FDA Approves Longer-Acting Calaspargase Pegol-mknl for ALL

The FDA has approved a longer-acting version of calaspargase pegol-mknl (Asparlas) 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 new 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.

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/m² intravenously (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.

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/m² of 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/m² IV 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.