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.
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
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
85
one injection of GRASPA 150 IU/kg at each cycle of chemotherapy
3 to 4 Injections of Native E.coli asparaginase 10000IU/m² (every 3 days) at each cycle of chemotherapy
Hopital Des Enfants Reine Fabiola
Brussels, Belgium
Chr de La Citadelle
Liège, Belgium
Chu D'Angers
Angers, France
Hopital Saint Jacques
Besançon, France
Hopital Pellegrin Enfants
Bordeaux, France
Chu Estaing
Clermont-Ferrand, France
Hopital Henri Mondor
Créteil, France
Chu Grenoble
Grenoble, France
Chru Lille - Hop Jeanne de Flandres
Lille, France
Institut Hematologie Oncologie Pediatrique
Lyon, France
...and 18 more locations
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.
Time frame: 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.
Time frame: Induction treatment period (i.e. 28 days)
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
Time frame: 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.
Time frame: 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.
Time frame: Overall trial period to 36 months
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