"The U.S. Food and Drug Administration today approved Erwinaze (asparaginase Erwinia chrysanthemi) to treat patients with acute lymphoblastic leukemia (ALL), who have developed an allergy (hypersensitivity) to E. coli derived asparaginase and pega"...
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Mechanism of Action
The mechanism of action of Oncaspar® (pegaspargase) is thought to be based on selective killing of leukemic cells due to depletion of plasma asparagine. Some leukemic cells are unable to synthesize asparagine due to a lack of asparagine synthetase and are dependent on an exogenous source of asparagine for survival. Depletion of asparagine, which results from treatment with the enzyme L-asparaginase, kills the leukemic cells. Normal cells, however, are less affected by the depletion due to their ability to synthesize asparagine.
In Study 1, pharmacodynamics were assessed in 57 newly diagnosed pediatric patients with standard-risk ALL who received three IM doses of Oncaspar® (pegaspargase) (2,500 IU/m2), one each during induction and two delayed intensification treatment phases. Pharmacodynamic activity was assessed through serial measurements of asparagine in sera (n=57) and cerebrospinal fluid (CSF) (n=50). The data for asparagine depletion are presented in CLINICAL STUDIES [see Clinical Studies].
Pharmacokinetic assessments were based on an enzymatic assay measuring asparaginase activity. Serum pharmacokinetics were assessed in 34 newly diagnosed pediatric patients with standard-risk ALL in Study 1 following IM administration of 2,500 IU/m2. The elimination half-life of Oncaspar® (pegaspargase) was approximately 5.8 days during the induction phase. Similar elimination half-lives were observed during Delayed Intensification 1 and Delayed Intensification 2. Concentrations greater than 0.1 IU/mL were observed in over 90% of the samples from patients treated with Oncaspar® (pegaspargase) during induction, Delayed Intensification 1, and Delayed Intensification 2 for approximately 20 days.
In 3 pharmacokinetic studies, 37 patients with relapsed ALL received Oncaspar® (pegaspargase) at 2,500 IU/m2 IM every 2 weeks. The plasma half-life of Oncaspar® (pegaspargase) was 3.2 ±1.8 days in 9 patients who were previously hypersensitive to native E coli L-asparaginase and 5.7 ± 3.2 days in 28 non-hypersensitive patients. The area under the plasma concentration-time curve (AUC) was 9.5 ± 4.0 lU/mL/day in the previously hypersensitive patients and 9.8 ± 6.0 lU/mL/day in the non-hypersensitive patients.
The safety and effectiveness of Oncaspar® (pegaspargase) was evaluated in an open-label, multicenter, randomized, active-controlled study (Study 1). In this study. 118 pediatric patients aged 1 to 9 years with previously untreated standard-risk ALL were randomized 1:1 to Oncaspar® (pegaspargase) or native E coli L-asparaginase as part of combination therapy. Oncaspar® (pegaspargase) was administered IM at a dose of 2,500 IU/m2 on Day 3 of the 4-week induction phase and on Day 3 of each of two 8-week delayed intensification phases. Native E coli L-asparaginase was administered IM at a dose of 6,000 IU/m2 three times weekly for 9 doses during induction and for 6 doses during each delayed intensification phase.
The primary determination of effectiveness was based on demonstration of similar asparagine depletion (magnitude and duration) in the Oncaspar® (pegaspargase) and native E coli L-asparaginase arms. The protocol-specified goal was achievement of asparagine depletion to a serum concentration of ≤ 1 µM. The proportion of patients with this level of depletion was similar between the 2 study arms during all 3 phases of treatment at the protocol-specified time points.
In all phases of treatment, serum asparagine concentrations decreased within 4 days of the first dose of asparaginase in the treatment phase and remained low for approximately 3 weeks for both Oncaspar® (pegaspargase) and native E coli L-asparaginase arms. Serum asparagine concentrations during the induction phase are shown in Figure 1. The patterns of serum asparagine depletion in the 2 delayed intensification phases are similar to the pattern of serum asparagine depletion in the induction phase.
FIGURE 1: MEAN (± STANDARD ERROR) SERUM ASPARAGINE
CONCENTRATIONS DURING STUDY 1 INDUCTION PHASE
Note: Oncaspar® (pegaspargase) (2,500 IU/m2 IM) was administered on Day 3 of the 4-week induction phase. Native E coli L-asparaginase (6,000 IU/m2 IM) was administered 3 times weekly for 9 doses during induction.
CSF asparagine concentrations were determined in 50 patients during the induction phase. CSF asparagine decreased from a mean pretreatment concentration of 3.1 µM to 1.7 µM on Day 4 ± 1 and 1.5 µM 25 ± 1 days after administration of Oncaspar® (pegaspargase) . These findings were similar to those observed in the native E coli L-asparaginase treatment arm.
While the 3-year Event-Free Survival (EFS) for the Oncaspar® (pegaspargase) and native E coli L-asparaginase study arms were similar and in the range of 80%. Study 1 was not designed to evaluate for differences in EFS rates.
ALL Patients Hypersensitive to Asparaginase
The safety and effectiveness of Oncaspar® (pegaspargase) was evaluated in 4 open-label studies enrolling a total of 42 patients with multiply-relapsed, acute leukemia [39 (93%) with ALL] with a history of prior clinical allergic reaction to asparaginase. Hypersensitivity to asparaginase was defined by a history of systemic rash. urticaria, bronchospasm, laryngeal edema, hypotension, or local erythema: urticaria, or swelling, greater than 2 centimeters, for at least 10 minutes following administration of any form of native E coli L-asparaginase. All patients received Oncaspar® (pegaspargase) at a dose of 2,000 or 2,500 IU/m2 administered IM or IV every 14 days. Patients received Oncaspar® (pegaspargase) as a single agent or in combination with multi-agent chemotherapy. The re-induction response rate was 50% (95% confidence interval: 35%, 65%), based upon 36% complete remissions and 14% partial remissions. These results were similar to the overall response rates reported for patients with ALL receiving second-line, native E coli L-asparaginase-containing re-induction chemotherapy. Anti-tumor activity was also observed with single-agent Oncaspar® (pegaspargase) . Three responses (1 complete remission and 2 partial remissions) were observed in 9 adult and pediatric patients with relapsed ALL and hypersensitivity to native E coli L-asparaginase.
Last reviewed on RxList: 3/2/2009
This monograph has been modified to include the generic and brand name in many instances.
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