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

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

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.

Study Overview

• Status: Completed
• Conditions: Acute Lymphoblastic Leukemia, in Relapse
• Intervention / Treatment: Drug: GRASPA; Drug: L-asparaginase

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)

• Study Type: Interventional
• Enrollment (Actual): 85
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Belgium
  • Bruxelles, Belgium
    • Hôpital des enfants Reine Fabiola
  • Liege, Belgium
    • CHR de la Citadelle
• France
  • Angers, France
    • CHU d'Angers
  • Besancon, France
    • Hopital Saint Jacques
  • Bordeaux, France
    • Hôpital Pellegrin enfants
  • Clermont Ferrand, France
    • CHU Estaing
  • Creteil, France
    • Hopital Henri Mondor
  • Grenoble, France
    • CHU Grenoble
  • Lille, France
    • Chru Lille - Hop Jeanne de Flandres
  • Lyon, France
    • Institut Hematologie Oncologie Pediatrique
  • Marseille, France
    • Institut Paoli Calmettes
  • Nantes, France
    • Hôpital Mère Enfant
  • Nantes, France
    • Hotel Dieu
  • Nice, France
    • Hopital de l'Archet 2
  • Paris, France
    • Hôpital Robert Debré
  • Paris, France
    • Hopital saint Louis
  • Paris, France
    • Hôpital Armand Trousseau
  • Pessac, France
    • Hôpital Haut-Lévêque
  • Pierre Benite, France
    • Hôpital Lyon Sud
  • Rennes, France
    • CHRU Hopital Sud
  • Rouen, France
    • Centre Henri Becquerel
  • Saint Etienne, France
    • CHU Hopital Nord
  • Saint Priest En Jarez, France
    • Institut Cancerologie de La Loire
  • Strasbourg, France
    • Hopital de Hautepierre
  • Toulouse, France
    • Chu de Toulouse Enfants
  • Valenciennes, France
    • Hotel Dieu
  • Vandoeuvre Les Nancy, France
    • Hôpital Brabois Enfants
  • Vandoeuvre Les Nancy, France
    • Hôpital de Brabois

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 55 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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)	Drug: GRASPA; one injection of GRASPA 150 IU/kg at each cycle of chemotherapy; Other Names: 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; Other Names: KIDROLASE

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Duration of Asparaginase Activity >100 U/L During Induction	Co-primary efficacy endpoint: duration in days of asparaginase activity >100 U/L in whole blood during the induction treatment phase: last available date/time of activity >100 UI/L before activity drops below 100 U/L - date/time of first activity >100 UI/L. Asparaginase activity is compared for GRASPA versus native ASNase to demonstrate the non-inferiority of GRASPA.	Induction treatment period (i.e. 28 days)
Allergic Reaction During Induction Phase	Co-primary safety endpoint: allergic reaction regardless of grade during induction phase. Only those reactions that were reported in relation to the treatment to which the patient was randomised were counted.	Induction treatment period (i.e. 28 days)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complete Remission (CR)	CR is defined as, no physical evidence of leukemia, normal CBC, cytologic remission: normally regenerating bone marrow, with <5% leukemic blasts and the absence of detectable CNS or extramedullary disease, evaluated with physical examination and CSF findings, at the end of induction	Induction treatment period (i.e. 28 days)
Overall Survival (OS)	OS is defined as the time from randomisation or date of inclusion (allergic arm) until death due to any cause. Patients who did not die were censored at 36 months of follow-up or the date of the patient's last visit, whichever was earlier.	Overall trial period to 36 months
Event Free Survival	EFS is defined as the time from randomisation until the first documented sign of disease relapse or death due to any cause. In line with CHMP guidance (CHMP, 2016), patients who did not achieve CR at the end of the induction period were considered to have had an event at time 0. For the patients enrolled in the GRASPA allergic arm, EFS is defined from the date of inclusion in the study. Patients who achieved CR at the end of induction and who did not have a documented relapse or death due to any cause were censored at 36 months of follow-up or the date of the patient's last visit, whichever was earlier.	Overall trial period to 36 months

Collaborators and Investigators

• Sponsor: ERYtech Pharma
• Investigators: Principal Investigator: Yves Bertand, MD

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2009
• Primary Completion (Actual): September 1, 2014
• Study Completion (Actual): October 1, 2016

Study Registration Dates

• First Submitted: January 10, 2012
• First Submitted That Met QC Criteria: January 25, 2012
• First Posted (Estimate): January 26, 2012

Study Record Updates

• Last Update Posted (Actual): February 2, 2022
• Last Update Submitted That Met QC Criteria: February 1, 2022
• Last Verified: February 1, 2022

More Information

Terms related to this study

• Keywords: relapse; acute lymphoblastic leukemia; asparaginase
• Additional Relevant MeSH Terms: Pathologic Processes; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Disease Attributes; Leukemia; Recurrence; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Antineoplastic Agents; Asparaginase
• Other Study ID Numbers: GRASPALL2009-06

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No