Preliminary results of an open-label, single-arm phase 2/3 trial (SPARK-ALL) of calaspargase pegol in adults with newly diagnosed Philadelphia chromosome–negative acute lymphoblastic leukemia.

6529 Background: Asparaginase is an important component of many regimens for acute lymphoblastic leukemia (ALL). In patients (pts) <21 years, calaspargase pegol (Cal-PEG) provides more sustained asparagine depletion than pegaspargase. SPARK-ALL is a multicenter phase 2/3 study (NCT04817761) assessing the safety and anti-leukemic activity of Cal-PEG in pts aged ≥22 years with newly diagnosed Philadelphia chromosome-negative (Ph−) ALL. Methods: Part 1 was a dose-finding study in pts with a body mass index (BMI) ≤35 kg/m 2 aged 22–39 and 40–54 years (Cal-PEG 2000 and 1500 U/m 2 , respectively) and pts with BMI >35 kg/m 2 or aged ≥55 years (Cal-PEG 1000 U/m 2 ). Part 2 was a dose-expansion study in pts with BMI ≤35 kg/m 2 aged 22–39 years (Cal-PEG 1750 U/m 2 ) or 40–54 years (Cal-PEG 1500 U/m 2 ). Six Cal-PEG IV infusions were given as part of a multiagent chemotherapy regimen based on CALGB 10403 (Stock W, et al. Blood 2019;133(14):1548–1559). The primary objectives are assessment of safety in all pts, and anti-leukemic activity using the surrogate marker of nadir plasma asparaginase activity (NPAA) ≥0.1 U/mL 21 days after the D43 consolidation dose in all evaluable pts who were treated at the recommended dose (primary NPAA [PNPAA]) analysis set). Results: A total of 42 pts received Cal-PEG treatment: 26 and 16 in parts 1 and 2, respectively. Overall, 31 (73.8%) and 16 (38.1%) pts experienced grade 3/4 treatment-related adverse events (TRAEs) and serious TRAEs, respectively. Overall, 15 pts (35.7%) had TRAEs leading to study drug discontinuation, including hypersensitivity-type events in 6 pts (14.3%); 4 (9.5%) had nervous system events, including cerebral venous sinus thrombosis in 2 pts (4.8%). Three pts (7.1%) had a grade 3 pulmonary embolism, which, per protocol, required study drug discontinuation. The most common grade 3/4 TRAEs included hypertriglyceridemia (9 pts; 21.4%), alanine aminotransferase increase (7 pts; 16.7%), and blood fibrinogen decrease (5 pts; 11.9%). In part 1, intolerable toxicities considered related to Cal-PEG were experienced by 2/8 pts who were older and 2/8 pts with a BMI >35 kg/m 2 ; 1 (11.1%) pt aged between 22–39 years experienced an event of hypersensitivity. One Cal-PEG-related death was reported as likely related to complications from embolic stroke in a pt aged 71 years with comorbidities. Dose expansion was pursued in the first two cohorts. At 21 days after the D43 post-consolidation dose, all pts in the PNPAA set had NPAA values above the 0.1 U/mL efficacy threshold. Conclusions: Cal-PEG has a safety profile consistent with asparaginase class toxicity and, as part of multidrug chemotherapy regimen, provides sustained asparagine depletion in newly diagnosed Ph− ALL pts aged ≥22 years. In light of the observed high-grade TRAEs, future studies will evaluate different Cal-PEG doses for this pt population. Clinical trial information: NCT04817761 .