A phase II/III study of JZP-458 in patients with acute lymphoblastic leukemia/lymphoblastic lymphoma who are hypersensitive to E. coli-derived asparaginases was announced at the 2020 ASCO Virtual Scientific Program.
A phase II/III study of JZP-458 in patients with acute lymphoblastic leukemia (ALL)/lymphoblastic lymphoma (LBL) who are hypersensitive to E. coli-derived asparaginases was announced at the 2020 American Society of Clinical Oncology (ASCO) Virtual Scientific Program.
The pivotal, open-label, multicenter, dose confirmation, and pharmacokinetic (PK) study (NCT04145531) is enrolling those who have ≥1 course of asparaginase remaining in their treatment plan. Thereafter, 6 doses of JZP-458 will be substituted for each remaining course. Treatment duration will depend on the number of asparaginase courses remaining in the treatment plan.
“The inability to receive asparaginase second to hypersensitivity has been associated with poor patient outcomes,” Luke Maese, DO, assistant professor at the University of Utah School of Medicine in the Division of Pediatric Hematology/Oncology, said in a presentation of the study. “Alternative asparaginase preparations are needed to ensure that patients who develop hypersensitive reactions are able to complete their full treatment course.”
The study consists of 2 sequential parts, with part A determining the dose of intramuscular (IM) JZP-458 and confirming safety and efficacy and part B exploring the appropriate dose and dosing schedule of intravenous (IV) JZP-458. Moreover, blood samples will be collected to determine SAA levels and patients will be monitored for adverse events. Immunogenicity of JZP-458 will also be evaluated.
Primary objectives for the study are to determine the efficacy of IM JZP-458 measured by the last 72-hour nadir SAA (NSAA) level (≥0.1 IU/mL) during the first treatment course, and the safety and tolerability of IM JZP-458.
Secondary objectives are to determine the efficacy (measured by the last 48-hour NSAA level [≥0.1 IU/mL] and the last 48- and 72-hour NSAA levels [≥0.4 IU/mL]), PK, and immunogenicity of IM JZP-458. Exploratory objectives include efficacy, safety, PK, and immunogenicity of IV JZP-458.
Additional eligibility criteria for the study include pediatric and adult patients with ALL/LBL (excluding relapsed ALL/LBL), full recovery from prior allergic reaction to long-acting E. coli-derived asparaginase or silent activation with undetectable SAA levels (≤0.02 IU/mL) (except for patients receiving < 10% E. coli-derived asparaginase IV before the reaction), adequate liver function, and no prior exposure to asparaginase Erwinia chrysanthemi or JZP-458.
“Safety and efficacy will be continuously reviewed throughout the trial by a study data review committee,” said Maese. “The study is active and currently enrolling patients.”
In a phase I study of healthy adult volunteers, JZP-458 treatment was found to maintain adequate (≥0.1 IU/mL) serum asparaginase activity, a surrogate marker for asparagine depletion, for up to 72 hours with an adequate safety profile.
Native L-asparaginases are immunogenic and can induce hypersensitivity reactions with neutralizing antibody titers that have the potential to limit their therapeutic effect. Even further, modifications to L-asparaginases can also be immunogenic (e.g. PEGlyation). Reportedly, hypersensitivity reactions occur in up to 30% of patients.
Maese L, Rau RE, Raetz EA, et al. A phase II/III study of JZP-458 in patients with acute lymphoblastic leukemia (ALL)/lymphoblastic lymphoma (LBL) who are hypersensitive to E. coli-derived asparaginases. Presented at: 2020 ASCO Virtual Scientific Meeting. Abstract #TPS7568.