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

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-)

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-).

Study Overview

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

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.

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Phase 2

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 55 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: GRASPA 50 IU/kg; 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.	Drug: GRASPA; 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
Experimental: GRASPA 100 IU/kg; 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	Drug: GRASPA; 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
Experimental: GRASPA 150 IU/kg; 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	Drug: GRASPA; 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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®	7 days after the first administration of GRASPA® during Induction 1
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.	Induction 1 and Induction 2

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Induction 1 & Induction 2
Plasma Concentrations of Aspartic Acid	Mean plasma concentration of aspartic acid over time.	Induction 1 and Induction 2
Plasma Concentrations of Glutamine	Mean glutamine concentration over time.	Induction 1 and Induction 2
Plasma Concentrations of Glutamic Acid.	Mean glutamic acid concentration over time.	Induction 1 and Induction 2
Cerebral Spinal Fluid Concentrations of Asparagine	Mean cerebral spinal fluid asparagine concentration over time.	Induction 1 and Induction 2
Cerebral Spinal Fluid Concentrations of Aspartic Acid	Mean cerebral spinal fluid aspartic acid concentration	Induction 1 and Induction 2
Cerebral Spinal Fluid Concentrations of Glutamine	Mean cerebral spinal fluid glutamine concentration	Induction 1 and Induction 2
Cerebral Spinal Fluid Concentrations of Glutamic Acid	Mean cerebral spinal fluid glutamic acid concentration	Induction 1 and Induction 2
Summary of Free Asparaginase Over Time		Induction 1 and Induction 2
Summary of Encapsulated Asparaginase (U/L) Over Time		Induction 1 and Induction 2
Number of Patients Positive for Anti-L-asparaginase Antibodies	Evaluation of the number of patients testing positive for anti-asparaginase antibodies.	Induction 1 and Induction 2
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%	1 and 2 months

Collaborators and Investigators

• Sponsor: ERYtech Pharma
• Investigators: Principal Investigator: Mathilde Hunault-Berger, Professor, University Hospital, Angers

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start: April 1, 2009
• Primary Completion (Actual): January 1, 2011
• Study Completion (Actual): October 1, 2012

Study Registration Dates

• First Submitted: January 16, 2012
• First Submitted That Met QC Criteria: January 30, 2012
• First Posted (Estimate): February 1, 2012

Study Record Updates

• Last Update Posted (Actual): October 15, 2021
• Last Update Submitted That Met QC Criteria: September 21, 2021
• Last Verified: June 1, 2018

More Information

Terms related to this study

• Keywords: Asparaginase; Elderly patient; Acute Lymphoblastic leukemia
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid
• Other Study ID Numbers: GRASPALL/GRAALLSA2-2008

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD Plan Description: Not applicable for this study