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Oncaspar (Pegaspargase) - Description and Clinical Pharmacology

 
 



DESCRIPTION

ONCASPAR®, the ENZON trademark for pegaspargase, is a modified version of the enzyme L-asparaginase. It is an oncolytic agent used in combination chemotherapy for the treatment of patients with acute lymphoblastic leukemia who are hypersensitive to native forms of L-asparaginase (as described in CLINICAL PHARMACOLOGY).

The generic name of ONCASPAR® is pegaspargase. The chemical name is monomethoxypolyethylene glycol succinimidyl L-asparaginase. L-asparaginase is modified by covalently conjugating units of monomethoxypolyethylene glycol (PEG), molecular weight of 5,000, to the enzyme, form-ing the active ingredient PEG-L-asparaginase. The L-asparaginase (L-asparagine amidohydrolase, type EC-2, EC 3.5.1.1) used in the manufacture of ONCASPAR® is derived from Escherichia coli. ENZON purchases the enzyme L-asparaginase in bulk from Merck, Sharp and Dohme, Division of Merck & Co., Inc., West Point, PA 19486, U.S. License Number 2, Merck & Co., Inc. supplies bulk L-asparaginase as a licensed intermediate for further manufacture by ENZON into PEG-L-asparaginase. Merck & Co., Inc. can only assume responsibility for the bulk intermediate supplied to ENZON.

ONCASPAR® is supplied as an isotonic sterile solution in phosphate buffered saline, pH 7.3, for intramuscular administration only. The solution is clear, colorless and contains no preservatives. It is supplied in 5 mL single-dose vials.

ONCASPAR® activity is expressed in International Units (IU) according to the recommendation of the International Union of Biochemistry. One IU of L-asparaginase is defined as that amount of enzyme required to generate 1 µ mol of ammonia per minute at pH 7.3 and 37°C.

Each milliliter of ONCASPAR® contains:

PEG-L-asparaginase................................... 750 IU ± 20 %

Monobasic sodium phosphate, USP............. 1.20 mg ± 5 %

Dibasic sodium phosphate, USP.................. 5.58 mg ± 5 %

Sodium chloride, USP................................. 8.50 mg ± 5 %

Water for injection, USP............................. qs to 1.0 mL

The specific activity of ONCASPAR® is at least 85 IU per milligram protein.

CLINICAL PHARMACOLOGY

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. Rapid depletion of asparagine which results from treatment with the enzyme L-asparagine, kills the leukemic cells. Normal cells, however, are less affected by the rapid depletion due to their ability to synthesize asparagine. This is an approach to therapy based on a specific metabolic defect in some leukemic cells which do not produce asparagine synthetase.1

In a study in predominately L-asparaginase naive adult patients with leukemia and lymphoma, initial plasma levels of L-asparaginase following intravenous administration were determined. Plasma half-life did not appear to be influenced by dose levels, and it could not be correlated with age, sex, surface area, renal or hepatic function, diagnosis or extent of disease. Apparent volume of distribution was equal to estimated plasma volume. L-asparaginase was measurable for at least 15 days following the initial treatment with ONCASPAR®. The enzyme could not be detected in the urine.2

In a study of newly diagnosed pediatric patients with acute lymphoblastic leukemia (ALL) who received either a single intramuscular injection of ONCASPAR® (2,500 IU/m2), E. coli L-asparaginase (25,000 IU/m2), or Erwinia (25,000 IU/m2), the plasma half-lives for the three forms of L-asparaginase were: 3

PLASMA HALF-LIVES OF THREE FORMS OF L-ASPARAGINASE
TREATMENT GROUP NO. OF
PATIENTS
MEAN
(DAYS)
STANDARD
DEVIATION
ONCASPAR® 10 5.73 3.24
E. coli L-asparaginase 17 1.24 0.17
Erwinia L-asparaginase 10 0.65 0.13

In this same study of newly diagnosed pediatric ALL patients, the in vivo early leukemic cell kill after a single intramuscular injection of native E. coli L-asparaginase (25,000 IU/m2), Erwinia L-asparaginase (25,000 IU/m2), and ONCASPAR® (2,500 IU/m2) during a five day "investigational window" was studied. 4 Bone marrow aspirates were taken before and five days after a single dose of one of the three different forms of L-asparaginase. Rhodamine-123 (RH-123), a selectively incorporated fluorescent mitochondrial dye, was used in an in vitro assay on the bone marrow aspirates to ascertain cell viability. The percent reduction of viable lymphoblasts at day five for each group is presented in the following table:4

RHODAMINE-123 (IN VIVO CELL KILL)
TREATMENT GROUP NO. OF
PATIENTS
PERCENT REDUCTION
OF VIABLE
LYMPHOBLASTS
AT DAY 5
MEAN ± S.D.
ONCASPAR® 21 55.7 ± 10.2
E. coli L-asparaginase 28 57.8 ± 10.1
Erwinia L-asparaginase 19 57.9 ± 13.8

In three pharmacokinetic studies, 37 relapsed ALL patients received ONCASPAR® at 2,500 IU/m2 every two weeks. The plasma half-life of ONCASPAR® was 3.24 ± 1.83 days in nine patients who were previously hypersensitive to native L-asparaginase and 5.69 ± 3.25 days in 28 non-hypersensitive patients. The area under the curve was 9.50 ± 3.95 IU/mL/day in the previously hypersensitive patients, and 9.83 ± 5.94 IU/mL/day in the non-hypersensitive patients.

HYPERSENSITIVITY REACTIONS

Hypersensitivity reactions to E. coli L-asparaginase have been reported in the literature in 3% to 73% of patients. 1 Patients in ONCASPAR® clinical studies were considered to be previously hypersensitive if they experienced a systemic rash, urticaria, bronchospasm, laryngeal edema, or hypotension following administration of any form of native L-asparaginase. Patients were also considered to be previously hypersensitive if they experienced local erythema, urticaria, or swelling, greater than two centimeters, for at least ten minutes following administration of any form of native L-asparaginase. The National Cancer Institute Common Toxicity Criteria (CTC) were used to classify the severity of the hypersensitivity reactions. These are: grade 1 -- transient rash (mild); grade 2 -- mild bronchospasm (moderate); grade 3 -- moderate bronchospasm and/or serum sickness (severe); grade 4 -- hypotension and/or anaphylaxis (life-threatening). Additionally, most transient local urticaria were considered grade 2 hypersensitivity reactions, while most sustained urticaria distant from the injection site were considered grade 3 hypersensitivity reactions. In general, the moderate to life-threatening hypersensitivity reactions were considered dose-limiting; that is, they required L-asparaginase treatment to be discontinued.

In separate studies, ONCASPAR® was administered intravenously to 48 patients and intramuscularly to 126 patients. The incidence of hypersensitivity reactions when ONCASPAR® was administered intramuscularly was 30% in patients who were previously hypersensitive to native L-asparaginase and 11% in non-hypersensitive patients (p-value of 0.007). The incidence of hypersensitivity reactions when ONCASPAR® was administered intravenously was 60% in patients who were previously hypersensitive to native L-asparaginase and 12% in non-hypersensitive patients. Since only five previously hypersensitive patients received ONCASPAR® intravenously, no meaningful analysis of the incidence of hypersensitivity reactions was possible between either the previously hypersensitive and non-hypersensitive patients, or between the intravenous and intramuscular routes of administration.

The overall incidence of hypersensitivity reactions in 174 patients who received ONCASPAR® in five clinical studies is shown in the table below:

INCIDENCE OF ONCASPAR® HYPERSENSITIVITY REACTIONS
PATIENT STATUS CTC GRADE OF
HYPERSENSITIVITY REACTION
N 1 2 3 4 TOTAL
Previously Hypersensitive
Patients
62 7 8 4 1 20 (32%)
Non-Hypersensitive
Patients
112 5 4 1 1 11 (10%)
Total Patients 174 12 12 5 2 31 (18%)

The probability of previously hypersensitive or non-hypersensitive patients completing 8 doses of ONCASPAR® therapy without developing a dose-limiting hypersensitivity reaction was 77% and 95%, respectively.

All of the 62 hypersensitive patients treated with ONCASPAR® in five clinical studies had previous hypersensitivity reactions to one or more of the native forms of L-asparaginase. Of the 35 patients who had previous hypersensitivity reactions to E. coli L-asparaginase only, 5 (14%) had ONCASPAR® dose-limiting hypersensitivity reactions. Of the 27 patients who had hypersensitivity reactions to both E. coli and Erwinia L-asparaginase, 7 (26%) had ONCASPAR® dose-limiting hypersensitivity reactions. The overall incidence of dose-limiting hypersensitivity reactions in 174 patients treated with ONCASPAR® was 9% (19% in 62 hypersensitive and 3% in 112 non-hypersensitive patients). Of the total of 9% dose-limiting hypersensitivity reactions, 1% were anaphylatic (CTC grade 4) and the other 8% were

CLINICAL ACTIVITY

ONCASPAR® was evaluated as part of combination therapy in four open label studies comprising 42 multiply-relapsed, previously hypersensitive acute leukemia patients [39 (93%) with ALL] at a dose of 2,000 or 2,500 IU/m2 administered intramuscularly or intravenously every 14 days during induction combination chemotherapy. The reinduction response rate was 50% (36% complete remissions and 14% partial remissions), with a 95% confidence interval of 35% to 65%. This response rate is comparable to that reported in the literature for relapsed patients treated with native L-asparaginase as part of combination chemotherapy.1

ONCASPAR® was also shown to have some activity as a single agent in multiply-relapsed hypersensitive ALL patients, the majority of whom were pediatric. Treatment with ONCASPAR® resulted in three responses (one complete remission and two partial remissions) in nine previously hypersensitive patients who would not have been able to receive any further L-asparaginase treatment.

ONCASPAR® was also studied in non-hypersensitive, relapsed ALL patients who were randomized to receive two doses of ONCASPAR® at 2,500 IU/m2 every 14 days or twelve doses of E. coli L-asparaginase at 10,000 IU/m2 three times a week during a 28 day induction combination chemotherapy regimen (which included vincristine and prednisone). Although the enrollment in this study was too small to be conclusive, the data showed that for 20 patients there was no significant difference between the overall response rates of 60% and 50%, respectively, or the complete remission rates of 50% and 50%, respectively.

ONCASPAR® was administered during maintenance therapy regimens to 33 previously hypersensitive patients. The average number of doses received during maintenance therapy was 5.8 (range of 1 to 24) and the average duration of maintenance therapy was 126 (range of 1 to 513) days for this patient population.

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