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

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ClinicalTrials.gov Identifier: NCT03267030
Recruitment Status : Recruiting
First Posted : August 30, 2017
Last Update Posted : August 6, 2019
Sponsor:
Collaborator:
ERYtech Pharma
Information provided by (Responsible Party):
Birgitte Klug Albertsen, Aarhus University Hospital

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.


Condition or disease Intervention/treatment Phase
Acute Lymphoblastic Leukemia Drug: GRASPA Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Single-Arm PharmacoKinetic/PharmacoDynamic and Safety Study of Eryaspase (GRASPA®) for Patients With Hypersensitivity to PEG-Asparaginase, Diagnosed With Ph(-) Acute Lymphoblastic Leukemia
Actual Study Start Date : August 23, 2017
Estimated Primary Completion Date : January 1, 2020
Estimated Study Completion Date : August 1, 2020


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 Name: Eryaspase




Primary Outcome Measures :
  1. Pharmacokinetic parameters [ Time Frame: 6 months ]
    Enzyme activity (IU/L)

  2. Pharmacokinetic parameters [ Time Frame: 6 months ]
    T1/2 (half-life time)

  3. Pharmacokinetic parameters [ Time Frame: 6 months ]
    Area under the plasma concentration versus time curve (AUC)

  4. Pharmacokinetic parameters [ Time Frame: 6 months ]
    Vss (Distribution Volume at steady state)

  5. Pharmacokinetic parameters [ Time Frame: 6 months ]
    Mean Residence Time (MRT)

  6. Pharmacodynamic profile [ Time Frame: 6 months ]

    Plasma concentrations of amino acids: asparagine, aspartate, glutamine, glutamate

    o Concentrations of amino acids in the cerebrospinal fluid (CSF): (asparagine, aspartate, glutamine, glutamate)


  7. Immunogenicity [ Time Frame: 6 months ]
    Titers of anti-asparaginase antibodies and neutralizing antibodies


Secondary Outcome Measures :
  1. Incidence of hypersensitivity [ Time Frame: 6 months ]
    allergic reactions (any grade) and silent inactivation

  2. Incidence of toxicity [ Time Frame: 6 months ]
    Incidence of Treatment-emergent adverse events

  3. Interactions with maintenance therapy [ Time Frame: 6 months ]
    Measurement of levels of maintenance metabolites from the maintenance



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Ages Eligible for Study:   1 Year to 45 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Male or female aged 1-45 years at diagnosis of ALL
  2. 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
  3. 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.

  4. Karnofsky/Lansky score ≥ 50.
  5. 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:

  1. Philadelphia chromosome positive ALL.
  2. 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.
  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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03267030


Contacts
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Contact: Birgitte Klug Albertsen, MD, PhD +4520224643 Biralber@rm.dk
Contact: Line Stensig Lynggaard, MD +4525112022 Line.stensig@rm.dk

Locations
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Denmark
Aahus University hospial, hematological department Recruiting
Aarhus, Aarhus C, Denmark, 8000
Contact: Mette Skov Holm, MD, phD       Mettehlm@rm.dk   
Contact: Line Stensig Lynggaard, MD    +45 25112022    Line.stensig@rm.dk   
Aarhus University hospital Recruiting
Aarhus, Aarhus N, Denmark, 8200
Contact: Line Stensig Lynggaard, MD    +25112022    Line.stensig@rm.dk   
Contact: Birgitte Klug Albertsen, MD, phd    +45 20224643    biralber@rm.dk   
Aalborg University Hospital, pediatric department Recruiting
Aalborg, Denmark
Contact: Ruta Tuckuviene         
Rigshospitalet, Hematological department Recruiting
Copenhagen, Denmark, 2100
Contact: Ulrik Malthe Overgaard         
Rigshospitalet, Child and Adolescent Medicine Recruiting
Copenhagen, Denmark
Contact: Thomas Frandsen         
Odense University hospital, pediatric department Recruiting
Odense, Denmark
Contact: Michael Thude Callesen         
Estonia
Tallin Childrens Hospital Recruiting
Tallin, Estonia
Contact: Kristi Lepik         
Tartu University Clinics Recruiting
Tartu, Estonia
Contact: Sirje Mikkel         
Finland
Childrens Hospital, Helsinki. University Central Hospital Not yet recruiting
Helsinki, Finland
Contact: Samppa Ryhänen         
Kuopio University Hospital Not yet recruiting
Kuopio, Finland
Contact: Tuuli Pöyhönen         
University Hospital of Oulu Recruiting
Oulu, Finland
Contact: Riita Niinimäki         
Tampere University Hospital Recruiting
Tampere, Finland
Contact: Olli Lohi         
Turku University Hospital Recruiting
Turku, Finland
Contact: Päivi Lähteenmäki         
Lithuania
Vilnius University Children's Hospital Recruiting
Vilnius, Lithuania
Contact: Goda Vaitkeviciene         
Norway
Helse Bergen Not yet recruiting
Bergen, Norway
Contact: Anne Kristine Lehmann         
Oslo Universitetssykehus, Rikshospitalet Recruiting
Oslo, Norway
Contact: Sigurd Liestøl         
St Olavs Hospital Recruiting
Trondheim, Norway
Contact: Petter Quist Paulsen         
Sweden
Drottning Silvias Barn- och ungdomssjukhus Recruiting
Göteborg, Sweden
Contact: cecilia Langenskiöld         
Universitetssjukhuset Linköping Recruiting
Linköping, Sweden
Contact: Mikael Behrendtz         
Skånes Universitets sjukhus Recruiting
Lund, Sweden
Contact: Anders Castor         
Astrid Lindgrens Barnsjukhus Karolinska Recruiting
Stockholm, Sweden
Contact: Johan Malmros         
arn- och Ungdomscentrum Norrlands Universitetssjukhus Recruiting
Umeå, Sweden
Contact: Ulrika Norén Nyström         
Akademiska sjukhuset Uppsala Recruiting
Uppsala, Sweden
Contact: Natalja Jackmann         
Sponsors and Collaborators
Birgitte Klug Albertsen
ERYtech Pharma
Investigators
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Principal Investigator: Brigitte Klug Albertsen, MD, PhD Pediatric and adolescent medicine, Aarhus University Hospital, Denmark

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Responsible Party: Birgitte Klug Albertsen, MD PhD, Aarhus University Hospital
ClinicalTrials.gov Identifier: NCT03267030     History of Changes
Other Study ID Numbers: NOR-GRASPALL 2016
2016-004451-70 ( EudraCT Number )
First Posted: August 30, 2017    Key Record Dates
Last Update Posted: August 6, 2019
Last Verified: August 2019

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Birgitte Klug Albertsen, Aarhus University Hospital:
Hypersensitivity to PEG-asparaginase
Additional relevant MeSH terms:
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Leukemia
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Lymphoid
Hypersensitivity
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Asparaginase
Pegaspargase
Antineoplastic Agents