: 71.9) with 9 Male and 3 female. No limiting toxicity has been found up to the GRASPA highest dose (150 IU/kg) planned in the study and the DLT was not reached. No specific other unexpected non limiting toxicity was evidenced. In addition, at all doses GRASPA was shown to be effective at depleting serum asparagine with a trend toward longer activity with increasing dose. Conclusions: Preliminary conclusion is that the dose of 150 IU/kg of GRASPA is safe and appears suitable for further clinical development in patients with pancreatic carcinoma. In order to maximise potential efficacy of this new therapy, selection of patients should be made according to their screening for a none or low expression of ASNS in their tumour cells.