Open-Label, Multicenter, Phase 2/3 Study of Recombinant Crisantaspase Produced in Pseudomonas Fluorescens (RC-P) in Patients with Acute Lymphoblastic Leukemia (ALL) or Lymphoblastic Lymphoma (LBL) Following Hypersensitivity to Escherichia coli-Derived Asparaginases

Background: L-asparaginase, an important component of ALL therapy, hydrolyzes the nonessential amino acid asparagine, depleting plasma levels and selectively killing leukemic lymphoblasts that are asparagine autotrophs. L-asparaginases are immunogenic and can induce hypersensitivity reactions; high neutralizing antibody titers may limit their therapeutic effect. The inability to receive asparaginase secondary to hypersensitivity has prognostic implications for patients with ALL and has been associated with significantly worse outcomes (Silverman LB, et al. Blood 2001;97:1211-1218; Gupta S, et al. J Clin Oncol. 2019;37[suppl]: Abstract 10005). Alternative preparations are needed to ensure that all patients unable to receive E. coli-derived asparaginase due to hypersensitivity are able to receive adequate treatment. RC-P is a recombinant crisantaspase. Due to the use of a novel Pseudomonas fluorescens technology expression platform, RC-P has no immunologic cross-reactivity to E. coli-derived asparaginases. In a study of RC-P administration in healthy adults (JZP458-101), the enzyme was well tolerated and maintained adequate (≥0.1 IU/mL) serum asparaginase activity (SAA), a surrogate marker for asparagine depletion, for up to 72 hours.

Study Design and Methods: This is an open-label, multicenter, dose confirmation and pharmacokinetic (PK) study (JZP458-201) of RC-P in patients with ALL or LBL who develop allergic reactions to an E. coli-derived asparaginase and have ≥1 dose of E. coli-derived asparaginase remaining in their treatment plan (Table). For these patients, 6 doses of RC-P will be substituted for each dose of long-acting E. coli-derived asparaginase. Individual patient treatment duration will vary depending on the number of E. coli-derived asparaginase doses that remain in the patient's original treatment plan.

The study will consist of 2 sequential parts: Part A will determine the dose of RC-P for intramuscular (IM) administration and confirm safety and efficacy; Part B will define the optimal dose and schedule of intravenous (IV) RC-P. Blood samples will be collected at prespecified time points to determine SAA levels, and patients will be monitored for adverse events. Immunogenicity of RC-P treatment will also be assessed.

The primary objectives are to (1) determine the efficacy of IM RC-P administration measured by the last 72-hour nadir SAA (NSAA) level being ≥0.1 IU/mL during the first course of treatment, and (2) assess the safety and tolerability of IM RC-P in patients with ALL/LBL who are hypersensitive to E. coli-derived asparaginases. Secondary objectives include determination of the efficacy of IM RC-P measured by the last 48-hour and last 72-hour NSAA levels being ≥0.4 IU/mL during the first course, characterization of PK of IM RC-P using a population PK approach, and assessment of immunogenicity following repeat administration of RC-P. Exploratory objectives include determination of the efficacy, safety, PK, and immunogenicity of IV RC-P.

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