FDA Approves pegaspargase (Oncaspar, Enzon Pharmaceuticals, Inc) for the first-line treatment of patients with acute lymphoblastic leukemia
On July 24, 2006, the U.S. Food and Drug Administration granted approval to pegaspargase (Oncaspar, Enzon Pharmaceuticals, Inc) for the first-line treatment of patients with acute lymphoblastic leukemia (ALL) as a component of a multi-agent chemotherapy regimen. Oncaspar was previously approved in February, 1994 for the treatment of patients with ALL who were hypersensitive to native forms of L-asparaginase.
Asparaginase exerts selective anti-leukemia activity by depletion of serum asparagine. The current approval is based on similar sustained reductions of serum asparagine concentrations in patients receiving an Oncaspar-containing regimen compared to patients receiving a native E. coli L-asparaginase-containing regimen. Due to the longer half-life of Oncaspar, similar anti-leukemic activity was achieved with a single Oncaspar dose compared to 6-9 doses of native E. coli asparaginase
The trial (Children’s Oncology Group Study 1962) supporting this new indication was an open‑label, randomized, multi-center clinical trial that enrolled 118 children (ages 1-9 years) with previously untreated, standard risk ALL. Treatment consisted of a 4-week induction phase (IP) and two 8-week delayed intensification (DI) phases. All patients received multi-agent chemotherapy regimen consisting of intrathecal cytosine arabinoside and systemic therapy with vincristine, prednisone, and methotrexate with either native E. coli asparaginase or Oncaspar during IP and intrathecal methotrexate and systemic therapy with mercaptopurine and either native E. coli asparaginase or Oncaspar during both DI phases. Oncaspar was administered intramuscularly at 2,500 IU/m2 on day 3 of the 4-week induction phase and on day 3 of each of two 8-week DI phases. Native E. coli L‑asparaginase was administered intramuscularly at 6,000 IU/m2 three times weekly for 9 doses during induction and for 6 doses during each DI phase.
The two study arms were balanced for most major prognostic factors; however, patients allocated to receive the native E. coli asparaginase-containing chemotherapy had a higher percentage of children ages 1-2 years (34% vs. 19%), with platelet counts <50,000 cells/µl (51% vs. 34%), and with equivocal CNS involvement (15% vs. 7%).
The study demonstrated similar mean asparagine concentrations between the two study arms at multiple time-points during all treatment phases. Event-free survival (time from randomization to either death, induction failure, relapse at any site, or start of new cancer treatment) was assessed in all patients. With a median follow-up of 3.2 years, the 3-year event-free survival rates were approximately 80% in both arms.
The most serious, sometimes fatal, Oncaspar 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.
Oncaspar is one of the first FDA approved products to provide prescription information in the new format for prescription drug package inserts. This new format is designed to provide health care professionals and patients with a more concise and clearer presentation of prescribing information. Full prescribing information in this new format including clinical trial information, safety, dosing, drug-drug interaction and contraindications is available at Drugs@FDA .