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

• Sponsor: ERYtech Pharma (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01518517
• Collaborator: (none)
• Enrollment: 85
• Locations: 28
• Arms: 2
• Actual Duration (Months): 82
• Patients Per Site: 3
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Acute Lymphoblastic Leukemia, in Relapse	Drug: GRASPA; Drug: L-asparaginase	Phase 2/Phase 3

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 Design

• Study Type: Interventional
• Actual Enrollment: 85 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (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
• Actual Study Start Date: Dec 1, 2009
• Actual Primary Completion Date: Sep 1, 2014
• Actual Study Completion Date: Oct 1, 2016

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Duration of Asparaginase Activity >100 U/L During Induction [Induction treatment period (i.e. 28 days)]

   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.

2. Allergic Reaction During Induction Phase [Induction treatment period (i.e. 28 days)]

   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.

Secondary Outcome Measures

1. Complete Remission (CR) [Induction treatment period (i.e. 28 days)]

   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

2. Overall Survival (OS) [Overall trial period to 36 months]

   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.

3. Event Free Survival [Overall trial period to 36 months]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 1 Year to 55 Years
• Sexes Eligible for Study: All
• 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

Locations

	Site	City	State	Country	Postal Code
1	Hopital Des Enfants Reine Fabiola	Bruxelles		Belgium
2	Chr de La Citadelle	Liege		Belgium
3	Chu D'Angers	Angers		France
4	Hopital Saint Jacques	Besancon		France
5	Hopital Pellegrin Enfants	Bordeaux		France
6	Chu Estaing	Clermont Ferrand		France
7	Hopital Henri Mondor	Creteil		France
8	Chu Grenoble	Grenoble		France
9	Chru Lille - Hop Jeanne de Flandres	Lille		France
10	Institut Hematologie Oncologie Pediatrique	Lyon		France
11	Institut Paoli Calmettes	Marseille		France
12	Hopital Mere Enfant	Nantes		France
13	Hotel Dieu	Nantes		France
14	Hopital de L'Archet 2	Nice		France
15	Hopital Armand Trousseau	Paris		France
16	Hopital Robert Debre	Paris		France
17	Hopital Saint Louis	Paris		France
18	Hopital Haut-Leveque	Pessac		France
19	Hopital Lyon Sud	Pierre Benite		France
20	Chru Hopital Sud	Rennes		France
21	Centre Henri Becquerel	Rouen		France
22	Chu Hopital Nord	Saint Etienne		France
23	Institut Cancerologie de La Loire	Saint Priest En Jarez		France
24	Hopital de Hautepierre	Strasbourg		France
25	Chu de Toulouse Enfants	Toulouse		France
26	Hotel Dieu	Valenciennes		France
27	Hopital Brabois Enfants	Vandoeuvre Les Nancy		France
28	Hopital de Brabois	Vandoeuvre Les Nancy		France

Sponsors and Collaborators

• ERYtech Pharma

Investigators

• Principal Investigator: Yves Bertand, MD,

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: ERYtech Pharma
• ClinicalTrials.gov Identifier: NCT01518517
• Other Study ID Numbers: GRASPALL2009-06
• First Posted: Jan 26, 2012
• Last Update Posted: Feb 2, 2022
• Last Verified: Feb 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by ERYtech Pharma: acute lymphoblastic leukemia; relapse; asparaginase
• Additional relevant MeSH terms: Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Recurrence; Asparaginase

Study Results

Participant Flow

Arm/Group Title	GRASPA (Non Allergic Population)	Reference L-asparaginase (Non Allergic Population)	GRASPA (Allergic Population)
Arm/Group Description	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) GRASPA: one injection of GRASPA 150 IU/kg at each cycle of chemotherapy	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). L-asparaginase: 3 to 4 Injections of Native E.coli asparaginase 10000IU/m² (every 3 days) at each cycle of chemotherapy	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) GRASPA: one injection of GRASPA 150 IU/kg at each cycle of chemotherapy
Period Title: Overall Study
STARTED	29	30	26
COMPLETED	1	3	0
NOT COMPLETED	28	27	26

Baseline Characteristics

Arm/Group Title	GRASPA (Non Allergic Population)	Reference L-asparaginase (Non Allergic Population	GRASPA (Allergic Population)	Total
Arm/Group Description	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) GRASPA: one injection of GRASPA 150 IU/kg at each cycle of chemotherapy	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). L-asparaginase: 3 to 4 Injections of Native E.coli asparaginase 10000IU/m² (every 3 days) at each cycle of chemotherapy	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) GRASPA: one injection of GRASPA 150 IU/kg at each cycle of chemotherapy	Total of all reporting groups
Overall Participants	29	30	26	85
Age (Count of Participants)
<=18 years	23 79.3%	23 76.7%	15 57.7%	61 71.8%
Between 18 and 65 years	6 20.7%	7 23.3%	11 42.3%	24 28.2%
>=65 years	0 0%	0 0%	0 0%	0 0%
Sex: Female, Male (Count of Participants)
Female	11 37.9%	10 33.3%	8 30.8%	29 34.1%
Male	18 62.1%	20 66.7%	18 69.2%	56 65.9%

Outcome Measures

1. Primary Outcome

Title	Duration of Asparaginase Activity >100 U/L During Induction
Description	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)

Outcome Measure Data

Analysis Population Description

Only non allergic population evaluated for efficacy (i.e. 2 randomized arms). Only patient receiving treatment are considered.

Arm/Group Title	GRASPA Non Allergic	Reference L-asparaginase
Arm/Group Description	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) GRASPA: one injection of GRASPA 150 IU/kg at each cycle of chemotherapy	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). L-asparaginase: 3 to 4 Injections of Native E.coli asparaginase 10000IU/m² (every 3 days) at each cycle of chemotherapy
Measure Participants	26	28
Mean (95% Confidence Interval) [days]	18.9	8.5

2. Primary Outcome

Title	Allergic Reaction During Induction Phase
Description	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)

Outcome Measure Data

Analysis Population Description

Only patient receiving treatment are considered.

Arm/Group Title	GRASPA (Non Allergic Population)	Reference L-asparaginase (Non Allergic Population)	GRASPA (Allergic Population)
Arm/Group Description	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) GRASPA: one injection of GRASPA 150 IU/kg at each cycle of chemotherapy	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). L-asparaginase: 3 to 4 Injections of Native E.coli asparaginase 10000IU/m² (every 3 days) at each cycle of chemotherapy	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) GRASPA: one injection of GRASPA 150 IU/kg at each cycle of chemotherapy
Measure Participants	26	28	26
Number [reactions]	0	13	3

3. Secondary Outcome

Title	Complete Remission (CR)
Description	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)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	GRASPA (Non Allergic Population)	Reference L-asparaginase (Non Allergic Population)	GRASPA (Allergic Population)
Arm/Group Description	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) GRASPA: one injection of GRASPA 150 IU/kg at each cycle of chemotherapy	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). L-asparaginase: 3 to 4 Injections of Native E.coli asparaginase 10000IU/m² (every 3 days) at each cycle of chemotherapy	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) GRASPA: one injection of GRASPA 150 IU/kg at each cycle of chemotherapy
Measure Participants	25	28	25
Count of Participants [Participants]	19 65.5%	13 43.3%	15 57.7%

4. Secondary Outcome

Title	Overall Survival (OS)
Description	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

Outcome Measure Data

Analysis Population Description

Entries given below are number of patients dying in each group

Arm/Group Title	GRASPA (Non Allergic Population)	Reference L-asparaginase (Non Allergic Population)	GRASPA (Allergic Population)
Arm/Group Description	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) GRASPA: one injection of GRASPA 150 IU/kg at each cycle of chemotherapy	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). L-asparaginase: 3 to 4 Injections of Native E.coli asparaginase 10000IU/m² (every 3 days) at each cycle of chemotherapy	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) GRASPA: one injection of GRASPA 150 IU/kg at each cycle of chemotherapy
Measure Participants	26	28	26
Count of Participants [Participants]	9 31%	12 40%	14 53.8%

5. Secondary Outcome

Title	Event Free Survival
Description	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

Outcome Measure Data

Analysis Population Description

Entries below are the numbers of patients with events in each treatment group

Arm/Group Title	GRASPA (Non Allergic Population)	Reference L-asparaginase (Non Allergic Population)	GRASPA (Allergic Population)
Arm/Group Description	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) GRASPA: one injection of GRASPA 150 IU/kg at each cycle of chemotherapy	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). L-asparaginase: 3 to 4 Injections of Native E.coli asparaginase 10000IU/m² (every 3 days) at each cycle of chemotherapy	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) GRASPA: one injection of GRASPA 150 IU/kg at each cycle of chemotherapy
Measure Participants	26	28	26
Count of Participants [Participants]	15 51.7%	17 56.7%	19 73.1%

Adverse Events

Time Frame	AEs were collected from the first trial related activity after the subject signs the informed consent and until 4 months after last dose of study drug depending on the number of doses of asparaginase patients received (depending on study drug exposure period, with a maximum of 1.5 months)
Adverse Event Reporting Description	Only patient receiving treatment are considered as safety population.
Arm/Group Title	GRASPA (Non Allergic Population)		Reference L-asparaginase (Non Allergic Population)		GRASPA (Allergic Population)
Arm/Group Description	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) GRASPA: one injection of GRASPA 150 IU/kg at each cycle of chemotherapy		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). L-asparaginase: 3 to 4 Injections of Native E.coli asparaginase 10000IU/m² (every 3 days) at each cycle of chemotherapy		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) GRASPA: one injection of GRASPA 150 IU/kg at each cycle of chemotherapy
All Cause Mortality
	GRASPA (Non Allergic Population)		Reference L-asparaginase (Non Allergic Population)		GRASPA (Allergic Population)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	9/26 (34.6%)		12/28 (42.9%)		14/26 (53.8%)
Serious Adverse Events
	GRASPA (Non Allergic Population)		Reference L-asparaginase (Non Allergic Population)		GRASPA (Allergic Population)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	23/26 (88.5%)		26/28 (92.9%)		23/26 (88.5%)
Blood and lymphatic system disorders
Febrile bone marrow aplasia	11/26 (42.3%)	23	7/28 (25%)	10	5/26 (19.2%)	7
Thrombocytopenia	0/26 (0%)	0	0/28 (0%)	0	3/26 (11.5%)	3
Febrile neutropenia	4/26 (15.4%)	4	5/28 (17.9%)	9	4/26 (15.4%)	7
Gastrointestinal disorders
Pancreatitis	1/26 (3.8%)	1	3/28 (10.7%)	3	1/26 (3.8%)	1
Intestinal ischaemia	0/26 (0%)	0	1/28 (3.6%)	1	0/26 (0%)	0
General disorders
Mucosal inflammation	15/26 (57.7%)	15	8/28 (28.6%)	8	6/26 (23.1%)	6
Immune system disorders
drug hypersensitivity	3/26 (11.5%)	3	7/28 (25%)	7	3/26 (11.5%)	3
Infections and infestations
Sepsis	4/26 (15.4%)	4	2/28 (7.1%)	2	0/26 (0%)	0
Anal Abscess	0/26 (0%)	0	2/28 (7.1%)	2	0/26 (0%)	0
Bacteraemia	0/26 (0%)	0	0/28 (0%)	0	2/26 (7.7%)	2
Septic shock	3/26 (11.5%)	3	1/28 (3.6%)	1	1/26 (3.8%)	1
Staphylococcal sepsis	3/26 (11.5%)	3	1/28 (3.6%)	1	0/26 (0%)	0
Fusarium infection	0/26 (0%)	0	0/28 (0%)	0	1/26 (3.8%)	1
Human herpesvirus 6 infection	0/26 (0%)	0	0/28 (0%)	0	1/26 (3.8%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Leukaemia recurrent	8/26 (30.8%)	9	9/28 (32.1%)	9	7/26 (26.9%)	8
Nervous system disorders
Cerebral haemorrhage	0/26 (0%)	0	0/28 (0%)	0	1/26 (3.8%)	1
Renal and urinary disorders
Renal failure	1/26 (3.8%)	1	1/28 (3.6%)	1	0/26 (0%)	0
Respiratory, thoracic and mediastinal disorders
Mucosal inflammation	3/26 (11.5%)	3	4/28 (14.3%)	4	5/26 (19.2%)	5
lung disorder	0/26 (0%)	0	2/28 (7.1%)	2	0/26 (0%)	0
Other (Not Including Serious) Adverse Events
	GRASPA (Non Allergic Population)		Reference L-asparaginase (Non Allergic Population)		GRASPA (Allergic Population)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	26/26 (100%)		28/28 (100%)		26/26 (100%)
Blood and lymphatic system disorders
Leukopenia	25/26 (96.2%)	76	27/28 (96.4%)	81	26/26 (100%)	74
Thrombocytopenia	24/26 (92.3%)	69	26/28 (92.9%)	71	22/26 (84.6%)	71
Neutropenia	24/26 (92.3%)	89	25/28 (89.3%)	93	25/26 (96.2%)	81
Lymphopenia	21/26 (80.8%)	43	23/28 (82.1%)	43	20/26 (76.9%)	49
Febrile bone marrow aplasia	5/26 (19.2%)	17	7/28 (25%)	17	8/26 (30.8%)	13
Hypofibrinogenaemia	9/26 (34.6%)	11	19/28 (67.9%)	37	11/26 (42.3%)	12
Febrile neutropenia	1/26 (3.8%)	4	5/28 (17.9%)	9	3/26 (11.5%)	6
Anaemia	7/26 (26.9%)	9	9/28 (32.1%)	14	6/26 (23.1%)	6
Bone marrow failure	2/26 (7.7%)	2	3/28 (10.7%)	4	1/26 (3.8%)	1
Blood phosphorus decreased	4/26 (15.4%)	5	3/28 (10.7%)	3	3/26 (11.5%)	3
Gastrointestinal disorders
Pancreatitis	1/26 (3.8%)	1	2/28 (7.1%)	2	0/26 (0%)	0
Abdominal pain	1/26 (3.8%)	2	2/28 (7.1%)	2	2/26 (7.7%)	2
Diarrhoea	3/26 (11.5%)	3	2/28 (7.1%)	3	2/26 (7.7%)	2
Rectal haemorrhage	0/26 (0%)	0	2/28 (7.1%)	2	0/26 (0%)	0
Vomiting	4/26 (15.4%)	4	1/28 (3.6%)	1	1/26 (3.8%)	1
General disorders
Pyrexia	2/26 (7.7%)	3	0/28 (0%)	0	4/26 (15.4%)	4
Asthenia	0/26 (0%)	0	0/28 (0%)	0	2/26 (7.7%)	2
Hepatobiliary disorders
Hepatotoxicity	2/26 (7.7%)	2	6/28 (21.4%)	12	8/26 (30.8%)	9
Cholestasis	0/26 (0%)	0	0/28 (0%)	0	2/26 (7.7%)	2
Immune system disorders
Drug hypersensitivity	7/26 (26.9%)	8	18/28 (64.3%)	21	17/26 (65.4%)	21
Graft versus host disease	2/26 (7.7%)	2	2/28 (7.1%)	2	0/26 (0%)	0
Infections and infestations
Sepsis	3/26 (11.5%)	3	1/28 (3.6%)	1	1/26 (3.8%)	1
Injury, poisoning and procedural complications
Allergic transfusion reaction	2/26 (7.7%)	2	2/28 (7.1%)	2	2/26 (7.7%)	2
Investigations
Transaminases increased	16/26 (61.5%)	40	16/28 (57.1%)	33	15/26 (57.7%)	21
Hypokalaemia	13/26 (50%)	13	11/28 (39.3%)	12	9/26 (34.6%)	12
Antithrombin III decreased	4/26 (15.4%)	7	20/28 (71.4%)	44	9/26 (34.6%)	11
Gamma-glutamyltransferase increased	8/26 (30.8%)	20	14/28 (50%)	15	7/26 (26.9%)	16
Blood albumin decreased	5/26 (19.2%)	5	11/28 (39.3%)	15	6/26 (23.1%)	7
Hyponatraemia	6/26 (23.1%)	6	10/28 (35.7%)	19	7/26 (26.9%)	8
blood bilirubin increased	4/26 (15.4%)	6	9/28 (32.1%)	11	7/26 (26.9%)	8
Hyperglycaemia	5/26 (19.2%)	6	7/28 (25%)	12	6/26 (23.1%)	12
Activated partial thromboplastin time prolonged	1/26 (3.8%)	2	4/28 (14.3%)	7	5/26 (19.2%)	5
Hypocalcaemia	3/26 (11.5%)	3	4/28 (14.3%)	4	1/26 (3.8%)	3
Blood triglycerides increased	2/26 (7.7%)	4	3/28 (10.7%)	4	3/26 (11.5%)	3
Prothrombin level decreased	0/26 (0%)	0	3/28 (10.7%)	5	0/26 (0%)	0
Blood lactate dehydrogenase increased	0/26 (0%)	0	2/28 (7.1%)	2	1/26 (3.8%)	1
Blood potassium increased	3/26 (11.5%)	3	2/28 (7.1%)	2	0/26 (0%)	0
C-reactive protein increased	2/26 (7.7%)	3	0/28 (0%)	0	0/26 (0%)	0
Metabolism and nutrition disorders
Decreased appetite	2/26 (7.7%)	2	2/28 (7.1%)	3	0/26 (0%)	0
Psychiatric disorders
Depression	0/26 (0%)	0	2/28 (7.1%)	2	1/26 (3.8%)	1
Renal and urinary disorders
renal failure acute	0/26 (0%)	0	0/28 (0%)	0	2/26 (7.7%)	2
Skin and subcutaneous tissue disorders
Drug hypersensitivity	0/26 (0%)	0	1/28 (3.6%)	1	2/26 (7.7%)	2
Vascular disorders
Haematoma	2/26 (7.7%)	2	0/28 (0%)	0	0/26 (0%)	0

Limitations/Caveats

[Not Specified]

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.