ALL-269 Safety and Pharmacokinetics of Calaspargase Pegol in Adults With Newly Diagnosed Philadelphia-Negative Acute Lymphoblastic Leukemia: A Phase 2/3 Study

Context: Asparaginase remains an important component in many adult regimens for acute lymphoblastic leukemia (ALL). In pediatric patients (<21 years), calaspargase pegol (Cal-PEG) provides sustained asparagine depletion as compared to pegaspargase, with similar rates of complete remission (CR), minimal residual disease (MRD), event-free survival (EFS), and overall survival (OS), with a similar safety profile. Objective: To confirm the recommended dose of Cal-PEG in adults (age ≥22 years) and to establish safety and PK/PD analysis. Design: Multicenter, phase 2/3 study (NCT04817761) assessing safety and anti-leukemic activity of Cal-PEG. Part 1 enrollment commenced in Q3 2021 and will establish the safety of Cal-PEG in four groups: patients aged 22-39, 40-54, and ≥55, and patients with an elevated BMI >35 kg/m². A minimum of 4 (initial cohort) and ~8 patients will be enrolled per group. The study will be conducted in ≤25 investigational centers in the US. Part 2 will comprise expansion cohorts after verifying safety and PK/PD analysis. Patients: Newly diagnosed patients with Philadelphia-negative B- or T-cell ALL ≥22 years with ECOG performance status 0-2, no known history of pancreatitis, coagulopathy, CNS thrombosis, or severe hepatic impairment. Approximately 114-122 patients are expected to be enrolled in the study, including 16-32 patients in Part 1. Interventions: Starting doses of Cal-PEG will be based on the patients' age and BMI, with older patient groups assigned to lower doses. Patients aged≥22-39 and 40-<55 will receive Cal-PEG 2000 and 1500 U/m^2, respectively. Patients with BMI >35 kg/m² and those aged ≥55 will receive 1000 U/m². A total of 6 Cal-PEG doses will be administered during the treatment period as part of a multiagent chemotherapy regimen based on CALGB 10403, with an end-of-treatment visit 1 year after the induction dose, and an additional 2 years of survival follow-up. Main Outcome Measures: The primary endpoints in part 1 are the safety of Cal-PEG, the incidence of pre-defined unacceptable toxicities within 30 days after the induction dose and achieving plasma asparaginase activity ≥0.1 U/mL 21 days after the consolidation day 43 dose. Secondary endpoints include immunogenicity, CR, end-of-induction and consolidation MRD, 1-, 2- and 3-year EFS, disease-free survival, and OS.