Longer-Acting Calaspargase Pegol-mknl Receives FDA Approval in ALL

A longer-acting version of calaspargase pegol-mknl (Asparlas) has been approved by the FDA as a component of a multiagent chemotherapy regimen for pediatric and young adult patients aged 1 month to 21 years with acute lymphoblastic leukemia (ALL).

The approval was based on data sets demonstrating the achievement and maintenance of nadir serum asparaginase activity (NSAA) above the level of 0.1 U/mL when using calaspargase pegol-mknl at 2500 mg U/m²intravenously (IV) every 3 weeks. Additionally, the pharmacokinetics of calaspargase pegol-mknl were investigated in combination with multiagent chemotherapy in 124 patients with B-cell lineage ALL.

Among these patients, for which the median age was 11.5 years (range 1-26), results showed that 99% of these patients (n = 123) maintained NSAA >0.1 U/mL at weeks 6, 12, 18, 24 and 30 of treatment.

The product is designed to provide a longer interval between doses compared with other available pegaspargase products. Calaspargase pegol-mknl contains an asparagine specific enzyme derived from Escherichia coli, as a conjugate of L-asparaginase and monomethoxypolyethylene glycol (mPEG), along with a succinimidyl carbonate (SC) linker. The SC linker is a chemically stable carbamate bond between the mPEG moiety and the lysine groups of L-asparaginase.

The enzyme L-asparaginase catalyzes the conversion of the amino acid L-asparagine into aspartic acid and ammonia. Calaspargase pegol-mknl is thought to initiate selective killing of leukemic cells due to depletion of plasma L-asparagine. As leukemic cells with low expression of asparagine synthetase have a reduced ability to synthesize L-asparagine, they rely on an exogenous source of L-asparagine for survival.

Investigators evaluated the safety of calaspargase pegol-mknl in the open-label, active-controlled, multicenter, randomized Study DFCI 11-001 trial, which treated 237 patients with newly diagnosed ALL or lymphoblastic lymphoma with calaspargase pegol-mknl at 2500 U/m²(n = 118) or pegaspargase at 2500 U/m²(n = 119), as part of a Dana-Farber Cancer Institute ALL Consortium backbone therapy.

On this study, the median age was 5 years (range, 1-20), and 62% of patients were male and 70% were Caucasian. Additionally, 59% of patients had standard-risk disease and 87% had B-cell lineage ALL.

A median 11 doses of calaspargase pegol-mknl was administered, which patients received every 3 weeks, and 16 doses of pegaspargase, which was given every 2 weeks. Median duration of treatment exposure was 8 months in both arms.

In the subgroup of patients with B-cell lineage ALL, the complete remission rate in the calaspargase pegol-mknl arm was 98% compared with 99% in the pegaspargase arm. Additionally, the Kaplan-Meier overall survival estimates were comparable between arms.

Regarding safety, results showed that the most common grade ≥3 adverse events (AEs) were elevated transaminase, increase bilirubin, pancreatitis, and abnormal clotting studies. In a randomized study, the safety profile when calaspargase pegol-mknl was administered every 3 weeks was similar to every-2-weeks of pegaspargase. There was 1 fatal AE, which was from multiorgan failure from chronic pancreatitis associated with a pancreatic pseudocyst. Grade 1/2 AEs were not all collected prospectively.

The open-label, active-controlled, multicenter, randomized Study AALL07P4 trial also evaluated the safety of calaspargase pegol-mknl. The study randomized patients with newly diagnosed, high-risk, B-precursor ALL of calaspargase pegol-mknl at 2500 mg U/m²(n = 43) or 2100 U/m²of pegaspargase at 2500 U/m²(n = 52) as a component of an augmented Berlin-Frankfurt-Münster treatment regimen. In this trial, the median age was 11 years (range, 1-26), and the median duration of treatment was 7 months in both arms. Induction mortality occurred in 2.8% of patients on the calaspargase pegol-mknl arm; there were 0 induction deaths on the pegaspargase arm.

The FDA recommended the dosage of calaspargase pegol-mknl at 2500 units/m²IV at a minimum dosing interval of every 21 days. Patients should be monitored weekly with bilirubin, transaminases, glucose, and clinical exams until recovery from the treatment cycle.

The calaspargase pegol-mknl injection is given as a clear, colorless, preservative-free, and isotonic sterile solution in phosphate-buffered saline, at a pH 7.3 level that requires dilution prior to IV infusion.

In February 2018, the FDA accepted a supplemental biologics license application for calaspargase pegol-mknl for this indication by Shire, the manufacturer of the compound.

References

1. FDA approves longer-acting calaspargase pegol-mknl for ALL. FDA. Published December 20, 2018. https://bit.ly/2CsBEcU?rel=0" . Accessed December 20, 2018.
2. Calaspargase pegol-mknl prescribing information. FDA. https://bit.ly/2LtevtC?rel=0" . Accessed December 20, 2018.