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Regulatory Issues: FDA |
Office of Oncology Drug Products, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA
Key Words. Pegaspargase • Oncaspar® • Pediatric ALL
Correspondence: Martin H. Cohen, M.D., U.S. Food and Drug Administration, White Oak Campus, 10903 New Hampshire Avenue, Building 22, Room 2102, Silver Spring, Maryland 20993-0002, USA. Telephone: 301-796-1344; Fax: 301-796-9845; e-mail: martin.cohen{at}fda.hhs.gov
Received January 4, 2007; accepted for publication May 17, 2007.
On July 24, 2006, the U.S. Food and Drug Administration granted approval to pegaspargase (Oncaspar®; Enzon Pharmaceuticals, Inc., Bridgewater, NJ; hereafter, O) for the first-line treatment of patients with acute lymphoblastic leukemia (ALL) as a component of a multiagent chemotherapy regimen. O was previously approved in February 1994 for the treatment of patients with ALL who were hypersensitive to native forms of L-asparaginase.
The trial supporting this new indication was an open label, randomized, multicenter clinical trial that enrolled 118 children (age, 1–9 years) with previously untreated, standard risk ALL. Patients received either native Escherichia coli asparaginase (Elspar®; Merck, Whitehouse Station, NJ; hereafter, E) or O along with multiagent chemotherapy during remission induction and delayed intensification (DI) phases of treatment. O, at a dose of 2,500 IU/m2, was administered i.m. on day 3 of the 4-week induction phase and on day 3 of each of two 8-week DI phases. E, at a dose of 6,000 IU/m2, was administered i.m. three times weekly for nine doses during induction and for six doses during each DI phase. This study allowed direct comparison of O and E for asparagine depletion, asparaginase activity, and development of asparaginase antibodies. An unplanned comparison of event-free survival (EFS) was conducted to rule out a deleterious O efficacy effect.
Following induction and DI treatment there was complete (
Similarly, depletion of cerebrospinal fluid asparagine levels during induction was similar between O-treated and E-treated subjects.
The number of days asparaginase activity exceeded >0.03 IU/ml in O-treated subjects was greater than the number of days in E-treated subjects during both the induction and DI phases of treatment. There was no correlation, however, between asparaginase activity and serum asparagine levels, making the former determination less clinically relevant.
Using the protocol-prespecified threshold for a positive result of >2.5 times the control, 7 of 56 (12%) O subjects tested at any time during the study demonstrated antiasparaginase antibodies and 16 of 57 (28%) E subjects tested at any time during the study had antiasparaginase antibodies. In both study arms EFS was in the range of 80% at 3 years.
The most serious, sometimes fatal, O toxicities were anaphylaxis, other serious allergic reactions, thrombosis (including sagittal sinus thrombosis), pancreatitis, glucose intolerance, and coagulopathy. The most common adverse events were allergic reactions (including anaphylaxis), hyperglycemia, pancreatitis, central nervous system thrombosis, coagulopathy, hyperbilirubinemia, and elevated transaminases.
Disclosure of potential conflicts of interest is found at the end of this article.
1 µM) or moderate (1–10 µM) depletion of serum asparagine levels in the large majority of samples tested over the 4-week period in both O-treated and E-treated subjects.
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