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4044 Efficacy, Safety, and Population Pharmacokinetic Modeling of Intravenous Recombinant Erwinia Asparaginase (JZP458) in Acute Lymphoblastic Leukemia/Lymphoblastic Lymphoma: Results from Study AALL1931Clinically Relevant Abstract

Program: Oral and Poster Abstracts
Session: 614. Acute Lymphoblastic Leukemias: Therapies, Excluding Transplantation and Cellular Immunotherapies: Poster III
Hematology Disease Topics & Pathways:
Lymphoid Leukemias, ALL, Research, clinical trials, Clinical Research, Diseases, Lymphoid Malignancies, emerging technologies, Technology and Procedures
Monday, December 12, 2022, 6:00 PM-8:00 PM

Luke Maese, DO1, Mignon L. Loh, MD2, Mi Rim Choi3, Tong Lin3*, Etsuko Aoki3*, Shirali Agarwal3*, Xiaotian Wu4*, Robert Iannone4*, Jeffrey A. Silverman4*, Lewis B. Silverman, MD5, Elizabeth A. Raetz, MD6 and Rachel E. Rau, MD7

1Primary Children's Hospital, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT
2Department of Pediatrics, Division of Pediatric Hematology/Oncology, University of California Benioff Children’s Hospital, Seattle, WA
3Jazz Pharmaceuticals, Palo Alto, CA
4Jazz Pharmaceuticals, Philadelphia, PA
5Dana-Farber Cancer Inst., Boston, MA
6Division of Pediatric Hematology and Oncology, Stephen D. Hassenfeld Children's Center for Cancer and Blood Disorders, NYU Langone Health, New York, NY
7Texas Children’s Cancer and Hematology Center, Baylor College of Medicine, Houston, TX

Introduction: L-asparaginase is an important component of multi-agent chemotherapy regimens for pediatric and adult patients with acute lymphoblastic leukemia (ALL)/lymphoblastic lymphoma (LBL). JZP458, a recombinant Erwinia chrysanthemi asparaginase with an identical amino acid sequence to the native compound, is derived from a novel Pseudomonas fluorescens expression platform to produce a reliable supply of a highly purified enzyme with minimal cross-reactivity to E. coli-derived asparaginases. JZP458 was developed to address historical global shortages of native asparaginase Erwinia chrysanthemi (Erwinaze®/Erwinase®). AALL1931 is a 2-part, open-label, phase 2/3 trial conducted in collaboration with the Children’s Oncology Group investigating efficacy, safety, and pharmacokinetics (PK) of JZP458 in patients with ALL/LBL (ClinicalTrials.gov Identifier: NCT04145531). Based on interim results from Part A of AALL1931, intramuscular (IM) JZP458 (Rylaze®) was approved in June of 2021 by the US Food and Drug Administration for the treatment of ALL/LBL. Here, we report the efficacy and safety of intravenous (IV) JZP458 from Part B of AALL1931. Part B was exploratory in nature and aims to determine an IV JZP458 dosing regimen that provides adequate serum asparaginase activity (SAA) with an acceptable safety profile in patients with ALL/LBL following hypersensitivity to E. coli-derived asparaginases.

Methods: Eligible patients with ALL/LBL had a grade ≥3 allergic reaction or silent inactivation to a pegylated E. coli-derived asparaginase (PEG). Each remaining dose of PEG was substituted with 6 doses of IV JZP458 over 2 weeks (1 course) at 25/25/50 mg/m2 on Monday/Wednesday/Friday (MWF). Efficacy was assessed by the proportions of patients achieving the last 72- and 48-hour nadir SAA (NSAA) levels ≥0.1 IU/mL during Course 1. A population PK (PopPK) model was also developed for JZP458 based on SAA data.

Results: 61 patients received ≥1 dose of IV JZP458 and were included in this analysis (data cutoff: July 19, 2021). The median (range) age was 10 (1, 24) years. The mean (95% CI) SAA levels (IU/mL) were 0.10 (0.07, 0.13) at 72 hours and 0.25 (0.20, 0.29) at 48 hours. The proportions (95% CI) of patients achieving NSAA levels ≥0.1 IU/mL at 72 and 48 hours in Course 1 were 40% (26%, 54%) and 90% (82%, 98%), respectively. PopPK modeling and simulation suggested that 51% (49%, 54%) and 91% (90%, 92%) of patients would achieve NSAA levels ≥0.1 IU/mL at 72 and 48 hours in Course 1, respectively. Grade 3/4 treatment-related adverse events (TRAEs) occurred in 29 (48%) patients. Incidences of any grade TRAEs of interest were: allergic reactions (23%), hepatotoxicity (11%), pancreatitis (0%), and thrombosis (0%). TRAEs leading to discontinuation occurred in 15 (25%) patients and included hypersensitivity reactions (15%), vomiting (3%), infusion-related reaction (3%), nausea (2%), and hyperammonemic encephalopathy (2%). No TRAEs led to death. The geometric mean half-life for JZP458 was estimated at 19.1 hours and 8.3 hours for IM and IV administration, respectively. PopPK model-based simulation predicted that NSAA levels ≥0.1 IU/mL are best maintained when IV JZP458 is administered at 25 mg/m2 every 48 hours (90% of patients [95% CI: 89%, 92%] at the last 48-hours) or when JZP458 is administered IV at 25 mg/m2 Monday/Wednesday and IM at 50 mg/m2 on Friday due to the longer half-life for IM (92% of patients [95% CI: 91%, 93%] at the last 72-hours; 93% of patients [95% CI: 92%, 94%] at the last 48-hours).

Conclusions: Results from the AALL1931 study demonstrate that IV administration of JZP458 at 25 mg/m2 every 48 hours is feasible and efficacious with a safety profile consistent with other asparaginases. PopPK modeling supports that JZP458 dosing at 25 mg/m2 IV every 48 hours or 25/25/50 mg/m2 IV/IV/IM MWF would achieve sustained asparaginase activity (NSAA levels ≥0.1 IU/mL in ≥90% of patients) thereby providing dosing flexibility to patients and physicians.

Disclosures: Maese: Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Choi: Jazz Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Lin: Jazz Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Aoki: Etsuko Aoki: Current Employment, Current equity holder in publicly-traded company. Agarwal: Jazz Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Wu: Jazz Pharmaceuticals: Current Employment, Current holder of stock options in a privately-held company. Iannone: Jazz Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Silverman: Jazz Pharmaceuticals: Other: Was an employee of Jazz Pharmaceuticals at the time of the study and holds stock ownership and/or stock options in Jazz Pharmaceuticals. Silverman: Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees. Raetz: BMS: Other: Data and Safety Monitoring Board; Pfizer: Research Funding. Rau: Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Servier Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie Pharmaceuticals: Other: Spouse is employee and stock holder.

*signifies non-member of ASH