A French Protocol for the Treatment of Acute Lymphoblastic Leukemia (ALL) in Children and Adolescents

Study Overview
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Brief Summary
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A still major question in the field of acute lymphoblastic leukemia (ALL) in children - an extremely heterogeneous disease though curable in 80-90% of children and 70-80% of the adolescents - is the optimal use of L-asparaginase (ASNase). It is known that administering ASNase results in the depletion of asparagine circulating in the blood, which starves the leukemic cells and results in their death. But indeed the use of ASNase varies between protocols considering the different brands, the dose and the administration modalities. Oncaspar (PEGylated E. coli asparaginase, pegaspargase) was thus developed with the goal of reducing the immunogenicity of the native ASNase. This is a French prospective multicentric cohort study of children and adolescents with ALL, stratified on (i) the type of ALL ( B vs T) and (ii) the anticipated risk (stratified in 3 groups for childhood B-cell precursor (BCP)-ALL and 2 groups for T-cell ALL). It aims to answer to two different issues: Randomized question: what is the best way to administer pegaspargase? A cohort of children and adolescents with standard or medium risk ALL will be randomized to receive during induction either one infusion of ONCASPAR® 2500 IU/m2 at D12 or two infusions of ONCASPAR® at 1250 IU/m2 each at D12 and D26. Patients will then receive 2500 IU/m2 or 1250 IU/m2 per dose during consolidation and delayed intensification according to the initial arm of randomization. Non randomized question: In the High/Very High Risk groups, a non randomized intensification of the scheme of asparaginase administration is proposed during induction therapy: 2 infusions of 2500 IU/m2/day (D12 and D26) will be administered. All patients will receive 2500 IU/m2 per dose during consolidation and delayed intensifications.

Official Title
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A French Protocol for the Treatment of Acute Lymphoblastic Leukemia (ALL) in Children and Adolescents

Conditions
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Acute Lymphoblastic Leukemia

Intervention / Treatment
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* Drug: pegaspargase 1250 IU/m2 x 2
* Drug: pegaspargase 2500 IU/m2 x 1


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ALL L1 or L2 B-lineage or T- lineage ALL Exclusion Criteria: L3 (Burkitt's leukemia) Mixed Phenotype Acute Leukemia (WHO criteria). Infant ALL (age ≤ 365 days) Philadelphia (Ph)+/Breakpoint Cluster region (BCR)-Abelson (ABL) ALL

Ages Eligible for Study
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Minimum Age: 12 Months
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm 1<br>pegaspargase 2500 IU/m2 x 1: infusion of a conventional dose of pegaspargase during induction therapy: 2500 IU/m2x1 | Drug: pegaspargase 2500 IU/m2 x 1<br>* only for ALL of standard risk and medium risk<br>* Other names: ONCASPAR 2500 IU/m2 x 1;|
| Experimental: Arm 2<br>pegaspargase 1250 IU/m2 x 2: fractionation of the 2500 IU/m2 pegaspargase dose in two infusions of 1250 IU/m2 each | Drug: pegaspargase 1250 IU/m2 x 2<br>* only for ALL of standard risk and medium risk<br>* Other names: ONCASPAR 1250 IU/m2 x 2;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adequate (> 100 IU/L) asparaginase activity measured in the plasma at day 33 of induction therapy | asparaginase activity > 100 IU/L | Day 33 | 
| Incidence of directly asparaginase-related severe toxicities (Grade ≥ 3 as assessed by CTCAE v4.0) observed during induction therapy | Incidence of severe toxicities (Grade ≥ 3) directly asparaginase-related (CNS thrombosis, pancreatitis, anaphylaxis, and hyperbilirubinemia) between Day 12 and Day 49 of treatment and anyway before Day 8 of consolidation | Between Day 12 of induction and Day 8 of consolidation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of asparagine depletion measured in plasma by a concentration below the Limit of Quantification (LOQ) of 0.4 micromol/L |  | Day 33 of induction | 
| Incidence of adequate (> 100 IU/L) asparaginase activity measured in the plasma at day 40 of induction therapy |  | Day 40 of induction | 
| Incidence of asparagine depletion measured in plasma by a concentration below the Limit of Quantification (LOQ) of 0.4 micromol/L |  | Day 40 of induction | 
| Incidence of antibodies against asparaginase, measured in serum |  | Day 4 of delayed intensification | 
| Incidence of silent inactivation | Silent inactivation or subclinical hypersensitivity is defined as a plasma PEGasparaginase activity level <100 IU/L at day 7+/- 1 or <20 IU/L at day 14 +/- 11 after administration in a patient without clinical symptoms of allergy | First 6-9 months | 
| Percentage of patients without switch to Erwinia asparaginase |  | First 6-9 months | 
| Percentage of patients receiving more than 95% of the intended dose of asparaginase |  | First 6-9 months | 
| Morphological Complete Remission (CR) rates | Assessed on the whole population or on subgroups (B-Lineage ALL, T-cell ALL). | Day 35-Day 42 | 
| Minimal Residual Disease (MRD) | MRD will be assessed by Ig/T cell receptor (TCR)-based real-time quantitative (RQ)-polymerase chain reaction (PCR), assessed on the whole population or on subgroups (B-Lineage ALL, T-cell ALL). Assessed on the whole population or on subgroups (B-Lineage ALL, T-cell ALL). | Day 35-Day 42, Day 65-Day 105 | 
| Cumulative Incidence of relapses | Assessed on the whole population or on subgroups (B-Lineage ALL, T-cell ALL). | 5 years | 
| Cumulative Incidence of relapse according to site of relapse | Bone-Marrow (BM) relapses, central nervous system (CNS) relapses, gonadal relapses, combined relapses. Assessed on the whole population or on subgroups (B-Lineage ALL, T-cell ALL). | 5 years | 
| All other adverse events related to asparaginase | Drug-induced hyperglycemia or diabetes, coagulopathy, allergy Non CNS thrombosis Grade 1-2 Adverse Events (AE): pancreatitis, hyperbilirubinemia | within the first 7 weeks (Day 49) of treatment and anyway before Day 8 of consolidation | 
| Late adverse events related to asparaginase |  | after Day 49 of induction or anyway at Day 8 of consolidation or after |