Acute Lymphoblastic Leukemia
Conditions
Keywords
Hypersensitivity to PEG-asparaginase
Brief summary
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.
Interventions
DRUGGRASPA
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).
Sponsors
ERYtech Pharma
Birgitte Klug Albertsen
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
1 Years to 45 Years
Healthy volunteers
No
Inclusion criteria
1. Male or female aged 1-45 years at diagnosis of ALL. 2. First line non-high risk ALL patients enrolled in NOPHO ALL2008 or ALLTogether pilot protocols including PEG-ASNase regimen. 3. Documented hypersensitivity reaction to PEG-ASNase with either: Clinical allergy to PEG-ASNase (mild/severe). Serum ASNase activity below the lower level of quantification. 4. Karnofsky/Lansky score ≥50. 5. Ability to understand and willingness to sign a written ICF 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 had to provide consent.
Exclusion criteria
1. Philadelphia chromosome positive ALL. 2. Participation in another clinical trial interfering with the study therapy with exception of NOPHO ALL-2008 or ALLTogether pilot protocol. Patients can participate in other clinical trials not interfering with the study drug. In case of doubt this is assessed by the PI. 3. 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. 4. 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. 5. 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). 6. Inadequate organ functions, which prohibit further asparaginase administration; 1. History of pancreatitis 2. History of serious hemorrhage or serious thrombosis with prior asparaginase therapy 3. Severe hepatic impairment at the time of administration (bilirubin \>3 times ULN, transaminases \>10 times ULN) 4. Pre-existing known coagulopathy (e.g. haemophilia) 7. 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. 8. Patient under concomitant treatment likely to cause hemolysis.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetics ASNase Activity >100 U/L at 14 Days | 14 days after first infusion | The primary endpoint was the percentage of patients with ASNase activity \>100 U/L at 14 days following the first infusion (nadir). ASNase activity \>100 U/L is considered adequate for complete asparagine depletion in the blood. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetic Parameters | 14 days after fourth infusion | Percentage of patients with ASNase activity \>100 U/L at 14 days following the fourth infusion of the 2-week dosing intervals. ASNase activity \>100 U/L is considered adequate for complete asparagine depletion in the blood. |
Countries
Denmark, Estonia, Finland, Lithuania, Norway, Sweden
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| GRASPA GRASPA will replace remaining PEG-asparaginase doses in case of hypersensitivity.
GRASPA: Administration of 1-7 doses of 150 U/kg IV infusion. (For patients coming from NOPHO 2008, eryaspase was administered every 2 weeks for a maximum of 4 doses and every 6 weeks for maximum 3 doses, for patients in the ALLTogether pilot protocol eryaspase was administered at a dose of 150 U/kg every 2 weeks for a maximum of 7 doses). | 55 |
| Total | 55 |
Baseline characteristics
| Characteristic | GRASPA | — |
|---|---|---|
| Age, Categorical <=18 years | 53 Participants | — |
| Age, Categorical >=65 years | 0 Participants | — |
| Age, Categorical Between 18 and 65 years | 2 Participants | — |
| Age, Continuous | 6.1 years | — |
| Race and Ethnicity Not Collected | — | — Participants |
| Region of Enrollment Denmark | 10 Participants | — |
| Region of Enrollment Estonia | 3 Participants | — |
| Region of Enrollment Finland | 8 Participants | — |
| Region of Enrollment Lithuania | 14 Participants | — |
| Region of Enrollment Norway | 5 Participants | — |
| Region of Enrollment Sweden | 15 Participants | — |
| Sex: Female, Male Female | 17 Participants | — |
| Sex: Female, Male Male | 38 Participants | — |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 55 |
| other Total, other adverse events | 18 / 55 |
| serious Total, serious adverse events | 6 / 55 |
Outcome results
Primary
Pharmacokinetics ASNase Activity >100 U/L at 14 Days
The primary endpoint was the percentage of patients with ASNase activity \>100 U/L at 14 days following the first infusion (nadir). ASNase activity \>100 U/L is considered adequate for complete asparagine depletion in the blood.
Time frame: 14 days after first infusion
Population: The primary Evaluable Patients (EP) Population was used for the analysis of the primary and key secondary endpoints, defined as all patients recruited into the study who provided data on ASNase level on Day 14 (±2 days) following the first administration of eryaspase.~All included patients (55) completed first infusion, only in 53 patients an ASNase activity measurement was available.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| GRASPA | Pharmacokinetics ASNase Activity >100 U/L at 14 Days | 92.5 percentage of patients |
Secondary
Pharmacokinetic Parameters
Percentage of patients with ASNase activity \>100 U/L at 14 days following the fourth infusion of the 2-week dosing intervals. ASNase activity \>100 U/L is considered adequate for complete asparagine depletion in the blood.
Time frame: 14 days after fourth infusion
Population: A total of 12 patients completed 4 infusions with a 2-week interval of these 9 patients had an ASNase activity measurement 14 days following the fourth infusion.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| GRASPA | Pharmacokinetic Parameters | 66.7 percentage of patients |