Abstract CT023: A phase I study of eryaspase (L-asparaginase encapsulated in red blood cells) in combination with induction and consolidation chemotherapy for adult patients (pts) with newly diagnosed acute lymphoblastic leukemia (ALL)
Authors: Walker Alison , Klisovic Rebecca , Rizzieri David , Emadi Ashkan , Kolitz Jonathan , Stock Wendy , Clancy Daniel E. , Hariry Iman El , Larson Richard A. 
Published: August 2018

Abstract
Background L-asparaginase (ASNase) is a key drug in the treatment of ALL. However, its toxicity profile includes hypersensitivity reactions, thromboses, pancreatitis and hepatic toxicity. Eryaspase is an investigational product under development with the aim of improving the tolerance of this enzyme. ASNase is encapsulated within red blood cells (RBCs) by a proprietary osmotic-based method. After eryaspase infusion, plasma asparagine is actively transported into RBCs, where it is hydrolyzed.
Methods We conducted this multicenter, open label, dose-escalating Phase I study to define the recommended Phase 2/3 dosing of eryaspase in combination with the CALGB 8811 chemotherapy regimen (Larson et al. Blood 1995) for the frontline treatment of adults with Philadelphia chromosome-negative ALL. Primary endpoint: The Maximum Tolerated Dose (MTD) of eryaspase when given during induction and consolidation phases of the CALGB 8811 chemotherapy. Secondary endpoints: pharmacokinetic (PK) and pharmacodynamics (PD) parameters, safety, immunogenicity, and clinical response. Pts received the modified CALGB 8811 regimen for a total of 24 months. Eryaspase was administered on Days 4 of Induction and Days 15 and 43 of both consolidation courses in place of pegylated asparaginase. Pts were treated in one of 3 dose cohorts of eryaspase (50, 100, and 150 U/kg). Dose escalation followed a 3+3 design. A Steering Committee reviewed the safety information and recommended dose escalation following completion of each dose cohort. The MTD was defined as the highest dose level at which ≤1/3 of at least 6 pts experienced a dose-limiting toxicity (DLT) during induction.
Results Fourteen pts were enrolled but one pt was not treated. Median age was 55 years (range, 21-71). Cohorts enrolled n=3 at 50; n=6 at 100, and n=4 at 150 U/kg of eryaspase. Treatment was generally well tolerated beyond typical ALL-related toxicities, with no eryaspase-related safety concerns. One DLT (Grade 3 hypertriglyceridemia) occurred at the 100 U/kg dose level. Thus, 3 additional pts were enrolled into the 100 U/kg cohort. No other DLTs were identified, and no DLTs were reported at 150 U/kg dose level. Further dose-escalation was discontinued as PK and PD suggested no differences between the 100 and 150 U/kg dose levels. The geometric mean terminal phase t½ for the 50, 100, and 150 U/kg treatment during the first induction phase was 20.76, 19.03 and 8.67days, respectively. Geometric mean Cmax for the 50, 100, and 150 U/kg treatment during the first induction phase was 1083, 1735 and 2471 U/L, respectively.
Conclusion Eryaspase was well-tolerated when combined with the CALGB 8811 chemotherapy regimen for frontline treatment of adults with ALL. Based on the PK data and the safety findings, the recommended phase 2/3 dose is 100 U/kg.
Citation Format: Alison Walker, Rebecca Klisovic, David Rizzieri, Ashkan Emadi, Jonathan Kolitz, Wendy Stock, Daniel E. Clancy, Iman El Hariry, Richard A. Larson. A phase I study of eryaspase (L-asparaginase encapsulated in red blood cells) in combination with induction and consolidation chemotherapy for adult patients (pts) with newly diagnosed acute lymphoblastic leukemia (ALL) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT023.