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

Phase 3

Recruiting

• Conditions: Acute Lymphoblastic Leukemia
• Interventions: Drug: pegaspargase 2500 IU/m2 x 1; Drug: pegaspargase 1250 IU/m2 x 2

• Registration Number: NCT02716233
• Lead Sponsor: Assistance Publique - Hôpitaux de Paris

Brief Summary

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:

1. 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.

2. 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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2016-02-15
• Study First Submitted QC: 2016-03-17
• Study First Posted: 2016-03-23
• Study Start: 2016-04
• Status Verified: 2019-02
• Last Update Submitted: 2019-02-18
• Last Update Posted: 2019-02-19
• Primary Completion: 2026-04
• Study Completion: 2026-04

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 1578

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm 1	pegaspargase 2500 IU/m2 x 1	pegaspargase 2500 IU/m2 x 1: infusion of a conventional dose of pegaspargase during induction therapy: 2500 IU/m2x1
Arm 2	pegaspargase 1250 IU/m2 x 2	pegaspargase 1250 IU/m2 x 2: fractionation of the 2500 IU/m2 pegaspargase dose in two infusions of 1250 IU/m2 each

Primary Outcome Measures

Name	Time	Method
Incidence of directly asparaginase-related severe toxicities (Grade ≥ 3 as assessed by CTCAE v4.0) observed during induction therapy	Between Day 12 of induction and Day 8 of consolidation	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
Incidence of adequate (> 100 IU/L) asparaginase activity measured in the plasma at day 33 of induction therapy	Day 33	asparaginase activity \> 100 IU/L

Secondary Outcome Measures

Name	Time	Method
Incidence of antibodies against asparaginase, measured in serum	Day 4 of delayed intensification
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	Day 35-Day 42	Assessed on the whole population or on subgroups (B-Lineage ALL, T-cell ALL).
Minimal Residual Disease (MRD)	Day 35-Day 42, Day 65-Day 105	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).
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 adequate (> 100 IU/L) asparaginase activity measured in the plasma at day 40 of induction therapy	Day 40 of induction
Incidence of silent inactivation	First 6-9 months	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
Cumulative Incidence of relapses	5 years	Assessed on the whole population or on subgroups (B-Lineage ALL, T-cell ALL).
Cumulative Incidence of relapse according to site of relapse	5 years	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).
All other adverse events related to asparaginase	within the first 7 weeks (Day 49) of treatment and anyway before Day 8 of consolidation	Drug-induced hyperglycemia or diabetes, coagulopathy, allergy Non CNS thrombosis Grade 1-2 Adverse Events (AE): pancreatitis, hyperbilirubinemia
Late adverse events related to asparaginase	after Day 49 of induction or anyway at Day 8 of consolidation or after

Trial Locations

Locations (7)

CHu; 🇫🇷 Tours, France

CHRU; 🇫🇷 Besançon, France

CHU; 🇫🇷 Toulouse, France

CHU Robert Debré; 🇫🇷 Paris, France

CHU Armand Trousseau; 🇫🇷 Paris, France

CHU Saint Louis; 🇫🇷 Paris, France

Chu-Ihope; 🇫🇷 Lyon, France