Background: Pegaspargase is a pegylated formulation of E. coli asparaginase. It is an effective and well-established therapy combined with multi-agent chemotherapy to treat ALL. Clinical development was conducted exclusively on the liquid formulation (LIQ). A lyophilized formulation (LYO) was then created to improve the stability (shelf life 36 vs. 8 months for LYO vs LIQ, respectively) and ensure continuous drug availability.
Aims: The primary study objective was to compare the pharmacokinetics (PK) of both formulations after a single dose administered in newly diagnosed untreated pediatric patients (1–17 years old) with ALL. Secondary objectives included safety, plasma asparaginase activity (PAA), and immunogenicity of both formulations. This abstract focuses on the PK and safety profile.
Methods: Each patient was randomly assigned (1:1) to receive one IV injection of LYO or LIQ pegaspargase over 1 hour at the dose of 2500 U/m². Assuming a coefficient of variation of 0.30 and a geometric mean ratio (GMR) of 100%, a sample size of 78 evaluable subjects was needed to provide 90% power to establish the PK comparability. The study lasted approximately 1.5 months for each participant (14-day screening + 30-day induction treatment). Eleven PK samples (pre-dose, at the end of infusion, and after infusion from day 3 to day 28) and four PAA samples (from day 10 to day 28) were collected. All adverse events were collected and graded according to CTCAE v5.0.
The PK parameters area under the concentration-time curve (AUC) and maximum observed plasma asparaginase activity (Cmax) were derived using non-compartmental analysis (NCA) approach based on observed PAA time profiles.
Descriptive statistical analyses were performed to assess the study endpoints. An analysis of variance (ANOVA) was performed on log-transformed PK parameters (AUC, Cmax). The GMR of each parameter between LYO and LIQ groups and the corresponding 90% confidence interval (CI) were calculated.
PK comparability was concluded if the 90% CI for AUC and Cmax GMR were within the predefined acceptance interval [80%,125%].
Results: 89 patients were included (LYO:44; LIQ:45) with similar baseline characteristics. The results showed no difference in PAA peak (Cmax) and total (AUCinf) exposures and a numerical increase in partial exposure (AUC0-tlast) after administration of LYO compared with LIQ. The GMR was 93.5% for Cmax and 102.8% for AUCinf with corresponding 90% CI (82.9%,105.5%) and (91.4%,115.6%), completely contained within the [80%,125%] interval. The GMR was 115.9% for AUC0-tlast with corresponding 90% CI (90.2%,148.9%), partially contained within the acceptance interval. This increase is not expected to impact efficacy or safety of the drug product.
The most frequent reported TEAEs (≥70% of patients) were blood fibrinogen decreased and antithrombin III decreased. Three deaths were reported with none considered as related to study drug. Overall, 42% patients experienced serious TEAEs with comparable frequencies in each group. Eight patients in the LYO group and 4 patients in the LIQ group experienced serious TEAEs related to pegaspargase, most of them related to gastrointestinal disorders. No clinically meaningful difference was observed in terms of safety and immunogenicity.
Summary/Conclusion: In summary, the results support the conclusion that the PK exposure of pegaspargase after IV administration at the dose of 2,500 U/m2 does not depend on the drug formulation. Pharmacokinetics and safety results of this study are consistent with previously observed pegaspargase data.
Keywords: Pediatric, Pharmacokinetic, Acute lymphoblastic leukemia