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

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

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.

Study Overview

• Status: Completed
• Conditions: Acute Lymphoblastic Leukemia
• Intervention / Treatment: Drug: GRASPA

• Study Type: Interventional
• Enrollment (Actual): 55
• Phase: Phase 2

Contacts and Locations

Study Locations

• Denmark
  • Aalborg, Denmark
    • Aalborg University Hospital, pediatric department
  • Copenhagen, Denmark, 2100
    • Rigshospitalet, Hematological department
  • Copenhagen, Denmark
    • Rigshospitalet, Child and Adolescent Medicine
  • Odense, Denmark
    • Odense University hospital, pediatric department
  • Aarhus C
    • Aarhus, Aarhus C, Denmark, 8000
      • Aahus University hospial, hematological department
  • Aarhus N
    • Aarhus, Aarhus N, Denmark, 8200
      • Aarhus University Hospital
• Estonia
  • Tallin, Estonia
    • Tallin Childrens Hospital
  • Tartu, Estonia
    • Tartu University Clinics
• Finland
  • Helsinki, Finland
    • Childrens Hospital, Helsinki. University Central Hospital
  • Kuopio, Finland
    • Kuopio University Hospital
  • Oulu, Finland
    • University Hospital of Oulu
  • Tampere, Finland
    • Tampere University Hospital
  • Turku, Finland
    • Turku University Hospital
• Lithuania
  • Vilnius, Lithuania
    • Vilnius University Children's Hospital
• Norway
  • Bergen, Norway
    • Helse Bergen
  • Oslo, Norway
    • Oslo Universitetssykehus, Rikshospitalet
  • Trondheim, Norway
    • St Olavs Hospital
• Sweden
  • Göteborg, Sweden
    • Drottning Silvias barn- och ungdomssjukhus
  • Linköping, Sweden
    • Universitetssjukhuset Linköping
  • Lund, Sweden
    • Skånes Universitets sjukhus
  • Stockholm, Sweden
    • Astrid Lindgrens Barnsjukhus Karolinska
  • Umeå, Sweden
    • arn- och Ungdomscentrum Norrlands Universitetssjukhus
  • Uppsala, Sweden
    • Akademiska sjukhuset Uppsala

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 45 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: GRASPA; GRASPA will replace remaining PEG-asparaginase doses in case of hypersensitivity.	Drug: GRASPA; 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).; Other Names: Eryaspase

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	14 days after first infusion

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	14 days after fourth infusion

Collaborators and Investigators

• Sponsor: Birgitte Klug Albertsen
• Collaborators: ERYtech Pharma
• Investigators: Principal Investigator: Brigitte Klug Albertsen, MD, PhD, Pediatric and adolescent medicine, Aarhus University Hospital, Denmark

Study record dates

Study Major Dates

• Study Start (Actual): August 23, 2017
• Primary Completion (Actual): August 1, 2020
• Study Completion (Actual): October 22, 2020

Study Registration Dates

• First Submitted: May 2, 2017
• First Submitted That Met QC Criteria: August 29, 2017
• First Posted (Actual): August 30, 2017

Study Record Updates

• Last Update Posted (Actual): March 15, 2024
• Last Update Submitted That Met QC Criteria: August 23, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Keywords: Hypersensitivity to PEG-asparaginase
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Hematologic Diseases; Hypersensitivity; Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Antineoplastic Agents; Eryaspase
• Other Study ID Numbers: NOR-GRASPALL 2016; 2016-004451-70 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No