Acute Lymphoblastic Leukemia, in Relapse
Conditions
Keywords
acute lymphoblastic leukemia, relapse, asparaginase
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.
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)
Interventions
DRUGGRASPA
one injection of GRASPA 150 IU/kg at each cycle of chemotherapy
DRUGL-asparaginase
3 to 4 Injections of Native E.coli asparaginase 10000IU/m² (every 3 days) at each cycle of chemotherapy
Sponsors
ERYtech Pharma
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
1 Years to 55 Years
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| 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. |
| 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. |
Countries
Belgium, France
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| GRASPA (Non Allergic Population) 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 | 29 |
| Reference L-asparaginase (Non Allergic Population 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 | 30 |
| GRASPA (Allergic Population) 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 | 26 |
| Total | 85 |
Baseline characteristics
| Characteristic | GRASPA (Non Allergic Population) | Reference L-asparaginase (Non Allergic Population | GRASPA (Allergic Population) | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 23 Participants | 23 Participants | 15 Participants | 61 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 6 Participants | 7 Participants | 11 Participants | 24 Participants |
| Sex: Female, Male Female | 11 Participants | 10 Participants | 8 Participants | 29 Participants |
| Sex: Female, Male Male | 18 Participants | 20 Participants | 18 Participants | 56 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 9 / 26 | 12 / 28 | 14 / 26 |
| other Total, other adverse events | 26 / 26 | 28 / 28 | 26 / 26 |
| serious Total, serious adverse events | 23 / 26 | 26 / 28 | 23 / 26 |
Outcome results
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.
Time frame: Induction treatment period (i.e. 28 days)
Population: Only patient receiving treatment are considered.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| GRASPA Non Allergic | Allergic Reaction During Induction Phase | 0 reactions |
| Reference L-asparaginase | Allergic Reaction During Induction Phase | 13 reactions |
| GRASPA (Allergic Population) | Allergic Reaction During Induction Phase | 3 reactions |
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.
Time frame: Induction treatment period (i.e. 28 days)
Population: Only non allergic population evaluated for efficacy (i.e. 2 randomized arms). Only patient receiving treatment are considered.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| GRASPA Non Allergic | Duration of Asparaginase Activity >100 U/L During Induction | 18.9 days |
| Reference L-asparaginase | Duration of Asparaginase Activity >100 U/L During Induction | 8.5 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
Time frame: Induction treatment period (i.e. 28 days)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| GRASPA Non Allergic | Complete Remission (CR) | 19 Participants |
| Reference L-asparaginase | Complete Remission (CR) | 13 Participants |
| GRASPA (Allergic Population) | Complete Remission (CR) | 15 Participants |
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.
Time frame: Overall trial period to 36 months
Population: Entries below are the numbers of patients with events in each treatment group
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| GRASPA Non Allergic | Event Free Survival | 15 Participants |
| Reference L-asparaginase | Event Free Survival | 17 Participants |
| GRASPA (Allergic Population) | Event Free Survival | 19 Participants |
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.
Time frame: Overall trial period to 36 months
Population: Entries given below are number of patients dying in each group
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| GRASPA Non Allergic | Overall Survival (OS) | 9 Participants |
| Reference L-asparaginase | Overall Survival (OS) | 12 Participants |
| GRASPA (Allergic Population) | Overall Survival (OS) | 14 Participants |