August 24, 2016
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Erwinaze

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Erwinaze




CLINICAL PHARMACOLOGY

Mechanism Of Action

Asparaginase Erwinia chrysanthemi catalyzes the deamidation of asparagine to aspartic acid and ammonia, resulting in a reduction in circulating levels of asparagine. The mechanism of action of ERWINAZE is thought to be based on the inability of leukemic cells to synthesize asparagine due to lack of asparagine synthetase activity, resulting in cytotoxicity specific for leukemic cells that depend on an exogenous credit of amino acid asparagine for their protein metabolism and survival.

Pharmacokinetics

Based on a population PK model, the mean (%CV) half-life of intravenous ERWINAZE was 7.51 (23.9%) hours in contrast to a mean (%CV) half-life of 15.6 (20%) hours reported for intramuscular ERWINAZE. These differences in PK between intravenous and intramuscular ERWINAZE are reflected in the proportion of patients with 2-day and 3-day nadir serum asparaginase activity (NSAA) levels of asparaginase Erwinia chrysanthemi ≥ 0.1 or 0.4 IU/mL [see Clinical Studies].

Following administration of ERWINAZE 25,000 International Units/m² intramuscularly to 48 ALL patients aged ≥ 2 years to ≤ 18 years in Study 1 on a Monday, Wednesday, and Friday schedule for 6 doses, 100% of patients who completed Course 1 achieved NSAA levels ≥ 0.1 International Units/mL at either 48 hours (n=35) or 72 hours (n=13) post dose 3. Eighty percent (28/35) of those evaluated at 48 hours and 38% (5/13) evaluated at 72 hours had nadir serum asparaginase activity levels > 0.4 International Units/mL [see Clinical Studies].

Following intravenous administration of ERWINAZE 25,000 International Units/m² to 24 evaluable patients (aged ≥ 1 year to ≤ 17 years) in Study 2 on a Monday, Wednesday, and Friday schedule, 83% (20/24) and 43% (9/21) of patients who completed Course 1 achieved NSAA levels ≥ 0.1 International Units/mL at 48 hours post-dose 5 and 72 hours post dose 6, respectively. Twenty-nine percent (7/24) of those evaluated at 48 hours and no patients (0/21) evaluated at 72 hours had nadir serum asparaginase activity levels > 0.4 International Units/mL [see Clinical Studies].

Clinical Studies

The safety and efficacy of ERWINAZE was established in Study 1, a single-arm, multi-center, open-label, safety and clinical pharmacology trial. Additional safety data were obtained in the ERWINAZE Master Treatment Protocol (EMTP), an expanded access program [see ADVERSE REACTIONS]. Study 1 enrolled patients treated on National Cancer Institute (NCI)-sponsored cooperative group ALL protocols who were unable to continue to receive pegaspargase due to hypersensitivity reactions. The main outcome measure was determination of the proportion of patients who achieved a serum trough asparaginase level greater than or equal to 0.1 International Units/ mL. Serum trough asparaginase activity ≥ 0.1 International Units/ mL has been demonstrated to correlate with asparagine depletion (asparagine < 0.4 mcg/mL or 3 μM) and to serum levels that predict clinical efficacy. Patients received ERWINAZE 25,000 International Units/m² intramuscularly for two weeks (total 6 doses) as a replacement for each scheduled dose of pegaspargase remaining on their original treatment protocol.

Fifty-eight patients were enrolled in Study 1, of these 48 were evaluable for the main outcome measure based on availability of pharmacokinetic samples in Course 1. The median age was 11 years (2 to 18 years); 59% were male, 78% were White, 10% were Black/African American, 5% were Asian, and 7% were other or unknown. A total of 35% were Hispanic or Latino.

Study 1 met its main outcome measure of demonstrating that greater than 50% of the patients achieved the prespecified trough asparaginase activity level of ≥ 0.1 International Units/ mL at 48 or 72 hours following the third dose. Results for the main outcome measure and for an exploratory analysis using a higher cut-off (trough serum asparaginase activity levels ≥ 0.4 International Units/mL are presented in Table 3 [see CLINICAL PHARMACOLOGY].

The safety and efficacy of intravenous administration were determined in Study 2 by characterizing the PK of a 25,000 International Units/m² ERWINAZE dose given 3 days per week on a Monday, Wednesday, and Friday schedule for up to 30 weeks. This open-label, single-arm, multicenter PK study enrolled 30 patients. The main outcome measure was determination of the proportion of patients with 2-day NSAA levels (48-hour levels taken after the fifth dose) ≥ 0.1 International Units/mL in the first 2 weeks of ERWINAZE treatment.

Of the thirty patients enrolled, 24 were evaluable for the main outcome measure based on the pharmacokinetic samples in Course 1. The median age was 7 years (1-17 years), 63% were male, 27% were Hispanic or Latino, 83% were White, 3% were Black/African American, 7% were Asian, and 7% were other (American Indian, Alaska Native, or Indian).

In Study 2, serum asparaginase activity of asparaginase Erwinia chrysanthemi was determined in 24 evaluable patients (aged ≥ 1 year to ≤ 17 years) following intravenous administration of ERWINAZE 25,000 International Units/m². Five minutes after the 60-minute infusion in Course 1, the mean asparaginase activity level was 12.65 ± 3.16 International Units/mL post-dose 1 and 12.11 ± 3.11 International Units/mL post dose 4. The main study objective was met with an asparaginase activity level of ≥ 0.1 International Units/mL 48 hours after the fifth dose observed in 83% of patients. The 72-hour post dose 6 asparaginase activity level of ≥ 0.1 International Units/mL was the secondary endpoint, with 43% of patients achieving this endpoint. Results are presented in Table 3 [see CLINICAL PHARMACOLOGY].

Table 3: Proportion of Patients with Sustained Asparaginase Activity in Study 1 (IM) and Study 2 (IV)

Trough sampling time Proportion (n/N) and 95% CI with asparaginase activity ≥ 0.1 International Units/mL Proportion (n/N) and 95% CI with asparaginase activity ≥ 0.4 International Units/mL
Study 1 (IM)a Study 2 (IV) b Study 1 (IM)a Study 2 (IV)b
48-hour 100% (35/35) [90 , 100] 83% (20/24) [63 , 95] 80% (28/35) [64 , 90] 29% (7/24) [13 , 51]
72-hour 100% (13/13) [77 , 100] 43% (9/21) [22 , 66] 38% (5/13) [18 , 65] 0% (0/21) [0 , 16]
a Trough sampling time is post-dose 3 at 48 and 72
b Trough sampling time is post-dose 5 at 48 hours and post-dose 6 for 72 hours

Last reviewed on RxList: 5/13/2016
This monograph has been modified to include the generic and brand name in many instances.

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