Safety and Pharmacokinetics of Calaspargase Pegol in Adults with Newly Diagnosed Philadelphia-Negative ALL: A Phase 2/3 Study

• Published in: Blood 2021-11, Vol.138 (Supplement 1), p.4406-4406
• Main Authors: Stock, Wendy, Park, Jae H, Emadi, Ashkan, Abdul-Hay, Maher, Cassaday, Ryan D., Pullarkat, Vinod A., Webster, Jonathan, Pandya, Shuchi S., Mogul, Mark J, Shvenke, Yelena, Zhu, Jian J, Tessier, Adrien, DeAngelo, Daniel J.
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2021-149463

Background: Overall survival (OS) in adults with ALL remains around 40%, but treatment with asparaginase (ASP)-containing pediatric-inspired regimens demonstrated a 3- or 4-year OS of 67-76%, including in patients with T-cell ALL, with manageable toxicities (Geyer 2020, Stock 2019, DeAngelo 2015). Recent studies in adults with reduced pegaspargase (PEG-ASP) doses showed survival outcomes similar to those with standard doses, with reduced toxicities, including pancreatitis, hepatic and thromboembolic events (Derman 2020, Patel 2020). Calaspargase pegol (ASPARLAS; Cal-PEG), similar to PEG-ASP, is an E. coli L-asparaginase covalently conjugated to monomethoxy polyethylene glycol, but with a more chemically stable succinimidyl carbonate linker, providing sustained asparagine depletion with less frequent dosing (every 21 days). The efficacy and safety of Cal-PEG 2500 U/m 2, vs PEG-ASP 2500 U/m 2, was evaluated in 2 multicenter, randomized clinical trials (AALL07P4 [n=166] and DFCI 11-001 [n=239]) in newly diagnosed patients with ALL ≤21 years. Complete remission (CR), minimal residual disease (MRD), event-free survival (EFS), and OS were similar in both arms, with a 94% 5-year OS for Cal-PEG. The safety profile was consistent with that of PEG-ASP, with similar rates of hypersensitivity, pancreatitis, thrombosis, and hyperbilirubinemia (Vrooman 2021). Plasma asparaginase activity (PAA) levels were ≥0.1 U/mL 25 days after the induction dose in 95% of patients (Angiolillo 2014). The absence of a standardized treatment and the inadequate outcome of adult treatment regimens, as well as a lack of targeted immunotherapies for T-ALL, highlight a critical unmet need for improved therapeutic approaches. A treatment protocol with less frequent Cal-PEG administration due to a more sustained asparaginase activity as well as age- and weight-based dose adjustments may improve clinical outcomes without added toxicities, and possibly extend the upper age limit of ASP-containing regimen for older adults. Trial Design: We present a clinical trial design of an ongoing, multicenter, phase 2/3 study (NCT04817761) assessing the safety and anti-leukemic activity of Cal-PEG in newly diagnosed patients with Philadelphia-negative B- or T-cell ALL. Patients aged ≥22 years are eligible with ECOG performance status 0-2, no known history of pancreatitis, coagulopathy, CNS thrombosis or severe hepatic impairment. This trial comprises two parts: dose confirmation run-in (part 1) and the expans