<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03267030</url>
  </required_header>
  <id_info>
    <org_study_id>NOR-GRASPALL 2016</org_study_id>
    <secondary_id>2016-004451-70</secondary_id>
    <nct_id>NCT03267030</nct_id>
  </id_info>
  <brief_title>Asparaginase Encapsulated in Erythrocytes for Patients With ALL and Hypersensitivity to PEG-asparaginase</brief_title>
  <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</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Birgitte Klug Albertsen</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>ERYtech Pharma</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Aarhus University Hospital</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Pegylated-asparaginase (PEG-ASP) is an important part of the treatment of childhood acute&#xD;
      lymphoblastic leukaemia (ALL). Unfortunately 13% of patients develops allergy and further&#xD;
      treatment is impossible. Furthermore, 6% of patients have developed antibodies (silent&#xD;
      inactivation) and have no effect of the PEG-ASP treatment. Truncated asparaginase therapy is&#xD;
      associated with inferior event-free survival outcomes, in particular relapse in central&#xD;
      nervous system (CNS).&#xD;
&#xD;
      Eryaspase is a new formulation of asparaginase encapsulated in erythrocytes. The erythrocyte&#xD;
      membrane protects asparaginase against fast degradation and elimination processes. The&#xD;
      encapsulation eliminates the direct somatic contact, and it is hypothesized that this&#xD;
      provides the potential to prolong the activity of the enzyme and reduce toxicities.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">August 23, 2017</start_date>
  <completion_date type="Actual">October 22, 2020</completion_date>
  <primary_completion_date type="Actual">August 1, 2020</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Pharmacokinetic parameters</measure>
    <time_frame>6 months</time_frame>
    <description>Enzyme activity (IU/L)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Pharmacokinetic parameters</measure>
    <time_frame>6 months</time_frame>
    <description>T1/2 (half-life time)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Pharmacokinetic parameters</measure>
    <time_frame>6 months</time_frame>
    <description>Area under the plasma concentration versus time curve (AUC)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Pharmacokinetic parameters</measure>
    <time_frame>6 months</time_frame>
    <description>Vss (Distribution Volume at steady state)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Pharmacokinetic parameters</measure>
    <time_frame>6 months</time_frame>
    <description>Mean Residence Time (MRT)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Pharmacodynamic profile</measure>
    <time_frame>6 months</time_frame>
    <description>Plasma concentrations of amino acids: asparagine, aspartate, glutamine, glutamate&#xD;
o Concentrations of amino acids in the cerebrospinal fluid (CSF): (asparagine, aspartate, glutamine, glutamate)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Immunogenicity</measure>
    <time_frame>6 months</time_frame>
    <description>Titers of anti-asparaginase antibodies and neutralizing antibodies</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Incidence of hypersensitivity</measure>
    <time_frame>6 months</time_frame>
    <description>allergic reactions (any grade) and silent inactivation</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of toxicity</measure>
    <time_frame>6 months</time_frame>
    <description>Incidence of Treatment-emergent adverse events</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Interactions with maintenance therapy</measure>
    <time_frame>6 months</time_frame>
    <description>Measurement of levels of maintenance metabolites from the maintenance</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">55</enrollment>
  <condition>Acute Lymphoblastic Leukemia</condition>
  <arm_group>
    <arm_group_label>GRASPA</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>GRASPA will replace remaining PEG-asparaginase doses in case of hypersensitivity.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>GRASPA</intervention_name>
    <description>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).</description>
    <arm_group_label>GRASPA</arm_group_label>
    <other_name>Eryaspase</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Male or female aged 1-45 years at diagnosis of ALL&#xD;
&#xD;
          2. First line non-high risk (HR) ALL patients enrolled in the treatment protocol Nordic&#xD;
             Society of pediatric hematology and oncology (NOPHO) ALL 2008 including&#xD;
             PEG-asparaginase regimen&#xD;
&#xD;
          3. Documented hypersensitivity reaction to PEG-asparaginase with either:&#xD;
&#xD;
             Clinical allergy to PEG-Asparaginase (mild/severe) OR Serum asparaginase activity&#xD;
             below the lower level of quantification.&#xD;
&#xD;
          4. Karnofsky/Lansky score ≥ 50.&#xD;
&#xD;
          5. Ability to understand, and willingness to sign, a written informed consent document&#xD;
             and to comply with the scheduled visits, treatment plans, laboratory tests, and other&#xD;
             study procedures. For patients under 18 years of age, either both parents or the&#xD;
             legally appointed representatives will need to provide consent.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Philadelphia chromosome positive ALL.&#xD;
&#xD;
          2. Participation in another clinical trial interfering with the study therapy with&#xD;
             exception of NOPHO ALL-2008. Patients can participate in other clinical trials not&#xD;
             interfering with the study drug. In case of doubt this is assessed by the PI.&#xD;
&#xD;
          3. Uncontrolled intercurrent illness including, but not limited to, patients receiving&#xD;
             combination antiretroviral therapy or patients with severe or systemic infection, or&#xD;
             psychiatric illness/social situations that would limit compliance with study&#xD;
             requirements.&#xD;
&#xD;
          4. Other severe acute/chronic medical or psychiatric condition or laboratory abnormality&#xD;
             that may increase the risk associated with study participation or study drug&#xD;
             administration, or may interfere with the interpretation of study results, and in the&#xD;
             judgment of the investigator would make the patient inappropriate for entry into this&#xD;
             study.&#xD;
&#xD;
          5. Pregnant or lactating females (serum human chorionic gonadotropin pregnancy test at&#xD;
             screening). Use of a highly effective contraceptive measure in women of child-bearing&#xD;
             potential and sexually active girls that are of child-bearing potential is required&#xD;
             (contraceptive measures are specified in section 6.0).&#xD;
&#xD;
          6. Inadequate organ functions, which prohibit further asparaginase administration;&#xD;
&#xD;
               1. History of pancreatitis&#xD;
&#xD;
               2. History of serious hemorrhage or serious thrombosis with prior asparaginase&#xD;
                  therapy&#xD;
&#xD;
               3. Severe hepatic impairment at the time of administration (bilirubin &gt;3 times ULN,&#xD;
                  transaminases &gt;10 times ULN)&#xD;
&#xD;
               4. Pre-existing known coagulopathy (e.g. haemophilia)&#xD;
&#xD;
          7. History of grade 3 or higher transfusion reactions or any contraindication to receive&#xD;
             blood transfusion. Presence of specific anti-erythrocytes antibodies (auto-antibodies&#xD;
             or anti-public antibodies) preventing from getting a compatible packed Red Blood Cells&#xD;
             for the patient.&#xD;
&#xD;
          8. Patient under concomitant treatment likely to cause hemolysis.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>1 Year</minimum_age>
    <maximum_age>45 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Brigitte Klug Albertsen, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Pediatric and adolescent medicine, Aarhus University Hospital, Denmark</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Aahus University hospial, hematological department</name>
      <address>
        <city>Aarhus</city>
        <state>Aarhus C</state>
        <zip>8000</zip>
        <country>Denmark</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Aarhus University hospital</name>
      <address>
        <city>Aarhus</city>
        <state>Aarhus N</state>
        <zip>8200</zip>
        <country>Denmark</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Aalborg University Hospital, pediatric department</name>
      <address>
        <city>Aalborg</city>
        <country>Denmark</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Rigshospitalet, Hematological department</name>
      <address>
        <city>Copenhagen</city>
        <zip>2100</zip>
        <country>Denmark</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Rigshospitalet, Child and Adolescent Medicine</name>
      <address>
        <city>Copenhagen</city>
        <country>Denmark</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Odense University hospital, pediatric department</name>
      <address>
        <city>Odense</city>
        <country>Denmark</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Tallin Childrens Hospital</name>
      <address>
        <city>Tallin</city>
        <country>Estonia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Tartu University Clinics</name>
      <address>
        <city>Tartu</city>
        <country>Estonia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Childrens Hospital, Helsinki. University Central Hospital</name>
      <address>
        <city>Helsinki</city>
        <country>Finland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Kuopio University Hospital</name>
      <address>
        <city>Kuopio</city>
        <country>Finland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Hospital of Oulu</name>
      <address>
        <city>Oulu</city>
        <country>Finland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Tampere University Hospital</name>
      <address>
        <city>Tampere</city>
        <country>Finland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Turku University Hospital</name>
      <address>
        <city>Turku</city>
        <country>Finland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Vilnius University Children's Hospital</name>
      <address>
        <city>Vilnius</city>
        <country>Lithuania</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Helse Bergen</name>
      <address>
        <city>Bergen</city>
        <country>Norway</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Oslo Universitetssykehus, Rikshospitalet</name>
      <address>
        <city>Oslo</city>
        <country>Norway</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>St Olavs Hospital</name>
      <address>
        <city>Trondheim</city>
        <country>Norway</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Drottning Silvias Barn- och ungdomssjukhus</name>
      <address>
        <city>Göteborg</city>
        <country>Sweden</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Universitetssjukhuset Linköping</name>
      <address>
        <city>Linköping</city>
        <country>Sweden</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Skånes Universitets sjukhus</name>
      <address>
        <city>Lund</city>
        <country>Sweden</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Astrid Lindgrens Barnsjukhus Karolinska</name>
      <address>
        <city>Stockholm</city>
        <country>Sweden</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>arn- och Ungdomscentrum Norrlands Universitetssjukhus</name>
      <address>
        <city>Umeå</city>
        <country>Sweden</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Akademiska sjukhuset Uppsala</name>
      <address>
        <city>Uppsala</city>
        <country>Sweden</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Denmark</country>
    <country>Estonia</country>
    <country>Finland</country>
    <country>Lithuania</country>
    <country>Norway</country>
    <country>Sweden</country>
  </location_countries>
  <verification_date>January 2021</verification_date>
  <study_first_submitted>May 2, 2017</study_first_submitted>
  <study_first_submitted_qc>August 29, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 30, 2017</study_first_posted>
  <last_update_submitted>January 22, 2021</last_update_submitted>
  <last_update_submitted_qc>January 22, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">January 25, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>Aarhus University Hospital</investigator_affiliation>
    <investigator_full_name>Birgitte Klug Albertsen</investigator_full_name>
    <investigator_title>MD PhD</investigator_title>
  </responsible_party>
  <keyword>Hypersensitivity to PEG-asparaginase</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Leukemia</mesh_term>
    <mesh_term>Precursor Cell Lymphoblastic Leukemia-Lymphoma</mesh_term>
    <mesh_term>Leukemia, Lymphoid</mesh_term>
    <mesh_term>Hypersensitivity</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Eryaspase</mesh_term>
  </intervention_browse>
  <pending_results>
    <submitted>February 22, 2022</submitted>
    <returned>May 9, 2022</returned>
    <submitted>August 23, 2023</submitted>
  </pending_results>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03267030
org study id: NOR-GRASPALL 2016
secondary id: 2016-004451-70
nct id: NCT03267030
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
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.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Pharmacokinetic parameters
time frame: 6 months
description: Enzyme activity (IU/L)
measure: Pharmacokinetic parameters
time frame: 6 months
description: T1/2 (half-life time)
measure: Pharmacokinetic parameters
time frame: 6 months
description: Area under the plasma concentration versus time curve (AUC)
measure: Pharmacokinetic parameters
time frame: 6 months
description: Vss (Distribution Volume at steady state)
measure: Pharmacokinetic parameters
time frame: 6 months
description: Mean Residence Time (MRT)
measure: Pharmacodynamic profile
time frame: 6 months
description: Plasma concentrations of amino acids: asparagine, aspartate, glutamine, glutamate
o Concentrations of amino acids in the cerebrospinal fluid (CSF): (asparagine, aspartate, glutamine, glutamate)
measure: Immunogenicity
time frame: 6 months
description: Titers of anti-asparaginase antibodies and neutralizing antibodies
measure: Incidence of hypersensitivity
time frame: 6 months
description: allergic reactions (any grade) and silent inactivation
measure: Incidence of toxicity
time frame: 6 months
description: Incidence of Treatment-emergent adverse events
measure: Interactions with maintenance therapy
time frame: 6 months
description: Measurement of levels of maintenance metabolites from the maintenance
arm group label: GRASPA
arm group type: Experimental
description: GRASPA will replace remaining PEG-asparaginase doses in case of hypersensitivity.
intervention type: Drug
intervention name: GRASPA
description: 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).
arm group label: GRASPA
other name: Eryaspase
criteria: 
gender: All
minimum age: 1 Year
maximum age: 45 Years
healthy volunteers: No
last name: Brigitte Klug Albertsen, MD, PhD
role: Principal Investigator
affiliation: Pediatric and adolescent medicine, Aarhus University Hospital, Denmark
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country: Denmark
country: Estonia
country: Finland
country: Lithuania
country: Norway
country: Sweden
responsible party type: Sponsor-Investigator
investigator affiliation: Aarhus University Hospital
investigator full name: Birgitte Klug Albertsen
investigator title: MD PhD
mesh term: Leukemia
mesh term: Precursor Cell Lymphoblastic Leukemia-Lymphoma
mesh term: Leukemia, Lymphoid
mesh term: Hypersensitivity
mesh term: Eryaspase
submitted: February 22, 2022
returned: May 9, 2022
submitted: August 23, 2023