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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.
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| ABSTRACT |
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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 (
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.
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.
| INTRODUCTION |
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Pegylation, the technology of polyethylene glycol covalent conjugation to a biopharmaceutical, increases the drug hydrodynamic radius, prolongs plasma retention time, decreases proteolysis, decreases renal excretion, and shields antigenic determinants from immune detection without obstructing the substrate-interaction site [7].
O, produced by covalent conjugation of monomethoxypolyethylene glycol (PEG) to native L-asparaginase, was approved in 1994 for use in ALL patients who developed hypersensitivity to the native form of asparaginase. This supplemental application requests that the indication statement for O be revised to include an additional indication for the initial therapy of patients with ALL.
The standard dosing schedule of E is 6,000 IU/m2 three times weekly for nine doses during remission induction and for six doses during delayed intensification. Administration of an equivalent antileukemic dose of pegylated asparaginase as one injection rather than six or nine injections would represent an important improvement in the morbidity of treatment for most children with ALL.
The Children's Cancer Group (CCG) conducted a study in children with standard-risk ALL to compare the pharmacokinetics, pharmacodynamics, immunogenicity, and pharmacoeconomics of pegylated versus native asparaginase administered as described above [8, 9]. Event-free survival (EFS) was also analyzed to assess whether O treatment had a possible detrimental effect.
| PATIENTS AND METHODS |
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Eligibility criteria included newly diagnosed previously untreated ALL, age 1–9 years, initial WBC at a treating institution of <50,000/µl, and
25% L3 blasts.
Patients with massive lymphadenopathy, massive splenomegaly, and/or a large mediastinal mass at diagnosis were eligible as were patients with central nervous system (CNS) or testicular leukemia.
Remission induction/consolidation treatment included intrathecal ara-C and methotrexate, vincristine, prednisone, 6-mercaptopurine, and methotrexate with either E or O. Delayed intensification therapy included intrathecal methotrexate, vincristine, dexamethasone, doxorubicin, cyclophosphamide, ara-C, thioguanine, and either E or O.
Serum (5 ml red top tube) for asparagine concentration, asparaginase levels, and asparaginase antibodies was obtained before the first dose of asparaginase and on days 7, 14, 21, and 28 of induction therapy and on days 0, 7 14, 21, and 28 of delayed intensification. Asparagine concentration in cerebrospinal fluid (CSF) (1–2 ml spinal fluid) was determined from samples obtained at the initial spinal tap and from induction day 7 and 28 spinal taps.
O (2,500 IU/m2) was administered i.m. on day 3 of the remission induction and delayed intensification phases of treatment. E (6,000 IU/m2) was administered i.m. on day 3 then Monday, Wednesday, and Friday for a total of nine doses during remission induction and on day 3 then Monday, Wednesday, and Friday for a total of six doses during each delayed intensification cycle.
The stated objective regarding asparagine levels in the CCG phase II study was to compare the duration of time serum asparagine levels were <1 µM for O-treated subjects with the duration in E-treated subjects during induction and delayed intensifications 1 and 2. This is somewhat different from the Berlin-Frankfort-Munich (BFM) group criteria that uses the following asparagine depletion grading system:
0.1 µM, complete depletion; >0.1 to
0.5 µM, nearly complete depletion; >0.5 to
1 µM, moderate reduction; >1 to
40 µM, slight reduction; >40 µM, no reduction [10].
The stated objective regarding asparaginase activity was to compare the duration of time serum asparaginase activity would remain >0.03 IU/ml for O-treated subjects with the duration in E-treated subjects during induction and delayed intensifications 1 and 2. The threshold of >0.03 IU/ml is based on data indicating that this level of asparaginase activity results in undetectable levels of asparagine [11, 12]. An alternative threshold of >0.1 IU/ml has been used in studies of asparaginase conducted by the BFM group [13, 14] because activity above this threshold has been postulated to be sufficient to result in adequate asparagine depletion in plasma and CSF [15]. A more recent review of the pharmacokinetic and pharmacodynamic properties of asparaginase formulations concluded that therapeutically effective depletion of asparagine is achieved with serum asparaginase activity levels
0.4–0.7 IU/ml in newly diagnosed ALL patients [16].
The development of a humoral immune response (antiasparaginase antibodies) against O or E was determined using an enzyme-linked immunosorbent assay method. A positive result was defined as any postexposure measurement that was >2.5x the control.
Safety data focused on known and prespecified asparaginase toxicities. Because there are decades of experience with asparaginase in this patient population and the toxicities of asparaginase are well known, this approach was expected to adequately compare the O and E toxicity profiles. Toxicity information was collected during remission induction and delayed intensification 1 and 2, the treatment phases that included asparaginase treatment.
| RESULTS |
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EFS
This study was not powered to analyze the superiority or noninferiority of O compared with E on EFS or survival. Using an intent-to-treat analysis with a median follow-up of 3.2 years, the 3-year EFS rates were approximately 80% in both arms.
Safety
There were 118 subjects enrolled and randomized 1:1 to O or to E (59 per arm). Forty-eight O-treated subjects received the three planned O doses, six received two doses, four received only one dose, and one was not treated. Fifty-seven E-treated subjects received all induction E doses; one patient received seven of nine doses because of decreased fibrinogen and another patient received six of nine doses (thrombotic event). Fifty-one patients received all delayed intensification 1 E doses and one patient received two of six doses. Forty-nine patients received all six delayed intensification 2 E doses and one patient received four of six doses. There were no treatment-related deaths in this study.
Prespecified grade 3 and 4 adverse reactions occurring in O and E patients are summarized in Table 4. Clinical allergic reactions were reported in 2 O-treated patients. One patient experienced a grade 1 allergic reaction and the other grade 3 hives; both occurred during the first delayed intensification phase of the study.
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| DISCUSSION |
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O is a modified version of E, produced by covalent conjugation of PEG to L-asparaginase. O is approved for use in ALL patients who have become hypersensitive to E. In addition to circumventing hypersensitivity to E, pegylation results in an enzyme with a longer half-life than E. In most ALL protocols, E is given three times weekly for six or nine doses. Because of the longer half-life of O, it is possible to achieve adequate asparagine depletion with fewer injections.
The study endpoint of interest to the U.S. Food and Drug Administration was asparagine depletion. Demonstration of a similar pattern and degree of asparagine depletion was considered a valid surrogate endpoint for clinical benefit so long as there was no indication of loss of clinical activity as determined by EFS.
Serum asparagine levels decreased after the first dose of either asparaginase preparation and remained low for approximately 3 weeks. The degree and duration of asparagine depletion was similar in O-treated and E-treated subjects. The depletion of CSF asparagine levels during induction was also similar between O-treated and E-treated subjects.
This study was not powered to analyze the effect of O compared with E on EFS or survival. With a median follow-up of 3.2 years, the 3-year EFS rates were approximately 80% in both arms, however, suggesting that O use will not compromise efficacy.
Immunogenicity of asparaginase preparations remains a clinical issue. Further evaluation of the incidence and clinical significance of the development of antiasparaginase antibodies will be a postmarketing commitment.
| DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST |
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| ACKNOWLEDGMENTS |
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