GRASPA (Erythrocytes Encapsulating L-asparaginase) in Patients With Relapse of Acute Lymphoblastic Leukemia (GRASPIVOTALL)

This study is ongoing, but not recruiting participants.
Information provided by (Responsible Party):
ERYtech Pharma Identifier:
First received: January 10, 2012
Last updated: March 17, 2016
Last verified: March 2016

Asparaginase is a cornerstone in the treatment of ALL, but its utility is limited by toxicities including hypersensitivity. Clinical allergy is associated with inactivation of asparaginase by antibodies (A-Abs), which can also neutralize asparaginase without any clinical signs of hypersensitivity (silent inactivation). GRASPA improves pharmacokinetics, tolerability and maintain circulating asparaginase activity due to the protective barrier of the erythrocyte membrane.

This study is run to confirm the benefit/risk profile of GRASPA at 150 IU/kg in combination with the COOPRALL regimen in adults and children patients with relapsed ALL, with or without known hypersensitivity to L-asparaginase.

Condition Intervention Phase
Acute Lymphoblastic Leukemia, in Relapse
Drug: L-asparaginase
Phase 2
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase 2/3 Study Evaluating Efficacy and Safety of Erythrocytes Encapsulating L-asparaginase (GRASPA)Versus Reference L-asparaginase Treatment in Combination With Standard Polychemotherapy in Patient With First Recurrence of Philadelphia Negative Acute Lymphoblastic Leukemia

Resource links provided by NLM:

Further study details as provided by ERYtech Pharma:

Primary Outcome Measures:
  • efficacy and toxicity combined [ Time Frame: 1 month ] [ Designated as safety issue: Yes ]
    efficacy assessed according mean duration of asparaginase activity / toxicity assessed according incidence of allergic reaction whatever the grade

Secondary Outcome Measures:
  • Molecular response rate [ Time Frame: 1 month ] [ Designated as safety issue: No ]
  • Plasma concentration of asparagine, aspartate, glutamine, glutamate and asparaginase [ Time Frame: 0,1,3,6, 9 days post-dose ] [ Designated as safety issue: No ]
  • Specific anti L-asparaginase antibodies [ Time Frame: 0,10 days post-dose ] [ Designated as safety issue: No ]
  • Event free survival [ Time Frame: 6 and 12 month ] [ Designated as safety issue: No ]
  • Relapse free survival [ Time Frame: 6 and 12 month ] [ Designated as safety issue: No ]
  • Overall survival [ Time Frame: 6 and 12 month ] [ Designated as safety issue: No ]
  • Percentage of patient with complete remission [ Time Frame: 1 month ] [ Designated as safety issue: No ]

Enrollment: 80
Study Start Date: December 2009
Estimated Study Completion Date: August 2016
Primary Completion Date: September 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: GRASPA

Each patient randomized in GRASPA® group is to receive at least 2 and up to 10 administration of GRASPA® 150 IU/kg, in combination with standard chemotherapy (COOPRALL).

GRASPA® administration takes place as below:

  • for induction phase: at Day 4 and D18 (F1-F2 induction ) or at D6 if Vanda induction applies (according disease severity)
  • for consolidation phase: at Day 6 of R2 / R1 blocks, each time block of chemotherapy is given (up to 8 cycles)
one injection of GRASPA 150 IU/kg at each cycle of chemotherapy
Other Name: ERY001
Active Comparator: reference L-asparaginase

For patient randomized in control group, reference L-asparaginase 10,000 IU/m² will be administered every 3 days intravenously, in combination with standard chemotherapy (COOPRALL).

•for induction phase:at Day 4 , D7, D10, D13 (F1 block ) then at Day 18, D21, D24, D27 (of F2 Blocks).

NB: administrations take place at D6, D9, D12 and D15 in case of F1-F2 Induction is replaced by VANDA (according disease severity)

•for consolidation phase: at D6, D9, D12 ofR2/R1 blocks, each time block of chemotherapy is given (up to 8 cycles).

Drug: L-asparaginase
3 to 4 Injections of Native E.coli asparaginase 10000IU/m² (every 3 days) at each cycle of chemotherapy

Detailed Description:
This open, randomized international Phase 2/3 study will enrol patients with relapsed ALL. The co-primary endpoints were the duration of asparagine depletion < 2µmol/L and the incidence of asparaginase hypersensitivity during induction. Key secondary endpoints are complete remission (CR), minimal residual disease (MRD), event free survival (EFS) and overall survival (OS).The study was powered to detect 3-fold difference in the incidence of allergic reactions between treatments. patients will be randomized to GRASPA or to Reference L-asparaginase. Patients with history of hypersensitivity to previous L-asparaginase treatment will be treated with GRASPA (exploratory arm)

Ages Eligible for Study:   1 Year to 55 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Patient from 1 to 55 years old (Children and adolescents from 1 to 17 years/ Adults from 18 to 55 years)
  • Patients with 1st ALL relapse, which could be either isolated bone marrow relapse, or combined (medullary and extra-medullary) relapse, or extra-medullary isolated relapse; or lymphoblastic lymphoma (excepted Burkitt lymphoma) OR Failure to ALL first line treatment (no complete remission obtained)
  • Patient previously treated with free E.Coli L-asparaginase form or pegylated one
  • Performance Status ≤ 2 (WHO score)
  • Patient informed and consent provided (the 2 parents need to consent when children are below 18)

Exclusion Criteria:

  • ALL t(9;22) and/or BCR-ABL positive (Philadelphia chromosome positive)
  • Patient with 2nd relapse and over
  • Women of childbearing potential without effective contraception as well as pregnant or breast feeding women
  • Patient unable to receive treatments used in global chemotherapy protocols, due to general or visceral conditions such as:Severe cardiac impairment (NYHA grade 3 or 4 cardiomyopathy)/Serum creatinine 2 x ULN unless related to ALL /ALT or AST 5 x ULN unless related to ALL /Pancreatitis history /Other malignancy that ALL / Severe Infection, HIV positive, active hepatitis related to B or C virus infection / Trisomy 21 / Other serious conditions according to investigator's opinion
  • Known grade 4 allergic reaction to E.Coli L-asparaginase (according NCI-CTCAE, Version 3.0)
  • History of grade 3 transfusional incident
  • Presence of specific anti-erythrocyte antibodies preventing from getting a compatible erythrocyte concentrate for the patient
  • Patient under concomitant treatment likely to cause hemolysis
  • Patient undergoing yellow fever vaccination
  • Patient under phenytoin treatment
  • Patient included in previous clinical study less than 6 weeks ago
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its identifier: NCT01518517

Hopital Des Enfants Reine Fabiola
Bruxelles, Belgium
Chr de La Citadelle
Liege, Belgium
Chu D'Angers
Angers, France
Hopital Saint Jacques
Besancon, France
Hopital Pellegrin Enfants
Bordeaux, France
Chu Estaing
Clermont Ferrand, France
Hopital Henri Mondor
Creteil, France
Chu Grenoble
Grenoble, France
Chru Lille - Hop Jeanne de Flandres
Lille, France
Institut Hematologie Oncologie Pediatrique
Lyon, France
Institut Paoli Calmettes
Marseille, France
Hopital Mere Enfant
Nantes, France
Hotel Dieu
Nantes, France
Hopital de L'Archet 2
Nice, France
Hopital Armand Trousseau
Paris, France
Hopital Robert Debre
Paris, France
Hopital Saint Louis
Paris, France
Hopital Haut-Leveque
Pessac, France
Hopital Lyon Sud
Pierre Benite, France
Chru Hopital Sud
Rennes, France
Centre Henri Becquerel
Rouen, France
Chu Hopital Nord
Saint Etienne, France
Institut Cancerologie de La Loire
Saint Priest En Jarez, France
Hopital de Hautepierre
Strasbourg, France
Chu de Toulouse Enfants
Toulouse, France
Hotel Dieu
Valenciennes, France
Hopital Brabois Enfants
Vandoeuvre Les Nancy, France
Hopital de Brabois
Vandoeuvre Les Nancy, France
Sponsors and Collaborators
ERYtech Pharma
Principal Investigator: Yves Bertand, MD
  More Information

Responsible Party: ERYtech Pharma Identifier: NCT01518517     History of Changes
Other Study ID Numbers: GRASPALL2009-06 
Study First Received: January 10, 2012
Last Updated: March 17, 2016
Health Authority: France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
Belgium: Federal Agency for Medicinal Products and Health Products

Keywords provided by ERYtech Pharma:
acute lymphoblastic leukemia

Additional relevant MeSH terms:
Leukemia, Lymphoid
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Immune System Diseases
Immunoproliferative Disorders
Lymphatic Diseases
Lymphoproliferative Disorders
Neoplasms by Histologic Type
Antineoplastic Agents processed this record on May 30, 2016