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

Acute Lymphoblastic Leukemia, in Relapse Clinical Trial

— GRASPIVOTALL  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01518517
• Other study ID #: GRASPALL2009-06
• Status: Completed
• Phase: Phase 2/Phase 3
• Start date: December 2009
• Est. completion date: October 2016

Study information

• Verified date: February 2022
• Source: ERYtech Pharma
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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)

Recruitment information / eligibility

• Status: Completed
• Enrollment: 85
• Est. completion date: October 2016
• Est. primary completion date: September 2014
• Accepts healthy volunteers: No
• Gender: All
• Age group: 1 Year to 55 Years

Eligibility

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

Related Conditions & MeSH terms

• Acute Lymphoblastic Leukemia, in Relapse
• Leukemia
• Leukemia, Lymphoid
• Precursor Cell Lymphoblastic Leukemia-Lymphoma
• Recurrence

Intervention

Drug:
• GRASPA
one injection of GRASPA 150 IU/kg at each cycle of chemotherapy
• L-asparaginase
3 to 4 Injections of Native E.coli asparaginase 10000IU/m² (every 3 days) at each cycle of chemotherapy

Locations

Country	Name	City	State
Belgium	Hopital Des Enfants Reine Fabiola	Bruxelles
Belgium	Chr de La Citadelle	Liege
France	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

Sponsors (1)

Lead Sponsor	Collaborator
ERYtech Pharma

Countries where clinical trial is conducted

Belgium,  France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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)
Primary	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	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)
Secondary	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
Secondary	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