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Administration of GRASPA (Suspension of Erythrocytes Encapsulating L-asparaginase) in Elderly Patients With First Line Acute Lymphoblastic Leukemia

Primary Purpose

Acute Lymphoblastic Leukemia

Status
Completed
Phase
Phase 2
Locations
Study Type
Interventional
Intervention
GRASPA
Sponsored by
ERYtech Pharma
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Acute Lymphoblastic Leukemia focused on measuring Acute Lymphoblastic leukemia, Elderly patient, Asparaginase

Eligibility Criteria

55 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Patient aged ≥55 years old
  • With newly diagnosed ALL without prior treatment
  • Capable to receive polychemotherapy (World Health Organization (WHO) performance status ≤2)
  • With or without meningeal disease
  • Having signed an Informed Consent Form
  • Subscribed to social security insurance

Exclusion Criteria:

  • ALL translocation(9;22) and/or BCR-ABL (Breakpoint Cluster Region-Abelson) positive
  • Performance status incompatible with chemotherapy treatment (WHO score >2)

  • Patient presenting with a general or visceral contraindication to intensive treatment including :

    • Cardiac insufficiency defined as Left Ventricular Ejection Fraction <50% of the theoretical value
    • Plasma creatinine concentration 2 times greater than the upper limit of laboratory ranges, except if related to ALL
    • Aspartate aminotransferase (ASAT) or alanine aminotransferase (ALAT) levels 5 times greater than the upper limit of laboratory ranges, except if related to ALL
    • Patient with another evolutive cancer other than ALL
    • Severe evolutive infection, or Human Immunodeficiency Virus (HIV) seropositive or, active hepatitis related to B or C viral infection
  • Prior treatment with L-asparaginase (irrespective of the form)
  • History of grade 3 transfusional incident (life threatening)
  • Patient presenting rare and/or dangerous anti-erythrocyte antibodies thus leading to the unavailability of phenotype compatible Red Blood Cells Concentrate
  • Patient included in another clinical trial during the last 4 weeks

Sites / Locations

    Arms of the Study

    Arm 1

    Arm 2

    Arm 3

    Arm Type

    Experimental

    Experimental

    Experimental

    Arm Label

    GRASPA 50 IU/kg

    GRASPA 100 IU/kg

    GRASPA 150 IU/kg

    Arm Description

    Each patient will receive GRASPA 50 IU/kg at day 3 of the induction 1 phase. If no toxicity related to investigational product is observed and if the patient's state of health allows it, a second injection, at the identical dose, will be administered at Day 6 of Induction 2 phase.

    Each patient will receive GRASPA 100 IU/kg at day 3 of the induction 1 phase. If no toxicity related to investigational product is observed and if the patient's state of health allows it, a second injection, at the identical dose, will be administered at Day 6 of Induction 2 phase

    Each patient will receive GRASPA 150 IU/kg at day 3 of the induction 1 phase. If no toxicity related to investigational product is observed and if the patient's state of health allows it, a second injection, at the identical dose, will be administered at Day 6 of Induction 2 phase

    Outcomes

    Primary Outcome Measures

    Efficacy Primary Endpoint - Percentage of Patients Responding to Treatment
    The main evaluation criterion is a composite efficacy/toxicity criterion. Efficacy, assessed during induction 1: percentage of patients responding to treatment, i.e. with plasma Asn concentration ≤2µM (depleted), for a duration of at least 7 days after the administration of GRASPA®
    Safety Endpoint - DLTs Assessed During Induction 1 and Induction 2
    Safety: Toxicity, assessed during Induction 1 and Induction 2: according to NCI-CTCAE v3.0 August 2006, with Dose Limiting Toxicities (DLT) defined as: Grade 2 to 4 pancreatic toxicity, Grade 3 or 4 hepatic toxicity, allergic toxicity or deep cerebral thrombosis, known as potentially related to L-asparaginase; hematological toxicity defined as bone marrow blast free aplasia, 30 days following the last injection of chemotherapy, all other Grade 4 toxicities.

    Secondary Outcome Measures

    Plasma Concentrations of Asparagine
    Mean plasma concentration of asparagine over time. Participants who were Below the Lower Limit of Quantification (BLLQ) were assigned a value of 0.51 μmol/L.
    Plasma Concentrations of Aspartic Acid
    Mean plasma concentration of aspartic acid over time.
    Plasma Concentrations of Glutamine
    Mean glutamine concentration over time.
    Plasma Concentrations of Glutamic Acid.
    Mean glutamic acid concentration over time.
    Cerebral Spinal Fluid Concentrations of Asparagine
    Mean cerebral spinal fluid asparagine concentration over time.
    Cerebral Spinal Fluid Concentrations of Aspartic Acid
    Mean cerebral spinal fluid aspartic acid concentration
    Cerebral Spinal Fluid Concentrations of Glutamine
    Mean cerebral spinal fluid glutamine concentration
    Cerebral Spinal Fluid Concentrations of Glutamic Acid
    Mean cerebral spinal fluid glutamic acid concentration
    Summary of Free Asparaginase Over Time
    Summary of Encapsulated Asparaginase (U/L) Over Time
    Number of Patients Positive for Anti-L-asparaginase Antibodies
    Evaluation of the number of patients testing positive for anti-asparaginase antibodies.
    Number of Participants With Complete Remission (CR) Rate Following Induction 1 and Induction 2
    CR was defined using: Clinical criteria: disappearance of clinical signs of acute lymphocytic leukemia (ALL) Blood criteria: neutrophils > 1 G/L and platelets >100 G/L Medullary criteria: normally rich bone marrow and percentage of blasts <5%

    Full Information

    First Posted
    January 16, 2012
    Last Updated
    September 21, 2021
    Sponsor
    ERYtech Pharma
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    1. Study Identification

    Unique Protocol Identification Number
    NCT01523782
    Brief Title
    Administration of GRASPA (Suspension of Erythrocytes Encapsulating L-asparaginase) in Elderly Patients With First Line Acute Lymphoblastic Leukemia
    Official Title
    An Escalating Dose Phase IIa Study of L-Asparaginase Encapsulated in Erythrocytes (GRASPA®) in Association With Polychemotherapy During Induction Phase for Treatment of Elderly Patients With Acute Lymphoblastic Leukaemia (ALL), Aged 55 Years and Over, With Philadelphia Chromosome-negative (ALL Ph-)
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    June 2018
    Overall Recruitment Status
    Completed
    Study Start Date
    April 2009 (undefined)
    Primary Completion Date
    January 2011 (Actual)
    Study Completion Date
    October 2012 (Actual)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Sponsor
    Name of the Sponsor
    ERYtech Pharma

    4. Oversight

    Data Monitoring Committee
    Yes

    5. Study Description

    Brief Summary
    The main purpose of this study is to determine the maximum tolerated and efficient dose of GRASPA® in combination with polychemotherapy treatment of elderly patients with ALL, 55 years and over, Philadelphia chromosome-negative (ALL Ph-).
    Detailed Description
    This open label, non randomised, multicentric and national phase IIa study was designed to evaluate the safety and efficacy of GRASPA®, a suspension of red blood cells encapsulating E. Coli L-asparaginase, at different doses and in combination with the polychemotherapy regimen recommended by the European Working Group on Adult ALL (EWALL) for frontline therapy of patients with ALL Ph-, aged 55 years old and over. Patients with a good performance status (WHO score ≤2) and a newly diagnosed ALL Ph- were treated with the backbone polychemotherapy consisting of a first 4-week induction phase comprising dexamethasone, vincristine and idarubicin, a second 4-week induction phase including cyclophosphamide, cytarabine, a 6-month consolidation phase consisting of 6 alternating cycles with methotrexate, asparaginase and folinic acid (cycles 1, 3 and 5) and high-dose cytarabine (cycles 2, 4 and 6) with Granulocyte colony stimulating factor (G-CSF) support followed by a 16-month maintenance period with mercaptopurine, methotrexate and vincristine/dexamethasone pulses. GRASPA® was administered on day 3 of induction 1 and on day 6 of induction 2 of the chemotherapy regimen.

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Acute Lymphoblastic Leukemia
    Keywords
    Acute Lymphoblastic leukemia, Elderly patient, Asparaginase

    7. Study Design

    Primary Purpose
    Treatment
    Study Phase
    Phase 2
    Interventional Study Model
    Parallel Assignment
    Masking
    None (Open Label)
    Masking Description
    Open label
    Allocation
    Non-Randomized
    Enrollment
    30 (Actual)

    8. Arms, Groups, and Interventions

    Arm Title
    GRASPA 50 IU/kg
    Arm Type
    Experimental
    Arm Description
    Each patient will receive GRASPA 50 IU/kg at day 3 of the induction 1 phase. If no toxicity related to investigational product is observed and if the patient's state of health allows it, a second injection, at the identical dose, will be administered at Day 6 of Induction 2 phase.
    Arm Title
    GRASPA 100 IU/kg
    Arm Type
    Experimental
    Arm Description
    Each patient will receive GRASPA 100 IU/kg at day 3 of the induction 1 phase. If no toxicity related to investigational product is observed and if the patient's state of health allows it, a second injection, at the identical dose, will be administered at Day 6 of Induction 2 phase
    Arm Title
    GRASPA 150 IU/kg
    Arm Type
    Experimental
    Arm Description
    Each patient will receive GRASPA 150 IU/kg at day 3 of the induction 1 phase. If no toxicity related to investigational product is observed and if the patient's state of health allows it, a second injection, at the identical dose, will be administered at Day 6 of Induction 2 phase
    Intervention Type
    Drug
    Intervention Name(s)
    GRASPA
    Intervention Description
    Each patient will receive GRASPA at day 3 of the induction 1 phase. If no toxicity related to investigational product is observed and if the patient's state of health allows it, a second injection, at the identical dose, will be administered at Day 6 of Induction 2 phase
    Primary Outcome Measure Information:
    Title
    Efficacy Primary Endpoint - Percentage of Patients Responding to Treatment
    Description
    The main evaluation criterion is a composite efficacy/toxicity criterion. Efficacy, assessed during induction 1: percentage of patients responding to treatment, i.e. with plasma Asn concentration ≤2µM (depleted), for a duration of at least 7 days after the administration of GRASPA®
    Time Frame
    7 days after the first administration of GRASPA® during Induction 1
    Title
    Safety Endpoint - DLTs Assessed During Induction 1 and Induction 2
    Description
    Safety: Toxicity, assessed during Induction 1 and Induction 2: according to NCI-CTCAE v3.0 August 2006, with Dose Limiting Toxicities (DLT) defined as: Grade 2 to 4 pancreatic toxicity, Grade 3 or 4 hepatic toxicity, allergic toxicity or deep cerebral thrombosis, known as potentially related to L-asparaginase; hematological toxicity defined as bone marrow blast free aplasia, 30 days following the last injection of chemotherapy, all other Grade 4 toxicities.
    Time Frame
    Induction 1 and Induction 2
    Secondary Outcome Measure Information:
    Title
    Plasma Concentrations of Asparagine
    Description
    Mean plasma concentration of asparagine over time. Participants who were Below the Lower Limit of Quantification (BLLQ) were assigned a value of 0.51 μmol/L.
    Time Frame
    Induction 1 & Induction 2
    Title
    Plasma Concentrations of Aspartic Acid
    Description
    Mean plasma concentration of aspartic acid over time.
    Time Frame
    Induction 1 and Induction 2
    Title
    Plasma Concentrations of Glutamine
    Description
    Mean glutamine concentration over time.
    Time Frame
    Induction 1 and Induction 2
    Title
    Plasma Concentrations of Glutamic Acid.
    Description
    Mean glutamic acid concentration over time.
    Time Frame
    Induction 1 and Induction 2
    Title
    Cerebral Spinal Fluid Concentrations of Asparagine
    Description
    Mean cerebral spinal fluid asparagine concentration over time.
    Time Frame
    Induction 1 and Induction 2
    Title
    Cerebral Spinal Fluid Concentrations of Aspartic Acid
    Description
    Mean cerebral spinal fluid aspartic acid concentration
    Time Frame
    Induction 1 and Induction 2
    Title
    Cerebral Spinal Fluid Concentrations of Glutamine
    Description
    Mean cerebral spinal fluid glutamine concentration
    Time Frame
    Induction 1 and Induction 2
    Title
    Cerebral Spinal Fluid Concentrations of Glutamic Acid
    Description
    Mean cerebral spinal fluid glutamic acid concentration
    Time Frame
    Induction 1 and Induction 2
    Title
    Summary of Free Asparaginase Over Time
    Time Frame
    Induction 1 and Induction 2
    Title
    Summary of Encapsulated Asparaginase (U/L) Over Time
    Time Frame
    Induction 1 and Induction 2
    Title
    Number of Patients Positive for Anti-L-asparaginase Antibodies
    Description
    Evaluation of the number of patients testing positive for anti-asparaginase antibodies.
    Time Frame
    Induction 1 and Induction 2
    Title
    Number of Participants With Complete Remission (CR) Rate Following Induction 1 and Induction 2
    Description
    CR was defined using: Clinical criteria: disappearance of clinical signs of acute lymphocytic leukemia (ALL) Blood criteria: neutrophils > 1 G/L and platelets >100 G/L Medullary criteria: normally rich bone marrow and percentage of blasts <5%
    Time Frame
    1 and 2 months

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    55 Years
    Accepts Healthy Volunteers
    No
    Eligibility Criteria
    Inclusion Criteria: Patient aged ≥55 years old With newly diagnosed ALL without prior treatment Capable to receive polychemotherapy (World Health Organization (WHO) performance status ≤2) With or without meningeal disease Having signed an Informed Consent Form Subscribed to social security insurance Exclusion Criteria: ALL translocation(9;22) and/or BCR-ABL (Breakpoint Cluster Region-Abelson) positive Performance status incompatible with chemotherapy treatment (WHO score >2) Patient presenting with a general or visceral contraindication to intensive treatment including : Cardiac insufficiency defined as Left Ventricular Ejection Fraction <50% of the theoretical value Plasma creatinine concentration 2 times greater than the upper limit of laboratory ranges, except if related to ALL Aspartate aminotransferase (ASAT) or alanine aminotransferase (ALAT) levels 5 times greater than the upper limit of laboratory ranges, except if related to ALL Patient with another evolutive cancer other than ALL Severe evolutive infection, or Human Immunodeficiency Virus (HIV) seropositive or, active hepatitis related to B or C viral infection Prior treatment with L-asparaginase (irrespective of the form) History of grade 3 transfusional incident (life threatening) Patient presenting rare and/or dangerous anti-erythrocyte antibodies thus leading to the unavailability of phenotype compatible Red Blood Cells Concentrate Patient included in another clinical trial during the last 4 weeks
    Overall Study Officials:
    First Name & Middle Initial & Last Name & Degree
    Mathilde Hunault-Berger, Professor
    Organizational Affiliation
    University Hospital, Angers
    Official's Role
    Principal Investigator

    12. IPD Sharing Statement

    Plan to Share IPD
    No
    IPD Sharing Plan Description
    Not applicable for this study
    Citations:
    PubMed Identifier
    26094614
    Citation
    Hunault-Berger M, Leguay T, Huguet F, Lepretre S, Deconinck E, Ojeda-Uribe M, Bonmati C, Escoffre-Barbe M, Bories P, Himberlin C, Chevallier P, Rousselot P, Reman O, Boulland ML, Lissandre S, Turlure P, Bouscary D, Sanhes L, Legrand O, Lafage-Pochitaloff M, Bene MC, Liens D, Godfrin Y, Ifrah N, Dombret H; Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL). A Phase 2 study of L-asparaginase encapsulated in erythrocytes in elderly patients with Philadelphia chromosome negative acute lymphoblastic leukemia: The GRASPALL/GRAALL-SA2-2008 study. Am J Hematol. 2015 Sep;90(9):811-8. doi: 10.1002/ajh.24093.
    Results Reference
    derived

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    Administration of GRASPA (Suspension of Erythrocytes Encapsulating L-asparaginase) in Elderly Patients With First Line Acute Lymphoblastic Leukemia

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