Asparaginase Encapsulated in Erythrocytes for Patients With ALL and Hypersensitivity to PEG-asparaginase

Study Overview
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Brief Summary
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Pegylated-asparaginase (PEG-ASP) is an important part of the treatment of childhood acute lymphoblastic leukaemia (ALL). Unfortunately 13% of patients develops allergy and further treatment is impossible. Furthermore, 6% of patients have developed antibodies (silent inactivation) and have no effect of the PEG-ASP treatment. Truncated asparaginase therapy is associated with inferior event-free survival outcomes, in particular relapse in central nervous system (CNS). Eryaspase is a new formulation of asparaginase encapsulated in erythrocytes. The erythrocyte membrane protects asparaginase against fast degradation and elimination processes. The encapsulation eliminates the direct somatic contact, and it is hypothesized that this provides the potential to prolong the activity of the enzyme and reduce toxicities.

Official Title
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Single-Arm PharmacoKinetic/PharmacoDynamic and Safety Study of Eryaspase (GRASPA®) for Patients With Hypersensitivity to PEG-Asparaginase, Diagnosed With Ph(-) Acute Lymphoblastic Leukemia

Conditions
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Acute Lymphoblastic Leukemia

Intervention / Treatment
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* Drug: GRASPA


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female aged 1-45 years at diagnosis of ALL First line non-high risk (HR) ALL patients enrolled in the treatment protocol Nordic Society of pediatric hematology and oncology (NOPHO) ALL 2008 including PEG-asparaginase regimen Documented hypersensitivity reaction to PEG-asparaginase with either: Clinical allergy to PEG-Asparaginase (mild/severe) OR Serum asparaginase activity below the lower level of quantification. Karnofsky/Lansky score ≥ 50. Ability to understand, and willingness to sign, a written informed consent document and to comply with the scheduled visits, treatment plans, laboratory tests, and other study procedures. For patients under 18 years of age, either both parents or the legally appointed representatives will need to provide consent. Exclusion Criteria: Philadelphia chromosome positive ALL. Participation in another clinical trial interfering with the study therapy with exception of NOPHO ALL-2008. Patients can participate in other clinical trials not interfering with the study drug. In case of doubt this is assessed by the PI. Uncontrolled intercurrent illness including, but not limited to, patients receiving combination antiretroviral therapy or patients with severe or systemic infection, or psychiatric illness/social situations that would limit compliance with study requirements. Other severe acute/chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results, and in the judgment of the investigator would make the patient inappropriate for entry into this study. Pregnant or lactating females (serum human chorionic gonadotropin pregnancy test at screening). Use of a highly effective contraceptive measure in women of child-bearing potential and sexually active girls that are of child-bearing potential is required (contraceptive measures are specified in section 6.0). Inadequate organ functions, which prohibit further asparaginase administration; History of pancreatitis History of serious hemorrhage or serious thrombosis with prior asparaginase therapy Severe hepatic impairment at the time of administration (bilirubin >3 times ULN, transaminases >10 times ULN) Pre-existing known coagulopathy (e.g. haemophilia) History of grade 3 or higher transfusion reactions or any contraindication to receive blood transfusion. Presence of specific anti-erythrocytes antibodies (auto-antibodies or anti-public antibodies) preventing from getting a compatible packed Red Blood Cells for the patient. Patient under concomitant treatment likely to cause hemolysis.

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GRASPA<br>GRASPA will replace remaining PEG-asparaginase doses in case of hypersensitivity. | Drug: GRASPA<br>* Administration of 1-7 doses of 150 IU/kg IV infusion. (every 2 weeks for a maximum of 4 doses and every 6 weeks for maximum 3 doses).<br>* Other names: Eryaspase;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic parameters | Enzyme activity (IU/L) | 6 months | 
| Pharmacokinetic parameters | T1/2 (half-life time) | 6 months | 
| Pharmacokinetic parameters | Area under the plasma concentration versus time curve (AUC) | 6 months | 
| Pharmacokinetic parameters | Vss (Distribution Volume at steady state) | 6 months | 
| Pharmacokinetic parameters | Mean Residence Time (MRT) | 6 months | 
| Pharmacodynamic profile | Plasma concentrations of amino acids: asparagine, aspartate, glutamine, glutamate o Concentrations of amino acids in the cerebrospinal fluid (CSF): (asparagine, aspartate, glutamine, glutamate) | 6 months | 
| Immunogenicity | Titers of anti-asparaginase antibodies and neutralizing antibodies | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of hypersensitivity | allergic reactions (any grade) and silent inactivation | 6 months | 
| Incidence of toxicity | Incidence of Treatment-emergent adverse events | 6 months | 
| Interactions with maintenance therapy | Measurement of levels of maintenance metabolites from the maintenance | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hypersensitivity to PEG-asparaginase